WO2015042596A1

WO2015042596A1 - Treatment of atopic dermatitis in non-human animals

Info

Publication number: WO2015042596A1
Application number: PCT/US2014/057031
Authority: WO
Inventors: Richard Chin; Noe REYES
Original assignee: Kindred Biosciences, Inc
Priority date: 2013-09-23
Filing date: 2014-09-23
Publication date: 2015-03-26

Abstract

Atopic dermatitis and pruritus can be efficaciously treated in non-human animals by administering fexofenadine. In a first aspect, the present invention provides a method for treating AD or pruritus, said method comprising orally administering to a non-human patient in need of treatment a therapeutically effective dose of fexofenadine at a dose of at least 20 mg/kg by weight per day. In some instances the present invention provides a method for treating AD in a canine or feline, said method comprising orally administering a therapeutically effective dose of fexofenadine at a dose of at least 20 mg/kg by weight per day. In many embodiments, treatment will continue on a consecutive daily basis for many weeks, if not for the rest of the animal's life.

Description

TREATMENT OF ATOPIC DERMATITIS IN

NON-HUMAN ANIMALS

BACKGROUND OF THE INVENTION

[0001] Atopic dermatitis (AD) is a genetically-predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features which most commonly is associated with IgE antibodies to environmental allergens. Typically, a non-human animal with AD will exhibit pruritis of the face, ears, paws, extremities, and/or ventrum. Orally administered glucocorticoids, such as prednisone, are often used to treat AD. However, steroid use can have numerous side effects, such as increased thirst, urination, hunger, and weight gain. Moreover, with prolonged use at high doses, steroids cause liver enlargement and increased liver enzymes, can cause high blood pressure and kidney disease, weakened muscles and ligaments, infections of the skin and bladder, and thinning of the skin and hair loss. Antihistamines have been used to treat canine atopic dermatitis (CAD), but the published Proceedings of the North America Veterinary Conference of 8-12 January 2005 reported that "[t]here is not good evidence at present time regarding efficacy of antihistamines in the therapy of CAD" and that published studies suggested hydroxyzine, clemastine, and chlorpheniramine were the most effective, although sedative action might be in part responsible for clinical benefit. A report on a six-week study comparing the efficacy of the antihistamine fexofenadine versus methylprednisolone in the treatment of CAD concluded that fexofenadine hydrochloride in oral doses of 18 mg/kg (by weight) once daily and methylprednisolone in doses of 0.5 mg/kg by weight administered for five days, followed by the same dose every other day, were effective in reducing the severity of pruritus and the presence of skin lesions but that additional studies were needed to confirm the findings (Plevnik et al., 2009, Slov. Vet. Res. 46(1): 5-12).

[0002] Accordingly, there remains a need for more effective treatment methods for AD. The present invention meets this need.

SUMMARY OF THE INVENTION

[0003] In a first aspect, the present invention provides a method for treating

AD or pruritus, said method comprising orally administering to a non-human patient in need of treatment a therapeutically effective dose of fexofenadine at a dose of at least 20 mg/kg by weight per day. In some instances, the present invention provides a method for treating AD in a canine or feline, said method comprising orally administering a therapeutically effective dose of fexofenadine at a dose of at least 20 mg/kg by weight per day. In many embodiments, treatment will continue on a consecutive daily basis for many weeks, if not for the rest of the animal's life.

[0004] In some embodiments, an orally administered glucocorticoid, including but not limited to prednisolone and methylprednisolone, and/or a cyclosporine will be co-administered with the fexofenadine. In some embodiments, the glucocorticoid will be co-administered on a daily basis for at least 7 consecutive days. In one embodiment, the glucocorticoid is co-administered every day for the first week of treatment, followed by every other day administration for a least one additional week, if not longer. In some embodiments, a Janus kinase inhibitor such as Apoquel (oclacitinib tablet marketed by Zoetis) is coadministered with fexofenadine to treat atopic dermatitis in a cat or dog, or to treat pruritus in a horse.

