NZ625506B2 - Compositions For Treatment of Heart Failure in Dogs. - Google Patents

Abstract

Disclosed is a fixed dose combination comprising benazepril hydrochloride and pimobendan in a ratio of 2: 1, in the form of a bilayer tablet, wherein the benazepril layer comprises 2.5, 5 or 10 mg benazepril hydrochloride which are contained in the form of pellets, and wherein the pimobendan layer comprises 1.25, 2.5 or 5 mg pimobendan. Also disclosed is a method for treating congestive heart failure in dogs comprising administering a fixed dose combination as defined above. omprises 1.25, 2.5 or 5 mg pimobendan. Also disclosed is a method for treating congestive heart failure in dogs comprising administering a fixed dose combination as defined above.

Description

Compositions For Treatment of Heart Failure In Dogs The present invention relates to a new combination of benazepril with pimobendan, and the uses and processes for the manufacturing of such combination. prii, ((3S)-3—((28)-1—Ethoxycarbonylphenylpropylamino)—2,3,4,5-tetrahydro-2—oxo- 1H-i-benzazepin—i-yl)acetic acid, is rapidly absorbed from the gastrointestinal tract and hydrolyzed to benazeprilat, a highly specific and potent inhibitor of angiotensin ting enzyme (ACE). It is indicated for the treatment of heart failure in dogs. it is commercially available as Fortekor® film coated tablets or flavoured tablets.

Pimobendan, (4,5-dihydro—6-(2-(4—methoxyphenyl)-1H-benzimidazol-S-yl)-5—methyl-3(2H))- pyridazinone, a benzimidazole-pyridazinone derivative, is a non-sympathomimetic, non- glycoside inotropic substance with potent vasodilatative properties. it is indicated for the treatment of canine congestive heart failure originating from valvular insufficiency (mitral and/or tricuspid itation) or dilated myopathy. it is commercially available as chewing tablets or capsules under the brand name Vetmedin®. it is well recognized by veterinarians and pet owners that oral administration of medications to pets can be very nging. Providing means to simplify the administration of medicines to pet patients can ensure that treatments are reliably given, that the ence for the owner and pet is positive and consequently the quality of life of pets is optimal.

Combining two core recommended therapies in one single dosage form for the treatment of tive heart failure in dogs would provide tremendous advantages as it would enable more convenient administration and by reducing the number of tablets increase compliance to the multiple therapeutic n advocated by veterinary cardiologists.

Accordingly, it is an ive of the present invention to provide a fixed dose combination combining benazepril, eg. in its hydrochloride form, and pimobendan. Such a fixed dose combination drug would be convenient to use, improve veterinarian and pet owner compliance and treatment outcomes. The ing object should be read disjunctively with the object of at least providing the public with a useful choice.

When combining two active ingredients in one single dosage form there is the possibility of interactions between the two active ingredients as well as between the active and inactive ingredients. in addition, the two actives may have different degradation characteristics which can lead to chemical stability issues of the final dosage form. Moreover, the release profiles of the two s may be different which in turn will impact the pharmacological cy and safety of the drugs. The combination of two different active ingredients in one fixed dosage form is a technical challenge and several obstacles have to be overcome before a fixed dose ation of drugs is obtained that combines pharmacological efficacy and adequate drug stability and can be produced by a reliable and robust manufacturing method.

Both active ingredients used according to the present invention are difficult to formulate drugs. Pimobendan is a poorly water soluble drug and when administered, shows high intra— and inter- patient variability. Benazepril hydrochloride has a strongly bitter taste, is susceptible to hydrolysis and incompatible with ingredients that have an amino group.

