WO2014036165A1 - Compositions de type aqueux pour traiter l'otite externe - Google Patents

Compositions de type aqueux pour traiter l'otite externe Download PDF

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Publication number
WO2014036165A1
WO2014036165A1 PCT/US2013/057126 US2013057126W WO2014036165A1 WO 2014036165 A1 WO2014036165 A1 WO 2014036165A1 US 2013057126 W US2013057126 W US 2013057126W WO 2014036165 A1 WO2014036165 A1 WO 2014036165A1
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WO
WIPO (PCT)
Prior art keywords
dosage form
pharmaceutical dosage
antibiotics
otitis externa
fungal
Prior art date
Application number
PCT/US2013/057126
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English (en)
Inventor
Neil E. Paulsen
Roland H. Johnson
Douglas I. Hepler
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Bayer Healthcare, Llc
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Publication date
Application filed by Bayer Healthcare, Llc filed Critical Bayer Healthcare, Llc
Publication of WO2014036165A1 publication Critical patent/WO2014036165A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention relates generally to non-invasive methods and compositions for treating otitis externa (outer ear infection or infestation and inflammation) and, more specifically, to an aqueous otic combination formulated for a single dose regimen.
  • a variety of bacteria, viruses and fungi can be responsible for causing otitis externa.
  • first-line treatment is limited to oral or topical antibiotics.
  • the use of orally administered medications may be diluted by the systemic distribution of the drug, and could place the patient at risk for side effects associated with systemic delivery (e.g., yeast infections in females).
  • side effects associated with systemic delivery e.g., yeast infections in females.
  • the risk for fungal overgrowth in the ear canals of patients treated only with topical antibiotics for bacterial infections emphasizes a need for careful diagnosis and treatment of all the causative agents associated with otitis externa and its sequalae (Schraeder and Issacson, Pediatrics, 111(5): 1123, 2003).
  • a preference is emerging for multiple agent topical treatment of otitis externa, especially in children and animals in whom compliance with a long-term oral dosing regimen can be difficult to obtain.
  • a formulation will not rely on use of gels, cellulose-based or adhesive compositions to increase viscocity for retention in the ear.
  • the present invention is based on the seminal discovery that acute otitis externa in an afflicted subject may be clinically cured with a single dose treatment regimen.
  • One dose of a formulation containing a combination of active agents in aqueous solution applied topically to affected subjects is effective in the treatment of otitis externa.
  • aqueous pharmaceutical dosage form is administered topically to, by way of example, the outer ear canal of the subject.
  • the aqueous pharmaceutical dosage form is a solution.
  • the pharmaceutical dosage form is administered as a single dose, with such dose being sufficient to resolve, or substantially resolve, an existing infection or prevent the onset, or reoccurrence, of an infection without introduction of a further infective agent.
  • the amount of the pharmaceutical dosage form to be administered to the subject may be in quantities of, for example, about 0.5 ml to 5 ml, and all dosage ranges in between. It will be understood, however, that lower or higher dosages may be administered in accord with the clinical judgment of a healthcare professional.
  • the aqueous pharmaceutical dosage form includes a therapeutically effective amount of at least two active agents, such as antibiotics, anti-fungals, anti-parasitics, anti- virals, non-steroidal anti-inflammatories, analgesics, anesthetics, steroids, and the like.
  • active agents such as antibiotics, anti-fungals, anti-parasitics, anti- virals, non-steroidal anti-inflammatories, analgesics, anesthetics, steroids, and the like.
  • antibiotics contemplated herein include, but are not limited to, quinolone antibiotics, penicillin antibiotics, macrolide antibiotics, cephalosporin antibiotics, sulfa antibiotics, beta-lactamase inhibitors, and bacteriostatic antibiotics.
  • allylamine anti-fungals are included in the pharmaceutical dosage form of the disclosed methods.
  • the pharmaceutical dosage form includes three active ingredients, such as an antibiotic, an anti-fungal, and a steroid.
  • the pharmaceutical dosage form contains florfenicol, terbinafme, and mometasone furoate.
  • the pharmaceutical dosage form contains about 1.0 to 2.0% (w/w) terbinafme and about 0.1 to 0.5% (w/w) mometasone furoate in aqueous solution.
  • the pharmaceutical dosage form used in the present methods also contains excipients including, but not limited to, propylene carbonate, propylene glycol, PEG 8000, and alcohol.
  • the subject is a mammal, such as a domestic animal or human. In one embodiment, the subject is a dog.
  • the invention provides a multiple agent composition for treating antibiotic or parasitic infections, fungal infestations, and inflammation which can be placed into and retained in the ear for a sufficient length of time to treat otitis externa without use of a gel, cellulose or other adhesive formulation.
  • aqueous formulations of the invention can be applied topically once to the afflicted subject and effectively resolve the treated condition entirely.
  • Preferred medicaments for delivery according to the invention are those useful in the treatment or prevention of otitis externa and its sequelae (such as pruritis).
  • 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-fungal agents, and antiinflammatory agents or other painkillers.
  • medicaments such as antibiotics or anti-viral agents (depending on the source of the infection present), anti-fungal agents, and antiinflammatory agents or other painkillers.
  • the methods of the invention may also be utilized between active infections to deliver prophylactic agents to the outer ear canal.
