WO2004035071A1 - Herbal medicine containing cyclodextrins for the treatment of ear disorders - Google Patents

Herbal medicine containing cyclodextrins for the treatment of ear disorders Download PDF

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Publication number
WO2004035071A1
WO2004035071A1 PCT/IL2003/000840 IL0300840W WO2004035071A1 WO 2004035071 A1 WO2004035071 A1 WO 2004035071A1 IL 0300840 W IL0300840 W IL 0300840W WO 2004035071 A1 WO2004035071 A1 WO 2004035071A1
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composition
ear
cyclodextrin
group
present
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PCT/IL2003/000840
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French (fr)
Inventor
David Nakar
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Nakar, Herzl
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Priority claimed from IL15234102A external-priority patent/IL152341A0/en
Application filed by Nakar, Herzl filed Critical Nakar, Herzl
Priority to AU2003278559A priority Critical patent/AU2003278559A1/en
Publication of WO2004035071A1 publication Critical patent/WO2004035071A1/en
Priority to IL168065A priority patent/IL168065A0/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/68—Plantaginaceae (Plantain Family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A61K36/718—Coptis (goldthread)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/736—Prunus, e.g. plum, cherry, peach, apricot or almond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/80—Scrophulariaceae (Figwort family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8962—Allium, e.g. garden onion, leek, garlic or chives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • the present invention relates to ear compositions for topical application and use thereof for treating ear disorders.
  • Otitis media is a painful inflammation of the middle ear.
  • Acute otitis media (AOM) is usually accompanied by fever, swelling, inflammation of the eardrum and considerable pain.
  • Otitis media develops when bacteria or viruses, most often during colds or sore throats, travel up the eustachian tube, from the upper part of the throat behind the nose to the middle ear. Determination of the precise etiology is not practical since the causative organism is often difficult to isolate and culture. Fluid accumulation in the middle ear is termed otitis media with effusion. The inflammation should be treated promptly to prevent complications which may result in hearing loss, tinnitus, facial nerve palsy, mastoiditis, labyrinthitis, vertigo, and possible encephalitis.
  • Standard treatment dictates the prescription of oral antibiotics over a course of several days. Seventy percent of ear infections are bacterial, with the remaining 30 percent being viral in origin. Regarding infections of the middle ear, fifty to ninety percent of infections are caused by one of three bacterias: Streptococcus pneumoniae, Hemophilus influenza or Moraxella catarrhalis. Many strains of these bacteria are now resistant to antibiotics.
  • U.S. Patent No. 6,093,417 discloses a composition for treatment of ear disorders, having as the essential composition components, anesthetics, zinc salts and penetration enliancers, however, the formulations disclosed and their clinical beneficial effect was not evaluated. Furthermore, the formulations disclosed does not include a cyclodextrin.
  • Herbal remedies have been utilized for centuries to relieve pain in . the ear.
  • Application of garlic, onion or olive oil are common folklore remedies for ear pain, used at least during the 16 th century.
  • Many additional herbs have been noted for their ability to ease the pain of one suffering from ailments in the ear.
  • the composition disclosed is disadvantageos since it does not include a penetration enhancer such as cyclodextrin and therefore its permeability through the tympanic membrane is limited.
  • the composition disclosed possess only local anaesthetic and anti-inflammatory activity and does not show antibiotic activity. Additionally, the composition has a short shelf-life and is stable for 1 year only.
  • Cyclodextrin is a family of cyclic oligosaccharides which are known to form inclusion complexes with many organic substances, including several drugs [H.W. Frijlink et al. The effect of cyclodextrins on drug absorption II. In vivo observations, Int. J. Pharm. 64 (1990) 195-210]. Complexation often changes the physico-chemical characteristic of the guest molecule and can be of importance in the pharmaceutical field.
  • Cyclodextrins have been used as complexing agent in various compositions [US patent Nos. 6,320,051, 6,274,554, 6,043,221, 5,861,433 and 5,834,512].
  • advantages such as improved bioavailability, reduction in unwanted side effects, improved stability or increased aqueous solubility of the drug have often been claimed [Stephen P. Jones et al. Cyclodextrins in the pharmaceutical sciences, Part I: Preparation, structure and properties of cyclodextrins and cyclodextrin inclusion compound, Ada Pharm. Technol.
  • solubility and therefore permeability of lypophilic drugs are increased in the presence of beta-cyclodextrin.
  • beta-cyclodextrin a 2:1 cyclodextrin complex of hydrocortisone or triacinolone acetonide was prepared, and shaken in water at 37°C, the concentration of dissolved hydrocortisone was 2-fold, and that of triamcinolone 27-fold, when compared to the free drugs.
  • the percutaneous absorption in rats and rabbits of these steroids, from paraffin based ointments containing the free drugs or their complexes was shown to be concordant with their in vitro solubility. No improvement of hydrocortisone when monitored by direct determination and by its biological effects was observed.
  • compositions for topical application to the ear which can replace or reduce the amount of oral antibiotics, or other active agents used for treatment of various ear disorders such as infections.
  • This is enabled in the present invention by using cyclodextrins for more efficient delivery of drugs applied topically.
  • the cyclodextrin would increase the therapeutic effect of the active ingredient present in the composition.
  • compositions of the present invention provide a simpler and lower costing natural solution.
  • the compositions counteract inflammatory processes and reduce the side effects of the active ingredients (because lower concentration of the active ingredients are required in the presence of cyclodextrin).
  • NHEED refers to Why Herbal Extract Ear Drops.
  • inclusion complex refers to molecular compounds having the characteristic structure of an adduct, in which one compound (host molecule) spatially encloses another.
  • the enclosed compound (guest molecule) is situated in the cavity of the host without significantly affecting the host framework structure.
  • borrow' s solution refers to a 13% w/v aluminum acetate solution in acetic acid.
  • cyclodextrin refers to any type of cyclodextrin such as beta-cyclodextrin, alpha-cyclodextrin, gama-cyclodextrin, hydroxypropyl-beta-cyclodextrin, derivatives of any of the above, or mixtures of any of the above.
  • active ingredient refers to a herbal medicine which may be a composition of matter comprising several ingredients at least one of which having a medical activity, a single active ingredient of a herbal medicine said ingredient having a medical activity, a pharmaceutically acceptable salt of a single active ingredient of a herbal medicine, or a chemical derivative of a single active ingredient of a herbal medicine, or any other non-herbal active ingredients, which are effective in treating, preventing or alleviating an ear disorder, symptom or complication.
  • the term "herbal medicine” refers also to a single active ingredient of a herbal medicine, a pharmaceutically acceptable salt of a single active ingredient of a herbal medicine, or a chemical derivative of a single active ingredient of a herbal medicine.
  • the term “single active ingredient” refers to the single ingredients of the herbal medicine which can be isolated and have a pharmacological effect.
  • an ear composition comprising:
  • an ear composition as defined in the present invention in the preparation of a medicament for treating, preventing or alleviating an ear disorder, symptom or complication selected from the group consisting of infection, inflammation, pain and oedema.
  • Figure 1 is a description of the level of pain (score from 1 to 10) of study group NHEED vs. NHEED and Antibiotics.
  • NHEED composition comprising Verbascum thapsus, Calendula Officinalis Fiores, Citrous Seed Extract, Plantin, beta-cyclodextrin, acid caprylic, Liqour burrowi, Essential oils: Lavender, Thyme red, Roman Chamomile, Allium sativum (garlic) in a hydro glycerin base, as described in example 2.
  • an active ingredient especially verbascum; calendula officinalis fiores; citrous seed; plantin; lavender; thyme; chammomile; allium sativum; caprylic acid
  • a cyclodextrin preferably beta-cyclodextrin is highly advantageous as an ear composition since the cyclodextrin increases the therapeutic effect of the active ingredient and thus decreases the amount of the active ingredient needed to be administered or applied in the treatment of pathogenic bacteria and yeasts.
  • a proposed mechanism for this effect is the increase in tissue permeability, probably by diffusion of the cyclodextrin- active ingredient inclusion complex through aqueous pores or by exchange of the drug complex in the cyclodextrin, with tissue lipids. It is proposed that the cyclodextrin serves as a penetration enhancer. Another proposed mechanism may be by increasing the dissolution of the drug in aqueous medium, which allows it to becomes more available and prone to contact the target membrane of the microorganism and attack it due to decrease in the surface tension.
  • the present invention is useful for treatment of ear disorders since inclusion of the cyclodextrin in the composition enables the active agent to penetrate the tympanic membrane and to affect the middle and inner ear.
  • the tympanic membrane When the tympanic membrane is swollen (being inflamed and containing fluid) it repels hydrophobic oily drugs. Therefore, there is a need to incorporate the hydrophobic oily active ingredient into the aqueous medium. This is done by incorporation of a cyclodextrin.
  • the cyclodextrin solubilizes the hydrophobic oily active ingredient in the aqueous medium and increases the active ingredient permeability to its target site.
  • the active agent of the present invention is preferably a hydrophobic, oil-soluble ingredient.
  • the active agent is mixed with the cyclodextrin in an aqueous media an inclusion complex is formed thus enabling the formulation of aqueous-based compositions containing hydrophobic, water- insoluble active agents. This is especially advantageous when formulating ear compositions since it was found that water-based ear drops provide the greatest coverage of the tympanic membrane after administration of the drops to the patients [P.S. Wilson et al. Distribution of ear drops in normal ear, The Journal of Laryngology and Otology, 105 (1991) 359-361].
  • the present invention relates to an ear composition
  • an ear composition comprising:
  • the above herbal medicines possess an antibacterial, anti- inflammatory, local anaesthetics, astrigent and anti oedema activity.
  • the herbal medicine is present in the composition in a form selected from the group consisting of a dry ground herb, a fresh dry herbal extract, a lyophilized dry herbal extract,_a liquid herbal extract, a herbal essential oil, and mixtures of any of the above.
  • the verbascum is verbascum thapsus.
  • the thyme is selected from the group consisting of thyme red, thyme sweet, thyme vulgaris and mixtures of any of the above. Most preferably the thyme is thyme red.
  • the chammomile is selected from the group consisting of chammomile roman, chammomile german and mixtures of any of the above. Most preferably the chammomile is chammomile roman.
  • the ear composition further comprises aluminum acetate.
  • the aluminum acetate is present in the composition in the form of liquour borrowi.
  • Aluminum acetate used in the present invention posses various pharmacological activities such as astringent, local anti-inflammatory, local anti oadema.
  • Aluminum acetate is also used to adjust the pH of the composition.
  • the preferred pH range of the ear compositions of the present invention is 3.5-5.5, more preferably 4-5.
  • pH adjusting agents such as lactic acid may be added to the compositions of the present invention.
  • the ear composition of the present invention comprises at least one of the following herbal medicines: allium sativum, caprylic acid, citrous seed or thyme.
  • the herbal medicine comprises a mixture of allium sativum, caprylic acid, citrous seed and thyme.
  • the dyclodextrin increases their antibacterial activity and the uniformity of the preparation.
  • These herbal medicines are lypophilic in nature and the cyclodextrin makes them more soluble in water, a factor that is important in increasing the drug (active agent) accessibility to and through the infected ear membrane.
  • the ear composition comprises a mixture of verbascum; calendula officinalis fiores; citrous seed; plantin; lavender; thyme; chammomile; allium sativum; caprylic acid; aluminum acetate; and a cyclodextrin.
  • the cyclodextrin is preferably a beta-cyclodextrin.
  • the verbascum is verbascum thapsus.
  • the thyme is thyme red.
  • the chammomile is chamomile roman.
  • the above composition is effective in treating ear disorders especially otitis media, otitis externa and otomycosis.
  • the composition may be formulated as a liquid, semi-solid or solid dosage form as described in the invention below. Most preferably the final form of the composition is liquid (such as a suspension).
  • the carrier (vehicle) of the composition is preferably liquid, more preferably an aqueous based carrier.
  • the aqueous based carrier is a mixture of glycerin and water.
  • the glycerin is present in the composition at a concentration of 10% to 90% (w/w) and most preferably at a concentration of 60% to 80%
  • the water is present in the composition at a concentration of
  • composition is preferably administered as ear drops.
  • the verbascum is present in the composition in a concentration of 10% to 70% w/w, more preferably from 15% to 50% w/w, and most preferably 20% to 40% w/w
  • the calendula officinalis fiores is present in the composition in a concentration of a 1% to 30%> w/w, more preferably from 5% to 20% w/w, and most preferably 10% to 15% w/w
  • the citrous seed is present in the composition in a concentration of 1% to 60% w/w, more preferably from 5% to 50% w/w, and most preferably 5% to 40% w/w
  • the plantin is present in the composition in a concentration of 5% to 20% w/w, more preferably from 5% to 15% w/w, and most preferably 5% to 10% w/w
  • the lavender is present in the composition in a concentration of 1% to 90% w/w, more preferably from 1% to 50% w/w, and most preferably 2% to
  • the verbascum is verbascum thapsus.
  • the thyme is thyme red.
  • the chammomile is chammomile roman.
  • the cyclodextrin is present in the composition in a concentration of 0.05% to 10% w/w and more preferably from 1% to 7% w/w.
  • the cyclodextrin is preferably a beta cyclodextrin.
  • Each of the above herbal medicines may be present in the composition as a single herb (in combination with the cyclodextrin) using the above concentration ranges, or in a mixture including a combination of at lease two herbs (in combination with the cyclodextrin) using the above concentration ranges.
  • concentrations refer to the raw materials of the herbal medicines as used in the examples (Example 2 -NHEED composition). It is appreciated that where the raw material is a herbal medicine including small percentage of an active ingredient, the concentrations should be adjusted accordingly (increase in the proportion of the pure material to he whole herbal medicine) as compared to a case where a more purified material including higher proportions of the active ingredient is used.
  • the aluminum acetate is present in the composition in a concentration of 0.1% to 13% w/w and more preferably from 0.1% to 7% w/w.
  • concentrations for aluminum acetate refer to liquor Burrowi (13% Aluminum Acetate solution) raw material as described in the examples (example 2). It is appreciated that when other concentrations of aluminum acetate in the raw material are used, the concentrations in the composition should be adjusted accordingly.
  • the above concentration ranges of the herbal medicines and the aluminum acetate relate to a liquid composition.
  • compositions such as solid or semisolid
  • other ranges of concentrations could be used.
  • solid or semi solid a 10-20 fold increase can be used.
  • the ear compositions of the present invention further comprises at least one of the following a herbal medicines: hydrastis, ruta, hammamelis, almond oil, jojoba oil, coptidis, capsicum or mixtures of any of the above.
  • the herbal medicines of the present invention posses various activities as described in British Herbal Pharmacopoea 1983; Blumental, Goldberg and Brinckman, Herbal Medicine - Expanded Commission - E monographs, Edition 2000; Martindle Extra Pharmacopea - 32 Edition].
  • Non limiting examples of herbal medicine which may be used in combination with the cyclodextrin according to the present invention includes: verbascum thapsus, calendula fiores, allium cepa, citrous seed, plantin species, lavender, thyme red, thyme vulgaris, thyme sweet, chammomile roman, chamomile german, caprylic acid, anemone pulsatilla, apocynum androsaemifolium, centella asiatica, chrysanthemum parthenium, datura, dipteryx odorata, euphorbia tirucalli, euphrasia officinalis, sorbus aucuparia, glechoma hederacea, hydrastis canadensis, hyoscymus niger, Illicium verum, laurus nobilis, lobelia inflata, lycospersicon esculentum, melaleuca leuca
  • Artemisia species may be for example artemisia capillaris (Yin chen hao), artemisia apiacea (Qing Hao) or artemisia argyi (Ai Ye).
  • acid caprylic is an oily extraction of the single active ingredient (acid caprylic) from the herb cocos nucifera.
  • Beta 1,3 D-glucan is a water extraction of the single active ingredient (beta 1,3 D-glucan) from the herb barely.
  • Boric acid is a single active ingredient of sassolite.
  • Menthol is a single active ingredient of menthae species, thyme vulgaris, red thyme and mentha peperata.
  • Camphor is a single active ingredient of cinnamun camphora.
  • Thymol and borneol are single active ingredients of thyme vulgaris.
  • Borneol is a single active ingredient of dryobalanops aromatica.
  • the herbal medicines of the present invention are known to have various activities. Some examples are given below:
  • Antibiotic herbal medicines include, but are not limited to hydrastis, echinacea, propolis, coptis, ruta, citrous seed, thyme, tea tree, oregano, azadiracta, uncaria tomentosa, or mixtures of any of the above.