[0005] In a second aspect, the present invention provides unit dose forms of fexofenadine suitable for use in the methods of the invention. In some embodiments, the fexofenadine is formulated in an immediate release or delayed release unit dose form such as a tablet or capsule. In one embodiment, the unit dose form is a chewable tablet. In one embodiment, the tablet or capsule contains about 200 mg of fexofenadine. In various embodiments, the tablet is scored to facilitate cleavage into 2 half-tablets or 4 quarter- tablets. Additionally, while the texture and formulation of the unit dose form for felines is generally the same or substantially similar to that for canines, the feline unit dose form may be made available in smaller sizes (100 mg, 80 mg, 40 mg) and/or concentrations more appropriate for small animals.

[0006] In many embodiments, the fexofenadine is formulated in a composition that comprises a flavoring palatable to a canine, such as beef flavor. Additional or different flavorings may be used in tablets or other unit dose forms to increase palatability in felines. In one embodiment, the composition contains, by weight percentage, at least 10% fexofenadine and at least 10% flavoring. In one embodiment, the composition comprises, by weight percentage, 23.33% microcrystalline cellulose; 15% beef flavor; 20% Di Pac; 16.67% fexofenadine; 24% lactose DC; and 1% magnesium stearate. [0007] Some canines may experience gastrointestinal distress from lactose, and the invention offers lactose free formulations and unit dose forms. In one embodiment, the formulation of the invention is a composition comprising, by weight percentage, 47.08% silicified microcrystalline cellulose; 15% beef flavor; 20% Di Pac; 16.67% fexofenadine; and 1.25% magnesium stearate.

DETAILED DESCRIPTION OF THE INVENTION

[0008] In one embodiment, the present invention provides a high-dose, orally administered, chewable, flavored formulation of fexofenadine for the treatment of atopic dermatitis in non-human animals, for example canines and felines. Fexofenadine is a potent and selective antihistamine that has been approved for treatment of allergic diseases in humans. Atopic dermatitis is a common, potentially chronic, allergic skin disease that affects up to 10% of all canines. It is the second most common allergic skin condition in canines, surpassed only by flea allergies. Non-human animals with atopic dermatitis often suffer from pruritus, or severe itching, hair loss, excoriation of the skin from deep scratching, frequent licking of their paws and excessive tear production. Secondary skin problems are also common, including skin infections and excessive sebum discharge. For example, horses can suffer from pruritus, although they are not generally susceptible to atopic dermatitis. Pruritus can be highly uncomfortable or even debilitating, and in extreme cases, euthanasia is necessary to avoid undue suffering.

[0009] The mainstay therapy for pruritus is oral corticosteroids and oral cyclosporine. A recently approved product known as a Janus kinase, or JAK, inhibitor is also available for treating atopic dermatitis. While these drugs are effective, they have significant side effects that can prevent their long-term use. For example, these drugs suppress the animal's immune system, which can lead to infections. Corticosteroids also can cause osteoporosis, endocrine problems and cataracts in canines and felines, as well as other non-human animals. In addition, corticosteroids tend to cause animals to eat, drink and urinate frequently, which is considered undesirable by pet owners. As atopic dermatitis in canines and felines is often a chronic condition, these safety and side effect issues create a significant unmet medical need for a safe and effective long-term treatment.

[0010] The present invention provides a chewable, flavored tablet of fexofenadine that has been shown as effective as a steroid in the treatment of atopic dermatitis in a placebo-controlled study in non-human animals, specifically canines and felines. Fexofenadine has an excellent track record of safety in non-human animals and humans. Because it is not an immunosuppressive drug, fexofenadine may be utilized both as a first-line therapy and also as a long-term maintenance therapy for chronic atopic dermatitis in canines and felines in accordance with the invention without increased risk of infections or other safety concerns associated with currently available therapeutics. In addition, fexofenadine does not induce excessive eating, drinking, and urinating in animals that steroids can cause.

