Pharmaceutical Compositions for Treating Ear Infections

Abstract

Disclosed is a novel pharmaceutical composition for treating ear infections in animals in a single dose, wherein the pharmaceutical composition comprises a gentamicin antibiotic, a posaconazole antifungal drug, and a mometasone anti-inflammatory drug.

Description

Background Art

[0001] Otitis externa is an inflammatory disease of the ear canal, including the pinna. Otitis externa can be acute or chronic (persistent or recurrent otitis lasting more than 3 months). Otitis externa may be associated with one or more etiologies. The bacteria most commonly isolated from the ear canal of dogs with otitis are Staphylococcus species. Other bacteria commonly associated with otitis include Pseudomonas, Proteus, Enterococcus, Streptococcus, and Escherichia coli. Some bacteria, such as Staphylococcus and Pseudomonas, can produce biofilms, which can lead to persistence of infection despite appropriate treatment because antimicrobial therapy must disrupt the biofilm to be effective in clearing the infection. Malassezia yeast is another common component of canine otitis externa. Some dogs have an allergic reaction to Malassezia species, causing severe discomfort and itching. Effective treatment of ear infections includes identifying the underlying factors that caused the otitis in the first place, in addition to treating the infection and inflammatory changes. While topical therapy is the primary treatment for otitis externa, systemic anti-inflammatory and antimicrobial therapy may be indicated for individual patients. Most dogs with otitis, regardless of the cause, will benefit from anti-inflammatory therapy. Glucocorticoids can be used for short periods of time to reduce pain and swelling, thus improving compliance and aiding in ear cleaning and medication. Glucocorticoids may also help to disrupt biofilm formation and prevent the development of chronic otic changes. Long-term use or reliance on glucocorticoids to manage ear disease is not recommended unless necessary. In general, systemic antibiotics are not recommended as a first-line treatment for otitis externa. See J. Bajwa, Can Vet J. 2019 Jan; 60(1): 97-99, the Merck Veterinary Manual, 8th Edition, 1998, pp 372-376 and Aziz et al, Asian Pacific Journal of Tropical Biomedicine,Volume 6, Issue 5, 2016, pp 390-395.

[0002] Otomax® (gentamicin sulfate, betamethasone valerate, and clotrimazole ointment) is indicated for the treatment of acute and chronic canine otitis externa associated with bacteria and / or yeast (Malassezia pachydermatis) susceptible to gentamicin. Each gram of Otomax® Otic Ointment contains gentamicin sulfate (USP, equivalent to 3 mg gentamicin base), betamethasone valerate (USP, equivalent to 1 mg betamethasone), and 10 mg clotrimazole (USP) in a mineral oil-based system containing a plasticized hydrocarbon gel. Otomax® is administered twice daily for seven days. See NADA 140-896 Otomax®, approved June 9, 1993.

[0003] Mometamax® Otic Suspension (gentamicin sulfate, mometasone furoate monohydrate, and clotrimazole; otic suspension) is indicated for the treatment of canine otitis externa due to susceptible strains of yeasts (Malassezia pachydermatis) and bacteria (Pseudomonas spp. [including Pseudomonas aeruginosa], coagulase-positive staphylococci, Enterococcus faecalis, Proteus mirabilis, and beta-hemolytic streptococci). Each gram of Mometamax® Otic Suspension contains gentamicin sulfate (equivalent to 3 mg of gentamicin base), mometasone furoate monohydrate (equivalent to 1 mg of mometasone furoate), and 10 mg of clotrimazole in a mineral oil-based system containing a plasticized hydrocarbon gel. Mometamax® is administered once daily for 7 days. See Mometamax® product insert and NADA 141-177 Freedom of Information Summary, January 9, 2003.

[0004] Posatex® Otic Suspension (orbifloxacin, mometasone furoate monohydrate and posaconazole; suspension) is a veterinary drug used to treat canine otitis externa associated with susceptible strains of yeast (Malassezia pachydermatis) and bacteria (coagulase-positive Staphylococcus aureus, Pseudomonas aeruginosa, and Enterococcus faecalis). Each gram of Posatex® Otic Suspension contains 10 mg of orbifloxacin, mometasone furoate monohydrate (equivalent to 1 mg of mometasone furoate) and 1 mg of posaconazole. Posatex® is administered once daily for 7 days. See NADA 141-266 FOI, dated February 18, 2010 and WO 2006 / 020689.

