CA2622001A1 - Methods for treatment and prevention of otitis media using chemical penetration enhancers to facilitate transmembrane drug delivery into the middle ear - Google Patents

Methods for treatment and prevention of otitis media using chemical penetration enhancers to facilitate transmembrane drug delivery into the middle ear Download PDF

Info

Publication number
CA2622001A1
CA2622001A1 CA002622001A CA2622001A CA2622001A1 CA 2622001 A1 CA2622001 A1 CA 2622001A1 CA 002622001 A CA002622001 A CA 002622001A CA 2622001 A CA2622001 A CA 2622001A CA 2622001 A1 CA2622001 A1 CA 2622001A1
Authority
CA
Canada
Prior art keywords
middle ear
antibiotic
transmembrane
chemical penetration
medicament
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002622001A
Other languages
French (fr)
Inventor
William R. Campbell
Neil E. Paulsen
Roland H. Johnson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Piedmont Pharmaceuticals LLC
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2622001A1 publication Critical patent/CA2622001A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0046—Ear
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Virology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

Methods for treating and preventing middle ear infections by transmembrane administration of medicament-containing transmembrane carrier compositions comprising a chemical penetration enhancer, such as propylene glycol. The compositions are applied to the ear so as to contact the outer surface of an intact tympanic membrane to deliver the medicament across the membrane and into the middle ear. The medicaments delivered according to the methods of the invention include antibiotic, anti- viral, anti-fungal and anti- inflammatory agents that are useful in treatment and/or prophylaxis of middle ear infections and their sequelae.

Description

METHODS FOR TREATMENT AND PREVENTION OF OTITIS MEDIA USING
CHEMICAL PENETRATION ENHANCERS TO FACILITATE TRANSMEMBRANE
DRUG DELIVERY INTO THE MIDDLE EAR
FIELD OF THE INVENTION

[0001] The present invention relates to non-invasive methods for treating otitis media (middle ear infection). More particularly, the invention relates to methods for administering medicament useful in treating otitis media to the middle ear by delivery thereof across the tympanic membrane (eardrum).

BACKGROUND
[0002] Millions of children are affected each year with otitis media; i.e., infection of the middle ear. Although adults are also susceptible to middle ear infections, children are particularly at risk, because their relatively short auditory canals can more easily be closed by inflammation. Fluid can then become trapped behind the tympanic membrane (eardrum), wllich can cause severe pain as well as provide microbes with an inviting environment in which to reproduce.
[0003] The tympanic membrane is a formidable barrier against introduction of drugs into the middle ear, and so antibiotics prescribed to treat middle ear infections are nearly always taken orally. However, a variety of bacteria and viruses can be responsible for causing middle ear infections, and it is frequently not possible to distinguish which is the cause of a particular infection, or whether it is susceptible to treatment with oral antibiotics.
Further, the impact of orally administered antibiotics on the middle ear may be diluted by the systemic distribution of the drug, which may also place the patient at risk for side effects associated with systemic delivery (e.g., yeast infections. in female patients).
[0004] Children who suffer from repeated infections may require surgery to relieve the fluid pressure on the tympanic membrane. In more severe cases, drainage tubes may be placed within the tympanic membrane. The tubes themselves don't prevent reoccurrences of infection (to the contrary, they can serve as conduits for entry of additional pathogens into the middle ear), but they can relieve pressure and reduce the extent to which fluid becomes trapped behind the eardrum. The tubes also offer a potential conduit for antibiotics to be introduced directly into the middle ear; e.g., by applying antibiotic drops and allowing them to flow into the drainage tube. However, this method is both invasive and painful, suggesting a strong need for an alternative route for introducing antibiotics into the middle ear.