  • Steroid herb medicines include but are not limited to chamomile oil, calendula officinalis, beta-sito sterol, or mixtures of any of the above.
  • Non-steroidal anti inflammatory herb medicines include but are not limited to plantin, chrysanthemum partaneum, scutelaria, or mixtures of any of the above.
  • Antifungal herb medicines include but is not limited to red thyme, caprylic acid, citrous seed, allium species, tea tree, ruta, azadiracta, oregano, hydrastis, coptis, sorbic acid, sorbus aucuparia, tabebuia, uncaria tomentosa, or mixtures of any of the above.
  • Local anaesthetic herb medicines may be, for example, lavender, menthae, myrrh, or mixtures of any of the above.
  • the anaelgetic herb medicine may be for example chamomile, calendula, mentha species, pulsatilla, humulus lupulus, calamus, or mixtures of any of the above.
  • the ear composition further comprises at least one ingredient selected from the group consisting of benzocain, hyaluronate sodium, salicylic acid, aluminum potassium sulphate, vitamin E, thymol, docusate sodium, beneficial flora of microorganisms and mixtures of any of the above.
  • the beneficial flora of microorganisms is lactic acid bacteria.
  • the beneficial flora of microorganisms control pathogenic overgrowth.
  • the lactic acid bacteria is selected from the group consisting of lactobacillus species, bifidobacterium species and mixtures of any of the above.
  • lactobacillus bacteria species may be for example lactobacillus acidophylus, lactobacillus plantarum, lactobacillus casei, lactobacillus bulgaricus or mixtures of any of the above.
  • the bifidobacterium species may be for example bifidobacterium infantis, bifidobacterium longum, bifidobacterium brevis or mixtures of any of the above.
  • the ear composition comprises a mixture of hydrastis, ruta, benzocain, aluminum potassium sulphate, thymol, garlic, hammamelis, calendula, lactobacillus and bifidobacterium species, and a cyclodextrin.
  • composition may further comprise a wax softener such as a surfactant preferably sodium ducusate.
  • a wax softener such as a surfactant preferably sodium ducusate.
  • the thymol and garlic oil are preferably present in the composition in the form of thymol-cyclodextrin complex and garlic- cyclodextrin complex.
  • the cyclodextrin is preferably a beta-cyclodextrin.
  • the final form of the above composition maybe a liquid, a semi-solid or a solid and most preferably a solid composition.
  • the solid ear compositions may include additional ingredients such as a wax softener for example a surfactant.
  • the surfactant for example docusate sodium functions as a wax softener and reduces the surface tension between the powder and the liquid excretions from the ear.
  • the solid compositions may further include a solid pharmaceutical carrier as described in the invention.
  • a solid pharmaceutical carrier as described in the invention.
  • Some of the pharmaceutical carriers such as zinc oxide may also function as astringents.
  • the ear compositions of the present invention may further comprise a synthetic drug, for example an anti-inflammatory agent, an antibiotics, a local anaesthetics or mixtures thereof.
  • a synthetic drug for example an anti-inflammatory agent, an antibiotics, a local anaesthetics or mixtures thereof.
  • the anti-inflammatory agent is aluminum acetate, aluminum potassium sulfate, aluminum potassium sulfate dodeca hydrate or mixtures thereof.
  • the anti-inflammatory agent may be for example a steroid, a non- steroidal anti inflammatory drug or mixtures thereof.
  • the steroids include but are not limited to, hydrocortisone, dexamethasone, betamethasone, beclomethasone, prednisolone, triamcinolone, alclomethasone, clobetasol, desonide, fluocinolone, fluocinonide, pharmaceutically acceptable salts thereof, derivatives thereof or mixtures thereof.
  • the non-steroidal anti inflammatory drug may be, for example, indomethacin, ibuprofen, diclofenac, hyaluronate, pharmaceutically acceptable salts thereof, derivatives thereof or mixtures thereof.
  • the antibiotics may be, for example, penicillins, cephalosporins, aminoglycosides, tetracyclines, erythromycines, quinolones, polymyxin B, bacitracin ? pharmaceutically acceptable salts thereof, derivatives thereof or mixtures thereof .
  • the aminoglycosides include, but are not limited to, neomycin, tobramycin, gentamycine, vancomycine, pharmaceutically acceptable salts thereof, derivatives thereof or mixtures thereof.
  • the local anaesthetic includes but is not limited to amethocaine, benzocaine, tetracaine, lodocaine, pharmaceutically acceptable salts thereof, derivatives thereof or mixtures thereof.
  • Additional drugs which may be used are fungal agents and/or keratolytic agents such as salicylic acid.
  • the steroid is present in the composition in a concentration of 0.1%) to 4% w/w and most preferably in a concentration of 0.1% to 2% w/w.
  • the non-steroidal anti inflammatory drug is present in the composition in a concentration of 0.1% to 5% w/w and most preferably in a concentration of 0.1% to 4% w/w.
  • the aluminum acetate, aluminum potassium sulfate, aluminum potassium sulfate dodeca hydrate are each present in the composition in a concentration of 0.1 % to 13 % w/w and most preferably in a concentration of 0.1% to 7% w/w.
  • the antibiotics is present in the composition in a concentration of 0.1% to 10% w/w and most preferably in a concentration of 0.5% to 8% w/w.
  • the local anaesthetics is present in the composition in a concentration of 0.1% to 15% w/w and most preferably in a concentration of 1% to 10% w/w.
  • cyclodextrin in the ear compositions of the present invention is highly advantageous since the cyclodextrin enables the active ingredient to penetrate the tympanic membrane and to affect the middle and inner ear.
  • the cyclodextrin is selected from the group consisting of beta-cyclodextrin, alpha- cyclodextrin, gama-cyclodextrin, hydroxypropyl-beta-cyclodextrin, derivatives of any of the above, and mixtures of any of the above. More preferred cyclodextrins are beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin. Most preferred cyclodextrin is beta-cyclodextrin.
  • the cyclodextrin is present in the pharmaceutical composition at a concentration of 1% to 90%) w/w.
  • the weight ratio of the cyclodextrin or cyclodextrin derivative to the active ingredient is from 1:4 to 30:1.
  • High concentration of the cyclodextrin in the compositions may be used since the cyclodextrin may also serve as a diluent in solid compositions. In this case the cyclodextrin serves also as a pharmaceutical carrier and no additional pharmaceutical acceptable carrier is needed. Additionally high concentrations of cyclodextrins might be used to absorb secretions in various disease conditions such as ear inflammation.
  • the ear compositions of the present invention are in a form of a liquid, a semisolid or a solid.
  • the composition is a liquid or semi solid dosage form and the cyclodextrin is present in the composition in a concentration of 0.05% to 10% w/w.
  • the cyclodextrin is present in the composition at a concentration of 0.05% to 10% w/w, more preferably at a concentration of 1% to 7% w/w.
  • the weight ratio of the cyclodextrin to the active ingredient in the liquid composition is from 1:4 to 30:1 and more preferably from 1 :4 to 18:1.
  • the cyclodextrin or cyclodextrin derivative is present in the pharmaceutical composition at a concentration of 0.05% to 10% w/w, more preferably at a concentration of 3% to 7% w/w.
  • the weight ratio of the cyclodextrin to the active ingredient in the semi-solid composition is from 1:4 to 30:1.
  • the cyclodextrin is used in the present invention at a concentration useful as a penetration enhancer.
  • concentrations used in a liquid composition (less than 10% w/w) will not completely solubilize the active ingredient. Therefore the active ingredient is partly solubilized in the composition and partly suspended in the pharmaceutical carrier.
  • concentration of cyclodextrin selected for a specific composition will depend on the concentration of the active ingredient and its physicochemical properties.
  • concentrations of cyclodextrin used in the present invention are the minimal therapeutic concentrations required. Higher concentrations of cyclodextrin (5-15 times higher) are also useful as a solubilizer, however such high concentrations may cause irritation when applied topically.
  • the cyclodextrin: active ingredient weight ratio is from 1:4 to 30:1.
  • the cyclodextrin: active ingredient weight ratio is from 10:1 to 30:1.
  • the cyclodextrin: active ingredient weight ratio is from 1:4 to 30:1 and more preferably from 1:4 to 18:1.
  • the cyclodextrin: active ingredient weight ratio depends on the molar ratio between the cyclodextrin and the 'guest' (active ingredient) molecule.
  • Our preliminary experiments showed that when beta-cyclodextrin was used as a solubilizer at high concentrations (higher than 10%> w/w) it caused local irritation when applied to the ear.
  • a solid dosage form such as granules or a powder can be prepared.
  • the composition is a solid dosage form and the cyclodextrin is present in the composition in a concentration of 1% to 90%> w/w.
  • the cyclodextrin is present in the solid dosage form, at a concentration of 5% to 25% w/w and most preferably at a concentration of 6% to 15%) w/w.
  • the cyclodextrin is preferably used to form an active ingredient-cyclodextrin complex.
  • the concentration of the cyclodextrin is determined according to the active ingredient physicochemical properties, its concentration and according to the final form of the composition.
  • the cyclodextrin in solid dosage forms can also be used as a diluent or filling agent excipient, and therefore high concentrations up to 90% w/w may be used.
  • the cyclodextrin may also serve as a pharmaceutical carrier, and the no additional pharmaceutical carriers may be required.
  • the weight ratio of the cyclodextrin or cyclodextrin derivative to the active ingredient in the solid dosage form is from 10:1 to 30:1.
  • the higher ratio of 30:1 may be used in solid compositions such as powder, for topical application to the ear to absorb secretions in various disease conditions such as ear infection and inflammation.
  • the ear compositions of the present invention may further comprise additional ingredients known in the art to serve as penetration enhancers such as oleum recini, surfactants, alcohols, polyols, sulphoxides, oleates, lactam compounds, alkanols, alkanoic acids, or mixtures thereof. These ingredients may serve as penetration enhancers in combination with the cyclodextrin.
  • the ear compositions of the present invention maybe present in various forms such as a liquid, a semi-solid or a solid depending on the pharmaceutical carrier used. Most preferred is the liquid form.
  • the pharmaceutical carrier is selected from the group consisting of a liquid carrier, a semi-solid carrier and a solid carrier.
  • the pharmaceutical carrier is a liquid carrier and the final form of said composition is selected from the group consisting of a suspension, a lotion and an emulsion.
  • liquid carrier is a hydrophilic carrier.
  • the hydrophilic carrier is selected from the group consisting of an aqueous- based carrier, propylene glycol, alcohol, polyethylene glycol, glycerin and an oil-in glycerin emulsion. Most preferably the hydrophilic carrier is an aqueous based carrier.
  • the aqueous-based carrier is selected from the group consisting of water, an oil-in water emulsion and a mixture of water with at least one liquid selected from the group consisting of glycerin, propylene glycol, alcohol, polyethylene glycol, burrow's solution, and mixtures of any of the above.
  • the liquid carrier is a hydrophobic carrier.
  • the hydrophobic carrier is selected from the group consisting of an oil and an water-in-oil emulsion.
  • the oil is selected from the group consisting of mineral oil, olive oil and almond oil.
  • the semi-solid carrier is selected from the group consisting of a gel, a cream and an ointment.
  • Semi-solid compositions are preferably applied to the ear by means of a long nostril tube or impregnated into a cotton swab and applied into the ear canal.
  • the pharmaceutical carrier is a solid carrier and the final form of the composition is selected from the group consisting of a powder and a granule.
  • Solid compositions are preferably applied to the ear by means of a suitable device such as a tube, a spray or a syringe containing the powder or granules.
  • compositions of the invention can be administered to the ear by a mean such as a porous device (such as a film) or an electronic installation device (such as an electronic pump).
  • a mean such as a porous device (such as a film) or an electronic installation device (such as an electronic pump).
  • the solid carrier is selected from the group consisting of lactose, zinc oxide, amylum, koalin, calamine, dextrin, magnesium oxide, potassium aluminum sulphate, cyclodextrin, argile verde and mixtures of any of the above.
  • compositions of the invention includes, but is not limited to a liquid, drops, an emulsion, a suspension, a cream, an ointment, a lotion, a gel, a paste, a spray, a powder, a granule.
  • the ear composition described in the present invention further comprises at least one additive selected from the group consisting of antioxidants, preservatives, surfactants, buffering agents, pH adjusting agents, thickening agents, gelling agents, suspending agents, wetting agents, binders, lubricants, vitamins, minerals and mixtures of any of the above.
  • the ear compositions of the present invention are useful for treating, preventing or alleviating an ear disorder, symptom or complication selected from the group consisting of infection, inflammation, pain and oedema.
  • the present invention further relates to a method of treating, preventing or alleviating an ear disorder, symptom or complication selected from the group consisting of infection, inflammation, pain and oedema, in a mammal in need of such treatment comprising topically administering to the mammal an effective amount of the ear composition as defined in the present invention, sufficient to ameliorate the effect of the ear disorder, symptom or complication.
  • the infection disorder is selected from the group consisting of otalgia, otitis media, otitis externa, and a fungal infection.
  • the fungal infection is otomycosis.
  • compositions for use in the context of the present invention include compositions wherein the active ingredient in combination with the cyclodextrin is contained in an amount effective to achieve the intended purpose. More specifically, a effective amount means an amount of an active ingredient which when combined with the cyclodextrin is effective to prevent, alleviate or ameliorate one or more causes, complications or symptoms of an ear disease of the subject being treated.
  • the treatment may be prophylactic, for preventing the disease, symptom or complication from occurring. Alternatively the administration may be performed after the disease, symptom or complication were already established so as to eliminate or decrease at least one of the manifestations of the disease, symptom or complication.
  • the amount of the active ingredient in the compositions of the present invention varies as desired for efficient delivery, and is dependent on the patient's age, weight, sex, disease and any other medical criteria, and is determined according to intended medical use by techniques known in the art.
  • the ear compositions of the invention may be administered topically to the ear once or more times per day. Preferably one to four times per day, as determined by the attending physician or health provider or as desired by the patient.
  • compositions of this invention general formulation techniques known in the art of pharmaceutical science will be used. See for example Remington's Pharmaceutical Sciences, 16 th ed., Mack Publishing
  • all methods include the step of bringing into association the carrier(s) with the active ingredient, which constitutes one or more necessary ingredients.
  • compositions of the present invention can be prepared by various methods depending on the final form of the composition.
  • the compositions such as suspensions, lotions, or gels may be prepared by simple mixing of all ingredients (active agent, cyclodextrin, the pharmaceutical carrier and other additives) and then homogenizing or stirring.
  • the cyclodextrin may be dissolved in boiling water at a temperature of 80°C - 100°C, preferably 90°C and then added to a prepared composition including the active ingredient for example a cream, a suspension, a lotion, a solution, a liquid, an ointment or a gel. If required, the composition is further homogenized or stirred.
  • the cyclodextrin is mixed with the active ingredient and a liquid or a semisolid vehicle to form a solution or a dispersion and then added to a prepared composition for example a cream, a suspension, a lotions, a solution,_a liquid, an ointment or a gel.
  • the cyclodextrin may be added to the oily phase or aqueous phase.
  • additives such as wetting agents, emulsifying agents (surfactants), suspending agents, thickening agents, gelling agents, may be used depending on the final form of the compositions.
  • the active ingredient-cyclodextrin complexes of the present invention were all prepared by the same general procedure described as follows:
  • the cyclodextrin preferably beta-cyclodextrin
  • deionized water for a period of 2-10 minutes most preferable 2-5 minutes at 20-25°C to form a homogeneous mixture (paste).
  • the active ingredient was added to the mixture and mixed until a uniform paste was obtained.
  • the mixture was filled into a close airtight glass vessel and kept for a period of 1 to 96 hrs, preferably 48 to 72 hrs, at a temperature of 20°C - 25°C, preferably in a dark place.
  • the mixture was dried in a drying oven at a temperature of 20°- 35°C, preferably 25°C - 30°C until dried, or by freeze drying.
  • the active ingredient-cyclodextrin complexes of the present invention are prepared using a weight ratio of about 1 :10 active ingredient: cyclodextrin.
  • compositions of the present invention are described below.
  • the term “occasionally stirring” refers to stirring or homogenizing every 6 to 8 hr for 10 minutes.
  • the term “occasionally stirring” refers to stirring or homogenizing every 24 hours for 5-10 minutes.
  • compositions such as gels or creams require more frequent stirring or homogenization (every 6 to 8 hr) depending on the gelling agent used and the composition constituents.