  • the invention is suitable for practice in the treatment of otitis externa in animals and humans.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • terapéuticaally effective amount means the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician; e.g., single dose substantial resolution of otitis externa and its sequalae to a degree sufficient to constitute treatment to a clinically significant extent. Most preferable, a therapeutically effective amount will be one in which, when administered in a single dose, prevents or resolves an infection to a degree sufficient to avoid reoccurrence without introduction of additional infective agents into the ear. A clinical score of less than 3 as described in Example II below is, in this context, the desired outcome achievable by single dose administration of an aqueous pharmaceutical composition containing a therapeutically effective amount of active agents according to the invention.
  • active agent or “active pharmaceutical ingredient” is meant any biologically active compound useful in the treatment and/or prevention of otitis externa and its sequalae, as well as associated pain and inflammation.
  • particularly preferred medicaments are antibiotics useful in the treatment or prevention of otitis externa in mammals.
  • 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), sulfisoxazole (as well as other sulfa drugs, such as
  • compositions of the invention will contain multiple agents useful in treating otitis externa including, without limitation, anti-fungal and anti-inflammatory compounds.
  • 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 drugs (NSAIDs), such as diclofenac, naproxen, ketoprofen, celecoxib, indomethacin, and pharmaceutically acceptable derivatives thereof.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Steroidal compounds may be administered as an alternative or additive to an NSAID when clinically indicated (e.g., in chronic cases of otitis externa with pruritis), but are not required for use in the invention.
  • the steroid may be betamethasone, betamethasone dipropionate, betamethasone acetate, fluocinonide, fluocinoline acetonide, hydrocortisone, methylprednisolone, mometasone furoate, clobetasol, beclomethasone, dexamethasone sodium phosphate, triamcinolone and pharmaceutically acceptable derivatives thereof.
  • the pharmaceutically active agents provided will include an anti-fungal agent.
  • Suitable anti-fungal agents primarily include those that act on the cell wall or membrane of the fungi, although others (e.g., intracellularly acting agents) may also be suitable when clinically indicated.
  • cell wall/membrane active anti-fungals include the allylamines, the azoles, the polyene antimicotics, and the echinocandins.
  • Non- limiting specific examples include terbinafine, miconazole, ketoconazole, amphotericins, fluconazole, flucytosine, natamycin, amphotericin B, nystatin, cromolyn, lodoxamide, levocabastin, naphazolin, antazoline, pheniramimane and pharmaceutically acceptable derivatives thereof. Unless its use is contraindicated (e.g., for certain lupus patients), terbinafine is the presently preferred anti-fungal agent for use in the invention.
  • the pharmaceutically active agent may also include a local anesthetic or analgesic agent.
  • suitable agents include benzocaine, benzyl benzoate, bupivacaine, calamine, chloroprocaine, chloroxylenol, cinchocaine, cocaine, dexivacaine, diamocaine, dibucaine, dyclonine, etidocaine, hexylcaine, ketamine,
  • levobupivacaine lidocaine, menthol, mepivacaine, oxethazaine, phenol, pramoxine, prilocaine, amethocaine, tetracaine, proparacaine, propoxycaine, pyrrocaine, resorcinol, risocaine, rodocaine, ropivacaine, tetracaine, and pharmaceutically acceptable derivatives thereof. Due to the rapid action of the compositions of the invention in resolving treated otitis externa, use of such anesthetic or analgesics may be unnecessary.
  • otitis externa is often linked to a parasitic infestation, most often an otocariosis, or Otodectes cynotis (ear mites) infestation.
  • Topical treatment with ear mites has often been accomplished with relatively long courses of topical insecticidal therapy, e.g., with a pyrethrin-containing composition.
  • mectin and mycin compounds e.g., avermectins (such as ivermectin and selamectin) and milbemycin, administered otically, by injection, or on the skin.
  • anti-parasiticidal compounds may be co-administered within, or as a separate adjunct to, the compositions of the invention.
  • anti-viral compounds such as acyclovir, may be administered in lieu of, or as an adjunct to, antibiotic compounds.
  • compositions administered according to the invention will be prepared in a pharmaceutically acceptable form.
  • pharmaceutically acceptable it is meant any inactive ingredients (e.g., a carrier, buffer, diluent or excipient, if any, used with the active ingredients of a composition) must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the active compounds utilized in the invention may be formulated into therapeutic compositions as natural or salt forms.
  • Pharmaceutically acceptable non-toxic salts include the base addition salts (formed with free carboxyl or other anionic groups) which may be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2- ethylamino-ethanol, histidine, procaine, and the like.
  • Such salts may also be formed as acid addition salts with any free cationic groups and will generally be formed with inorganic acids such as, for example, hydrochloric, sulfuric, or phosphoric acids, or organic acids such as acetic, citric, /?-toluenesulfonic, methanesulfonic acid, oxalic, tartaric, mandelic, and the like.
  • Salts of the disclosure include amine salts formed by the protonation of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like.
  • Salts of the disclosure may also include amine salts formed by the protonation of an amino group with suitable organic acids, such as p-toluenesulfonic acid, acetic acid, and the like.
  • suitable organic acids such as p-toluenesulfonic acid, acetic acid, and the like.