After extensive testing the present inventors have surprisingly found a fixed dose combination that advantageously integrates all the above teristics resulting in a practical and convenient treatment. The combination demonstrates optimal ity and release profile of both active ingredients and is a product of le and robust manufacturing procedure. Moreover, the fixed dose combination of the invention is surprisingly small in size and shows excellent bility thus ensuring ease of stration. in a first aspect the present invention provides a fixed dose combination comprising benazepril hydrochloride and pimobendan, e.g. in a ratio of 2 : 1, e.g. benazepril hydrochloride in an amount of 1 to 20 mg, for example 2.5, 5 or 10 mg, and pimobendan in an amount of 1 to 10 mg, for example 1.25, 2.5 or 5 mg, which fixed dose combination is in form of a tablet, e.g. a r tablet. ably the tablet, e.g. bilayer tablet, comprises 1.25 mg pimobendan and 2.5 mg benazepril hydrochloride or 5 mg pimobendan and 10 mg benazepril hydrochloride.

In a r aspect the present invention provides the use of a fixed dose combination sing benazepril hydrochloride and pimobendan, e.g. in form of a tablet, e.g. bilayer tablet the treatment of congestive heart failure in dogs, e.g. of congestive heart failure at , for lSACHC stage 2 and 3 (modified New York Heart Association Class ll, Ill & lV, ACVIM class C and D) due to atrioventricular valve insufficiency or dilated cardiomyopathy in dogs. in yet a further aspect the present invention provides a process for the cture of a fixed dose combination comprising benazepril hydrochloride and pimobendan in form of a bilayer , n (a) a pimobendan formulation, e.g. in form of a granulate, is ed, (b) a benazepril hydrochloride formulation, e.g. in form of a pellet, e.g. comprising further pharmaceutically excipients, is obtained and (c) the pimobendan and benazepril hydrochloride formulation are compressed together to form a bilayer .

These and other features, advantages and ives of the present invention will be further understood and iated by those skilled in the art by references to the following specification and claims .

As used herein, the term "drug" means any compound, substance, drug, medicament or active ingredient having a therapeutic or pharmacological effect, and which is suitable for administration to a mammal, e.g. a companion animal, e.g. a dog. Such drugs should be administered in a "therapeutically effective amount".

As used herein, the term "therapeutically effective amount" refers to an amount or concentration which is effective in ng, eliminating, treating, preventing or controlling the symptoms of a disease or condition affecting a mammal. The term "controlling" is ed to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of the diseases and conditions affecting the mammal. However, "controlling" does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment.

The appropriate therapeutically effective amount is known to one of ordinary skill in the art as the amount varies with the companion animal treated and the indication which is being addressed.

As used herein, the term “excipient” means a pharmaceutically acceptable ingredient that is commonly used in the ceutical logy for preparing granulate and/or solid oral dosage formulations, e.g. pellets or tablets. Examples of categories of excipients include, but are not limited to, binders, egrants, lubricants, glidants, fillers and diluents. One of ry skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granulate and/or solid oral dosage form, e.g. pellet or tablet. The amount of each excipient used may vary within ranges conventional in the art.

The following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms. See The Handbook of Pharmaceutical Excipients, 6th edition, Rowe et al., Eds., American Pharmaceuticals Association (2011); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2000).

The active ingredient benazepril is generally supplied in its hydrochloride form.

Suitable excipients to formulate the benazepril layer of the fixed dose ation of the invention include but are not limited to those disclosed in European patent EP 1 490 037 which is hereby incorporated by reference.

Benazepril s may be prepared according to a process described in European patent EP 1 490 037 which is hereby incorporated by reference.

The process for the production of benazepril pellets may be performed as follows: (a) neutral—tasting, physiologically acceptable, solid, rained particles with an average diameter of less than 0.8 mm, for example of 0.05 to 0.8 mm, or 0.09 to 0.8 mm, preferably 0.15 to 0.4 mm, are coated with benazepril, (b) benazepril coated particles ed in a) are r coated with a tive, masking layer ting of a physiologically acceptable polymer matrix.

Suitable physiologically able carrier materials for ing the particles include but are not limited to cellulose, starch, saccharose, lactose or other different types of sugar.