  • room temperature refers to a temperature of 20°C - 25°C.
  • the process comprises at least the following step of: mixing at room temperature an active ingredient, a cyclodextrin and optionally a pharmaceutical carrier (liquid carrier) and leaving it at room temperature for about 15 min to about 48 hr, while occasionally stirring, to form a suspension.
  • a pharmaceutical carrier liquid carrier
  • the composition in the case wherein part or all the active ingredients of the composition are present in the form of liquid extracts, the composition my be prepared as described above by mixing the active ingredients and the cyclodextrin. In this case the addition of a pharmaceutical carrier may be omitted since the extract medium may serve as the pharmaceutical carrier.
  • Cream or emulsion compositions are prepared by conventional methods known to those skilled in the art.
  • the oily phase including hydrophobic components with or without a surfactant is heated to 70°C until all ingredients are melted to form a uniform liquid.
  • the aqueous phase including the hydrophilic water soluble components are heated to 70°C.
  • the aqueous phase may further include a surfactant (emulsifying agent).
  • the hydrophobic (oily) phase is added to the hydrophilic (aqueous) phase and then cooled and mixed or homogenized to obtain a cream or emulsion.
  • an emulsifying agent is present in the aqueous phase or oily phase or both phases.
  • Hydrophilic emulsifying agents are preferably added to the aqueous phase.
  • Hydrophobic emulsifying agents are preferably added to the hydrophobic phase.
  • hydrophobic and/or hydrophilic ingredients are added to the obtained cream or emulsion and then mixed or homogenized to form a uniform mixture (cream or emulsion).
  • the cyclodextrin may be added to the aqueous phase described above or to the obtained cream or emulsion. After the cyclodextrin is added, the aqueous phase or cream or emulsion is left for 24 - 48 hours at room temperature, preferably for 24 hours at room temperature and then mixed until a uniform mixture is obtained.
  • Creams or emulsions may also prepared according to the following process comprising the steps of:
  • step (e) a step selected from the group consisting of: (i) adding the mixture prepared in step (a) comprising least one active ingredient and a cyclodextrin to the homogenized mixture obtained in step (d);
  • step (ii) adding the mixture prepared in step (a) comprising least one active ingredient without a cyclodextrin to the homogenized mixture obtained in step (d) and then homogenizing;
  • step (f) adding a cyclodextrin dissolved in 10 - 30% of the water of the aqueous phase to the mixture in step (e)(ii) and then stirring until dissolved;
  • step (g) leaving the mixture obtained in step (f) for about 24 hours to about 48 hours while occasionally stirring.
  • the temperature in steps (b) and (c) is preferably 70°C.
  • an emulsifying agent is present in the aqueous or oily phase or both phases.
  • Hydrophilic emulsifying agents are preferably added to the aqueous phase.
  • Hydrophobic emulsifying agents are preferably added to the hydrophobic phase.
  • Water soluble active ingredients are preferably dissolved in the aqueous phase.
  • the homogenizing in steps (d) and e(ii) is performed for about lminute to about 15 minute;
  • the temperature of the water in step (f) is 80°C to 100°C, most preferably 90°C.
  • the weight ratio of the cyclodextrin to water in step (f) is 1 : 1.
  • the process may further comprise the step of adding at least one polymer and/or other additives to the homogenized mixture obtained in step (d) and homogenizing.
  • the process may further comprise the step of adding at least one hydrophilic surfactant to the water in step (c).
  • the selection of the process for preparing a cream composition depends on the properties of the active ingredient. When a solid active ingredient is present, it is occasionally preferable to prepare the active ingredient- cyclodextrin complex in water before preparation of the emulsion (cream), and after achieving a steady state, to combine all the components.
  • Gel Compositions may be prepared by the following method: The water is heated to 80°C - 100°C, preferably to 90°C. Next, the cyclodextrin is added and mixed until dissolved. The gelling polymer is added and the mixture is homogenized until uniformly dispersed. The obtained mixture is cooled to a temperature of 25°C-40°C, preferably 35°C and then the other active ingredients are added and mixed to obtain a uniform mass. The preparation is left for about 12 hours to complete the gel swelling process and then homogenized to obtain a uniform and smooth gel.
  • Solid compositions are preferably prepared by the following process comprising the steps of:
  • each mixture is comprised of an active ingredient, a cyclodextrin and a suitable liquid medium, and leaving each of said mixtures at room temperature for about 15 min to about 48 hr, while occasionally stirring at room temperature, to form a paste;
  • drying the paste of each mixture by a method selected from the group consisting of spray drying, oven drying, room temperature drying and lyophilization;
  • step (d) optionally, adding a pharmaceutical carrier to the mixture obtained in step (c) and preparing a suitable solid dosage form.
  • the liquid in step (a) may be for example water, buffer solution, mineral salt solution or mixtures thereof.
  • Step (a) may require special conditions depending on the active ingredient used. For example, certain additives such as salts, pH adjustment agents and solvents may be added.
  • the wet granulation or dry method may be used.
  • the granules may be prepared by wet granulation in the presence of either water or any aqueous solution of a binder or polymers as granulating fluid.
  • organic solvents such as isopropyl alcohol, ethanol and the like may be employed with or without water or a binder. If desired additives such as binders may be added.
  • all the ingredients including the active ingredient, cyclodextrin and optionally a pharmaceutical carrier are combined as described above and granulated.
  • the wet granulation process is used.
  • Red thyme oil (Daniel, U.K.) Citrous seed liquid extract (Bio/chem, USA) Allium sativum essential oil (Daniel, U.K.) Caprylic acid oil (Fluka, Switzerland) Dex Otic R (Teva Industries, Israel). Beta-cyclodextrin (Roquette, France).
  • Caprylic acid oil 7. Dex Otic R(c) .
  • Reagent 2 (NHEED (without beta-CD)) includes a combination of all
  • Reagent 5 includes a combination of all ingredients 1, 3, 4 and 6
  • NHEED Naturopathic Herbal Extract Ear Drops.
  • the test was conducted in a totally blind manner, the reagent bottles were alike and marked with numbers so that the technician who tested the reagents did not know its content.
  • the above reagents were dissolved in normal saline.
  • the basic dilution was 1 :10 (one unit of reagent and 9 units of normal saline).
  • 100 ⁇ L of culture media (Mhuller Hinton Broth supplemented with 5% lyzed horse blood for streptococcus pneumoniae (SP) and antibiotic media 3 for hemophilus influenza (HI), Moraxella catharhallis (MC)), Candida Gilabrata (CG), Candida albicans (CA) and Trichophyton Rubrum (TR)) was added to each well of a 96 wells micro titer plate.
  • MIC Minimum Inhibitory Concentration
  • Table 1 The results are expressed as the log dilution of the lower dilution that inhibits bacterial growth (Table 1 and Table 2).
  • Table 1 MIC of reagents 1-7 against 5 strains of Streptococcus pneumonia (SP1-SP5), 2 strains of Haemophilus Influenza (HU, HI2) and 2 strains of Moraxella Catharhallis (MCI, MC2).
  • Table 2 MIC of reagents 1-7 against 2 strains of Candida albicans (CA1,CA2), 2 strains of Candida Glabrata (CGI, CG2) and one strain of Trichphyton Rubrum (TR).
  • reagent 5 which includes a combination of all ingredients 1, 3, 4 , 6 and cyclodextrin (in significantly lower amounts than were tested for each individual ingredient), is the most potent against all types of bacteria.
  • the other reagents: 1, 2, 3, 4, 6 and 7 do not include cyclodextrin at all.
  • NHEED natural herbal extract eardrop
  • Verbascum thapsus containing: Verbascum thapsus, Calendula Officinalis Fiores, Citrous Seed Extract, Plantin, beta-cyclodextrin, acid caprylic (caprylic acid), Liqour burrowi.
  • Essential oils Lavender, Thyme red, Roman Chamomile, Allium sativum (garlic) in a hydro glycerin base) with systemic antibiotics and NHEED in the management of Acute Otitis Media (AOM) and the associated ear pain.
  • AOM Acute Otitis Media
  • Acid caprylic (Fluka, Switzerland), 01. thyme red (Daniel, U.K.), 01. Allium sativum (Daniel, U.K.), 01. Chamomile roman (Daniel, UK.), 01. lavender (Daniel, U.K.)
  • Citrous seed dry extract (Citricidal R Bio/chem, USA), Calendula officinalis dried flowers (Ambro, Germany), Verbascum thapsus dried flowers (Ambro, Germany), Plantin dried herb (Ambro, Germany), Liqour Borrowi (Reka Industries, Israel), Beta- cyclodextrin (Roquette, France).
  • the NHEED ear drop composition includes:
  • Thyme vulgaris and 01. Thyme sweet can be used as substituents to 01. Thyme red.
  • Most preferable oil is 01. Thyme red.
  • Calendula can be used as substituent to Calendula extract glycerin/tincture. Most preferable is calendula extract glycerin/tincture.
  • glycol/tincture refers to an extraction of the herb with glycerin.
  • a mixture of water and alcohol or mixture of water and propylene glycol may be used.
  • Most preferred is the extraction of plantin, calendula and verbascum herbs with glycerin.
  • citrous seed extract refers to an extract of 10% w/w of citrous seed in 70/30 glycerin/aqua, ingredients (7), (8) and (9) are similarly extracted using a concentration of 10% w/w of the herb in the extraction medium - glycerin. The extraction was performed for 24 hr.
  • extraction with water or glycerin may be used, however, such extracting agents when used alone result in a very potent extraction.
  • the NHEED ear drops composition was prepared by the following method:
  • PATIENTS AND METHODS A total of 200 children aged 5 to 18 years experiencing ear pain associated with AOM were eligible for enrollment. The study was conducted in an open randomized manner.
  • AOM required the presence of middle ear effusion, ear pain and at least one other indicator of acute inflammation.
  • Indicators of acute inflammation were marked redness of the tympanic membrane (TM) and/or distinct fullness or bulging of the TM.
  • Determination of the presence of middle ear effusion was based on the presence of at least 2 of the following criteria: decreased or absent TM motility by pneumatic otoscopy, an "A" flat or "B" curve revealed in tympanogram images, visible bubbles or air fluid level behind the TM or opacification of the TM, other than that, secondary to scarring. All examinations were preformed by one physician unaware of physician investigator performing the physical examination.
  • Amoxycillin or to herbal medication ear disease other than AOM; known immunodeficiency; suffering from defects of the ear or nasopharynx; past history of complications of AOM; presence of otorhea, ear drum perforation or ventilating tube(s); inability to reliably use a visual analog pain score.
  • Group A 5 drops of NHEED ear drops were applied into the external canal(s) of the affected ear(s) 3 times daily for a total of 3 days; (Table 1).
  • Group B Amoxycillin was administered orally at a dosage of 50-80 mg/Kg to max of 500 mg per day per patient for 7 days and NHEED ear drops were applied in the external canals of affected ear(s), 5 drops 3 times daily for a total of 3 days.
  • the Pain-O-Meter is a linear scale (from 1 to 10) and a color scale (ranging from blue to red).
  • the first data point Day 1-0 was assessed at the diagnosis of AOM. After administration of the NHEED ear drops (group A), NHEED eardrops and the first dose of antibiotics (group B), the patients and parents, under physician guidance, recorded the pain scores after 15 and 30 minutes (Day 1-15, Dayl- 30) respectively. "
  • the Observational Scale of Behavioral Distress was used to assess ear pain.
  • On the reverse side of the card is the face scale, which is composed of five facial representations from a broad smile, indicating no pain, to a sad and crying child indicating the worst possible pain. The parents and children were educated in the use of the pain scale. Eligibility for study participation required a baseline score (Day 1-0) of 3 or more out of 10. Measurement of both the facial, and the linear scales were recorded separately for each time evaluation and then averaged to determine an overall ear pain score.
  • Table 2 Step-wise linear regression model of the modification of the level of pain (score from 0 to 10) from time 0 to last follow-up, against possible explanatory variables
  • the patients in both groups showed a mean ear pain reduction at each evaluation time with a higher reduction in the NHEED than NHEED & Antibiotics group.
  • the mean ear pain score level was 8.31 (CI: 7.96-8.66) in the NHEED group and 8.26 ( CI: 7.91-8.53) in the NHEED & Antibiotics group.
  • the mean ear pain score was 0.62 (CI: 0.43-0.38) in the NHEED group (a reduction of 92.5%) and 2.41 (95% confidence interval CI: 2.05-2.76) (a reduction of 70.8%%), in the NHEED & Antibiotics group ( Figure 1).
  • Pain reduction may be achieved by time alone, similar to recent reports published by other investigators [Little P et al. Pragmatic randomized controlled trial of two prescribing strategies for childhood acute otitis media. _3_t_72001;322(7282):336-42].
  • Antibiotic use is prevalent in the treatment of AOM presented with middle ear effusion, despite growing evidence that it has little benefit in the prevention or reduction of the risk of mastoditis and meningitis and bactermia [Takata GS et al. Evidence assessment of acute otitis media: I.The role of antibiotics in treatment of uncomplicated acute otitis media. Ped 2001;108(2):239-247].
  • ear pain associated with AOM was assessed with the Pain-O- Meter. A reduction in the pain score was apparent in both groups at each evaluation time. A statistical significant difference in favor of Naturopathic herbal extract medications was observed. This may offer, significant benefits in the management of ear pain associated with AOM.
  • This study suggests that an ear drop solution of herbal extract applied in the affected ear canal reduces the ear pain associated with AOM and reduces the need for systemic antibiotic treatment without an increased risk of secondary complications. In children older than 5 years of age, initial antibiotic treatment at the diagnosis of AOM may be withheld. If, however, at follow-up no improvement is observed, antimicrobial treatment probably should be initiated. Using NHEED may prevent the development of allergies, staggering costs, the risks of over-treatment and increasing bacterial resistance to antibiotics.
  • NHEED an eardrop formulation of naturopathic origin alone is at least as effective as the combination of antibiotics with NHEED and was proven to be significantly better for the management of ear pain associated AOM.
  • Using NHEED in the treatment of AOM may allow the withholding of initial systemic antibiotic treatment for AOM. Should the clinical need be established, systemic antibiotic treatment may be initiated.
  • EXAMPLE 3 A solid composition for treating ear disorders
  • lactobacillus bulgaricus lactobacillus bulgaricus, bifidobacterium infantis, bifidobacterium longum and bifidobacterium brevis (180 billion live bacteria per gram).
  • composition was prepared by simple mixing of all ingredients for 10 minutes to form a homogeneous mixture.
  • the thymol- beta CD (cyclodextrin) complex was prepared by the following method:
  • beta cyclodextrin was blended with 90g of deionized water for a period of 2-5 minutes at 20-25°C to form a homogeneous mixture (paste). 20 g of thymol were added to the mixture and mixed until a uniform paste was obtained.
  • the mixture was filled into a close airtight glass vessel and kept for a period of 48 to 72 hrs, at a temperature of 20°C - 25°C, in a dark place.
  • the mixture was dried in a drying oven at a temperature of 25°C - 30°C until dried.
  • Garlic oil-beta CD complex was prepared by the above method (as described for thymol- beta CD) using 20 g garlic oil and 200 g beta-cyclodextrin.
  • the gel composition is prepared according to the following procedure:
  • the aqua hammamelis is heated to a temperature of 60°C (preferred temperature range 50-80°C), in order to dissolve the beta-cyclodextrin and disperse the hydroxyl ethy cellulose in water to allow swelling.
  • the beta- cyclodextrin is added until dissolved.
  • the hydroxyl ethylcellulose (Natrosol)) is added and mixed until a clear dispersion is obtained.
  • the mixture is cooled to 40°C, then hyaluronate sodium is added, mixed till uniformity.
  • the other ingredients are added and mixed till a uniform mixture is obtained.
  • the mixture is left for 6-12 hours and homogenized to obtain a uniform gel.
  • the preparation conditions of the gel are dependent on the dispersion and swelling properties of the gelling agent.
  • cellulose derivatives such as hydroxyl ethyl cellulose or hydroxyl propyl cellulose
  • gelling agents such as pluronic 127 or carbopols there is a need to first disperse these gelling agent in cold water (preferably 5°C).
  • Cellulose derivatives are more preferred for gel preparations with cyclodextrins. However, other gelling agents may also be used.
  • Phase A was heated on water bath at 70°C till all ingredients were melted, to form a clear solution.
  • Phase B was heated on a water bath until a temperature of 70°C was reached.
  • Phase A was added to phase B, homogenized for 5-15 minutes and then cooled to 40°C to obtain a cream.