SUMMARY OF THE INVENTION
[0005] The invention provides methods for treating and preventing otitis media through administration of medicaments useful in prophylaxis or treatment of middle ear infections and their sequelae in a transmembrane carrier composition. The invention derives from the surprising discovery that, in a carrier comprised of one or more chemical penetration enhancers, medicaments can be delivered across an intact tympanic membrane;
i.e., one without tears (e.g., from bursting under pressure) or punctures (e.g., from insertion of tubes or injection).
[0006] According to the invention, the medicament is supplied as an active ingredient of a transmeinbrane carrier composition applied to the ear so as to put the composition into contact with an intact tympanic membrane (eardrum). The transmembrane carrier composition is further comprised of a chemical penetration enhancer, such as propylene glycol or a mixture of propylene glycol and other penetration enhancers. The penetration enhancer makes up less than 50% v/v of the transmembrane carrier composition, most preferably from about 2% to 15% of the composition.
[0007] Preferred medicaments for delivery into the middle ear according to the invention are those that are useful in the treatment or prevention of otitis media (middle ear infection) and its sequelae. The invention is particularly well-suited to the delivery of medicaments such as antibiotics or anti-viral agents (depending on the source of the infection present), anti-fiuigal agents, and anti-inflammatory agents or other painkillers. For prevention of chronically recurring middle ear infections, the methods of the invention may also be utilized between active infections to deliver prophylactic agents to the middle ear.
[0008] The summary of the invention described above is not limiting and other features and advantages of the invention will be apparent from the following detailed description of the preferred embodiments, as well as from the claims.

DETAILED DESCRIPTION OF THE INVENTION

A. Penetration Enhancers For Use In Transmembrane Treatment of Otitis Media [0009] The use of chemical penetration enhancers in the ear has not, to the inventors' knowledge, been successfully applied to deliver drugs across the tympanic membrane.
However, otic compositions containing such agents as vehicles have been delivered to the middle ear through tympanostomy tubes, and have been found to be ototoxic at concentrations typically utilized in topical preparations.
[0010] For example, at concentrations at or in excess of 50% v/v, propylene glycol applied to the middle ear produces inflammation-related damage to the middle ear, such as cholesteatoma and middle ear adhesions (see, e.g., Vassalli, et al., Am JOtolafyngol., 9(4):180-8, 1988). Propylene glycol has also been implicated in inner ear ototoxicity; e.g., to the round window membrane of the inner ear and cochlea (see, e.g., Marsh and Tom, Otolar.yngol Head Neck Surg., 100(2):134-6, 1989). Other common penetration enhancing, solvents have also been demonstrated to be ototoxic at concentrations present in common otic preparations (see, e.g., Jinn, et al., Laryngoscope, 111(12):2105-8, 2001 [in vitro toxicity of acetic acid on cochlear outer hair cells]).
[0011] The present invention derives from the inventor's discovery that (1) penetration enhancers can facilitate delivery of drugs across the tympanic membrane barrier into the middle ear; and (2) they can do so when used in sub-ototoxic concentrations.
[0012] Chemical penetration enhancers suitable for topical use are known in the art and include low molecular weight alcohols (e.g., ethanol, oleyl alcohol), alkyl methanol sulphoxides, N-methyl-2-pyrrolidone, fatty amines (e.g., oleylamine), fatty acids (e.g., oleic acid, palmitoleic acid, linoleic acid, myristate acid), azone and propylene glycol, singly or in combination. At present, a particularly preferred penetration enhancer for use in the invention is propylene glycol, either alone or in up to a 1:1 ratio with another enhancer, such as oleic acid or ethanol.
[0013] Where ototoxicity is a concern, the penetration enliancer utilized is less than 50%
v/v of the transmembrane composition. Ototoxic reactions to chemical penetration enhancers may be dose-dependent, and can be reduced or substantially avoided at concentrations of about 10% v/v or less. Surprisingly, such relatively low concentrations of penetration enhancers are sufficient to effect delivery of drugs across an intact tympanic membrane and into the middle ear. Therefore, the transmembrane carrier compositions of the invention will preferably comprise about 25% v/v or less of any one or more chemical penetration enhancer(s), most preferably from about 2% to 15% v/v, although the exact formulation will vary depending on the presence and amounts of excipients, preservatives, water, pH modulators, and the like included therein.
[0014] In addition to the penetration enhancer and medicament, the transmembrane compositions of the invention may contain conventional pharmaceutical excipients and preservatives. In this respect, 'preservative' refers to an ingredient added to the transmembrane carrier composition that prevents microbes from substantially growing and multiplying in the formulation. Preferred preservatives include those that are water-soluble and can function as an antimicrobial, such as a benzethonium salt; e.g., benzethonium chloride.
[0015] In general, the amount of the preservative ingredient will range from about 0.005-2.0%. Buffers or acids will be added as necessary to adjust the pH of the composition to the preferred range of 3-6, most preferably 4.5 pH. Other preservatives and excipients that may be present in the transmembrane carrier compositions at less than 2% w/w or less than 1% or even 0% include alkanolamine chloride, sulfate, phosphate, salts of benzoic acid, acetic acid, salicyclic acid, oxalic acid phthalic acid, gluconic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, tartaric acid, maleic acid, malonic acid, succinic acid, fumaric acid, propionic acid, ascorbic acid, mandelic acid, malic acid, citric acid, triethanolammonium chloride, triethanolammonium dihydrogen phosphate, triethanolammonium sulfate, sodium benzoate, potassium benzoate, ammonium benzoate, sodium acetate, potassium acetate, ammonium acetate, sodium salicylate, potassium salicylate, ammonium salicylate, soditun oxalate, potassium oxalate, ammonium oxalate, sodium phthalate, potassium phthalate, ammonium phthalate, sodium gluconate, potassium gluconate, ammonium gluconate, anunonium 1-naphthalenesulfonate, potassium 2-naphthalenesulfonate, ammonium 2-naphthalenesulfonate, sodium 2-naphthalenesulfonate, potassium tartarate, sodium maleate, potassium maleate, sodium malonate, sodium succinate, sodium fumarate, sodium propionate, trietlianolammonium propionate, sodium ascorbate, triethanolammonium ascorbate, potassium ascorbate, sodium mandelate, sodium malate, soditun citrate, potassium citrate, and triethanolammonium citrate. Chelating agents may also be utilized; e.g., disodium ("EDTA");
edetate trisodium, edetate tetrasodium, or diethyleneamine pentaacetate.
[0016] The composition may also contain other active ingredients, such as anti-inflammatories, analgesics, and steroidal compounds (e.g., hydrocortisone, dexamethasone).
Those of ordinary skill in the art will be able to identify suitable compounds and dosages thereof for use in treating pain or inflammation associated with otitis media, such as 0.01-0.5%
dexamethasone (e.g., dexamethasone alcohol (preferred), dexamethasone acetate or dexamethasone phosphate).
[0017] The compositions are preferably administered with the transmembrane carrier composition itself as a carrier, but in various embodiments the transmembrane carrier may be administered in a carrier gel or other suitable carrier. Buffers or acids;
e.g., sodium hydroxide or hydrochloric acid, may be added for adjustment of pH.