Preferably, particles made of microcrystailine cellulose, e.g. as commercially available under the name Celphere CP203®, e.g. from the company ASAHI Japan, are used.

In order to coat the particles, benazepril is conveniently dissolved in a le, physiologically acceptable solvent or solvent mixture, e.g. a volatile alcohol, or l-water mixture, for example ethanol : water (1 :1), and applied to the les by a spraying process.

Suitable solvents are known to those skilled in the art, readily volatile solvents are preferred.

After the spraying procedure, the solvent or solvent e is d, preferably under careful conditions, e.g. under vacuum. After the drying process, the pellets may be further sieved.

The particles coated with benazepril are preferably further coated with a protective, e.g. g, layer consisting of a physiologically acceptable polymer matrix.

Polymers which are le for masking are known to those skilled in the art. Suitable classes of polymer include but are not limited to shellac, a polymer on a cellulose, acrylic acid or methacrylic acid, maleic acid anhydride, nyl pyrrolidone or polyvinyl alcohol basis. Other rs may also be ered, e.g. polymers on a cellulose basis, e.g. produced from cellulose e phthalate or cellulose acetate-N,N-di—n- butylhydroxypropylether. The starting materials for rs on an acrylic acid or methacrylic acid basis may be methacrylate / methacrylic acid copolymer, 2-methylvinyl—pyridine/ methacrylate / methacrylic acid copolymer, methyl methacrylate / methacrylic acid copolymer, methyl methacrylate / methacrylic acid copolymer, methyl methacrylate / maleic acid anhydride copolymer or methyl methacrylate / maleic acid anhydride copolymer.

Polymers on an acrylic acid or methacrylic acid basis are preferably used according to the t invention, e.g. polymerisation products of c acid and acrylic acid esters with a low content of quaternary ammonium groups, e.g. as commercially available under the names Eudragit® E, L or S from the company Rohm, Darmstadt, Germany. Eudragit® E is a cationic polymer of dimethylaminoethyl methacrylate and a neutral methacrylic acid ester. it ®L and S are anionic copolymers of methacrylic acid and methacrylic acid methylester. Eudragit ®E 100 is a pH—dependent cationic r, which dissolves in the gastricjuices at an acidic pH value of up to pH 5.0. Above pH 5.0, it is e of swelling. In powder form, it is known and commercially available as Eudragit® EPO. Eudragit® EPO has the advantage that the process can be d out in an aqueous medium and without organic solvents.

Masking is effected by dissolving the shellac or polymer in an organic solvent, optionally adding water, spraying the solution onto the particles which are already coated by benazepril. The solvent or solvent mixture is subsequently removed under careful conditions, e.g. under vacuum.

Suitable organic solvents for dissolution of the polymer are, for example, solvents which are relatively readily volatile, e.g. one or more of the follwing: methanol, ethanol, isopropanol, l, benzyl alcohol, ethylene glycol, propylene glycol, phenol, e, acetic acid, acetic acid anhydride, nitromethane, ethylene diamine, acetic acid cellosolve, e.g. an acetone - ethanol mixture, e.g. in a ratio of 1:1. Very good results are obtained by adding water, e.g. about 1 to 5 parts by volume of water to 10 to 50 parts by volume of organic t. Water - e mixtures, e.g. in a ratio of 1:30, are preferred.

Advantageously, aqueous suspensions or solutions may be used, for example coating may be carried out with Eudragit® EPO from an aqueous suspension. According to this process, safety aspects, environmental protection and economical advantages are optimally combined.

Advantageously, the size of the carrier les is in the range of less than 0.8 mm, for example of 0.05 to 0.8 mm, or 0.09 to 0.8 mm, preferably 0.15 to 0.4 mm diameter.

Such double-coated particles, e.g. first coated with benazepril and then with the polymer matrix, may be further processed with suitable pharmaceutically acceptable excipients, e.g. fillers, disintegrants, glidants and/or lubricants, to obtain a blend, e.g. dry mixture, to form one layer of the final tablet, e.g. bilayer tablet, of the invention.