  • Phase C was then added to the homogenized mixture of A and B and then homogenized at 40°C.
  • Phase D was added to the homogenized mixture of phases A, B and C and homogenized at 35°C, until a uniform mixture (cream) was obtained.
  • Phase E was added to the mixture (cream) of phases A,B,C,D and mixed at 35°C until a uniform mixture (cream) was obtained.
  • the mixture was left for 24 hours at room temperature and then mixed until a uniform mixture (cream) was obtained.

Abstract

The invention relates to an ear composition comprising: (a) at least one of the following herbal medicines: (i) verbascum; (ii) calendula officinalis flores; (iii) citrous seed; (iv) plantin; (v) lavender; (vi) thyme; (vii) chammomile; (viii) allium sativum; (ix) caprylic acid; (x) a combination of at least two of (i) - (ix); (b) a cyclodextrin; and (c) optionally a pharmaceutical carrier. The invention further relates to the use of the composition for treating ear disorders.

Description

HERBAL MEDICINE CONTAINING CYCLODEXTRINS FOR TREATMENT OF EAR DISORDERS
FIELD OF THE INVENTION
The present invention relates to ear compositions for topical application and use thereof for treating ear disorders.
BACKGROUND OF THE INVENTION
Ear disorders
Otitis media is a painful inflammation of the middle ear. Acute otitis media (AOM) is usually accompanied by fever, swelling, inflammation of the eardrum and considerable pain.
Otitis media develops when bacteria or viruses, most often during colds or sore throats, travel up the eustachian tube, from the upper part of the throat behind the nose to the middle ear. Determination of the precise etiology is not practical since the causative organism is often difficult to isolate and culture. Fluid accumulation in the middle ear is termed otitis media with effusion. The inflammation should be treated promptly to prevent complications which may result in hearing loss, tinnitus, facial nerve palsy, mastoiditis, labyrinthitis, vertigo, and possible encephalitis.
The middle ear effusion which usually follows an episode of AOM takes at least 23 days to resolve [Schappert SM. Office Visits for Otitis Media: United States, 1975-90. Advance Data from Vital and Health Statistics. Haytsville, MD: National Center for Health Statistics; 1992; Pichichero M.E Acute otitis media: part II. Treatment in an era of increasing antibiotic resistance. Am Fam Physician 2000;61:2410-6; Dagan R. Clinical significance of resistant organisms in otitis media. Pediatr Infect Dis J. 2000;19:378-82]. A spontaneous resolution can be expected in 80-90% of children by the third month after diagnosis [Rosenfield RM. What to expect from medical treatment of otitis media. Pediatr Infect Dis J. 1995;14:731-738].
Approximately 70% of U.S. children have experienced an episode of otitis media by the age of two. The eustachian tube in children is shorter, wider, and more horizontal than in adults, thus Otitis media is more frequently seen in children. Children become less susceptible to infection by age 5. Over half of children experiencing acute otitis media have repeated episodes and the condition may become chronic.
Standard treatment dictates the prescription of oral antibiotics over a course of several days. Seventy percent of ear infections are bacterial, with the remaining 30 percent being viral in origin. Regarding infections of the middle ear, fifty to ninety percent of infections are caused by one of three bacterias: Streptococcus pneumoniae, Hemophilus influenza or Moraxella catarrhalis. Many strains of these bacteria are now resistant to antibiotics.
The overall goals for the use of antibiotics in the treatment of AOM are: the reduction or elimination of ear pain, the prevention of secondary complications, and the elimination of Middle Ear Effusion (MEE), which may have detrimental effects on learning and performance [Rosenfeld RM. Comprehensive management of acute otitis media with effusion. Otolaryngol Clin North Am. 1994;27:443-455].
The use of antibiotics to treat uncomplicated AOM is controversial. Overuse of antimicrobial agents has been associated with emergence and spread of antimicrobial-resistant bacteria [Pichichero M.E Acute otitis media: part II. Treatment in an era of increasing antibiotic resistance. Am Fam Physician 2000;61:2410-6; Dagan R. Clinical significance of resistant organisms in otitis media. Pediatr Infect Dis J. 2000;19:378-82].
Therefore, it is not surprising that at least 42% of the general public in the USA [Eisenberg DM. Davis RB. Ettner S, at el. Trends in alternative medicine use in the United State, 1990-1997. JAMA. 1997;280:1569-75] and 30-50% of general adults in the UK have tried some form of alternative medicine in the last years [Ernst E, White A. The BBC survey of complementary medicine use in the UK. Complementary Therapies in Medicine (2000); 8,32-36].
It has been suggested that herbal extracts have the potential to meet all of the requirements of appropriate medication that could routinely be used in the pediatric population [Spigelblat L. et al. The use of alternative medicine by children. Pediatrics 1994;94:811-4; Murray RH, Ruble AJ. Physicians and healers-unwitting partners in health care. N EnglJMed 1992;326:61-4].
Since prescription of oral antibiotics is not a localized site-specific treatment, it is desirable to avoid overuse of oral antibiotics; natural bacterial flora arc harmed by the ingcstion, and misuse can result in development of resistant bacterial strains. The need exists for a localized treatment therapy for Otitis media, that can replace oral antibiotic therapy.
Various attempts were made to develop topical compositions for treating ear disorders.
U.S. Patent No. 6,093,417 discloses a composition for treatment of ear disorders, having as the essential composition components, anesthetics, zinc salts and penetration enliancers, however, the formulations disclosed and their clinical beneficial effect was not evaluated. Furthermore, the formulations disclosed does not include a cyclodextrin.
The use of herbal medication is widespread and growing, with an increasing number of herbal products available in conjunction with, or as a replacement for, conventional therapy.
Herbal remedies have been utilized for centuries to relieve pain in . the ear. Application of garlic, onion or olive oil are common folklore remedies for ear pain, used at least during the 16th century. Many additional herbs have been noted for their ability to ease the pain of one suffering from ailments in the ear.
Naturopathic eardrops have been shown to have in vitro bacteriostatic and bacteriocidal activity against common pathogens [Kolesnikova AG. Bactericidal and immunocorrective properties of plant extracts. Zh Mϊkrobiol Epidemiol Immunobiol, Mar Abstract (3) 75-78 1986]. Herbal extracts have been shown to stimulate the immune system [Atta AH. Alkofahi A. Anti-nocieptive and anti-inflamatory effects of some Jordanian medicinal plant extract. J Ethnopharmacology 1998; 60:117-124], to serve as antioxidants [Anti-inflammatory action of Pluchea Sagittalis involvement of an antioxidant mechanism. Life Sci. 1996; 59(24):2033-40], to have anti- inflammatory effects [Tubaro E, Tragani, P. Del-Negro,C. Galli, L. Anti- inflammatory activity of a polysaccharide fraction of Echinacea Angustifolia. J. Pharm. Pharmacol 1987;39:567-569] and to have local anaesthetic activity [C. Ghelardin et al. Local anaesthetic activity of the essential oil of Lavandula angustifolia. Planta Medica 1999; 65; 700-703]. They act via local enhancement of anti-inflammatory and immunological activity [Atta AH. Alkofahi A. Anti-nocieptive and anti-inflamatory effects of some Jordanian medicinal plant extract. J Ethnopharmacology 1998; 60:117-124; Perez-Garcia F. et al. Anti-inflammatory action of Pluchea Sagittalis involvement of an antioxidant mechanism. Life Sci. 1996; 59(24):2033-40]. The bactericidal and the immunologic abilities of plant extracts are well documented in the treatment of middle ear infection. Herbal extracts are well tolerated, have a long half-life, and are easy to administer. There are no documented major adverse effects [Shaparenko BA; Slivko AB; Bazarova OV; Vishnevetskaia EN; Selezneva GT.Use of medicinial plants for the treatment of chronic suppurative otitis Zh Ushn Nos Gorl Ro/ezn, (3):48-51 1979 May-Jun]. E. Michael Sarrel et al. [E. Michael Sarrel et al.; Avigdor Mandelberg; Herman Avner Cohen. Efficacy of Naturopathic Extracts in the management of ear pain associated with accute otitis media, Arch Pediatr Adolesc Med, 155, 796-799] descibes a naturopathic herbal ear drop composition. The composition disclosed is disadvantageos since it does not include a penetration enhancer such as cyclodextrin and therefore its permeability through the tympanic membrane is limited. The composition disclosed possess only local anaesthetic and anti-inflammatory activity and does not show antibiotic activity. Additionally, the composition has a short shelf-life and is stable for 1 year only. Cyclodextrin is a family of cyclic oligosaccharides which are known to form inclusion complexes with many organic substances, including several drugs [H.W. Frijlink et al. The effect of cyclodextrins on drug absorption II. In vivo observations, Int. J. Pharm. 64 (1990) 195-210]. Complexation often changes the physico-chemical characteristic of the guest molecule and can be of importance in the pharmaceutical field.
In the past decades the use of cyclodextrins as excipients in various drug dosage forms has received much attention. Cyclodextrins have been used as complexing agent in various compositions [US patent Nos. 6,320,051, 6,274,554, 6,043,221, 5,861,433 and 5,834,512]. Upon complexation with the drug, advantages such as improved bioavailability, reduction in unwanted side effects, improved stability or increased aqueous solubility of the drug have often been claimed [Stephen P. Jones et al. Cyclodextrins in the pharmaceutical sciences, Part I: Preparation, structure and properties of cyclodextrins and cyclodextrin inclusion compound, Ada Pharm. Technol. 30 (1984) 213-223; H.W. Frijlink et al. The effect of cyclodextrins on drug absorption II. In vivo observations, Int. J. Pharm. 64 (1990) 195-210; Jozsef Szejtli, Cyclodextrin Technology, pp. 79-293, 335-362, 1988 Kluwer Academic Publisher].
It was shown that the solubility and therefore permeability of lypophilic drugs are increased in the presence of beta-cyclodextrin. For example, when a 2:1 cyclodextrin complex of hydrocortisone or triacinolone acetonide was prepared, and shaken in water at 37°C, the concentration of dissolved hydrocortisone was 2-fold, and that of triamcinolone 27-fold, when compared to the free drugs. The percutaneous absorption in rats and rabbits of these steroids, from paraffin based ointments containing the free drugs or their complexes, was shown to be concordant with their in vitro solubility. No improvement of hydrocortisone when monitored by direct determination and by its biological effects was observed. The absorption of triamcinolon acetonide, and its biological effects, such as glycogen content of skin, blood sugar level, etc., were significantly improved (more than 2-fold) [Jozsef Szejtli, Cyclodextrin Technology, p. 281-282, 1988, Kluwer Academic Publisher].
The improved absorption and biological effects of triamcinolon acetonide were related to its higher in vitro solubility (compared to the free drug). However, the beneficial effect of treating affected and inflamed tissues such as the ear was not taught or suggested.
Since the structure of the affected ear is different and much more dense than the skin, there is a need for an enhancer capable of delivering the active ingredients to their target sites with the capability of crossing hydrophilic and hydrophobic barriers including significant amount of water due to ear inflammation.
Thus there is a widely recognized need for, and it would be highly advantageous to have a composition for topical application to the ear, which can replace or reduce the amount of oral antibiotics, or other active agents used for treatment of various ear disorders such as infections. This is enabled in the present invention by using cyclodextrins for more efficient delivery of drugs applied topically. The cyclodextrin would increase the therapeutic effect of the active ingredient present in the composition.
The compositions of the present invention provide a simpler and lower costing natural solution. The compositions counteract inflammatory processes and reduce the side effects of the active ingredients (because lower concentration of the active ingredients are required in the presence of cyclodextrin).
These and other advantages of the present invention will become more apparent from the summary of the invention and the detailed description that follow. DEFINITIONS
For purposes of this specification and accompanying claims, the term "NHEED" refers to Naturopathic Herbal Extract Ear Drops.
For purposes of this specification and accompanying claims, the term "inclusion complex" refers to molecular compounds having the characteristic structure of an adduct, in which one compound (host molecule) spatially encloses another. The enclosed compound (guest molecule) is situated in the cavity of the host without significantly affecting the host framework structure.
For purposes of this specification and accompanying claims, the term "borrow' s solution" refers to a 13% w/v aluminum acetate solution in acetic acid.
For purposes of this specification and accompanying claims, the term "cyclodextrin" refers to any type of cyclodextrin such as beta-cyclodextrin, alpha-cyclodextrin, gama-cyclodextrin, hydroxypropyl-beta-cyclodextrin, derivatives of any of the above, or mixtures of any of the above.
For purposes of this specification and accompanying claims, the term active ingredient" or "active agent" refers to a herbal medicine which may be a composition of matter comprising several ingredients at least one of which having a medical activity, a single active ingredient of a herbal medicine said ingredient having a medical activity, a pharmaceutically acceptable salt of a single active ingredient of a herbal medicine, or a chemical derivative of a single active ingredient of a herbal medicine, or any other non-herbal active ingredients, which are effective in treating, preventing or alleviating an ear disorder, symptom or complication.
For purposes of this specification and accompanying claims, the term "herbal medicine" refers also to a single active ingredient of a herbal medicine, a pharmaceutically acceptable salt of a single active ingredient of a herbal medicine, or a chemical derivative of a single active ingredient of a herbal medicine. For purposes of this specification and accompanying claims, the term "single active ingredient" refers to the single ingredients of the herbal medicine which can be isolated and have a pharmacological effect.
SUMMARY OF THE INVENTION
According to one aspect of the invention there is provided an ear composition comprising:
(a) at least one of the following herbal medicines:
(i) verbascum;
(ii) calendula officinalis fiores;
(iii) citrous seed;
(iv) plantin;
(v) lavender;
(vi) thyme;
(vii) chammomile;
(viii) allium sativum;
(ix) caprylic acid;
(x) a combination of at least two of (i) - (ix);
(b) a cyclodextrin; and
(c) optionally a pharmaceutical carrier.
According to another aspect of the present invention there is provided use of an ear composition as defined in the present invention in the preparation of a medicament for treating, preventing or alleviating an ear disorder, symptom or complication selected from the group consisting of infection, inflammation, pain and oedema. BRIEF DESCREPTION OF FIGURE
Figure 1 is a description of the level of pain (score from 1 to 10) of study group NHEED vs. NHEED and Antibiotics.
The NHEED composition comprising Verbascum thapsus, Calendula Officinalis Fiores, Citrous Seed Extract, Plantin, beta-cyclodextrin, acid caprylic, Liqour burrowi, Essential oils: Lavender, Thyme red, Roman Chamomile, Allium sativum (garlic) in a hydro glycerin base, as described in example 2.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it was found that the combination of an active ingredient (especially verbascum; calendula officinalis fiores; citrous seed; plantin; lavender; thyme; chammomile; allium sativum; caprylic acid) with a cyclodextrin preferably beta-cyclodextrin is highly advantageous as an ear composition since the cyclodextrin increases the therapeutic effect of the active ingredient and thus decreases the amount of the active ingredient needed to be administered or applied in the treatment of pathogenic bacteria and yeasts.
Without being bound to theory, a proposed mechanism for this effect is the increase in tissue permeability, probably by diffusion of the cyclodextrin- active ingredient inclusion complex through aqueous pores or by exchange of the drug complex in the cyclodextrin, with tissue lipids. It is proposed that the cyclodextrin serves as a penetration enhancer. Another proposed mechanism may be by increasing the dissolution of the drug in aqueous medium, which allows it to becomes more available and prone to contact the target membrane of the microorganism and attack it due to decrease in the surface tension.
The present invention is useful for treatment of ear disorders since inclusion of the cyclodextrin in the composition enables the active agent to penetrate the tympanic membrane and to affect the middle and inner ear.
When the tympanic membrane is swollen (being inflamed and containing fluid) it repels hydrophobic oily drugs. Therefore, there is a need to incorporate the hydrophobic oily active ingredient into the aqueous medium. This is done by incorporation of a cyclodextrin. The cyclodextrin solubilizes the hydrophobic oily active ingredient in the aqueous medium and increases the active ingredient permeability to its target site.
Unexpectedly it was found that addition of a cylodextrin to the composition leads to a considerable reduction of the amount of drug (active agent) needed to be administered or applied to achieve the desired therapeutic effect. The cyclodextrin was found to increase the therapeutic effect of the active drug.