B. Useful Medicaments for Treatment and Prophylaxis of Otitis Media [0018] By "medicament" is meant any biologically active coinpound useful in the treatment and/or prevention of middle ear infections and their sequelae, as well as associated pain and inflammation. In this respect, therefore, particularly preferred medicaments are antibiotics useful in the treatment or prevention of middle ear infections in mammals, especially humans. Depending on the severity of the infection and its cause, such antibiotics include, without limitation, amoxicillin (and other penicillins), ciprofloxacin (and other quinolone antibiotics, such as ofloxacin), clavulanate (and other beta-lactamase inhibitors), cefaclor (and other cephalosporins, such as cefixime), azithromycin (and other macrolide antibiotics, such as clarithromycin), and sulfisoxazole (as well as other sulfa drugs, such as sulfamethoxazole). Of the antibiotics useful in the invention, ciprofloxacin is presently preferred.
[0019] Sulfisoxazole and amoxicillin are the principal antibiotics that are also accepted for use in prophylaxis of recurring middle ear infections. Broad spectrum antibiotics such as amoxicillin and ciprofloxacin are especially preferred for use in treating middle ear infections, especially in persons in whom an antibiotic-resistant infection is suspected.
[0020] Useful anti-inflammatory compounds for co-administration or use independent of antibiotic therapy include those that are sometimes less effective or well-tolerated in oral administration; e.g., non-steroidal anti-inflammatory compounds, such as naproxen, ketoprofen, celecoxib and indomethacin. Anti-viral compounds, such as acyclovir, may be administered in lieu of, or as an adjunct to, antibiotic compounds when clinically indicated, as may anti-fungal compositions. Other medicaments for use in the treating and preventing middle ear infections and their sequelae may also be administered by application of the transmembrane carrier compositions of the invention to the tympanic membrane.
[0021] In some embodiments, the transmembrane carrier compositions of the present invention contain more than one medicament. For example, CLAMOXYLO and AUGMENTINO are both combination agent compositions for oral administration that are commonly prescribed for treatment of otitis media. Each composition contains two active antibiotic ingredients, amoxicillin and clavulanate. Transmembrane carrier compositions providing such multiple agents are particularly preferred for use in appropriate indications.
[0022] Overall, the medicament is present in whatever concentration is desirable to treat the condition presented. Generally, concentrations of between 0.1 and 10% w/w will be useful, with most useful concentrations falling within the range of 0.2 to 0.5% w/w;
i.e., 0.3% to 0.4%
w/w will be a typical choice.