[0005] Neptra® (known as Claro® in the United States) is a veterinary medicine used to treat dogs suffering from short-term or recurrent ear infections (otitis externa) caused by two microorganisms: Staphylococcus pseudintermedius (bacteria) and Malassezia pachydermatitis (yeast). Neptra® contains three active substances: florfenicol, terbinafine, and mometasone. One dose (1 mL) of Neptra contains 16.7 mg of florfenicol, 16.7 mg of terbinafine hydrochloride (equivalent to 14.9 mg of terbinafine base) and 2.2 mg of mometasone furoate. Neptra® also contains the following excipients: propylene carbonate, propylene glycol, ethanol (96%), Macrogol 8000, and purified water. The product is provided in a single-use sealed tube containing 1 mL of solution. The recommended dose of Neptra® is one dose container (i.e., 1 mL of solution) per infected ear. Neptra® is considered a possible severe eye irritant in both animals and humans. See EMA / 560411 / 2019, EMEA / V / C / 004735, European Medicines Agency, updated October 2019 and the NOAH Compendium (http: / / www.noahcompendium.co.uk), accessed September 24, 2021. Neptra® is also referred to as Claro® otic solution. See NADA 141-440 Freedom of Information Summary, September 20, 2015.

[0006] Osurnia® is a veterinary drug containing three active substances: terbinafine, florfenicol, and betamethasone acetate. Osurnia® is used to treat short-term or recurrent ear infections (otitis externa) caused by Staphylococcus pseudintermedius (bacteria) and Malassezia pachydermatitis (yeast). Each mL of Osurnia® otic gel contains 10 mg of florfenicol, 10 mg of terbinafine, and 1 mg of betamethasone acetate (equivalent to 0.9 mg of betamethasone base) in an off-white to slightly yellow translucent gel. The product contains the following excipients: butylated hydroxytoluene (E321), hypromellose, lecithin, oleic acid, propylene carbonate, and glycerol formal. Treatment with Osurnia® requires two doses, 7 days apart. Please see "EMA / 315814 / 2014, EMEA / V / C / 003753, European Medicines Agency, June 2014".

[0007] Neptra® and Osurnia® are used to treat otitis externa associated with susceptible strains of the bacteria (Staphylococcus pseudintermedius) and yeast (Malassezia pachydermatis) in dogs. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO 2006 / 020689 [Non-patent literature]

[0009] [Non-Patent Document 1] J. Bajwa, Can Vet J. 2019 Jan; 60(1): 97-99, the Merck Veterinary Manual, 8th Edition, 1998, pp 372-376 [Non-Patent Document 2] Aziz et al, Asian Pacific Journal of Tropical Biomedicine, Volume 6, Issue 5, 2016, pp 390-395 [Non-Patent Document 3] NADA 140-896 Otomax® [Non-Patent Document 4] NADA 141-177 Freedom of Information Summary, January 9, 2003 [Non-Patent Document 5] NADA 141-266 FOI, dated February 18, 2010 [Non-Patent Document 6] EMA / 560411 / 2019, EMEA / V / C / 004735, European Medicines Agency, updated October 2019 [Non-Patent Document 7] the NOAH Compendium (http: / / www.noahcompendium.co.uk), accessed September 24, 2021 [Non-Patent Document 8] NADA 141-440 Freedom of Information Summary, September 20, 2015 [Non-Patent Document 9] EMA / 315814 / 2014, EMEA / V / C / 003753, European Medicines Agency, June 2014 Summary of the Invention [Problem to be solved by the invention]

[0010] The drawback of these veterinary drugs is that some of their active compounds are not optimal for combating the bacteria or fungi that cause otitis externa.