The amount of benazepril pellets in the benazepril layer is iently between 5 and 75%, e.g. 10%, 15%, 20%, 25%, 30%, or greater, by weight of the layer. ing to one aspect of the invention, the le size of all excipients may be adjusted to the one of benazepril pellets, e.g. ning 5% benazepril, e.g. to a size of from 200 pm to 400 um, e.g. between 200 um and 350um, to avoid segregation during compression.

Suitable excipients to formulate the pimobendan layer of the fixed dose combination of the invention include but are not d to those sed in published patent application WO 2010/055119 which is hereby incorporated by reference.

The pimobendan layer may be prepared according to a process described hereinbelow using suitable excipients known to those skilled in the art and exemplified below.

According to one aspect of the invention, the pimobendan layer may be obtained by a spray granulation process. For example, pimobendan may be introduced to the granulate partially from an aqueous/ethanolic solution and partially from an aqueous suspension. Appropriate amounts of binders, fillers and lubricants, e.g. hypromeliose, e, starch and/or magnesiumstearate may be added to ensure compressibility. Appropriate amounts of an acid, e.g. organic acid, e.g. succinic acid, s and disintegrants, e.g. Kollidon VA64 and/or croscarmellose sodium, may be added to ensure disintegration of tablets and ution of pimobendan from the fixed dose combinations, e.g. in form of tablets, e.g. bilayer tablets, of the invention.

Other pharmaceutically acceptable excipients can be added to the benazepril and/or pimobendan formulation which form part of the fixed dose combination of the ion. es of pharmaceutically acceptable binders include, but are not limited to, starches; celluloses and derivatives thereof, for example, hypromellose, e.g. Pharmacoat 603; microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia, PA), Copovidone, e.g.

Kollidon VA64; hydroxypropyl cellulose hydroxylethyl cellulose and yipropylmethyl cellulose METHOCEL from Dow Chemical Corp. (Midland, Ml); sucrose; dextrose; starch corn; starch pregelatinized; corn syrup; polysaccharides; and gelatin. The binder may be t in an amount from about 0.1% to about 50%, e.g., 10—40% by weight of the composition.

Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; starch corn; starch pregelatinized; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone; ASDONE XL from International Specialty Products (Wayne, NJ); cross-linked sodium carboxymethylcellulose or croscarmellose , e.g., AC-Dl-SOL from FMC; and cross- linked calcium carboxymethylcellulose; soy polysaccharides; and guar gum. The disintegrant may be t in an amount from about 0.1% to about 10% by weight of the composition.

Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner’s sugar; compressible sugar; dextrates; dextrin; dextrose; e; lactose monohydrate; mannitol; rystalline cellulose, e.g. Avicel PH101 or PH102; powdered cellulose; sorbitol; e and talc. The filler and/or diluent, e.g., may be present in an amount from about 15% to about 80% by weight of the composition, for example from about 15%, 25%, 35% or 45% to about 60% by weight of the composition.

Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not d to, colloidal silica, e.g. Aerosil 200; magnesium icate; starches; talc; tribasic calcium phosphate; magnesium stearate; sodium stearyl fumarate; aluminum sterate; calcium stearate; magnesium carbonate; magnesium oxide; polyethylene glycol; powdered cellulose and rystalline cellulose. The lubricant may be present in an amount from about 0.1% to about 5% by weight of the composition; the glidant may be t in an amount from about 0.1% to about 10% by weight. ln certain exemplary embodiments of the present invention, the composition may comprise additional excipients ly found in pharmaceutical compositions, examples of such excipients include, but are not limited to idants, antimicrobial agents, colorants, enzyme inhibitors, stabilizers, preservatives, , sweeteners and other components.