C. Methods for Treating Otitis Media Using the Transmembrane Carriers of the Invention [0023] Although the invention shall not be limited by any theory as to the mechanism of action for such delivery, it is presently believed that the chemical penetration enhancers present in the transmembrane compositions of the invention stimulate permeation to an extent sufficient to allow the drug to pass into and through the tympanic membrane.
[0024] To this end, a transmembrane composition of the invention is delivered, by transmembrane administration, into the middle ear. By "transmembrane administration" is meant that application of a transtnembrane carrier composition including a medicament to the outer ear side of the tympanic membrane results in delivery of the medicament to the middle ear. Thus, the invention provides methods for preventing and/or treating infections of the middle ear and their sequelae by transmembrane administration of a medicament to the tympanic membrane of the affected individual.
[0025] Transmembrane administration is achieved via, for example, applying the transmembrane carrier composition of the invention to the tympanic membrane via any medically acceptable means for application of a pharmaceutical composition to the tympanic membrane; e.g., by applying the carrier composition to the membrane by insertion of a needleless syringe or dropper into the auditory canal. Care will be taken to avoid piercing or puncturing the intact tympanic meinbrane.
[0026] Administration is repeated as required to achieve the therapeutically effective dosage level for the antibiotic compound and/or other medicament(s) given.
Pain may be treated by administration in the same general manner of pain killing and/or anti-inflammatory containing transmembrane carrier compositions of the invention.
[0027] Based on current protocols utilized to introduce antibiotics into the middle ear through an in-situ tympanic drainage tube, a suitable regimen of dosing with the exemplary formulation described in Example 1 below (having 0.3% w/w of antibiotic) would be 5 drops/twice a day for a child under age 12, and 10 drops/twice a day for a child of age 12 or older.
[0028] Prophylactic treatment against recurrence of a middle ear infection may be provided in the same manner, utilizing a transmembrane carrier composition of the invention containing a prophylactically effective antibiotic or other medicament.
[0029] Those of ordinary skill in the art will be familiar with, and readily able to select, dosing regimens suitable for following to treat a particular infection. The dosing regimen selected will be in accord with established clinical protocols for delivery and use of the particular carrier and medicaments provided according to the invention.
[0030] The invention having been fully described, its practice is illustrated by the examples below. The invention shall not, however, be limited by the examples, but shall instead be defined in scope by the appended claims.

EXEMPLARY FORMULATION
This section provides an example of the a transmembrane carrier composition of the present invention containing ciprofloxacin and a mixture of propylene glycol and ethyl alcohol, as follows (the composition is sterilized and placed in a phannaceutically acceptable container until use):

Component(s) Percentage(s) Ciprofloxacin HCL 0.3 Boric Acid 1.6 Water, Distilled 62.1 Propylene Glycol 10.0 Ethyl alcohol 190 12.0 K-Y Jelly 14.0 100%