[0011] There is a need for a composition for treating otitis in animals that is safe, has broad antibacterial effectiveness, and is administered once to each infected ear. [Means for solving the problem]

[0012] The inventors have identified combinations of selected active compounds that form pharmaceutical compositions that exhibit several advantageous properties. Thus, the present invention provides (a) an effective amount of gentamicin or a pharma- ceutically acceptable salt thereof; (b) an effective amount of posaconazole; (c) an effective amount of mometasone or a pharma- ceutically acceptable salt thereof; and (d) a pharma- ceutically acceptable carrier; The present invention is directed to a pharmaceutical composition for treating ear infections in an animal, comprising:

[0013] The present invention is directed to a pharmaceutical composition comprising gentamicin, posaconazole and mometasone, which is useful in the treatment of ear infections in animals, particularly dogs.

[0014] The unique combination of high concentrations of these three active ingredients (gentamicin, mometasone furoate, and posaconazole) and excipients results in a stable and effective product for treating ear infections in a single dose.

[0015] The claimed pharmaceutical compositions offer several advantages over known pharmaceutical agents used to treat ear infections. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Advantages The main advantage of the claimed composition containing three active compounds is that only one administration is required to treat or cure an animal / dog's ear infection. In addition, the claimed composition can be formulated as a stable suspension without potential adverse safety concerns when handling the composition.

[0017] The claimed compositions can be administered as a single dose treatment, compared to prior art ear treatments such as Otomax®, Mometamax®, Posatex® and Osurnia®, which require multiple doses to achieve treatment.

[0018] When the claimed compositions are administered to the ear of an animal, sufficient gentamicin remains in the ear canal to prevent the spread of gentamicin-resistant bacteria.

[0019] Gentamicin, the antibiotic used in the claimed composition, has a broader antibacterial spectrum than furofenicol (the antibiotic used in Neptra® and Osurnia®). Mometasone furoate exhibits greater and longer lasting anti-inflammatory potency than betamethasone (the anti-inflammatory component in Osurnia®).

[0020] The claimed pharmaceutical composition is a self-preserving formulation, and therefore does not require preservatives. The formulation remains stable on the shelf for extended periods. Based on accelerated aging studies, the pharmaceutical composition has been confirmed to remain stable on the shelf for 36 months. The pharmaceutical composition can also be stored in a multi-dose bottle that can be opened and closed multiple times. Once opened by the user, the pharmaceutical composition has been demonstrated to be stable for 3 months. This feature provides convenience to veterinarians when administering the formulation. Additionally, the multi-dose container, capable of treating up to 20 animals, reduces the amount of packaging waste generated during the treatment of each animal.

[0021] The clinical response of the claimed formulation is rapid (within 7 days) and lasts for at least 1 month.

[0022] The active pharmaceutical ingredient (API) remains in the ear for 45 days after treatment.

[0023] Gentamicin, mometasone furoate and posaconazole otic suspension is used to treat otitis externa associated with susceptible strains of bacteria susceptible to gentamicin (Streptococcus spp., Staphylococcus pseudintermedius, beta-hemolytic Streptococcus canis, Pseudomonas aeruginosa, Escherichia coli, Proteus spp., Proteus mirabilis, Enterococcus spp.) and fungi susceptible to posaconazole (Malassezia pachydermatis) in dogs. The claimed formulation is effective against multiple bacterial and fungal ear infections.

[0024] Gentamicin is a broad-spectrum aminoglycoside antibiotic produced by fermentation by Micromonospora purpurea or M. echinospora. Gentamicin is an antibiotic complex consisting of four major components (C1, C1a, C2, and C2a) and several minor components. The drug binds irreversibly to the bacterial 30S ribosomal subunit. Specifically, the antibiotic is lodged within the 30S subunit between the 16S rRNA and the S12 protein. This allows it to interfere with the translation initiation complex and cause misreading of mRNA, thereby inhibiting protein synthesis and resulting in a bactericidal effect. See Pubchem https: / / pubchem.ncbi.nlm.nih.gov / compound / Gentamicin.