These additional excipients may comprise from about 005—1 1% by weight of the total pharmaceutical com position, e.g. from about 0.5 to about 2% by weight of the total composition. Antioxidants, anti—microbial agents, colorants, enzyme inhibitors, stabilizers or vatives typically provide up to about 0.05-1% by weight of the total pharmaceutical composition. Sweetening or flavoring agents typically provide up to about 2.5% or 5% by weight of the total pharmaceutical ition.

According to the invention therapeutically effective amounts of benazepril and pimobendan are used, e.g. 1 to 20 mg, for example 2.5, 5 or 10 mg benazepril per fixed dose combination, and 1 to 10 mg, for example 1.25, 2.5 or 5 mg of pimobendan, e.g. in the form of a , e.g. bilayer tablet. ln one aspect of the invention, the fixed dose combination, e .g. in the form of a tablet, e.g. bilayer tablet, is administered to a dog in need of such treatment in an amount of 0.25 to 0.5 mg benazepril/kg and 0.125 to 0.25 mg ndan per kg, e.g. twice daily, e.g. 12 hours apart, e.g. in the morning and in the evening.

The fixed dose combinations of the invention are useful for the treatment of congestive heart failure (CHF) in dogs, for example of congestive heart failure at ISACHC stage 2 and 3 (modified New York Heart Association Class ll, lll & lV, ACVlM class C and D) due to atrioventricular valve iciency or dilated cardiomyopathy in dogs.

The fixed dose combinations of the invention show surprisingly good benazepril and pimobendan e characteristics, e.g. with efficacy and safety comparable to the active ingredients benazepril and ndan given alone as single products, e.g. as commercially ble under the names Fortekor® and Vetmedin®.

A further object of the invention is directed to methods for producing the bilayer tablets described before.

The tablet layers comprising pimobendan may be ed by dissolving and/or suspending pimobendan in a granulation liquid, e.g. ethanol or ethanol/water mixture, together with appropriate amounts of a suitable acid, e.g. c acid, e.g. succinic acid, a surfactant, e.g. nonionic surfactant, e.g. polysorbate 80, and/or a binder, e.g. Kollidon VA64. The granulation liquid may be sprayed on a dry mixture sing disintegrants, fillers and other excipients conveniently used by those skilled in the art, e.g. starch, lactose and/or colorant, e.g. iron oxide colorant, e.g. iron oxide brown. Granules may be sieved after drying and a dry mixture of s, e.g. colloidal silica, flavors, e.g. natural or synthetic meat, fish, cheese or vegetarian flavors, and lubricants, e.g. magnesium stearate, may be added.

Benazepril pellets may be conveniently obtained by those skilled in the art according to the process described hereinabove and in EP 1 490 037 which is hereby incorporated by reference.

The tablet layers comprising benazepril hydrochloride may be prepared by using benazepril pellets, containing, e.g., 2.5, 5, 10, 20, 30 or 35%, ably 5, 10 or 20%, even more preferably 5% of benazepril, which are mixed with appropriate amounts of fillers, disintegrants, lubricants, glidants and s, e.g. microcrystalline cellulose, crospovidone, sucrose, e.g. as commercially available under the name Di—Pac sugar, colloidal silica and/or -10_ magnesium stearate, to obtain a blend, e.g. dry mixture, containing the active ingredient prii in the form of a benazeprii pellets.

On the rotary tableting machine, the granulation for the first layer, e.g. comprising the pimobendan granulate, may be placed in the hopper and the machine may be adjusted until the desired weight is achieved, then the second hopper may be filled with benazeprii pellets dry mixture, and the machine may be adjusted until the correct tablet weight is obtained. it will be appreciated by those skilled in the art that each layer needs e correction to e uniformity of dosage for both actives. ably the ratio of the compression force applied during compression of the bilayer talet is performed at a force of 8 to 50 kN, for example at a force of 8, 10 or 17 to 30 kN, for example at a force of 17 to 29 kN.