The active agent of the present invention is preferably a hydrophobic, oil-soluble ingredient. When the active agent is mixed with the cyclodextrin in an aqueous media an inclusion complex is formed thus enabling the formulation of aqueous-based compositions containing hydrophobic, water- insoluble active agents. This is especially advantageous when formulating ear compositions since it was found that water-based ear drops provide the greatest coverage of the tympanic membrane after administration of the drops to the patients [P.S. Wilson et al. Distribution of ear drops in normal ear, The Journal of Laryngology and Otology, 105 (1991) 359-361].
The present invention relates to an ear composition comprising:
(a) at least one of the following herbal medicines:
(i) verbascum;
(ii) calendula officinalis fiores;
(iii) citrous seed;
(iv) plantin;
(v) lavender;
(vi) thyme;
(vii) chammomile;
(viii) allium sativum;
(ix) caprylic acid;
(x) a combination of at least two of (i) - (ix);
(b) a cyclodextrin; and (c) optionally a pharmaceutical carrier.
Preferably the above herbal medicines possess an antibacterial, anti- inflammatory, local anaesthetics, astrigent and anti oedema activity.
According to a preferred embodiment of the present invention the herbal medicine is present in the composition in a form selected from the group consisting of a dry ground herb, a fresh dry herbal extract, a lyophilized dry herbal extract,_a liquid herbal extract, a herbal essential oil, and mixtures of any of the above.
Additionally according to a preferred embodiment of the present invention the verbascum is verbascum thapsus.
Further according to a preferred embodiment of the present invention the thyme is selected from the group consisting of thyme red, thyme sweet, thyme vulgaris and mixtures of any of the above. Most preferably the thyme is thyme red.
Still further according to a preferred embodiment of the present invention the chammomile is selected from the group consisting of chammomile roman, chammomile german and mixtures of any of the above. Most preferably the chammomile is chammomile roman.
Moreover according to a preferred embodiment of the present invention the ear composition further comprises aluminum acetate.
Preferably the aluminum acetate is present in the composition in the form of liquour borrowi.
Aluminum acetate used in the present invention, posses various pharmacological activities such as astringent, local anti-inflammatory, local anti oadema. Aluminum acetate is also used to adjust the pH of the composition. The preferred pH range of the ear compositions of the present invention is 3.5-5.5, more preferably 4-5.
If desired additional pH adjusting agents such as lactic acid may be added to the compositions of the present invention.
Preferably the ear composition of the present invention comprises at least one of the following herbal medicines: allium sativum, caprylic acid, citrous seed or thyme. Most preferably the herbal medicine comprises a mixture of allium sativum, caprylic acid, citrous seed and thyme.
Each of these herbal medicines in combination with cyclodextrin, preferably a beta cyclodextrin, is highly efficient in treating ear disorders. The dyclodextrin increases their antibacterial activity and the uniformity of the preparation. These herbal medicines are lypophilic in nature and the cyclodextrin makes them more soluble in water, a factor that is important in increasing the drug (active agent) accessibility to and through the infected ear membrane.
According to another preferred embodiment of the present invention the ear composition comprises a mixture of verbascum; calendula officinalis fiores; citrous seed; plantin; lavender; thyme; chammomile; allium sativum; caprylic acid; aluminum acetate; and a cyclodextrin. The cyclodextrin is preferably a beta-cyclodextrin.
Preferably the verbascum is verbascum thapsus. Preferably the thyme is thyme red. Preferably the chammomile is chamomile roman.
The above composition is effective in treating ear disorders especially otitis media, otitis externa and otomycosis.
The composition may be formulated as a liquid, semi-solid or solid dosage form as described in the invention below. Most preferably the final form of the composition is liquid (such as a suspension). The carrier (vehicle) of the composition is preferably liquid, more preferably an aqueous based carrier. Preferably the aqueous based carrier is a mixture of glycerin and water.
Preferably the glycerin is present in the composition at a concentration of 10% to 90% (w/w) and most preferably at a concentration of 60% to 80%
(w/w).
Preferably the water is present in the composition at a concentration of
5% to 95% (w/w) and most preferably at a concentration of 10% to 30%.
The composition is preferably administered as ear drops.
Additionally according to a preferred embodiment of the present invention: the verbascum is present in the composition in a concentration of 10% to 70% w/w, more preferably from 15% to 50% w/w, and most preferably 20% to 40% w/w, the calendula officinalis fiores is present in the composition in a concentration of a 1% to 30%> w/w, more preferably from 5% to 20% w/w, and most preferably 10% to 15% w/w, the citrous seed is present in the composition in a concentration of 1% to 60% w/w, more preferably from 5% to 50% w/w, and most preferably 5% to 40% w/w, the plantin is present in the composition in a concentration of 5% to 20% w/w, more preferably from 5% to 15% w/w, and most preferably 5% to 10% w/w, the lavender is present in the composition in a concentration of 1% to 90% w/w, more preferably from 1% to 50% w/w, and most preferably 2% to 10% w/w, the thyme is present in the composition in a concentration of 0.05% to 6% w/w, more preferably from 0.5% to 4% w/w, and most preferably 1% to 3% w/w, the chammomile is present in the composition in a concentration of 0.01% to 7% w/w, more preferably from 0.1% to 5% w/w, and most preferably 0.5 to 2% w/w, the allium sativum is present in the composition in a concentration of 0.01% to 30% w/w, more preferably from 0.05%> to 20% w/w, and most preferably 0.05 to 5%, the caprylic acid is present in the composition in a concentration of 0.01% to 30% w/w, more preferably from 0.05% to 20% w/w, and most preferably 0.05% to 5% w/w.
Preferably the verbascum is verbascum thapsus.
Preferably the thyme is thyme red. Preferably the chammomile is chammomile roman.
Preferably, the cyclodextrin is present in the composition in a concentration of 0.05% to 10% w/w and more preferably from 1% to 7% w/w.
The cyclodextrin is preferably a beta cyclodextrin.
Each of the above herbal medicines may be present in the composition as a single herb (in combination with the cyclodextrin) using the above concentration ranges, or in a mixture including a combination of at lease two herbs (in combination with the cyclodextrin) using the above concentration ranges.
The above concentrations refer to the raw materials of the herbal medicines as used in the examples (Example 2 -NHEED composition). It is appreciated that where the raw material is a herbal medicine including small percentage of an active ingredient, the concentrations should be adjusted accordingly (increase in the proportion of the pure material to he whole herbal medicine) as compared to a case where a more purified material including higher proportions of the active ingredient is used.
Preferably, the aluminum acetate is present in the composition in a concentration of 0.1% to 13% w/w and more preferably from 0.1% to 7% w/w.
The above concentrations for aluminum acetate refer to liquor Burrowi (13% Aluminum Acetate solution) raw material as described in the examples (example 2). It is appreciated that when other concentrations of aluminum acetate in the raw material are used, the concentrations in the composition should be adjusted accordingly.
The above concentration ranges of the herbal medicines and the aluminum acetate relate to a liquid composition.
It should be appreciated by a person versed in the art that for other compositions, such as solid or semisolid other ranges of concentrations could be used. Typically, for solid or semi solid a 10-20 fold increase can be used.
Moreover, according to a preferred embodiment of the present invention the ear compositions of the present invention further comprises at least one of the following a herbal medicines: hydrastis, ruta, hammamelis, almond oil, jojoba oil, coptidis, capsicum or mixtures of any of the above.
The herbal medicines of the present invention posses various activities as described in British Herbal Pharmacopoea 1983; Blumental, Goldberg and Brinckman, Herbal Medicine - Expanded Commission - E monographs, Edition 2000; Martindle Extra Pharmacopea - 32 Edition].
Non limiting examples of herbal medicine which may be used in combination with the cyclodextrin according to the present invention includes: verbascum thapsus, calendula fiores, allium cepa, citrous seed, plantin species, lavender, thyme red, thyme vulgaris, thyme sweet, chammomile roman, chamomile german, caprylic acid, anemone pulsatilla, apocynum androsaemifolium, centella asiatica, chrysanthemum parthenium, datura, dipteryx odorata, euphorbia tirucalli, euphrasia officinalis, sorbus aucuparia, glechoma hederacea, hydrastis canadensis, hyoscymus niger, Illicium verum, laurus nobilis, lobelia inflata, lycospersicon esculentum, melaleuca leucadendron, momordica charantia, nicotiana tabacum, ocimum basilicum, pancratium trianthum, papaver somniferum, peumus boldus, ruta graveolens, satureja montana, sophora secundiflora, viscum album, propolis, calamus, allium sativum (garlic), azadircta indica, camphor, sassolite (boric acid), thymol, borneol, menthol, menthae species, menthae piperata, indigo powder, coptis chinesis, phellodendron chinesis, scutellaria, astragalus membranaceus, eucalyptus glabra, rosemarin officinalis, salvia officinallis, verbena officinalis, olea europea, rosa canina, sinapis orvensis, ecbalium elaterium, artemisia judaica, artemisia species, mecurialis annua, laurus nobilis, capparis spinosa, allium ampeloprasum, amygdalus cammunis, tabebuia impetiginosa, achyrocline species,larrea divarticulata, rosa borboniana, punica granatum, psidium guineese, lithrea ternifolia, cassia alata, angelica archangelica, usnea barbata, syzygium aromaticum, amomm subulatum, neurospora crassa, polygonum punctatum, polygonum ferrugineum, luehea divearicata, xanthium spinosum, polygonum acuminatum, polygonum stelligerum, peschiera australis, tea tree oil, tabernaemontana australis, inga uruguensis, curcuma longa, echinacea species, oregano, uncaria tomentosa, hammamelis virginiana, myrrh, cocos nucifera, barley, beta 1,3 D-glucan, halloisitum rubrum, grifolia frondosa, ganoderma lucidum, lentinus edodes, frondosa edodes, tebebuia impetignosa, dryobalanops aromatica, cinnamum camphora, capsicum, their single active ingredients, pharmaceutically acceptable salts thereof, derivatives thereof or mixtures of any of the above.
Artemisia species may be for example artemisia capillaris (Yin chen hao), artemisia apiacea (Qing Hao) or artemisia argyi (Ai Ye).
For each specific herbal medicine described in the present invention, its single active ingredients, a pharmaceutically acceptable salt of its single active ingredients and a chemical derivative of its single active ingredients are also within the scope of the present invention.
For example, acid caprylic (caprylic acid) is an oily extraction of the single active ingredient (acid caprylic) from the herb cocos nucifera.
Beta 1,3 D-glucan is a water extraction of the single active ingredient (beta 1,3 D-glucan) from the herb barely. Boric acid is a single active ingredient of sassolite. Menthol is a single active ingredient of menthae species, thyme vulgaris, red thyme and mentha peperata.
Camphor is a single active ingredient of cinnamun camphora. Thymol and borneol are single active ingredients of thyme vulgaris. Borneol is a single active ingredient of dryobalanops aromatica.
The herbal medicines of the present invention are known to have various activities. Some examples are given below:
Antibiotic herbal medicines include, but are not limited to hydrastis, echinacea, propolis, coptis, ruta, citrous seed, thyme, tea tree, oregano, azadiracta, uncaria tomentosa, or mixtures of any of the above.
Steroid herb medicines include but are not limited to chamomile oil, calendula officinalis, beta-sito sterol, or mixtures of any of the above.
Non-steroidal anti inflammatory herb medicines include but are not limited to plantin, chrysanthemum partaneum, scutelaria, or mixtures of any of the above.
Antifungal herb medicines include but is not limited to red thyme, caprylic acid, citrous seed, allium species, tea tree, ruta, azadiracta, oregano, hydrastis, coptis, sorbic acid, sorbus aucuparia, tabebuia, uncaria tomentosa, or mixtures of any of the above.
Local anaesthetic herb medicines may be, for example, lavender, menthae, myrrh, or mixtures of any of the above.
The anaelgetic herb medicine may be for example chamomile, calendula, mentha species, pulsatilla, humulus lupulus, calamus, or mixtures of any of the above.
According to a preferred embodiment of the present invention, the ear composition further comprises at least one ingredient selected from the group consisting of benzocain, hyaluronate sodium, salicylic acid, aluminum potassium sulphate, vitamin E, thymol, docusate sodium, beneficial flora of microorganisms and mixtures of any of the above.
Additionally according to a preferred embodiment of the present invention, the beneficial flora of microorganisms is lactic acid bacteria.
The beneficial flora of microorganisms control pathogenic overgrowth.
Further according to a preferred embodiment of the present invention the lactic acid bacteria is selected from the group consisting of lactobacillus species, bifidobacterium species and mixtures of any of the above.
The lactobacillus bacteria species may be for example lactobacillus acidophylus, lactobacillus plantarum, lactobacillus casei, lactobacillus bulgaricus or mixtures of any of the above.
The bifidobacterium species may be for example bifidobacterium infantis, bifidobacterium longum, bifidobacterium brevis or mixtures of any of the above.
According to a preferred embodiment of the present invention the ear composition comprises a mixture of hydrastis, ruta, benzocain, aluminum potassium sulphate, thymol, garlic, hammamelis, calendula, lactobacillus and bifidobacterium species, and a cyclodextrin.
The composition may further comprise a wax softener such as a surfactant preferably sodium ducusate.
The thymol and garlic oil are preferably present in the composition in the form of thymol-cyclodextrin complex and garlic- cyclodextrin complex.
The cyclodextrin is preferably a beta-cyclodextrin. The final form of the above composition maybe a liquid, a semi-solid or a solid and most preferably a solid composition. When the compositions of the present invention are formulated in a solid form, the solid ear compositions may include additional ingredients such as a wax softener for example a surfactant. The surfactant for example docusate sodium functions as a wax softener and reduces the surface tension between the powder and the liquid excretions from the ear.
The solid compositions may further include a solid pharmaceutical carrier as described in the invention. Some of the pharmaceutical carriers such as zinc oxide may also function as astringents.
The ear compositions of the present invention may further comprise a synthetic drug, for example an anti-inflammatory agent, an antibiotics, a local anaesthetics or mixtures thereof.
Preferably the anti-inflammatory agent is aluminum acetate, aluminum potassium sulfate, aluminum potassium sulfate dodeca hydrate or mixtures thereof.
The anti-inflammatory agent may be for example a steroid, a non- steroidal anti inflammatory drug or mixtures thereof.
The steroids include but are not limited to, hydrocortisone, dexamethasone, betamethasone, beclomethasone, prednisolone, triamcinolone, alclomethasone, clobetasol, desonide, fluocinolone, fluocinonide, pharmaceutically acceptable salts thereof, derivatives thereof or mixtures thereof.
The non-steroidal anti inflammatory drug may be, for example, indomethacin, ibuprofen, diclofenac, hyaluronate, pharmaceutically acceptable salts thereof, derivatives thereof or mixtures thereof.
The antibiotics may be, for example, penicillins, cephalosporins, aminoglycosides, tetracyclines, erythromycines, quinolones, polymyxin B, bacitracin? pharmaceutically acceptable salts thereof, derivatives thereof or mixtures thereof . The aminoglycosides include, but are not limited to, neomycin, tobramycin, gentamycine, vancomycine, pharmaceutically acceptable salts thereof, derivatives thereof or mixtures thereof.
The local anaesthetic includes but is not limited to amethocaine, benzocaine, tetracaine, lodocaine, pharmaceutically acceptable salts thereof, derivatives thereof or mixtures thereof.
Additional drugs which may be used are fungal agents and/or keratolytic agents such as salicylic acid.
Preferably, the steroid is present in the composition in a concentration of 0.1%) to 4% w/w and most preferably in a concentration of 0.1% to 2% w/w.
Preferably, the non-steroidal anti inflammatory drug is present in the composition in a concentration of 0.1% to 5% w/w and most preferably in a concentration of 0.1% to 4% w/w.
Preferably the aluminum acetate, aluminum potassium sulfate, aluminum potassium sulfate dodeca hydrate are each present in the composition in a concentration of 0.1 % to 13 % w/w and most preferably in a concentration of 0.1% to 7% w/w.
Preferably, the antibiotics is present in the composition in a concentration of 0.1% to 10% w/w and most preferably in a concentration of 0.5% to 8% w/w.
Preferably, the local anaesthetics is present in the composition in a concentration of 0.1% to 15% w/w and most preferably in a concentration of 1% to 10% w/w.
The above concentration ranges relate to liquid and semi-solid compositions.
As discussed above, the use of cyclodextrin in the ear compositions of the present invention is highly advantageous since the cyclodextrin enables the active ingredient to penetrate the tympanic membrane and to affect the middle and inner ear.