[0025] Mometasone is a synthetic steroid hormone of the glucocorticoid family. Glucocorticoid hormones are potent anti-inflammatory agents. It also exhibits antipruritic and vasoconstrictor properties. It is used topically in the treatment of corticosteroid-responsive skin diseases such as psoriasis and atopic dermatitis. Mometasone furoate is an anti-inflammatory corticosteroid with the chemical name "9,21-dichloro-11(β),17-dihydroxy-16(α)-methylpregna-1,4-diene-3,20-dione 17-(2 furoate)". It is practically insoluble in water; slightly soluble in methanol, ethanol and isopropanol; soluble in acetone and chloroform; and freely soluble in tetrahydrofuran. The partition coefficient between octanol and water is greater than 5000. Mometasone can exist in various hydrate, crystalline and enantiomeric forms, for example as a monohydrate.

[0026] Posaconazole is a broad-spectrum, second-generation triazole compound with antifungal activity. Posaconazole potently inhibits the 14-α-demethylase enzyme, a cytochrome P450-dependent enzyme. Inhibition of 14-α-demethylase prevents the conversion of lanosterol to ergosterol, a key component of the fungal cell wall. Inhibition of ergosterol synthesis alters the composition and integrity of the fungal cell membrane, alters membrane permeability, and ultimately leads to fungal cell lysis. Compared to other azole antifungals, posaconazole inhibits sterol 14-α-demethylase with significantly greater potency. See Pubchem.

[0027] An effective amount of an active ingredient, ie, gentamicin, posaconazole or mometasone, is the amount of active ingredient required in a single administration to treat an ear infection in an animal's ear.

[0028] A pharma- ceutically acceptable carrier is a substance capable of delivering an active ingredient to the required location on or within a patient's body and compatible with other ingredients of the formulation. Examples of pharma-ceutically acceptable carriers are mineral oil, isopropyl myristate glycerol, dimethylacetamide, monothioglycerol, polysorbate, propylene glycol, microcrystalline cellulose, sodium carboxymethylcellulose, triacetin, cellulose acetate, isopropyl myristate, silica, stearyl alcohol, diethylene glycol monoethyl ether, oil, water or mixtures thereof.

[0029] Mineral oil is a clear, odorless liquid and a common ingredient in a variety of cosmetic and personal care products. Mineral oil is made from highly refined, purified, and processed petroleum. See United States Pharmacopeia Reference 1443952 and CAS # 8012-95-1. Mineral oil is also known as liquid paraffin oil (e.g., CAS number: 8042-47-5; commonly available as Drakeol® 6VR (Penreco), Marcol® 52 (Exxon Mobile), and Klearol® (Sonneborn)).

[0030] Thickening agents, also known as viscosity enhancers, can be incorporated into the compositions according to the invention and include, but are not limited to, carboxyvinyl polymers, carrageenan, hydroxyethylcellulose, laponite, and water-soluble salts of cellulose ethers (e.g., sodium carboxymethylcellulose and sodium carboxymethylhydroxyethylcellulose), methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, and povidone. Natural gums such as acacia, karaya, xanthan gum, arabic gum, and tragacanth gum can also be used. Other thickening agents include colloidal magnesium aluminum silicate or micronized silica, which can be used as part of the thickening agent to further improve the texture. The compositions of the invention can include 25% to 45% w / v thickening agent.

[0031] A preferred thickening agent is Plastibase® 50W (Bristol-Myers Squibb), a plasticized hydrocarbon gel. Plastibase® 50W contains 5% polyethylene in 95% mineral oil. Polyethylene is an inert hydrocarbon with a high molecular weight and high melting point. It is used as a thickening agent to increase the viscosity of the mineral oil and therefore the pharmaceutical product. Another preferred thickening agent is Pioneer® PLW plasticized hydrocarbon gel (Hansen & Rosenthal).

[0032] The minimum inhibitory concentration (MIC) is defined as the lowest concentration of an antibiotic that inhibits the growth of bacteria visible in culture. Therapeutically, this value is used to estimate the concentration that must be exceeded at the site of infection for an antibiotic to be considered effective.

[0033] A "susceptible" MIC breakpoint is an in vivo determined value (μg / mL) applied in clinical microbiology to indicate that a bacterial isolate is susceptible to a given antimicrobial. The susceptibility designation is a category that means that infections caused by that microorganism can be adequately treated with the recommended dosing regimen. Antimicrobial susceptibility is used by veterinarians to guide appropriate drug selection.