In one aspect of the invention, the tablets, e.g. bilayer, e.g. scored, tablets, are surprisingly small in size. For example, a bilayer tablet containing 1.25 mg pimobendan and 2.5 mg benazeprii may have a width of 6.5 to 7 mm, e.g. 6.6 to 6.8 mm, a length of 11.5 to 12 mm, e.g. 11.6 to 11.8 mm, and a thickness of4.0 to 4.5 mm. A bilayer tablet containing 5 mg pimobendan and 10 mg benazeprii may have a width of 10 to 10.5 mm, e.g. 10.0 to 10.2 mm, a length of 19 to 19.5 mm of 6.5 to 7.5 mm. , e.g.19.0 to 19.2 mm, and a thickness In a further aspect of the invention, the bilayer tablets obtained by the s hereinabove described are stable at VICH ions 30°Cl65°rh, e.g. over 6, 12 or 24 months, for example over 12 months. In yet a r , the s of the invention are stable at VICH conditions 25°C/60°rh, e.g. over 24, 36 or 48 months, for example over 36 months.

In yet a further aspect of the invention the tablets are packed in suitable packaging material, e.g. to ensure safety and stability, e.g. in child resistant g, e.g. made of aluminium, e.g. in alu-alu blisters, as conveniently used by those skilled in the art.

The fixed dose combinations of the invention are described by the following embodiments of the invention which alone or in combination contribute to solving the objective of the invention: A fixed dose combination comprising benazepril hydrochloride and pimobendan in form of a tablet, e.g. a bilayer tablet.

A fixed dose ation according to numbered paragraph 1 which is stable over 24 months, e.g. over 36 months at 25°C.

Afixed dose combination of any preceding numbered paragraph comprising 1 to 10 mg of pimobendan and 1 to 20 mg of pril hydrochloride.

Afixed dose combination of any preceding numbered paragraph comprising 1.25 mg of pimobendan and 2.5 mg of benazepril hydrochloride, or 2.5 mg of pimobendan and 5 mg of benazepril hydrochloride, or 5 mg of pimobendan andiO mg of benazepril hydrochloride.

A fixed dose combination of any preceding numbered paragraph wherein the benazepril layer contains the active ingredient benazepril hydrochloride in the form of benazepril s.

A fixed dose combination of any preceding numbered paragraph n the ndan layer is in form of a granulate.

A fixed dose combination of any preceding numbered paragraph for use in the treatment of tive heart failure in dogs.

A fixed dose combination of any preceding numbered aph for use in the treatment of congestive heart failure in dogs wherein the fixed dose combination is administered twice daily, e.g. 12 hours apart, e.g. in the morning and in the g.

A fixed dose combination of any preceding numbered paragraph for use in the treatment of congestive heart failure in dogs wherein the release characteristics of benazepril hydrochloride and pimobendan from the fixed dose ation are equivalent to the release teristics of benazepril hydrochloride and pimobendan when given as single products.

. Use of a fixed dose combination of any preceding numbered paragraph for the manufacture of a medicament for the treatment of congestive heart failure in dogs. 11. A process for manufacturing of a fixed dose combination wherein a) a pimobendan granulate is obtained, b) benazepril hydrochloride pellets are obtained, c) the benazepril pellets obtained in b) are further mixed with excipients to obtain a blend, and d) the granulate and the blend obtained in a) and c) are compressed together to obtain a bilayer tablet. 12. A method for treating congestive heart failure in dogs comprising administering a fixed dose ation of any one of numbered paragraph 1 to 6. 13. A method according to numbered paragraph 12 n the fixed dose combination is administered twice daily, e.g. 12 hours apart, e.g. in the morning and in the evening. 14. A method ing to numbered paragraph 12 or 13 wherein the release characteristics of benazepril hydrochloride and pimobendan from the fixed dose combination are equivalent to the release characteristics of benazepril hydrochloride and pimobendan when given as single products.

The following non-limiting examples further illustrate the invention.

EXAMPLES The composition of two ations prepared using different technological procedures is shown in the Table 1. ity testing of the described s was performed, results of the study are presented in the Table 2.