According to a preferred embodiment of the present invention, the cyclodextrin is selected from the group consisting of beta-cyclodextrin, alpha- cyclodextrin, gama-cyclodextrin, hydroxypropyl-beta-cyclodextrin, derivatives of any of the above, and mixtures of any of the above. More preferred cyclodextrins are beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin. Most preferred cyclodextrin is beta-cyclodextrin.
Preferably, the cyclodextrin is present in the pharmaceutical composition at a concentration of 1% to 90%) w/w.
Preferably the weight ratio of the cyclodextrin or cyclodextrin derivative to the active ingredient is from 1:4 to 30:1.
High concentration of the cyclodextrin in the compositions (up to 90% w/w) may be used since the cyclodextrin may also serve as a diluent in solid compositions. In this case the cyclodextrin serves also as a pharmaceutical carrier and no additional pharmaceutical acceptable carrier is needed. Additionally high concentrations of cyclodextrins might be used to absorb secretions in various disease conditions such as ear inflammation.
Preferably the ear compositions of the present invention are in a form of a liquid, a semisolid or a solid.
According to a preferred embodiment of the present invention the composition is a liquid or semi solid dosage form and the cyclodextrin is present in the composition in a concentration of 0.05% to 10% w/w.
When preparing liquid compositions, preferably the cyclodextrin is present in the composition at a concentration of 0.05% to 10% w/w, more preferably at a concentration of 1% to 7% w/w.
Preferably the weight ratio of the cyclodextrin to the active ingredient in the liquid composition is from 1:4 to 30:1 and more preferably from 1 :4 to 18:1. When preparing semi-solid compositions, for example, ointments, cream or gels, preferably the cyclodextrin or cyclodextrin derivative is present in the pharmaceutical composition at a concentration of 0.05% to 10% w/w, more preferably at a concentration of 3% to 7% w/w.
Preferably the weight ratio of the cyclodextrin to the active ingredient in the semi-solid composition is from 1:4 to 30:1.
The cyclodextrin is used in the present invention at a concentration useful as a penetration enhancer. The cyclodextrin concentrations used in a liquid composition (less than 10% w/w) will not completely solubilize the active ingredient. Therefore the active ingredient is partly solubilized in the composition and partly suspended in the pharmaceutical carrier. The concentration of cyclodextrin selected for a specific composition, will depend on the concentration of the active ingredient and its physicochemical properties.
Higher concentrations of a cyclodextrin, when used in liquid compositions (above 10% w/w) may solubilize completely the active ingredient (depending on the cyclodextrin: active ingredient weight ratio) and may cause irritation.
The concentrations of cyclodextrin used in the present invention are the minimal therapeutic concentrations required. Higher concentrations of cyclodextrin (5-15 times higher) are also useful as a solubilizer, however such high concentrations may cause irritation when applied topically.
According to a preferred embodiment of the present invention the cyclodextrin: active ingredient weight ratio is from 1:4 to 30:1. For solid dosage forms the cyclodextrin: active ingredient weight ratio is from 10:1 to 30:1. For liquid compositions the cyclodextrin: active ingredient weight ratio is from 1:4 to 30:1 and more preferably from 1:4 to 18:1. The cyclodextrin: active ingredient weight ratio depends on the molar ratio between the cyclodextrin and the 'guest' (active ingredient) molecule. Our preliminary experiments showed that when beta-cyclodextrin was used as a solubilizer at high concentrations (higher than 10%> w/w) it caused local irritation when applied to the ear.
Alternatively, a solid dosage form such as granules or a powder can be prepared.
According to a preferred embodiment of the present invention the composition is a solid dosage form and the cyclodextrin is present in the composition in a concentration of 1% to 90%> w/w.
More preferably, the cyclodextrin is present in the solid dosage form, at a concentration of 5% to 25% w/w and most preferably at a concentration of 6% to 15%) w/w. When these concentrations are used the cyclodextrin is preferably used to form an active ingredient-cyclodextrin complex.
The concentration of the cyclodextrin is determined according to the active ingredient physicochemical properties, its concentration and according to the final form of the composition.
In solid dosage forms the cyclodextrin can also be used as a diluent or filling agent excipient, and therefore high concentrations up to 90% w/w may be used. In this case the cyclodextrin may also serve as a pharmaceutical carrier, and the no additional pharmaceutical carriers may be required.
Preferably the weight ratio of the cyclodextrin or cyclodextrin derivative to the active ingredient in the solid dosage form is from 10:1 to 30:1.
The higher ratio of 30:1 may be used in solid compositions such as powder, for topical application to the ear to absorb secretions in various disease conditions such as ear infection and inflammation.
The ear compositions of the present invention may further comprise additional ingredients known in the art to serve as penetration enhancers such as oleum recini, surfactants, alcohols, polyols, sulphoxides, oleates, lactam compounds, alkanols, alkanoic acids, or mixtures thereof. These ingredients may serve as penetration enhancers in combination with the cyclodextrin.
The ear compositions of the present invention maybe present in various forms such as a liquid, a semi-solid or a solid depending on the pharmaceutical carrier used. Most preferred is the liquid form.
According to a preferred embodiment of the present invention, the pharmaceutical carrier is selected from the group consisting of a liquid carrier, a semi-solid carrier and a solid carrier.
Additionally according to a preferred embodiment of the present invention, the pharmaceutical carrier is a liquid carrier and the final form of said composition is selected from the group consisting of a suspension, a lotion and an emulsion.
Moreover according to a preferred embodiment of the present invention, liquid carrier is a hydrophilic carrier.
Further according to a preferred embodiment of the present invention, the hydrophilic carrier is selected from the group consisting of an aqueous- based carrier, propylene glycol, alcohol, polyethylene glycol, glycerin and an oil-in glycerin emulsion. Most preferably the hydrophilic carrier is an aqueous based carrier.
Still further according to a preferred embodiment of the present invention, the aqueous-based carrier is selected from the group consisting of water, an oil-in water emulsion and a mixture of water with at least one liquid selected from the group consisting of glycerin, propylene glycol, alcohol, polyethylene glycol, burrow's solution, and mixtures of any of the above.
Additionally according to a preferred embodiment of the present invention, the liquid carrier is a hydrophobic carrier.
Moreover according to a preferred embodiment of the present invention, the hydrophobic carrier is selected from the group consisting of an oil and an water-in-oil emulsion. Further according to a preferred embodiment of the present invention, the oil is selected from the group consisting of mineral oil, olive oil and almond oil.
Additionally according to a preferred embodiment of the present invention, the semi-solid carrier is selected from the group consisting of a gel, a cream and an ointment.
Semi-solid compositions are preferably applied to the ear by means of a long nostril tube or impregnated into a cotton swab and applied into the ear canal.
Moreover according to a preferred embodiment of the present invention, the pharmaceutical carrier is a solid carrier and the final form of the composition is selected from the group consisting of a powder and a granule.
Solid compositions are preferably applied to the ear by means of a suitable device such as a tube, a spray or a syringe containing the powder or granules.
The compositions of the invention can be administered to the ear by a mean such as a porous device (such as a film) or an electronic installation device (such as an electronic pump).
Further according to a preferred embodiment of the present invention, the solid carrier is selected from the group consisting of lactose, zinc oxide, amylum, koalin, calamine, dextrin, magnesium oxide, potassium aluminum sulphate, cyclodextrin, argile verde and mixtures of any of the above.
The final form of the compositions of the invention includes, but is not limited to a liquid, drops, an emulsion, a suspension, a cream, an ointment, a lotion, a gel, a paste, a spray, a powder, a granule.
According to a preferred embodiment of the present invention the ear composition described in the present invention further comprises at least one additive selected from the group consisting of antioxidants, preservatives, surfactants, buffering agents, pH adjusting agents, thickening agents, gelling agents, suspending agents, wetting agents, binders, lubricants, vitamins, minerals and mixtures of any of the above.
The ear compositions of the present invention are useful for treating, preventing or alleviating an ear disorder, symptom or complication selected from the group consisting of infection, inflammation, pain and oedema.
The present invention further relates to a method of treating, preventing or alleviating an ear disorder, symptom or complication selected from the group consisting of infection, inflammation, pain and oedema, in a mammal in need of such treatment comprising topically administering to the mammal an effective amount of the ear composition as defined in the present invention, sufficient to ameliorate the effect of the ear disorder, symptom or complication.
According to a preferred embodiment of the present invention, the infection disorder is selected from the group consisting of otalgia, otitis media, otitis externa, and a fungal infection.
Additionally according to a preferred embodiment of the present invention, the fungal infection is otomycosis.
The ear compositions for use in the context of the present invention include compositions wherein the active ingredient in combination with the cyclodextrin is contained in an amount effective to achieve the intended purpose. More specifically, a effective amount means an amount of an active ingredient which when combined with the cyclodextrin is effective to prevent, alleviate or ameliorate one or more causes, complications or symptoms of an ear disease of the subject being treated. The treatment may be prophylactic, for preventing the disease, symptom or complication from occurring. Alternatively the administration may be performed after the disease, symptom or complication were already established so as to eliminate or decrease at least one of the manifestations of the disease, symptom or complication.
The amount of the active ingredient in the compositions of the present invention varies as desired for efficient delivery, and is dependent on the patient's age, weight, sex, disease and any other medical criteria, and is determined according to intended medical use by techniques known in the art. The ear compositions of the invention may be administered topically to the ear once or more times per day. Preferably one to four times per day, as determined by the attending physician or health provider or as desired by the patient.
Methods for preparing the compositions of the present invention
In preparing compositions of this invention general formulation techniques known in the art of pharmaceutical science will be used. See for example Remington's Pharmaceutical Sciences, 16th ed., Mack Publishing
Company, Easton, Pennsylvania. (1980).
In general all methods include the step of bringing into association the carrier(s) with the active ingredient, which constitutes one or more necessary ingredients.
The compositions of the present invention can be prepared by various methods depending on the final form of the composition. For example, the compositions such as suspensions, lotions, or gels may be prepared by simple mixing of all ingredients (active agent, cyclodextrin, the pharmaceutical carrier and other additives) and then homogenizing or stirring.
Alternatively, the cyclodextrin may be dissolved in boiling water at a temperature of 80°C - 100°C, preferably 90°C and then added to a prepared composition including the active ingredient for example a cream, a suspension, a lotion, a solution, a liquid, an ointment or a gel. If required, the composition is further homogenized or stirred.
In another method the cyclodextrin is mixed with the active ingredient and a liquid or a semisolid vehicle to form a solution or a dispersion and then added to a prepared composition for example a cream, a suspension, a lotions, a solution,_a liquid, an ointment or a gel.
When preparing creams or emulsion compositions the cyclodextrin may be added to the oily phase or aqueous phase.
Various additives such as wetting agents, emulsifying agents (surfactants), suspending agents, thickening agents, gelling agents, may be used depending on the final form of the compositions.
The active ingredient-cyclodextrin complexes of the present invention were all prepared by the same general procedure described as follows:
First, the cyclodextrin, preferably beta-cyclodextrin, was blended with deionized water for a period of 2-10 minutes most preferable 2-5 minutes at 20-25°C to form a homogeneous mixture (paste). Then the active ingredient was added to the mixture and mixed until a uniform paste was obtained.
The mixture was filled into a close airtight glass vessel and kept for a period of 1 to 96 hrs, preferably 48 to 72 hrs, at a temperature of 20°C - 25°C, preferably in a dark place. The mixture was dried in a drying oven at a temperature of 20°- 35°C, preferably 25°C - 30°C until dried, or by freeze drying.
Preferably the active ingredient-cyclodextrin complexes of the present invention are prepared using a weight ratio of about 1 :10 active ingredient: cyclodextrin.
Examples of preparing the compositions of the present invention are described below.
A person skilled in the art will be able to choose the appropriate form and its method of preparation on the basis of his general knowledge, taking into account the nature of the constituents used, in particular their solubilities in the vehicle (carrier).
As used herein, the term "occasionally stirring" refers to stirring or homogenizing every 6 to 8 hr for 10 minutes. For liquid ear drops compositions the term "occasionally stirring" refers to stirring or homogenizing every 24 hours for 5-10 minutes.
Semi solid compositions such as gels or creams require more frequent stirring or homogenization (every 6 to 8 hr) depending on the gelling agent used and the composition constituents.
As used herein, the term "room temperature" refers to a temperature of 20°C - 25°C.
When preparing a liquid pharmaceutical composition such as a suspension, the process comprises at least the following step of: mixing at room temperature an active ingredient, a cyclodextrin and optionally a pharmaceutical carrier (liquid carrier) and leaving it at room temperature for about 15 min to about 48 hr, while occasionally stirring, to form a suspension.
Alternatively, in the case wherein part or all the active ingredients of the composition are present in the form of liquid extracts, the composition my be prepared as described above by mixing the active ingredients and the cyclodextrin. In this case the addition of a pharmaceutical carrier may be omitted since the extract medium may serve as the pharmaceutical carrier.
Cream or emulsion compositions (oil-in-water or water-in-oil) are prepared by conventional methods known to those skilled in the art.
Briefly, the oily phase including hydrophobic components with or without a surfactant (emulsifying agent) is heated to 70°C until all ingredients are melted to form a uniform liquid.
The aqueous phase including the hydrophilic water soluble components (with or without the cyclodexterin) are heated to 70°C. The aqueous phase may further include a surfactant (emulsifying agent). The hydrophobic (oily) phase is added to the hydrophilic (aqueous) phase and then cooled and mixed or homogenized to obtain a cream or emulsion.
Preferably an emulsifying agent is present in the aqueous phase or oily phase or both phases. Hydrophilic emulsifying agents are preferably added to the aqueous phase. Hydrophobic emulsifying agents are preferably added to the hydrophobic phase.
If desired additional hydrophobic and/or hydrophilic ingredients are added to the obtained cream or emulsion and then mixed or homogenized to form a uniform mixture (cream or emulsion).
The cyclodextrin may be added to the aqueous phase described above or to the obtained cream or emulsion. After the cyclodextrin is added, the aqueous phase or cream or emulsion is left for 24 - 48 hours at room temperature, preferably for 24 hours at room temperature and then mixed until a uniform mixture is obtained.
Creams or emulsions may also prepared according to the following process comprising the steps of:
(a) preparing a mixture comprising at least one active ingredient and a cyclodextrin, or a mixture comprising at least one active ingredient without a cyclodextrin in a suitable liquid medium, and leaving the mixture for about 24 hours at room temperature while occasionally stirring;
(b) heating an oily phase comprising at least one oil or wax and optionally at least one hydrophobic emulsifying agent to a temperature from about 60°C to about 80°C;
(c) heating 70% - 100% of an aqueous phase comprising water and optionally at least one hydrophilic emulsifying agent until a temperature of about 60°C to about 80°C is reached;
(d) adding the oily phase to the aqueous phase and then homogenizing;
(e) a step selected from the group consisting of: (i) adding the mixture prepared in step (a) comprising least one active ingredient and a cyclodextrin to the homogenized mixture obtained in step (d);
(ii) adding the mixture prepared in step (a) comprising least one active ingredient without a cyclodextrin to the homogenized mixture obtained in step (d) and then homogenizing;
(f) adding a cyclodextrin dissolved in 10 - 30% of the water of the aqueous phase to the mixture in step (e)(ii) and then stirring until dissolved; and
(g) leaving the mixture obtained in step (f) for about 24 hours to about 48 hours while occasionally stirring.
The temperature in steps (b) and (c) is preferably 70°C.
Preferably an emulsifying agent is present in the aqueous or oily phase or both phases. Hydrophilic emulsifying agents are preferably added to the aqueous phase. Hydrophobic emulsifying agents are preferably added to the hydrophobic phase.
Water soluble active ingredients are preferably dissolved in the aqueous phase.
Preferably the homogenizing in steps (d) and e(ii) is performed for about lminute to about 15 minute;
Preferably the temperature of the water in step (f) is 80°C to 100°C, most preferably 90°C.
Preferably the weight ratio of the cyclodextrin to water in step (f) is 1 : 1.
The process may further comprise the step of adding at least one polymer and/or other additives to the homogenized mixture obtained in step (d) and homogenizing. The process may further comprise the step of adding at least one hydrophilic surfactant to the water in step (c).
The selection of the process for preparing a cream composition depends on the properties of the active ingredient. When a solid active ingredient is present, it is occasionally preferable to prepare the active ingredient- cyclodextrin complex in water before preparation of the emulsion (cream), and after achieving a steady state, to combine all the components.