[0011] Fexofenadine has been widely used to treat allergies in humans and is marketed under the brand name Allegra in the United States. Fexofenadine has been used by veterinarians off-label in canines and felines for the treatment of allergies, typically at the same low dose used for humans (approximately 2-4 mg/kg). Reported results at this dosage have been mixed.

[0012] The present invention provides unit dose forms of fexofenadine suitable for oral administration at a dose of 20 mg/kg once daily. In one embodiment, the doses are administered to canines or felines of one year of age or older with atopic dermatitis. Successful treatment in accordance with the invention results in a lowering of the Atopic Dermatitis Lesion Index, or ADLI, and Pruritus Visual Analog Score, or PVAS in treated non-human animals. The ADLI score is a validated composite index of six clinical symptoms associated with canine atopic dermatitis evaluated in five specified body regions. At each specified body region, each parameter is scored by the scorer from zero to five, with a score of zero defined as no lesion and a score of five defined as a severe/extensive lesions. PVAS is scored by the scorer using a zero- to-ten analog scale, with a score of zero representing no pruritus/chewing and a score of ten equating to incessant and intense pruritus/chewing.

[0013] The present invention provides a method for treating atopic dermatitis, the method comprising orally administering to a non-human animal, such as a canine or feline in need of treatment, a therapeutically effective dose of fexofenadine at a dose of at least 20 to no more than 40 mg/kg by weight per day. Typically, treatment is continued with daily administration repeated for at least 7 consecutive days, if not longer, i.e., for at least a month. In many embodiments, daily treatment is continued for at least a year, if not longer, i.e., 5 years to the rest of the animal's life. [0014] In some embodiments, a glucocorticoid, such as prednisolone, is coadministered during at least the first week of treatment on a daily basis for at least 7 consecutive days. Thereafter, treatment with the glucocorticoid may continue for another one to several weeks, either on a daily or every other day basis.

[0015] In various embodiments, the fexofenadine is formulated in unit dose form as a tablet or capsule. In some embodiments, the tablet or capsule is chewable. In various embodiments, the unit dose form contains about 200 mg of fexofenadine. In one embodiment, the unit dose form is a tablet scored to facilitate cleavage into 2 half-tablets or 4 quarter-tablets. Additionally, while the texture and formulation of the unit dose form for cats is generally the same or substantially similar to that for the dog, the cat unit dose form may be made available in smaller sizes (100 mg, 80 mg, 40 mg) and/or concentrations more appropriate for smaller animals.

[0016] The present invention also provides pharmaceutical formulations in the form of pastes and gels that contain a therapeutically effective dose of fexofenadine. In one embodiment, especially suitable for administration to a horse, the appropriate dose of fexofenadine is administered in the form of a paste that is applied to the horse's gums and/or teeth. In another embodiment, especially suitable for administration to a cat, the appropriate dose of fexofenadine is administered in the form of a paste that is applied to the cat's paws and/or fur.

[0017] In various embodiments, the fexofenadine is formulated in a composition that comprises a flavoring palatable to an intended non-human animal. For example, in some instances a formulation is provided comprising a flavoring palatable to a canine. In other instances, a formulation is provided comprising a flavoring palatable to a feline. Suitable flavorings include beef, chicken, pork, fish, and turkey flavorings, or any other flavoring used for canine and feline foods. In one embodiment, the flavoring is a preparation comprising one or more of beef liver, chicken liver, pork liver, and turkey liver. Suitable vendors of flavorings include, without limitation, PF Inc., Pet Food Ingredients (see http://www.petfoodingredients.com/index.html) and Pharmachem Laboratories, Inc. In one embodiment, the flavoring is beef flavor.

[0018] In one embodiment, the composition comprises at least 10% fexofenadine (for the HC1 salt) and at least 10% flavoring. While any pharmaceutically acceptable salt of fexofenadine may be used in the compositions, and any amorphous or polymorph form of any such fexofenadine salt, the HC1 salt is suitable for most purposes and can be obtained commercially from a variety of vendors, including but not limited to Hetero Drugs Ltd., Hyderabad, India.