[0034] In an embodiment of the invention, the effective amount of gentamicin or a pharma- ceutically acceptable salt thereof is in an amount of about 0.40 to about 1.00% w / v.

[0035] In an embodiment of the invention, the effective amount of posaconazole is in an amount of about 0.15 to about 0.35% w / v.

[0036] In an embodiment of the invention, the effective amount of mometasone or a pharma- ceutically acceptable salt thereof is in an amount of about 0.15 to about 0.35% w / v.

[0037] In an embodiment of the invention, the pharmaceutical composition further comprises a thickening or viscosity enhancing agent.

[0038] In an embodiment of the invention, the thickening agent is a plasticized hydrocarbon gel.

[0039] In an embodiment of the invention, the plasticized hydrocarbon gel is 5% polyethylene in 95% mineral oil.

[0040] In embodiments of the invention, the viscosity increasing agent is present in an amount of about 25%-40% w / v, about 25%-45% w / v, about 28%-35% w / v or about 40%.

[0041] In an embodiment of the invention, the pharmaceutical composition is a suspension.

[0042] In an embodiment of the invention, the pharma- ceutically acceptable carrier is mineral oil.

[0043] In alternative embodiments, the pharma- ceutically acceptable carrier is glycerol, dimethylacetamide, monothioglycerol, or mixtures thereof.

[0044] In alternative embodiments, the pharma- ceutically acceptable carrier is glycerol, polysorbate, propylene glycol, microcrystalline cellulose, sodium carboxymethylcellulose, water or mixtures thereof.

[0045] In alternative embodiments, the pharma- ceutically acceptable carrier is triacetin, cellulose acetate, monothioglycerol, or mixtures thereof.

[0046] In alternative embodiments, the pharma- ceutically acceptable carrier is isopropyl myristate, silica, stearyl alcohol, diethylene glycol monoethyl ether, or mixtures thereof.

[0047] In an embodiment of the invention, the gentamicin is gentamicin sulfate.

[0048] In an embodiment of the invention, the mometasone is mometasone furoate monohydrate.

[0049] In an embodiment of the invention, the pharmaceutical composition is stable when stored in multi-dose containers for extended periods of time.

[0050] In the context of the present invention, a long period of time is about 36 months.

[0051] In another embodiment of the invention, the pharmaceutical composition is stored in a multi-dose container.

[0052] In an embodiment of the invention, the multi-dose container contains from about 10 doses to about 100 doses, preferably at least 20 doses.

[0053] An alternative embodiment of the present invention is a method of treating an ear infection in an animal, the method comprising administering to the ear of the animal any of the above pharmaceutical compositions.

[0054] In an embodiment of the invention, the pharmaceutical composition is administered once.

[0055] In an embodiment of the invention, the animal is a dog.

[0056] In an embodiment of the invention, the animal is a cat.

[0057] In an embodiment of the invention, the ear infection is caused by one or more of Staphylococcus pseudintermedius, beta-hemolytic Streptococcus spp., Pseudomonas aeruginosa, Escherichia coli, Proteus spp., Enterococcus spp., or Malassezia pachydermatis. EXAMPLES

[0058] Working Example Example 1 – Preparation of a pharmaceutical composition A 175 L (153 kg) batch of the pharmaceutical formulation was manufactured according to the following process: 1. Approximately 80% of the paraffin liquid was charged into the main blending tank; 2. Approximately 8% of the paraffin liquid was charged into the premix container; 3. Charge the required amount of gentamicin sulfate to the stage 2 premix tank; mix using homogenizer for approximately 5 minutes; 4. Mometasone was added; (A) The required amount of mometasone furoate monohydrate was weighed into a 5 L bottle; (B) 2 kg of mineral oil (paraffinum liquid) was added to the bottle and shaken until the mometasone furoate monohydrate was well dispersed; (C) The contents of the bottle were transferred to a premix container; (D) The bottle was rinsed three times with 1 kg of mineral oil (paraffin liquid) and the rinse was transferred to the premix container; (E) The contents of the premix tank were mixed using a homogenizer for approximately 5 minutes; 5. The required amount of posaconazole was charged to a premix container; mixed using a homogenizer for approximately 5 minutes; 6. The premix was charged to the main blend tank while mixing; the premix tank was rinsed with some of the paraffin liquid and the rinse was added to the main blend tank; 7. The main blend tank was homogenized for a minimum of 60 minutes using an in-line recirculating homogenizer; 8. While mixing, the required amount of plasticized hydrocarbon gel was continuously charged to the batch; mixing continued for approximately 18 minutes; the product temperature in the main blend tank was maintained below 35°C; 9. While continuing to mix the bulk suspension with the low shear agitator, begin homogenization using the in-line recirculating homogenizer for a minimum of 70 minutes; 10. After completion of step 9, the bulk suspension during filling was continued to be mixed with a low shear mixer; 11. The batch was filled into HDPE bottles and capped.