Gel Compositions may be prepared by the following method: The water is heated to 80°C - 100°C, preferably to 90°C. Next, the cyclodextrin is added and mixed until dissolved. The gelling polymer is added and the mixture is homogenized until uniformly dispersed. The obtained mixture is cooled to a temperature of 25°C-40°C, preferably 35°C and then the other active ingredients are added and mixed to obtain a uniform mass. The preparation is left for about 12 hours to complete the gel swelling process and then homogenized to obtain a uniform and smooth gel.
It is appreciated that other methods may also be used as known to those skilled in the art.
Solid compositions are preferably prepared by the following process comprising the steps of:
(a) preparing at least one mixture, wherein each mixture is comprised of an active ingredient, a cyclodextrin and a suitable liquid medium, and leaving each of said mixtures at room temperature for about 15 min to about 48 hr, while occasionally stirring at room temperature, to form a paste; (b) drying the paste of each mixture by a method selected from the group consisting of spray drying, oven drying, room temperature drying and lyophilization;
(c) combining and mixing together said mixtures prepared in steps (a) and (b); and
(d) optionally, adding a pharmaceutical carrier to the mixture obtained in step (c) and preparing a suitable solid dosage form.
The liquid in step (a) may be for example water, buffer solution, mineral salt solution or mixtures thereof.
Step (a) may require special conditions depending on the active ingredient used. For example, certain additives such as salts, pH adjustment agents and solvents may be added.
Additional active ingredients and/or additives may be added in step (c).
When preparing solid dosage forms such as granules, the wet granulation or dry method may be used.
The granules may be prepared by wet granulation in the presence of either water or any aqueous solution of a binder or polymers as granulating fluid. In an alternative, organic solvents such as isopropyl alcohol, ethanol and the like may be employed with or without water or a binder. If desired additives such as binders may be added.
In a preferred embodiment all the ingredients including the active ingredient, cyclodextrin and optionally a pharmaceutical carrier are combined as described above and granulated. Preferably , the wet granulation process is used.
It should be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description. The invention includes other embodiments and can be practiced or implemented in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description only and should not be regarded as limiting.
EXAMPLES
Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non limiting fashion.
EXAMPLE 1
Materials: Red thyme oil (Daniel, U.K.) Citrous seed liquid extract (Bio/chem, USA) Allium sativum essential oil (Daniel, U.K.) Caprylic acid oil (Fluka, Switzerland) Dex OticR (Teva Industries, Israel). Beta-cyclodextrin (Roquette, France).
The following reagents were evaluated for their antibacterial activity.
1. Red thyme oil; 2. NHEED (a) (without beta-CD0^);
3. Citrous seed liquid extract; 4. Allium sativum essential oil; 5. NHEED; 6.
Caprylic acid oil; 7. Dex OticR(c).
Reagent 2 (NHEED (without beta-CD)) includes a combination of all
ingredients 1, 3, 4 and 6, without beta-CD.
Reagent 5 (NHEED) includes a combination of all ingredients 1, 3, 4 and 6
including beta-CD. (a) NHEED = Naturopathic Herbal Extract Ear Drops.
(b) CD = Cyclodextrin.
(c) Dex Otic = Commercial ear drops composition containing (for each l ml):
Dexamethasone sodium phosphate 1 mg; Neomycin Sulphate 5 mg; Polymyxin B Sulphate 10,000 units; In aqueous buffered solution.
The test was conducted in a totally blind manner, the reagent bottles were alike and marked with numbers so that the technician who tested the reagents did not know its content.
The above reagents were dissolved in normal saline. The basic dilution was 1 :10 (one unit of reagent and 9 units of normal saline). 100 μL of culture media (Mhuller Hinton Broth supplemented with 5% lyzed horse blood for streptococcus pneumoniae (SP) and antibiotic media 3 for hemophilus influenza (HI), Moraxella catharhallis (MC)), Candida Gilabrata (CG), Candida albicans (CA) and Trichophyton Rubrum (TR)) was added to each well of a 96 wells micro titer plate. 100 ul of the basic solution was added to the first well and than 8 times two fold dilution was performed leading to a final concentration of 1:20, 40, 80, 160, 320, 640, 1280, 2560. Culture media was selected according to the NCCLS (National Committee for clinical laboratories standards recommendation).
5-10 colonies of the bacterial strains isolated were suspended in MH broth to a final concentration of 10 CFU/MI. 10 ul of the bacterial suspension was inoculated in each well. The plate was incubated with antibiotic for 24 hr at 37° C at an atmosphere of 5% C02.
Minimum Inhibitory Concentration (MIC) was determined as the last clear well, meaning the last well to inhibit bacterial growth.
The results are expressed as the log dilution of the lower dilution that inhibits bacterial growth (Table 1 and Table 2). Table 1 : MIC of reagents 1-7 against 5 strains of Streptococcus pneumonia (SP1-SP5), 2 strains of Haemophilus Influenza (HU, HI2) and 2 strains of Moraxella Catharhallis (MCI, MC2).
Figure imgf000037_0001
Table 2: MIC of reagents 1-7 against 2 strains of Candida albicans (CA1,CA2), 2 strains of Candida Glabrata (CGI, CG2) and one strain of Trichphyton Rubrum (TR).
Figure imgf000037_0002
The results show that reagent 5 (NHEED) which includes a combination of all ingredients 1, 3, 4 , 6 and cyclodextrin (in significantly lower amounts than were tested for each individual ingredient), is the most potent against all types of bacteria. The other reagents: 1, 2, 3, 4, 6 and 7 do not include cyclodextrin at all.
The results teach that a synergistic antibacterial effect occurs when beta-cyclodextrin is added to the mixture including all ingredients (reagent 5). This effect is not seen when the ingredients are mixed without beta- cyclodextrin (reagent 2), or for each single ingredient.
These results are in accordance with the clinical results. Preliminary trial of a formulation without beta cyclodextrin forced the use of larger amounts of the active ingredients compared to a formulation with beta cyclodextrin, in order to achieve the same clinical effect.
Furthermore, side effects were more pronounced with the formulation without beta cyclodextrin.
EXAMPLE 2
The study was designed to compare the effectiveness of a natural herbal extract eardrop "NHEED" (containing: Verbascum thapsus, Calendula Officinalis Fiores, Citrous Seed Extract, Plantin, beta-cyclodextrin, acid caprylic (caprylic acid), Liqour burrowi. Essential oils: Lavender, Thyme red, Roman Chamomile, Allium sativum (garlic) in a hydro glycerin base) with systemic antibiotics and NHEED in the management of Acute Otitis Media (AOM) and the associated ear pain.
Materials: Acid caprylic (Fluka, Switzerland), 01. thyme red (Daniel, U.K.), 01. Allium sativum (Daniel, U.K.), 01. Chamomile roman (Daniel, UK.), 01. lavender (Daniel, U.K.) Citrous seed dry extract (CitricidalR Bio/chem, USA), Calendula officinalis dried flowers (Ambro, Germany), Verbascum thapsus dried flowers (Ambro, Germany), Plantin dried herb (Ambro, Germany), Liqour Borrowi (Reka Industries, Israel), Beta- cyclodextrin (Roquette, France).
The NHEED ear drop composition includes:
Figure imgf000040_0001
a 01. Thyme vulgaris and 01. Thyme sweet can be used as substituents to 01. Thyme red. Most preferable oil is 01. Thyme red.
(b) 01. Chamomile german can be used as substituent to 01. Chamomile roman. Most preferable oil is 01. Chamomile roman.
(c) 01. Calendula can be used as substituent to Calendula extract glycerin/tincture. Most preferable is calendula extract glycerin/tincture.
(d) The term "glycerin/tincture" refers to an extraction of the herb with glycerin. Alternatively a mixture of water and alcohol or mixture of water and propylene glycol may be used. Most preferred is the extraction of plantin, calendula and verbascum herbs with glycerin.
(e) citrous seed extract refers to an extract of 10% w/w of citrous seed in 70/30 glycerin/aqua, ingredients (7), (8) and (9) are similarly extracted using a concentration of 10% w/w of the herb in the extraction medium - glycerin. The extraction was performed for 24 hr.
(*) Ingredients 6,7,8,9 were prepared from Citrous seed dry extract, Calendula officinalis dried flowers, Verbascum thapsus dried flowers, Plantin dried herb. ® 01. = essential oil. For citrous seed extract, the most preferred extracting agent is a mixture of 70/30 glycerin and water, because of their high safety levels, efficacy and minimal adverse effects.
Alternatively, extraction with water or glycerin may be used, however, such extracting agents when used alone result in a very potent extraction.
The NHEED ear drops composition was prepared by the following method:
First, all ingredients were mixed at room temperature for 10 - 20 minutes. Then the mixture was homogenized for 10 minutes to form a uniform suspension. The mixture was left for 48 hours at room temperature while homogenizing for 5-10 minutes every 24 hours.
PATIENTS AND METHODS: A total of 200 children aged 5 to 18 years experiencing ear pain associated with AOM were eligible for enrollment. The study was conducted in an open randomized manner.
The diagnosis of AOM required the presence of middle ear effusion, ear pain and at least one other indicator of acute inflammation. Indicators of acute inflammation were marked redness of the tympanic membrane (TM) and/or distinct fullness or bulging of the TM. Determination of the presence of middle ear effusion was based on the presence of at least 2 of the following criteria: decreased or absent TM motility by pneumatic otoscopy, an "A" flat or "B" curve revealed in tympanogram images, visible bubbles or air fluid level behind the TM or opacification of the TM, other than that, secondary to scarring. All examinations were preformed by one physician unaware of physician investigator performing the physical examination.
Children were excluded from the study if any of the following conditions were present at the initial examination: prior use of any kind of eardrops or oral antibiotics within the preceding 14 days; known allergy to
Amoxycillin or to herbal medication; ear disease other than AOM; known immunodeficiency; suffering from defects of the ear or nasopharynx; past history of complications of AOM; presence of otorhea, ear drum perforation or ventilating tube(s); inability to reliably use a visual analog pain score.
Assessment of AOM severity: In order to evaluate AOM severity we created a clinical score: mild 1-4, moderate 5-8 and severe 9-12 (Table 1), modified from Del Cas F et al [Del Cas F et al. Influence of recent antibiotics therapy on antimicrobial resistance of Streptococcus pneumonia in children with acute otitis media in Spain. Pediatr Infect Dis J, 1998;17:94-7].
Study Design: At study enrollment, informed consent was obtained from one of the parents of each child, and the children were then randomly assigned to one of the 2 groups.
Group A: 5 drops of NHEED ear drops were applied into the external canal(s) of the affected ear(s) 3 times daily for a total of 3 days; (Table 1). Group B: Amoxycillin was administered orally at a dosage of 50-80 mg/Kg to max of 500 mg per day per patient for 7 days and NHEED ear drops were applied in the external canals of affected ear(s), 5 drops 3 times daily for a total of 3 days.
Table 1
AOM severity score
Figure imgf000042_0001
• The Pain-O-Meter is a linear scale (from 1 to 10) and a color scale (ranging from blue to red).
• Modified from Del Cas F at el . Method: Instrument of Ear Pain Assessment
The first data point Day 1-0 was assessed at the diagnosis of AOM. After administration of the NHEED ear drops (group A), NHEED eardrops and the first dose of antibiotics (group B), the patients and parents, under physician guidance, recorded the pain scores after 15 and 30 minutes (Day 1-15, Dayl- 30) respectively. "
On day 2 and day 3, patients and parents carried out the pain evaluation scale at home. Telephone interviews with the parents were then conducted 24 and 48 hours before and after the treatment periods [(Day 2-0, Day 2- 15, Day2- 30); and (Day3-0,Day3-i55 Day-30 )]. The frame of reference for each data point was the time before the first eardrops were installed at Dayl-0 [lst-day evaluation], Day2-0 [2nd-day evaluation] and Day3-0 [3rd-day evaluation].
The Observational Scale of Behavioral Distress (the Pain-O-Meter) was used to assess ear pain. On one side of the Pain-O-Meter there is a linear scale (from 1 to 10) and a color scale (ranging from blue to red). The color begins with blue, indicating no pain, and darkens to the color red indicating the elevated level of pain experienced. On the reverse side of the card is the face scale, which is composed of five facial representations from a broad smile, indicating no pain, to a sad and crying child indicating the worst possible pain. The parents and children were educated in the use of the pain scale. Eligibility for study participation required a baseline score (Day 1-0) of 3 or more out of 10. Measurement of both the facial, and the linear scales were recorded separately for each time evaluation and then averaged to determine an overall ear pain score.
Success was determined if after 48 hours the child had a reduction in ear pain of at least 75%, if there was improvement in the child's appearance and if there was improvement in activity level and quality of sleep, as reported by patients and parents. ANALYSIS: The data was processed with the SPSSWIN, Version 9.01b software (Statistical Package for the Social Sciences, SPSS Inc. Chicago). The χ and Fisher exact test were used to test categorical variables. Analysis of Variance (ANOVA) and paired t Test were used for continuous variables. One model of multivariate step wise linear regression analysis was used to test explanatory variables for the variation of the level of pain from time 0 (of day one) to time 30' of the second follow up (day3) (dependent variable). Independent explanatory variables were: a) Group; b) Severity mild; c) Severity moderate; d) Severity severe; e) Temperature; f) Age (years); g) Medical history ; h) More than 1 child in the household; i) Day care attendance; j) Tobacco use at home; k) Major symptoms; 1) Related symptoms and, m) Number of all other symptoms (see table 2).
Statistical significance was defined at P < .05. In order to evaluate the influence of the variable time (alone and interaction with the variable group) on the variance of the level of pain, we used repeated measurements analysis in three times: Day 1 before treatment, day 2 at 30', and day 3 at 30' (last follow up).
Table 2 : Step-wise linear regression model of the modification of the level of pain (score from 0 to 10) from time 0 to last follow-up, against possible explanatory variables
Figure imgf000045_0001
R2 of variables in the last step = 0.239, R2 of variables not on the last step = 0.038 Total R2 - 0.458 NOTES:
(1) Variables rejected from the model due to lack of significance (PO.05).
(2) Group (dummy variable): NHEED = 1 ; Antibiotics = 0
(3) Severity mild (dummy variable): Mild = 1 ; Moderate + severe = 0
(4) Severity moderate (dummy variable): Moderate = 1 ; Mild + severe = 0
(5) Severity severe (dummy variable): Severe = 1 ; Mild + Moderate = 0
(6) Temperature (dummy variable): >38.5 C = 1 ; 37.5 - 38.4 C = 0
(7) Medical History (dummy variable) ; good health = 1 ; persistent illnesses = 0
(8) More than 1 child at home (dummy variable) one child = 1 more than 1 child = 0
(9) Day care attendance (dummy variable): in day care = 1 ; at home = 0
(10) Tobacco use at home (dummy variable): no smoking in the house = 1 ; smoking = 0 RESULTS: A total of 200 children were enrolled in the study. Six children were excluded due to non-compliance: those who could not be reached by telephone for the interview, who forgot to take the medication, or were overcome by the smell of the eardrops. The excluded six children included two children from the antibiotics & NHEED group, and 4 children from NHEED eardrops group.
One hundred ninety four children completed the study. Their sociodemographic characteristics are described in Table 3. Both groups were similar in their sociodemographic characteristics (Table 3), excepting the family size, which in the group using NHEED had more than 1 child in the household and was statistically significant.
In both groups, more children were diagnosed with bilateral AOM than unilateral AOM. A higher score of AOM severity was observed among the children treated with NHEED alone, 59.4% (95% confidence interval [CTJ: 0.15-0.64) than in the NHEED & Antibiotics group, 39.8 % (95% confidence interval [CI]: 0.46-0.87) (Table 3).
Table 3
Baseline Patient Sociodemographic Characteristics, Medical History, and Otitis
Media Symptoms by Treatment Group (% in parenthesis)
Figure imgf000047_0001
The severity of pain experienced by patients in each of the groups was graded on a scale from 0 to 10, with 0 signifying no pain and 10 signifying excruciating pain. The mean pain score was evaluated for 3 days. The reduction in the pain score is apparent in both groups (Figure 1). Error bars in Figure 1 represent standard deviation. Subscription Day 1, 2, 3 indicate 1st, 2nd, 3rd study days, respectively, of pain evaluation; subscripted numbers 0, 15 and 30 are time intervals in minutes, after administration of eardrops, when pain evaluation took place.
The patients in both groups showed a mean ear pain reduction at each evaluation time with a higher reduction in the NHEED than NHEED & Antibiotics group.