[0019] In some embodiments, the active pharmaceutical ingredient is administered in pill or tablet form, wherein the active pharmaceutical ingredient is combined with one or more compatible excipients. A compatible excipient generally describes an inactive substance that serves as the vehicle or medium for the active pharmaceutical ingredient and which is compatible for use with the intended patient. In some instances, the compatible excipient includes or is one or more directly compressible adjuvants that may be readily compressed into the desired tablet form. These excipients include diluents, binders, fillers, disintegrants, and/or lubricant agents. Compatible excipients are non-toxic and acceptable to the regulatory agencies. In some embodiments, an acceptable excipient is low cost, physiologically inert, commercially available in an acceptable grade in all countries, color compatible, free of allergens, and free from deleterious effect on the bioavailability of the active pharmaceutical ingredient of the composition.

[0020] In some embodiments, the compatible excipient comprises a directly compressible diluent. In some embodiments the composition comprises lactose or a lactose derivative as a directly compressible diluent (including but not limited to lactose DC). In other embodiments the composition comprises a lactose-free, directly compressible diluent (which is a solid when the unit dose form is a pill or tablet). For example, in some embodiments the veterinary composition of the invention includes a diluent selected from the group consisting of a starch, a cellulose derivative, such as microcrystalline cellulose, and a sugar or sugar alcohol, including but not limited to sucrose, dextrose, sorbitol, mannitol, and maltodextrin, any of which may be in directly compressible form.

[0021] In some embodiments, the compatible excipient comprises a suitable sugar bulking agent or other pharmaceutically acceptable taste masking agent that acts to mask the taste of one or more ingredients of the pharmaceutical composition. Taste masking is defined by a perceived reduction of an undesirable taste that would otherwise exist. Various methods and taste masking agents exist that are compatible for use in the instant invention. In one embodiment, the pharmaceutical composition comprises Di Pac as a taste masking agent. Some embodiments of the present invention comprise a polymer coating which is applied as a physical barrier to the active pharmaceutical ingredient or other ingredients which comprise an undesirable taste. Some embodiments further comprise a flavoring agent, as discussed previously.

[0022] In some embodiments, a pharmaceutical composition contains, by weight percentage, from approximately 20% to approximately 25% filler; from approximately 22% to approximately 26% diluent; from approximately 18% to approximately 23% taste masking agent; from approximately 13% to approximately 18% flavoring agent; from approximately 4% to approximately 20% active pharmaceutical ingredient (i.e., fexofenadine); and from approximately 0.75% to approximately 2% lubricant.

[0023] In one embodiment, the pharmaceutical composition contains, by weight percentage, 23.33% microcrystalline cellulose; 15% beef flavor; 20% Di Pac; 16.67% fexofenadine (for the HC1 salt; percentages can be adjusted accordingly if a different salt is used); 24% lactose DC; and 1% magnesium stearate. In another embodiment, providing a "lactose-free formulation", the composition contains, by weight percentage, 47.08% silicified microcrystalline cellulose; 15% beef flavor; 20% Di Pac; 16.67% fexofenadine; and 1.25% magnesium stearate.

Examples

[0024] Example 1. Overcoming Bitter Taste with Flavoring

[0025] Fexofenadine is known to have a bitter and generally unpleasant taste to humans. Dogs were administered over the counter fexofenadine (Allegra), and it was evident that the dogs did not like the taste or texture of the tablets. Many animals had to be "pilled" directly (pill manually inserted into the throat and mouth held shut until dog swallowed) to assure ingestion of the dose. Dogs that crushed the pills by chewing tended to reject the pill by "spitting" out the tablet(s), with some animals exhibiting hypersalivation in the process. Hypers alivation after ingestion is indicative that the dog found the ingested material distasteful. Various beef or chicken flavored chewable formulations were developed and tested on client owned animals. A formulation that contained 15% beef flavor was the most readily palatable to the dogs on which it was tested. The more than 10 client owned animals used to evaluate palatability readily took the pills when offered to them as a "treat".