  • Additional excipients which are contemplated for use in the practice of the disclosure are those available to those of ordinary skill in the art, for example, those found in the United States Pharmacopeia Vol. XXII and National Formulary Vol. XVII, U.S. Pharmacopeia Convention, Inc., Rockville, Md. (1989), the relevant contents of which is incorporated herein by reference.
  • polymorphs, hydrates, and solvates of the active compounds are included in the disclosure.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Viscocity-enhancing/viscogenic or gelling agents are not required and may be excluded. If a suspending agent or solvent is utilized, its composition and concentration need not, and preferably will not, provide the suspension with a viscosity in excess of 5 cps. Penetration enhancers need not, and will preferably not, be present in the suspension, which is intended for treating the portion of the ear canal outside of the tympanic membrane.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more
  • the present disclosure provides methods for topically treating and preventing otitis externa through administration of multiple active agents, preferably at least two and most preferably at least three active agents, which are useful in prophylaxis or treatment of external ear infections, infestations and inflammation.
  • administering a should be understood to mean providing one or more active compounds of the disclosure or a pharmaceutical composition containing such actives to the subject in need of treatment.
  • compositions of the invention are applied to the external ear canal, i.e., on the outer ear side of the tympanic membrane (eardrum).
  • the compositions of the invention do not contain gelling agents, methylcellulose or other adhesive elements, yet are sufficiently potent to ameliorate or resolve otitis externa through a single dose course of treatment.
  • Topical administration to the outer ear canal may be achieved by, for example, introducing the composition of the invention into the outer ear canal by any medically acceptable means, e.g., application of the carrier composition to the membrane by insertion of a needleless syringe, dropper or swab into the auditory canal. Administration is repeated as required to achieve the therapeutically effective dosage level for the antibiotic compound given.
  • a particular advantage offered by the invention is that it enables
  • otitis externa proves to be unusually refractive to treatment, but the clinical symptoms of the condition are ameliorated after the first dose administered, a follow up dose can be delivered after a medically suitable period of time.
  • a follow up dose can be delivered after a medically suitable period of time.
  • compositions of the invention to treat otitis externa in dogs.
  • the condition was resolved in most animals (24 out of 30 dogs or 80%) with a single dose course of treatment.
  • For the negative control group i.e., animals receiving the delivery vehicle only, clinical cures were observed in only 2 of 15 dogs or 13.3%. Animals who continued to show signs of the condition at day 7 following single dose treatment were withdrawn from the study for inefficacy and were considered treatment failures.
  • the invention may be utilized to treat otitis externa in any mammal, in whom the pharmaceutically acceptable, cellulose-free, non-gelled aqueous compositions of the invention will be applied topically to the outer ear canal in a dose sufficient to clinically ameliorate (significantly reduce symptoms to susceptibility to resolution with re-treatment, preferably a single dose re-treatment) or to resolve the treated condition.
  • concentrations and dosing ranges expected to be efficacious in most clinical situations and species are 0.1 to 2.0% active pharmaceutical ingredient w/w, delivered in unit dosages of about 1 ml, depending on the clinician's judgment of the appropriate course of treatment and the strength of the dosage delivered.
  • Sample pharmaceutically acceptable compositions for use in the methods of the invention to treat otitis externa in test subjects were prepared as follows.
  • the endpoint for effectiveness i.e., a clinical cure was a clinical score improvement to 3 or less in the infected ear, or in the right ear if both ears were infected.
  • CVP control veterinary product
  • Dogs enrolled in the study presented to the clinic with signs of otitis externa On Day 0, a physical examination, including an aural and otoscopic exam, was conducted in order to verify an intact tympanic membrane, absence of foreign bodies and ear mites, and to assign a clinical score to the study ear based on erythema, exudate, swelling and ulceration. In order to be included in the study, the minimum clinical score had to be greater than or equal to 6, A hearing test was conducted, one ear swab was obtained for bacterial culture, one ear swab was obtained for fungal identification via cytology, and the ear was subsequently cleaned with saline.
  • the dogs were dosed by administering 1.0 mi of the assigned IVP or CVP per infected ear. If both ears were infected, the right ear was designated as the study ear.
  • the IVP was identified as both ⁇ - ⁇ and IVP-C, while the CVP was dentified as I VP- A.
  • Clinical score measurement Investigator evaluated the ear and assigned an objective clinical score.
  • Clinical endpoints ability or inability to hear was recorded as supportive information.
  • Randomization method Each animal was assigned in presentation order using randomization forms generated using the SAS statistical package. Each study site utilized a separate randomization form.
  • Age > 8 weeks .
  • Ages of IVP -treated dogs ranged from 7 months to 11.6 years old.
  • Table 1 below includes study population distribution by age.
  • Gender Varied. Table 3 below includes study population distribution by gender.
  • Post-inclusion removal criteria No dogs were removed for serious adverse events or for failing to return for follow-up visits. There were eight dogs removed at Day 7 due to lack of improvement in the clinical score. Seven of these dogs received the CVP, while one dog received the IVP. All eight dogs were considered treatment failures.
  • Protocol Amendments and Deviations There were no protocol amendments. The following protocol deviations occurred:

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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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Abstract

Cette invention concerne des méthodes destinées à traiter et à prévenir l'otite externe à l'aide d'un schéma posologique unique d'administration d'une formulation aqueuse constituée de principes actifs en une quantité thérapeutiquement efficace. Des principes actifs utiles pour traiter la douleur, l'inflammation, les infestations et/ou infections fongiques ou parasitaires de l'oreille externe sont formulés sous forme de solution aqueuse. Les méthodes sont mises en œuvre par administration topique de la formulation aqueuse dans le canal de l'oreille externe.
PCT/US2013/057126 2012-08-29 2013-08-28 Compositions de type aqueux pour traiter l'otite externe WO2014036165A1 (fr)

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Cited By (4)

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CN105395484A (zh) * 2015-12-25 2016-03-16 武汉回盛生物科技有限公司 一种复方特比萘芬喷剂及其制备方法
CN106727281A (zh) * 2016-12-08 2017-05-31 吴燕 一种治疗真菌感染的复方外用制剂及其制备方法和应用
CN109453172A (zh) * 2018-12-26 2019-03-12 湖北中博绿亚生物技术有限公司 药物组合物、其制备方法及其应用
US10610513B2 (en) * 2016-01-11 2020-04-07 Klox Technologies Limited Biophotonic compositions for the treatment of otitis externa

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105395484A (zh) * 2015-12-25 2016-03-16 武汉回盛生物科技有限公司 一种复方特比萘芬喷剂及其制备方法
CN105395484B (zh) * 2015-12-25 2018-05-18 武汉回盛生物科技股份有限公司 一种复方特比萘芬喷剂及其制备方法
US10610513B2 (en) * 2016-01-11 2020-04-07 Klox Technologies Limited Biophotonic compositions for the treatment of otitis externa
US11154532B2 (en) 2016-01-11 2021-10-26 Vetoquinol S.A. Biophotonic compositions for the treatment of otitis externa
CN106727281A (zh) * 2016-12-08 2017-05-31 吴燕 一种治疗真菌感染的复方外用制剂及其制备方法和应用
CN106727281B (zh) * 2016-12-08 2020-12-08 吴燕 一种治疗真菌感染的复方外用制剂及其制备方法和应用
CN109453172A (zh) * 2018-12-26 2019-03-12 湖北中博绿亚生物技术有限公司 药物组合物、其制备方法及其应用

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