ANIMAL (CHINCHILLA) MODEL OF OTITIS MEDIA
[0031] Chinchilla langer is ideally suited as an animal species for studying the efficacy of treatment for otitis media in humans. Chinchillas are small, have auditory capabilities quite similar to those of humans, have a cochlea with membranous architecture similar to the human cochlea, do not manifest presbycusis in long-term studies, and lack susceptibility to naturally occurring middle ear infections, which are common to the guinea pig and rabbit. See, e.g., Hajek DM, Yuan Z, Quartey MK, Giebink GS., Otitis Media: Tlae Chinchilla Model. in: Zalc 0, Sande M, editors, Handbook ofAnimal Models ofIn ection, San Diego, CA:
Academic Press (1999), at pages 389-403, the contents of which are incorporated herein by reference to illustrate the nature and acceptance in the art of this animal model.
[0032] To establish and evaluate the animal model, each chinchilla was inoculated with Haemophilus influenzae directly into the middle ear of each ear by transbullar injection at a concentration of 100 cfu in a volume of 0.2 mL. Each chinchilla was given an otoscope ear exam prior to being placed on study. Dosing with a composition of the invention or control oral amoxicillin began approximately 48 hours after the bacterial inoculation.
All animals were administered Buprenorphine 0.05mg/kg twice a day subcutaneously for analgesia for the duration of the study.
[0033] At the end of the dosing period (8 days after bacteriaf inoculation), each animal was euthanized, their ear canals washed with saline, and examined. In particular, samples from the middle ear from each chinchilla were collected. One ear sample was cultured overnight per laboratory procedures. Approximately 24 hours after the samples plated out, they were counted and the colony forming units (cfu) recorded.

TREATMENT OF OTITIS MEDIA IN CHINCHILLA MODEL

[00341 The formulation described in Example 1 was administered orally by gavage to three chinchillas twice per day for 6 days, approximately 8 hours apart. 2, 4 or 6 drops of the formulation was administered to two groups of three chinchillas each as a maximal feasible dose for these animals. The animals were examined, and samples were taken from the middle ear of each as described in Example 2. The following results were obtained:

Group Concentration (ng/ml) of Number ears ciprofloxacin infected / total detected in middle ear number ears 1 None 7 of 10 (Untreated) Group Concentration (ng/ml) of Number ears ciprofloxacin infected / total detected in middle ear number ears 2 1031 L 1801.39 O of 10 (Treated) R 3251.27 1032 L 1036.93 R 6295.08 1033 L 3393.74 R 6001.52 1034 L 6060.4 R 5209.15 1035 L 1205.3 R 4746.68 [0035] These results demonstrate the efficacy of the present invention in treating middle ear infection in a relevant animal model.

[0036] The invention illustratively described herein may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be witliin the scope of this invention as defined by the appended claims.

[0037] The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
Applicants reserve the right to physically incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other documents.

[0038] The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein.
Thus, for example, the terms "comprising", "including," containing", etc.
shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

[0039] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. Other embodiments are set forth within the following claims.

[0040] In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

Claims (18)