[0059] The resulting formulations are shown in Table 1. [Table 1]

[0060] Example 2 - Gentamicin Concentrations in Pilot Ear Depression Tests According to minimum inhibitory concentration (MIC) studies on gentamicin performed in the United States, the highest MIC for gentamicin-resistant P. aeruginosa is 64 μg / mL. Ear depression tests were performed to evaluate the concentration of gentamicin in earwax. The concentration of gentamicin detected in earwax was found to be high enough to be effective against gentamicin-resistant P. aeruginosa.

[0061] [Table 2]

[0062] Example 3 Efficacy of the pharmaceutical composition in treating ear infections in dogs The objective of this study was to evaluate the efficacy and safety of a single dose (0.8 mL) of an investigational veterinary product (IVP), an otic suspension pharmaceutical composition (prepared as described in Example 1) containing 8.6 mg / mL gentamicin, 2.1 mg / mL mometasone furoate and 2.6 mg / mL posaconazole, for bacterial and / or fungal otitis externa in customer-owned dogs at multiple locations. Efficacy was compared to a registered product (Osurnia®, Elanco Europe Ltd.) (comparator product).

[0063] Materials and Methods This GCP-compliant, multi-center field study was a positive-controlled, investigator-blinded study. It was conducted in 316 customer-owned dogs suffering from otitis externa. 153 were treated with IVP and 163 with the control product. On average, animals in each treatment group were 5.7 years old and weighed 24.1 kg (IVP group) and 22.4 kg (CP group). Animals were eligible for inclusion if they presented an ear examination score of at least 5 in at least one ear on study day (SD) 0 using the OTIS-3 scoring criteria (see Nuttall and Bensignor, Vet Dermatol 2014; 25: 530). Physical examination, ottic scoring, swab sampling, and treatment of inflamed ears were performed on SD 0. Physical examinations and ear scoring were performed on SD days 7, 14±2, 28±2, and 42±2. Control animals also received treatment according to the manufacturer's instructions on SD day 7. Ear swab samples were taken on SD day 28±2. On SD days 7 and 14±2, ear swab samples were taken only in case of treatment failure, and on SD day 42±2, ear swab samples were taken only in case of relapse. Ear swab samples were also taken at any time after SD day 7 if the otitis worsened.

[0064] The primary efficacy measure was treatment success rate, defined as: total score ≤4 at SD day 14 and ≤3 at SD day 28. Dogs that were not treatment successful at SD day 28 or that were withdrawn from the study before SD day 28 (due to the need for alternative treatment for otitis) were classified as "treatment failures." Secondary efficacy measures were median treatment success rate (score ≤4 at SD day 14), relapse rate (score ≥5 at SD day 42), and microbiological cure rate at SD day 28.