[0026] This example demonstrates the efficacy of formulations of the invention in masking bitterness of the active pharmaceutical ingredient (API) fexofenadine. This example also describes 50 and 200 mg tablets suitable for the veterinary market. The tablet has a hardness that allows it to be broken into quarters as needed for dosing.

[0027] The flavor profile and matrix were developed using a surrogate API with a bitter flavor that could be administered to canines for flavor studies. Guaifenesen was selected as the surrogate API due to its safety and bitter flavor. A rapid dissolving tablet formulation (RTF-027A) was developed using a combination of API (20% by weight), Pearitol Flash (mannitol based ODT excipient) (49% by weight), Artificial beef flavor (20% by weight), and DiPac (directly compressible sugar) (10% by weight). Magnesium stearate (1%) was used as a lubricant. The unit dose form tablet had a tablet weight of 1000 mg and hardness of 5 kp. A second formulation (RTF-027B) varied the flavor profile: API (13% by weight), Pearitol Flash (37% by weight), Artificial beef flavor (20% by weight), DiPac (30% by weight), Magnesium stearate (0.6%), to provide a lower Pearlitol Flash and higher DiPac levels. The results demonstrated that formulations comprising 4-20% API could be masked suitably using 15% beef flavoring and 20% sugar.

[0028] Illustrative unit dose forms of fexofenadine provided by the invention include the following 50 mg and 200 mg chewable tablets described in Table 1 and Table 2.

[0030] Table 2: 50mg Chewable Tablet

Ingredient MG/Tablets % Tablet Function

Supertab USD 437.76 36.48 Diluent

(^"lactose)

Microcrystalline 279.96 23.33 Filler

Cellulose

Di-Pac 240.00 20.00 Filler/ Taste masking agent

Artificial Beef Flavor 180.00 15.00 Flavor

Fexofenadine 50.00 4.16 Active Ingredient

Magnesium Stearate 12.00 1.00 Lubricant [0031] Release specifications for various tablet formulations of the instant invention are provided in Table 3. A suitable process for manufacturing the chewable tablet is to charge the blender with Supertab USD, Microcrystalline Cellulose, Di- Pac, Artificial beef flavor, and Fexofenadine and blend for 10 min. Once the first blend has completed, the Magnesium Stearate is charged into the blender and blending continued an additional 5 minutes. The blend is discharged from the blender and placed on a tablet press for compression. Tablets specifications are: Weight 1200 mg (range 1140-1260 mg), Hardness 6 kp (range 5-9 kp), and Round flat faced bevel edged punch. The tablets were compressed using a gravity fed feed frame. A switch to a power feed frame improves flow characteristics by allowing the die cavity to be filled with the assistance of the feeder paddles. Tablets can be produced on a Rimek 8 station D-tooled press at a speed of 15 rpm. Compression force required is less than 1 ton. Packaging tablets were packaged 10 tablets in 30 cc HDPE with CRC cap induction sealed.

[0032] Table 3: Release Specifications

[0033] Example 2. Fexofenadine Efficacy

[0034] Table 4 shows data from an open label pilot study using over-the- counter fexofenadine tablets. The table shows CAD LI and PVAS scores at the 1^st and

3 rd (final) visits, with lower numbers indicating better efficacy. CADLI scores reflect the degree of skin lesions, while the PVAS scores reflect how itchy the animals are

(both scored from 1-10).

[0035] Table 4: OTC 1 Fexofenadine Test

Animal Visit 1 Visit 2 Visit 3 CADLI / PVAS CADLI / PVAS CADLI / PVAS

1 8/5.8 2/0.4 0/1.5

2 8/4.0 4/3.2 6/3.8

3 24 / 6.3 17/6.5 15/3.4

4 17/7.4 13/7.1 6/3.9

5 15/5.5 13/5.3 11/3.0

6 19/7.5 16/5.4 20/5.4

7 26/10 21/7.7 Withdrawn

8 21/10 21/9.5 27/9.4 (dog difficult to pill)

9 22/8.8 24 / 9.5 22/9

10 12/6 18/5.5 13/7

[0036] Example 3. Fexofenadine Drug Formulation

[0037] The following ingredients were blended in a blender for 15 minutes: microcrystalline cellulose (20-25%; all percentages are wt./wt.), beef flavor (13-18%), DiPac (18-23%), fexofenadine (16.67%), and lactose DC or other directly compressible diluent (22-26%). Then, 1% magnesium stearate was added and blending continued for an additional 5 minutes. The resulting formulation was tableted.