Table 1: Detailed composition of examples 1 and 2 ndan+benazepril Example 1 Example 2 combination 5+20 mg 5+20 mg Pimobendan granule Monolayer tablet Bilayer tablet Polysorbate 80 V Copovidone (Kollidon) lron oxide-colorant Starch pregelatinised Lactose monohydrate 557.20 mg 557.20 mg rian flavo 40.00 mg Copovidone (Kollidon) 35.00 mg Silica colloidal 2.40 mg 2.40 mg Magnesium stearate 8.40 mg 8.40 mg Weight of l. layer with 795.00 mg pimobendan Benazepril pellets 100.00 mg (20%)* 100.00 mg (20%)* Tablet weight 970.00 mg 1112.50 mg Example 1: monolayer tablet with 5 mg of pimobendan and 20 mg of benazepril Example 2: bilayer tablet with 5 mg of pimobendan and 20 mg of benazepril *Alternatively, a 5% benazepril pellet ation may be used.

#Alternatively, natural or synthetic meat, fish or cheese flavor may be used.

Short description of the s: Example1: Pimobendan granules are prepared by dissolving a first part of pimobendan, succinic acid and polysorbate 80 in ethanol. A second part of pimobendan is dispersed in water to obtain pimobendan suspension. Water dispersion of hypromellose is mixed with pimobendan suspension to obtain final water sion of ndan and hypromellose.

The ed ethanol solution and water suspension are sprayed on the dry mixture of starch, lactose, croscarmellose sodium and colorant. Granules are sieved after drying and the dry mixture of binder, vegetarian flavor, colloidal silica and magnesium stearate are added. 870 mg of ndan granules (containing 5 mg of pimobendan) and 100 mg of benazepril pellets (containing 20 mg of benazepril) are mixed, and compressed into monolayer tablets with the total weight of 970 mg.

Example 2: Describes the r tablets of ndan and pril. The mixtures are prepared separately. The procedure for pimobendan granules is the same as in example 1.

Benazepril pellets (containing 20 mg of benazepril), are mixed with microcrystalline cellulose, binder copovidone, dry flavor vegetarian, colloidal silica and stearic acid.

On the rotary tableting machine, the granulation for the first layer is placed in the hopper and the machine is adjusted until the desired weight is achieved, then the second hopper is filled with benazepril pellets dry mixture, and the same procedure is followed until the t tablet weight is obtained. Since weight is related to the fill volume each layer need precise tion to achieve uniformity of dosage for both actives.

Table 2: Stability results Source Relative initial initial of Retention impurity Rr—0,32 (IMP Rr—1 ,18 (IMP Rr—1,27 (IMP Rr—0,61 Rr—1,43 (IMP * BNZ ** PMB = benazepril hydrochloride, = pimobendan s from stress ity study of Example 1 and Example 2 are presented in the table above. ity of the product is reflected and evaluated by the increase of benazepril hydrolytic degradation product Impurity C. Only this impurity is seen to show increasing , other impurities that were detected, are present as related substances, or they don’t show any increasing trends.

Levels of Impurity C are significantly lower for the bilayer tablet formulation.

Further optimization with regard to chemical stability was done according to Example 3, which has similar composition as Example 2, only that 5% benazepril s were used, instead of 20% benazepril pellets. Results are presented in the table 3 below, as % of formed Impurity C.

Table 3: al ity of example 1, 2 and 3 % of Impurity C 50°C 40°C 14 40°C 1 25/60 1 Sample initial 7 days days month month e1 0,17 11,62 Nottested 11,82 Example2 <0,05 1,75 Not tested Example 3 Not tested Not tested Results, obtained at chosen stress conditions speak in favour of using 5% benazepril pellets instead of 20% benazepril pellets. With this optimization levels of formed Impurity C are reduced from previously about 2% to final 1%.