[0065] result The treatment success rate at SD day 28 for dogs treated with gentamicin, mometasone furoate, and posaconazole otic suspension was 89.5%. This rate was significantly non-inferior to the treatment success rate of 87.2% for dogs treated with Osurnia® (p<0.0001). The median treatment success rate at SD day 14 was 93.7% for dogs treated with gentamicin, mometasone furoate, and posaconazole otic suspension. This rate was significantly non-inferior to the median treatment success rate of 90.2% for dogs treated with Osurnia® (p<0.0001). The recurrence rate at SD day 42 for dogs that were treatment successful at SD day 28 was 4.7% for dogs treated with gentamicin, mometasone furoate, and posaconazole otic suspension. This rate was significantly non-inferior (p=0.0002) compared with a relapse rate of 1.7% in dogs treated with Osurnia®. Microbiological cure rates at SD28 were 81.1% for Malassezia pachydermatis and 73.5% for Staphylococcus pseudintermedius in dogs treated with gentamicin, mometasone furoate and posaconazole otic suspension. In dogs treated twice with Osurnia®, 7 days apart, microbiological cure rates at SD28 were 83.8% for Malassezia pachydermatis and 90% for Staphylococcus pseudintermedius. Microbiological cure rates for P. aeruginosa, E. coli, S. canis, and P. mirabilis ranged from 60% to 100% in the IVP group and from 42.9% to 100% in the CP group.

[0066] conclusion A novel otic suspension containing 8.6 mg / mL gentamicin, 2.1 mg / mL mometasone furoate and 2.6 mg / mL posaconazole administered as a single 0.8 mL dose was effective against canine otitis externa and was well tolerated and safe at the doses tested. When compared with two treatments with Osurnia® (SD days 0 and 7), it showed significant non-inferiority in terms of treatment success rate at SD day 28, median treatment success rate at SD day 14 and overall treatment success rate at SD day 42.

[0067] These results for the IVP pharmaceutical composition containing gentamicin, mometasone and posaconazole were achieved with only a single administration, whereas results for the control product (Osurnia®) required two administrations, seven days apart.

[0068] Example 3 – Stability The pharmaceutical composition of Example 1 (see Table 1 above) was evaluated for long-term stability under accelerated conditions. The composition was packaged in a 35 mL white HDPE bottle with an LDPE cap. The bottles were filled to at least 24 mL to allow for the removal of at least 20 doses of 0.8 mL each from each bottle. The removal of each dose was accomplished with a 1.0 mL syringe using an LDPE press-in-bottle adapter (PIBA).

[0069] The bottles were maintained under accelerated conditions (40° C. / 75% relative humidity (RH)), refrigerated conditions (5° C. / ambient humidity), and long-term storage conditions (30° C. / 65% RH and 30° C. / 75% RH) for 12 months.

[0070] Samples were taken from each bottle at 0, 6 and 12 months. Samples were examined for appearance, density, viscosity, moisture content, particle size distribution, weight change, and the identity and analysis of gentamicin, mometasone furoate and posaconazole. Samples were also evaluated for API particle morphology (i.e., whether the particles were still crystalline) and agglomeration of API particles.

[0071] The appearance of the sample doses was initially described as a smooth, homogeneous, white to off-white viscous suspension, and under stability testing, the samples maintained this appearance throughout the duration of the study under each of the conditions applied.

[0072] The initial density values ​​of the samples, 0.850 g / mL and 0.900 g / mL (measured at 20° C. according to Ph.Eur.2.2.5), were maintained throughout the stability study under all conditions.

[0073] The viscosity (measured with a Brookfield viscometer) was initially measured to be 800-2200 centipoise and remained in this range at all conditions during the stability study.

[0074] Moisture content was assessed by the Karl Fischer method and was initially determined to be less than 1.0%. At accelerated and long-term conditions, moisture content increased slightly from 0.1% to 0.4%. This data indicates that the composition does not gain enough moisture during shelf life to affect the efficacy and safety of the composition.

[0075] The particle size was measured by laser diffraction. 10 , D 50 and D. 90 The particle size distribution measured by D was consistent over a 12-month period under accelerated, refrigerated, and long-term conditions. 50 The results show that the particle size distribution of is stable throughout the test period under refrigerated, long-term and accelerated conditions.

[0076] Optical microscopy data determines whether the particles are crystalline (mostly 10 μm or less) and the number of aggregates (i.e., particles larger than 250 μm). For all samples, the crystallinity criteria were met, and no aggregates were observed over 12 months under accelerated, refrigerated, and long-term conditions. These data indicate that no aggregates form, even under accelerated conditions.