1. A method for treating or preventing a middle ear infection and sequelae thereof by transmembrane administration of a medicament thereto, said method comprising:
applying a transmembrane carrier composition to the outer surface of an intact tympanic membrane, said transmembrane carrier composition comprising a medicament useful in treating or preventing infections of the middle ear and sequelae thereof.
2. The method according to claim 1, wherein the transmembrane carrier is a chemical penetration enhancer.
3. The method according to claim 2, wherein the chemical penetration enhancer is selected from the group of chemicals consisting of low molecular weight alcohols, alkyl methanol sulphoxides, N-methyl-2-pyrrolidone, fatty amines, fatty acids, azone and propylene glycol, singly or in combination.
4. The method according to claim 3, wherein the chemical penetration enhancer is propylene glycol.
5. The method according to claim 3, wherein the chemical penetration enhancer is propylene glycol and at least one other chemical pentration enhancer.
6. The method according to claim 1, wherein said medicament is an antibiotic.
7. The method according to claim 6, wherein the antibiotic is selected from the group consisting of quinolone antibiotics, penicillin antibiotics, macrolide antibiotics, cephalosporin antibiotics, sulfa antibiotics, and beta-lactamase inhibitors.
8. The method according to claim 7, wherein said antibiotic comprises ciprofloxacin, and is administered to treat or prevent a middle ear infection.
9. The method according to claim 7, wherein said antibiotic comprises ofloxacin, and is administered to treat or prevent a middle ear infection.
10. The method according to claim 7, wherein said antibiotic comprises sulfisoxazole, and is administered to treat or prevent a middle ear infection.
11. The method according to claim 7, wherein said antibiotic comprises amoxicillin, and is administered to treat or prevent a middle ear infection.
12. The method according to claim 7, wherein the antibiotic is provided in a concentration of 0.1 % to 10% w/w of the composition.
13. The method according to claim 12, wherein the antibiotic is provided in a concentration of 0.3% w/w of the composition.
14. The method according to claim 2, wherein the total concentration of chemical penetration enhancer is provided is about 1.0 to 25% v/v.
15. The method according to claim 14, wherein the nonionic polymer surfactant is provided in a concentration of about 2% to about 15% v/v.
16. The method according to claim 1, wherein said medicament is an anti-viral agent.
17. The method according to claim 16, wherein the anti-viral agent is acyclovir.
18. The method according to claim 1, wherein the transmembrane carrier composition is applied to the tympanic membrane during an acute phase of middle ear infection.
CA002622001A 2005-09-26 2006-08-24 Methods for treatment and prevention of otitis media using chemical penetration enhancers to facilitate transmembrane drug delivery into the middle ear Abandoned CA2622001A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US72053505P 2005-09-26 2005-09-26
US60/720,535 2005-09-26
PCT/US2006/033346 WO2007037874A2 (en) 2005-09-26 2006-08-24 Methods for treatment and prevention of otitis media using chemical penetration enhancers to facilitate transmembrane drug delivery into the middle ear

Publications (1)

Publication Number Publication Date
CA2622001A1 true CA2622001A1 (en) 2007-04-05

Family

ID=37900207

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002622001A Abandoned CA2622001A1 (en) 2005-09-26 2006-08-24 Methods for treatment and prevention of otitis media using chemical penetration enhancers to facilitate transmembrane drug delivery into the middle ear

Country Status (11)

Country Link
US (2) US20080269187A1 (en)
EP (1) EP1928439A4 (en)
JP (1) JP2009509955A (en)
CN (1) CN101272772A (en)
AU (1) AU2006295236A1 (en)
BR (1) BRPI0616363A2 (en)
CA (1) CA2622001A1 (en)
EA (1) EA200800949A1 (en)
IL (1) IL190080A0 (en)
WO (1) WO2007037874A2 (en)
ZA (1) ZA200803367B (en)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102014957B (en) 2008-04-21 2014-12-10 奥德纳米有限公司 Auris formulations for treating otic diseases and conditions
US11969501B2 (en) 2008-04-21 2024-04-30 Dompé Farmaceutici S.P.A. Auris formulations for treating otic diseases and conditions
RU2469726C2 (en) 2008-05-14 2012-12-20 Отономи, Инк. Corticosteroid-based composition with controlled release for treatment of ear diseases
US8648119B2 (en) 2008-05-23 2014-02-11 Otonomy, Inc. Controlled release immunomodulator compositions and methods for the treatment of otic disorders
US8846770B2 (en) 2008-06-18 2014-09-30 Otonomy, Inc. Controlled release aural pressure modulator compositions and methods for the treatment of OTIC disorders
US8349353B2 (en) 2008-06-27 2013-01-08 Otonomy, Inc. Controlled release cytotoxic agent compositions and methods for the treatment of otic disorders
WO2010011466A2 (en) 2008-06-27 2010-01-28 Otonomy, Inc. Controlled-release cns modulating compositions and methods for the treatment of otic disorders
US8399018B2 (en) 2008-07-21 2013-03-19 Otonomy, Inc. Controlled release ion channel modulator compositions and methods for the treatment of otic disorders
US8318817B2 (en) 2008-07-21 2012-11-27 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US8496957B2 (en) 2008-07-21 2013-07-30 Otonomy, Inc Controlled release auris sensory cell modulator compositions and methods for the treatment of otic disorders
US10092580B2 (en) 2008-07-21 2018-10-09 Otonomy, Inc. Controlled-release otic structure modulating and innate immune system modulating compositions and methods for the treatment of otic disorders
US8784870B2 (en) 2008-07-21 2014-07-22 Otonomy, Inc. Controlled release compositions for modulating free-radical induced damage and methods of use thereof
US9486405B2 (en) 2013-08-27 2016-11-08 Otonomy, Inc. Methods for the treatment of pediatric otic disorders
WO2018053173A1 (en) 2016-09-16 2018-03-22 Otonomy, Inc. Otic gel formulations for treating otitis externa
WO2019118330A1 (en) 2017-12-12 2019-06-20 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Thermoresponsive hydrogel containing polymer microparticles for controlled drug delivery to the ear
CN116265023B (en) * 2021-12-16 2024-10-18 北京远大九和药业有限公司 Pharmaceutical composition for preventing and/or treating ear infection, and preparation method and application thereof