[0038] A lactose free formulation was prepared as described above, but with the ingredients shown in the following table.

[0039] Table 5: 200 mg Chewable Tab let

Ingredient mg/Tablet % Tablet Function

Silicified 565.00 47.08 Filler

Microcrystalline

Cellulose

Di-Pac 240.00 20.00 Filler/ Taste masking agent

Artificial Beef Flavor 180.00 15.00 Flavor

Fexofenadine 200.00 16.67 Active Ingredient

Magnesium Stearate 15.00 1.25 Lubricant

Claims

1. A method for treating atopic dermatitis in a non-human animal, said method comprising orally administering to a non-human animal in need of treatment a therapeutically effective dose of fexofenadine at a dose of at least 20 mg/kg by weight per day.

2. The method of claim 1, wherein said administration is repeated on a daily basis for at least 7 consecutive days.

3. The method of claim 3, wherein said administration is repeated on a daily basis for at least a year.

4. The method of any of claims 2 or 3, wherein a glucocorticoid is coadministered on a daily basis for at least 7 consecutive days.

5. The method of claim 4, wherein said fexofenadine is administered on a daily basis for at least 2 weeks, and the glucocorticoid is co-administered every day for the first week and is co-administered either daily or every other day for the second week.

6. The method of any of claims 1 to 5, wherein said fexofenadine is formulated as a tablet or capsule.

7. The method of claim 6, wherein said fexofenadine is formulated as a tablet.

8. The method of claim 7, wherein said tablet contains about 200 mg of fexofenadine.

9. The method of claim 8, wherein said tablet is scored to facilitate cleavage into 4 approximately equally sized quarter- tablets.

10. The method of any of claims 1 to 9, wherein said composition comprises a flavoring palatable to a canine.

11. The method of claim 10, wherein the flavoring is beef flavor.

12. The method of claim 13, wherein the composition comprises, by weight percentage, either (a) 23.33% microcrystalline cellulose; 15% beef flavor; 20% Di Pac; 16.67% fexofenadine; 24% lactose DC; and 1% magnesium stearate; or (b) 47.08% silicified microcrystalline cellulose; 15% beef flavor; 20% Di Pac; 16.67% fexofenadine; and 1.25% magnesium stearate.

13. A composition suitable for oral administration to a canine comprising, by weight percentage, at least 10% fexofenadine and at least 10% flavoring.

14. The composition of claim 13, wherein said composition is in the form of a tablet or capsule that contains about 200 mg fexofenadine and is scored to facilitate cleavage into 4 approximately equally sized quarter- tablets.

15. The tablet of claim 14 that is composed, by weight percentage, of either (a) 23.33% microcrystalline cellulose; 15% beef flavor; 20% Di Pac; 16.67% fexofenadine; 24% lactose DC; and 1% magnesium stearate; or (b) 47.08% silicified microcrystalline cellulose; 15% beef flavor; 20% Di Pac; 16.67% fexofenadine; and 1.25% magnesium stearate.

16. A veterinary composition, comprising: from 20% to 25% filler; from 22% to 26% diluent; from 18% to 23% taste masking agent; from 13% to 18% flavoring agent; from 4% to 20% active pharmaceutical ingredient; and from 0.75% to 2% lubricant agent.

17. The composition of claim 16, wherein the filler is a cellulose derivative.

18. The composition of claim 17, wherein the cellulose derivative is microcrystalline cellulose.

19. The composition of claim 18, wherein the diluent is selected from the group consisting of directly compressible lactose, starch, a cellulose derivative, a sugar, and a sugar alcohol.

20. The composition of claim 19, wherein the composition is lactose-free.