At diagnosis, the mean ear pain score level was 8.31 (CI: 7.96-8.66) in the NHEED group and 8.26 ( CI: 7.91-8.53) in the NHEED & Antibiotics group. At the final ear pain evaluation, the mean ear pain score was 0.62 (CI: 0.43-0.38) in the NHEED group (a reduction of 92.5%) and 2.41 (95% confidence interval CI: 2.05-2.76) (a reduction of 70.8%%), in the NHEED & Antibiotics group (Figure 1).
In order to clarify the reasons for the differences in the reduction of the mean pain score between the two groups, a miultivariate step-wise linear regression analysis was performed. This analysis shows that only the severity of symptoms at diagnosis ( Day 1-0) and the addition of antibiotics, significantly influenced the reduction in mean pain score along the study. The pure influence of adding antibiotics caused 17.3% less reduction in pain than treating the patient with NHEED alone, this influence was statistically significant (p< .001).
Of note is that this contribution was seen after controlling for the concomitant use of age, temperature, medical history, daycare attendance and tobacco use at home (that were rejected due to lack of significance) and the variable "other symptoms" (cough, rhinorrhea, sore-throat, headache, post- nasal-drip, facial-pain, lymphadenopathy, malaise and sleeping problems) that may explain the influence of pain other than from the ear.
The variance of the level of pain evaluated using repeated measurement analysis showed that time was significant as a variable (3 days) (p< .001), this analysis also demonstrated an interaction between the group and time (Table 3).
All patients included in the study completed all data collection points. No adverse events were documented. OUTCOME MEASURE and FOLLOW-UP RESULTS: No secondary complications such as sinusitis, mastoiditis or meningitis were observed in either groups during the study period. Eight children (8.1%) receiving antibiotics reported mild gastrointestinal symptoms that did not require discontinuation of treatment ( 95% confidence interval [CI]: 0.4-2.1). The evaluation for middle ear effusion was performed at 1, 6-8 and 12-14 weeks after treatment completion. Tymphanoscopic evaluation at 1 week revealed a 45 % of MEE (middle ear effusion) in the NHEED group, and 55% in the NHEED & Amoxycillin group. At week 6-8, 10% in the NHEED group and 9% in the NHEED & Amoxycillin group had MEE, and 5% of all the children still remain with MEE at week 12-14. There were no statistical differences between the two groups.
All children with AOM were effectively treated with NHEED or oral antibiotics & NHEED ear drops. We did not observe a significant difference between the two groups according to: their functional status, the rate of relapse or the number of secondary complications due to AOM.
DISCUSSION:
We observed a greater pain control in children treated with herbal extracted ear drops (NHEED) alone, in comparison to the children receiving ear-drops & antibiotics, with a statistical significance emerging on the 2 and 3rd day (p<.0001). The comparative ear pain evaluation between the 2 groups showed that topically applying ear drops of naturopathic origin appears to provide a better control of the otalgia associated with AOM than ear drops and antibiotics.
Possible explanations for our finding may be that antibiotics might interfere with the healing process in the middle ear fluid either by encouraging growth of resistant bacteria or viruses [Del Cas F et al. Influence of recent antibiotics therapy on antimicrobial resistance of Streptococcus pneumonia in children with acute otitis media in Spain. Pediatr Infect Dis J, 1998;17:94-7], or by interfering with the inflammatory protective mechanism of the mucocillary-clearance-system of the middle ear, leading to dysfunction of the eustachain tube which is a well known factor for the development of Otitis Media with effusion [Takahashi H et al. Influence of upper respiratory tract inflammation upon tubal function. Otolaryng 1995;20:216-8].
Pain reduction may be achieved by time alone, similar to recent reports published by other investigators [Little P et al. Pragmatic randomized controlled trial of two prescribing strategies for childhood acute otitis media. _3_t_72001;322(7282):336-42].
We have not found statistically significant differences in the outcome of the middle ear effusion, in children treated with NHEED alone, compared to children treated with antibiotics and NHEED.
The clinical picture matched the in-vitro antibacterial activity of NHEED. At the end of the trial, the parents preferred the treatment with NHEED compared to the antibiotic treatment.
Antibiotic use is prevalent in the treatment of AOM presented with middle ear effusion, despite growing evidence that it has little benefit in the prevention or reduction of the risk of mastoditis and meningitis and bactermia [Takata GS et al. Evidence assessment of acute otitis media: I.The role of antibiotics in treatment of uncomplicated acute otitis media. Ped 2001;108(2):239-247].
Safety: all children participating in this study recovered without complication during the study period.
In this study, ear pain associated with AOM was assessed with the Pain-O- Meter. A reduction in the pain score was apparent in both groups at each evaluation time. A statistical significant difference in favor of Naturopathic herbal extract medications was observed. This may offer, significant benefits in the management of ear pain associated with AOM. This study suggests that an ear drop solution of herbal extract applied in the affected ear canal reduces the ear pain associated with AOM and reduces the need for systemic antibiotic treatment without an increased risk of secondary complications. In children older than 5 years of age, initial antibiotic treatment at the diagnosis of AOM may be withheld. If, however, at follow-up no improvement is observed, antimicrobial treatment probably should be initiated. Using NHEED may prevent the development of allergies, staggering costs, the risks of over-treatment and increasing bacterial resistance to antibiotics.
Conclusions: NHEED, an eardrop formulation of naturopathic origin alone is at least as effective as the combination of antibiotics with NHEED and was proven to be significantly better for the management of ear pain associated AOM. Using NHEED in the treatment of AOM may allow the withholding of initial systemic antibiotic treatment for AOM. Should the clinical need be established, systemic antibiotic treatment may be initiated.
EXAMPLE 3 A solid composition for treating ear disorders
Figure imgf000052_0001
lactobacillus bulgaricus, bifidobacterium infantis, bifidobacterium longum and bifidobacterium brevis (180 billion live bacteria per gram).
Materials: Hydrastis dry extract (AMBRO, Geπnay), Ruta dry extract (AMBRO, Germay) Benzocain (Spectrum, USA) Aluminum potassium sulphate 12 H20 (Carlo-Erba, Italy) Thymol (Riedel dehaen, Germany) Garlic oil (Daniel, U.K) Aqua hammamelis dry extract (CTR Chemicals, Israel) Calendula dry extract (AMBRO, Germany) Lactobacillus and Bifidobacterium (Rhodia, USA), Zinc oxide (Tamar Chemicals, Israel) Argile verde (Tamar Chemicals, Israel) Docusate sodium (Reidel dehaen, Germany).
The composition was prepared by simple mixing of all ingredients for 10 minutes to form a homogeneous mixture.
The thymol- beta CD (cyclodextrin) complex was prepared by the following method:
240 g of beta cyclodextrin was blended with 90g of deionized water for a period of 2-5 minutes at 20-25°C to form a homogeneous mixture (paste). 20 g of thymol were added to the mixture and mixed until a uniform paste was obtained.
The mixture was filled into a close airtight glass vessel and kept for a period of 48 to 72 hrs, at a temperature of 20°C - 25°C, in a dark place. The mixture was dried in a drying oven at a temperature of 25°C - 30°C until dried.
Garlic oil-beta CD complex was prepared by the above method (as described for thymol- beta CD) using 20 g garlic oil and 200 g beta-cyclodextrin.
EXAMPLE 4
An ear gel composition
Table 1
Figure imgf000054_0001
a) Obtained from Sun Ten Pharmaceutical Company LTD. (Taiwan).
(b) Homeopatic dosage (1D=10"1%, D5=10"5%). ^ Prepared from citrous seed dry extract as described in example 2 (NHEED composition).
The gel composition is prepared according to the following procedure:
First, the aqua hammamelis is heated to a temperature of 60°C (preferred temperature range 50-80°C), in order to dissolve the beta-cyclodextrin and disperse the hydroxyl ethy cellulose in water to allow swelling. Next, the beta- cyclodextrin, is added until dissolved. Then, the hydroxyl ethylcellulose (Natrosol)) is added and mixed until a clear dispersion is obtained. The mixture is cooled to 40°C, then hyaluronate sodium is added, mixed till uniformity. The other ingredients are added and mixed till a uniform mixture is obtained. The mixture is left for 6-12 hours and homogenized to obtain a uniform gel.
It is appreciated that the preparation conditions of the gel are dependent on the dispersion and swelling properties of the gelling agent. For cellulose derivatives such as hydroxyl ethyl cellulose or hydroxyl propyl cellulose there is a need to disperse the gelling agent in hot water in order to allow the gellation to occur with cooling of the mixture. For other gelling agents such as pluronic 127 or carbopols there is a need to first disperse these gelling agent in cold water (preferably 5°C).
Cellulose derivatives are more preferred for gel preparations with cyclodextrins. However, other gelling agents may also be used.
Table 2: An ear cream composition
Figure imgf000056_0001
(a) prepared from citrous seed dry extract as described in example 2 (NHEED composition).
(Citrous seed dry extract -CitricidalR , producer: Bio/Chem, USA)
Method of preparation:
Phase A was heated on water bath at 70°C till all ingredients were melted, to form a clear solution. Phase B was heated on a water bath until a temperature of 70°C was reached. Phase A was added to phase B, homogenized for 5-15 minutes and then cooled to 40°C to obtain a cream. Phase C was then added to the homogenized mixture of A and B and then homogenized at 40°C.
Phase D was added to the homogenized mixture of phases A, B and C and homogenized at 35°C, until a uniform mixture (cream) was obtained.
Phase E was added to the mixture (cream) of phases A,B,C,D and mixed at 35°C until a uniform mixture (cream) was obtained.
The mixture was left for 24 hours at room temperature and then mixed until a uniform mixture (cream) was obtained.
While this invention has been shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that many alternatives, modifications and variations may be made thereto without departing from the spirit and scope of the invention. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.
All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

CLAIMS:
1. An ear composition comprising:
(a) at least one of the following herbal medicines:
(i) verbascum;
(ii) calendula officinalis fiores;
(iii) citrous seed;
(iv) plantin;
(v) lavender;
(vi) thyme;
(vii) chammomile;
(viii) allium sativum;
(ix) caprylic acid;
(x) a combination of at least two of (i) - (ix);
(b) a cyclodextrin; and
(c) optionally a pharmaceutical carrier.
2. The ear composition of claim 1 wherein said herbal medicine is present in the composition in a form selected from the group consisting of a dry ground herb, a fresh dry herbal extract, a lyophilized dry herbal extract, a liquid herbal extract, a herbal essential oil, and mixtures of any of the above.
3. The ear composition of claim 1 wherein said vervascum is verbascum thapsus.
4. The ear composition of claim 1 wherein said thyme is selected from the group consisting of thyme red, thyme sweet, thyme vulgaris and mixtures of any of the above.
5. The ear composition of claim 1 wherein said chammomile is selected from the group consisting of chammomile roman, chammomile german and mixtures of any of the above.
6. The ear composition of claim 1 further comprising aluminum acetate.
7. The ear composition of claim 1 wherein said herbal medicine comprises a mixture of allium sativum, caprylic acid, citrous seed and thyme.
8. The ear composition according to any one of claims 1-6 comprising a mixture of verbascum; calendula officinalis fiores; citrous seed; plantin; lavender; thyme; chammomile; allium sativum; caprylic acid; aluminum acetate; and a cyclodextrin.
9. The ear composition of claim 1 or 8 wherein said verbascum is present in the composition in a concentration of 10% to 70% w/w, said calendula officinalis fiores is present in the composition in a concentration of 1% to 30% w/w, said citrous seed is present in the composition in a concentration of 1%> to 60% w/w, said plantin is present in the composition in a concentration of 5% to 20% w/w, said lavender is present in the composition in a concentration of 1%» to 90% w/w, said thyme is present in the composition in a concentration of 0.05% to 6% w/w, said chammomile is present in the composition in a. concentration of 0.01% to
7% w/w, said allium sativum is present in the composition in a concentration of 0.01% to 30% w/w, said caprylic acid is present in the composition in a concentration of 0.01 to
30% w/w.
10. The ear composition of claim 6 or 8 wherein said aluminum acetate is present in the composition at a concentration of 0.1% to 13 > w/w.
11. The ear composition of claim 1 further comprising at least one of the following a herbal medicines: hydrastis, ruta, hammamelis, almond oil, jojoba oil, coptidis, capsicum or mixtures of any of the above.
12. The ear composition of claim 1 furhter comprising at least one ingredient selected from the group consisting of benzocain, hyaluronate sodium, salicylic acid, aluminum potassium sulphate , vitamin E, thymol, docusate sodium, beneficial flora of microorganisms and mixtures of any of the above.
13. The ear composition of claim 12 wherein said beneficial flora of microorganisms is lactic acid bacteria.
14. The ear composition of claim 13 wherein said lactic acid bacteria is selected from the group consisting of lactobacillus species, bifidobacterium species and mixtures of any of the above.
15. The ear composition according to any one of claims 1 -14 comprising a mixture of hydrastis, ruta, benzocain, aluminum potassium sulphate, thymol, garlic, hammamelis, calendula, lactobacillus and bifidobacterium species, and a cyclodextrin.
16. The ear composition of claim 1 wherein said cyclodextrin is selected from the group consisting of beta-cyclodextrin, alpha-cyclodextrin, gama- cyclodextrin, hydroxypropyl-beta-cyclodextrin, derivatives of any of the above, and mixtures of any of the above.
17. The ear composition of claim 1 wherein said cyclodextrin is beta- cyclodextrin.
18. The ear composition of claim 1 in a form of a liquid, a semisolid or a solid.
19. The ear composition of claim 1 wherein said composition is a liquid or semi solid dosage form and wherein said cyclodextrin is present in the composition in a concentration of 0.05% to 10% w/w.
20. The ear composition of claim 1 wherein said composition is in a solid dosage form and wherein said cyclodextrin is present in the composition in a concentration of 1% to 90%> w/w.
21. The ear composition of claim 1 wherein said pharmaceutical carrier is selected from the group consisting of a liquid carrier, a semi-solid carrier and a solid carrier.
22. The ear composition of claim 1 wherein said pharmaceutical carrier is a liquid carrier and the final form of said composition is selected from the group consisting of a suspension, a lotion and an emulsion.
23. The ear composition of claim 21 wherein said liquid carrier is a hydrophilic carrier.
24. The ear composition of claim 23 wherein said hydrophilic carrier is selected from the group consisting of an aqueous-based carrier, propylene glycol, alcohol, polyethylene glycol, glycerin and an oil-in glycerin emulsion.
25. The ear composition of claim 24 wherein said aqueous-based carrier is selected from the group consisting of water, an oil-in water emulsion and a mixture of water with at least one liquid selected from the group consisting of glycerin, propylene glycol, alcohol, polyethylene glycol, burrow's solution, and mixtures of any of the above.
26. The ear composition of claim 21 wherein said liquid carrier is a hydrophobic carrier.
27. The ear composition of claim 26 wherein said hydrophobic carrier is selected from the group consisting of an oil and an water-in-oil emulsion.
28. The ear composition of claim 27 wherein said oil is selected from the group consisting of mineral oil, olive oil and almond oil.
29. The ear composition of claim 21 wherein said semi-solid carrier is selected from the group consisting of a gel, a cream and an ointment.
30. The ear composition of claim 21 wherein said pharmaceutical carrier is a solid carrier and the final form of the composition is selected from the group consisting of a powder and a granule.
31. The ear composition of claim 21 wherein said solid carrier is selected from the group consisting of lactose, zinc oxide, amylum, koalin, calamine, dextrin, magnesium oxide, potassium aluminum sulphate, cyclodextrin, argile verde and mixtures of any of the above.
32. The ear composition according to any one of claims 1-31 further comprising at least one additive selected from the group consisting of antioxidants, preservatives, surfactants, buffering agents, pH adjusting agents, thickening agents, gelling agents, suspending agents, wetting agents, binders, lubricants, vitamins, minerals and mixtures of any of the above.
33. A method of treating, preventing or alleviating an ear disorder, symptom or complication selected from the group consisting of infection, inflammation, pain and oedema, in a mammal in need of such treatment comprising topically administering to the mammal an effective amount of the ear composition as defined in any of claims 1-32, sufficient to ameliorate the effect of said ear disorder, symptom or complication.
34. Use of an ear composition as defined in any one of claims 1-32 in the preparation of a medicament for treating, preventing or alleviating an ear disorder, symptom or complication selected from the group consisting of infection, inflammation, pain and oedema.
35. The use of claim 34 wherein said infection is selected from the group consisting of otalgia, otitis media, otitis externa, and a fungal infection.
36. The use of claim 35 wherein said fungal infection is otomycosis.
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