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3128227A (en) * 1954-06-17 1964-04-07 American Cyanamid Co Antibiotic intramuscular composition
US3549770A (en) * 1963-12-09 1970-12-22 Crown Zellerbach Corp Therapeutic administration of effective amounts of dimethyl sulfoxide to human and animal subjects
US5231112A (en) * 1984-04-12 1993-07-27 The Liposome Company, Inc. Compositions containing tris salt of cholesterol hemisuccinate and antifungal
US4761288A (en) * 1984-09-24 1988-08-02 Mezei Associates Limited Multiphase liposomal drug delivery system
US4897269A (en) * 1984-09-24 1990-01-30 Mezei Associates Limited Administration of drugs with multiphase liposomal delivery system
CA1234717A (en) * 1985-06-28 1988-04-05 Leslie F. Knebl Moist chewing gum composition
US4710390A (en) * 1986-07-07 1987-12-01 Warner-Lambert Company Ingestible, high density, compressed-tablet fruit fiber composition
DE3936328A1 (en) * 1989-10-27 1991-05-02 Schering Ag PHARMACEUTICAL PREPARATIONS
US5542935A (en) * 1989-12-22 1996-08-06 Imarx Pharmaceutical Corp. Therapeutic delivery systems related applications
US5540930A (en) * 1993-10-25 1996-07-30 Pharmos Corporation Suspension of loteprednol etabonate for ear, eye, or nose treatment
ES2088742B1 (en) * 1994-06-29 1997-03-16 Salvat Lab Sa ANTIBIOTIC COMPOSITION OF OTIC APPLICATION.
US5891913A (en) * 1994-10-10 1999-04-06 Novartis Finance Corporation Ophthalmic and aural compositions containing diclofenac potassium
US5843930A (en) * 1995-06-06 1998-12-01 Bayer Corporation Method of treating otitis with ciprofloxacin-hydrocortisone suspension
US5735603A (en) * 1996-05-03 1998-04-07 Littleford Day, Inc. Horizontal mixer apparatus and method with improved shaft and seal structure
US6344222B1 (en) * 1998-09-03 2002-02-05 Jsr Llc Medicated chewing gum delivery system for nicotine
US6716830B2 (en) * 1998-09-30 2004-04-06 Alcon, Inc. Ophthalmic antibiotic compositions containing moxifloxacin
US6740664B2 (en) * 1998-09-30 2004-05-25 Alcon, Inc. Methods for treating otic and ophthalmic infections
US6093417A (en) * 1999-01-11 2000-07-25 Advanced Medical Instruments Composition to treat ear disorders
US6723714B2 (en) * 1999-07-06 2004-04-20 Blansett Pharmacal Co., Inc. Aqueous solvent for corticosteroids
AU2001291219A1 (en) * 2000-09-25 2002-04-08 Bayer Healthcare Llc Otic microbial combinations for treatment of animals with ruptured tympanic membrane
US6716813B2 (en) * 2000-11-28 2004-04-06 House Ear Institute Use of antimicrobial proteins and peptides for the treatment of otitis media and paranasal sinusitis
US6613346B2 (en) * 2001-06-28 2003-09-02 Wm. Wrigley, Jr. Company Chewable product including active ingredient
US6763085B2 (en) * 2001-10-22 2004-07-13 Cleaner Food, Inc. Irradiation apparatus and method
US6672252B2 (en) * 2002-01-31 2004-01-06 Sergeant's Pet Products, Inc. Pet chew
US7220431B2 (en) * 2002-11-27 2007-05-22 Regents Of The University Of Minnesota Methods and compositions for applying pharmacologic agents to the ear
US20040175383A1 (en) * 2002-12-06 2004-09-09 Barr Philip J. Methods and compositions for treatment of otitis media
EP1438942A1 (en) * 2003-01-17 2004-07-21 Schering Oy An otorhinological drug delivery device
MXPA05010659A (en) * 2003-04-04 2005-12-12 Merial Ltd Topical anthelmintic veterinary formulations.
US20050058673A1 (en) * 2003-09-09 2005-03-17 3M Innovative Properties Company Antimicrobial compositions and methods