[0077] The weight change was less than 0.5% over a 12 month period under accelerated, refrigerated and long-term conditions. The lack of weight change indicates that the container closure system is suitable for use as a packaging material.

[0078] The identification and degradation of posaconazole and mometasone furoate was performed by ultra-high pressure liquid chromatography coupled to a UV detector (UPLC / UV). The degradation product tracked for posaconazole was the formate ester. For mometasone furoate, the 17-alcohol and compound E were tracked. No identified or unidentified degradation products of mometasone furoate and posaconazole were observed under accelerated, refrigerated and long-term conditions over a 12-month period.

[0079] Gentamicin identity and assay were confirmed by microbiological titration. Gentamicin assay was maintained at 90%-105% over 12 months under accelerated, refrigerated, and long-term conditions.

[0080] Available data indicates that the composition does not exhibit significant changes with respect to important quality attributes; no special storage conditions are necessary.

[0081] Example 4 In-use stability test In-use stability studies were conducted to evaluate the stability of the formulation of Example 1 under simulated in-use conditions for up to 3 months. Sample bottles contained an initial fill volume of 24 mL. To administer the appropriate amount of product, a press-in bottle adapter (PIBA) was inserted into the neck of the bottle to allow the product to be administered via a syringe. After shaking each bottle, 0.8 mL of product was removed in 10 aliquots using the syringe (8 mL total). The bottles were then stored at 30° C. / 65% RH and tested after 3 months. Results of the initial and 3-month samples are summarized in Table 2.

[0082] [Table 3]

[0083] In-use stability testing was also performed on aged samples of the formulation of Example 1, i.e., at the end of the planned 24 month storage period. Sample bottles from this batch were subjected to the same in-use procedure as the previous batch. After shaking each bottle, 0.8 mL of product was removed in 10 aliquots using a syringe (8 mL total). The bottles were then stored at 30° C. / 65% RH for 24 months and tested up to 3 months after the planned 24 month shelf life. The results are summarized in Table 3.

[0084] [Table 4]

[0085] A lower gentamicin assay (92.5% LC) was observed in the aged samples, but was still within the expected shelf life of the product. The study demonstrated that gentamicin, mometasone furoate and posaconazole otic suspension are stable for up to 3 months after first use and after shelf life when stored in HDPE bottles at the planned long-term storage conditions (30°C / 65% RH).

[0086] Based on accelerated stability data, a shelf life of 36 months is expected.

Claims

1. 1. A pharmaceutical composition for treating ear infections in an animal, comprising: (a) an effective amount of 0.40 to 1.00% w / v of gentamicin or a pharmaceutically acceptable salt thereof; (b) an effective amount of 0.15 to 0.35% w / v posaconazole; (c) an effective amount of 0.15 to 0.35% w / v mometasone or a pharmaceutically acceptable salt thereof; and (d) a pharmaceutically acceptable carrier; The pharmaceutical composition comprising:

2. 10. The pharmaceutical composition of claim 1, further comprising a viscosity increasing agent.

3. 3. The pharmaceutical composition of claim 1, wherein the composition is a suspension.

4. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable carrier is mineral oil.

5. 3. The pharmaceutical composition of claim 2, wherein the viscosity increasing agent is 5% polyethylene in 95% mineral oil.

6. 6. The pharmaceutical composition of claim 2 or 5, wherein the viscosity increasing agent is present in an amount of 25% to 40% w / v.

7. 10. The pharmaceutical composition of claim 1 for use in treating ear infections by administration to the ear of an animal.

8. The pharmaceutical composition of claim 7 , wherein the composition is administered once.

9. The pharmaceutical composition according to claim 7 or 8, wherein the animal is a dog.

10. The pharmaceutical composition according to claim 7 or 8, wherein the animal is a cat.

11. 8. The pharmaceutical composition of claim 7, wherein the ear infection is caused by one or more of Staphylococcus pseudomintermedius beta-hemolytic, Streptococcus canis, Streptococcus spp., Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis Proteus spp., Enterococcus spp., or Malassezia pachydermatis.

12. A multi-dose container comprising the pharmaceutical composition of claim 1.