Also Published As

Publication number Publication date
AU2006295236A1 (en) 2007-04-05
EP1928439A2 (en) 2008-06-11
US20070218050A1 (en) 2007-09-20
CN101272772A (en) 2008-09-24
WO2007037874B1 (en) 2008-02-28
EA200800949A1 (en) 2008-08-29
IL190080A0 (en) 2008-12-29
WO2007037874A2 (en) 2007-04-05
BRPI0616363A2 (en) 2011-06-14
US20080269187A1 (en) 2008-10-30
EP1928439A4 (en) 2009-04-29
ZA200803367B (en) 2009-09-30
WO2007037874A3 (en) 2007-11-08
JP2009509955A (en) 2009-03-12

Similar Documents

Publication Publication Date Title
US20080269187A1 (en) Methods for Treatment and Prevention of Otitis Media Using Chemical Penetration Enhancers to Facilitate Transmembrane Drug Delivery Into the Middle Ear
US20080318918A1 (en) Methods for Treatment and Prevention of Otitis Media Using Nonionic Surfactants to Facilitate Transmembrane Drug Delivery into the Middle Ear
US5843930A (en) Method of treating otitis with ciprofloxacin-hydrocortisone suspension
JP5469511B2 (en) Use of antimicrobial agents such as taurolidine or taurultam in the manufacture of medicaments for the treatment of microbial nosocomial infections
US20160022735A1 (en) Methods and Compositions for Promoting Wound Healing
US20080085301A1 (en) Method for transdermal administration of antimicrobial medications
US20170027930A1 (en) Methods for the treatment of pediatric otic disorders
US20220040306A1 (en) Topical formulations and treatments
US20220117924A1 (en) Compositions of Glycerol and /or Non-Toxic Amino Acids for Inhibiting and Destroying Biofilm, including Related Methods
US20050159369A1 (en) Method of treatment of otitis externa
JP2002500189A5 (en)
Goldenberg et al. The use of otic powder in the treatment of acute external otitis
WO2018053173A1 (en) Otic gel formulations for treating otitis externa
US20070054844A1 (en) Method for treating otitis externa
EP0689832B1 (en) Antibiotic preparation for aural application
US20180092911A1 (en) Otic gel formulations for treating otitis media
MX2008004061A (en) Methods for treatment and prevention of otitis media using nonionic surfactants to facilitate transmembrane drug delivery into the middle ear
Slattery et al. Otic preparations
DE102023116278A1 (en) ANTIBACTERIAL COMPOSITION FOR MEDICAL USE IN THE ORAL AND THROATARY CAVITY
TWI382839B (en) Controlled release corticosteroid compositions and methods for the treatment of otic disorders
O’Rourke et al. Antimicrobial therapy of mastitis
JP2000229863A (en) Composition for pharyngeal diseases
Andrews Antibiotic treatment of ophthalmic infection: new developments
US20070185202A1 (en) Methods and compositions for ophthalmic treatment of fungal and bacterial infections

Legal Events

Date Code Title Description
FZDE Discontinued