We have detected the degradation products by UPLC equipped with BEH ShieldRP18, 1.7 um, 100 x 2.1 mm column which was ined in a column oven at 55 °C. The mobile phase A consisted of a mixture of methanol, water, acetic acid in volume ratio of 200:800: 0.2 and 0.81 g of tetrabutylammonium bromide and mobile phase B consisted of a mixture of a methanol, water and acetic acid in ratio 800:200:0.2 (V/VN) and 0.81 g of tetrabutylammonium bromide. The flow rate was 0.5 ml/min, using following gradient: WO 92673 -16~ Time (minutes) 1 2 60 and the detection wavelength was 240 and 330 nm.

Example 4: Benazepril pellets are prepared ing to the following process: 4.1 Preparation of a solution of benazepril Composition Weight benazepril HCl (active substance) 2.856 kg ents ethanol 96% 8.16 kg water 12.24 kg polyvinyl pyrrolidone 1.071 kg Ethanol and water are mixed in a vessel until a homogeneous solution is formed. Benazeprii hydrochloride is added to the solvent mixture and stirred for 5 minutes until a clear solution is obtained. nyl pyrrolidone is subsequently added and stirred for a further 10 minutes until a clear solution is obtained. 4.2 Coating of particles with benazepril ents Weight Celphere CP 203®* 31.15 kg Celphere® is a commercial product of the company ASAHI, Japan. it consists of round rystalline cellulose particles or pellets.

Celphere® s are placed in a fluidised bed equipment and heated to a product temperature of 35°C. The required amount of benazepril solution obtained in step 4.1 (23.9 kg) is sprayed onto the pellets. After spraying, the pellets are dried at an admission temperature of 55°C until ing residual moisture of <4%. The pellets are subsequently sieved through a 0.5 mm sieve. The yield of benazepril s is >95%. 4.3 Masking of the particles Excipients Weight sodium lauryl sulphate 0.75 kg dibutyl sebacate 1.61 kg Eudragit EPO®* 10.71 kg Syloid 244 FP® 4.28 kg water 89.75 kg Aerosil 200® 0.26 kg Eudragit® is a commercial product of the company Rbhm, Germany. it consists of butyl methacrylate - (2-dimethylaminoethyl)methacrylate - methacrylate copolymer (1 :2:1 ).

Syloid 244 FP® is a precipitated silicon dioxide, which is able from the company Grace GmbH, in Worms, Germany. Aerosil 200® is colloidal silicon dioxide from the company Degussa in Frankfurt/Main, Germany.

Sodium lauryl sulphate and dibutyl sebacate are ved in 89.75 kg of water.

Subsequently, the Eudragit EPO® is added to the solution and carefully stirred for at least 3 hours until a homogeneous suspension is obtained. Syloid 244 FP® is added and the mixture is stirred until a homogeneous suspension is produced. In order to remove larger les from the suspension, the solution is sieved through a 1.0 mm sieve before coating the benazepril pellet. During the entire coating s, the spray suspension is carefully d, so that no particles can settle in the . Then, 35 kg of benazepril pellets are filled into the fluidised bed equipment and heated to a product temperature of 28°C. The g suspension is sprayed onto the benazepril pellets. After spraying, the pellets are dried at an admission temperature of 55°C until attaining residual moisture of <4%. The pellets are subsequently sifted through a 0.5 mm sieve. The yield of benazepril pellets is >90%. In order to avoid adhesion of the taste-masked pellets during storage, 0.26 kg of Aerosil 200® are sifted onto the pellets through a 1.4 mm sieve. The dry mixture is mixed for minutes in a drum mixer.

Examples 5, 6 and 7: - 18 _ Example —_-7 Component Function 1.25 + 2.5 2.5 + 5 5 + 10 mg Per- L_mg mg cent Active P'mObenda”. substance 1.250 2.500 5.000 0.38 Succinic acid Acidifying agent 15.000 30.000 60.000 4.51 _F:glysorbate 80 Wetting agent 2.500 5.000 10.000 0.75 1 Granulation Ethanol liquid, solvent 170.000 0 680.000 - ellose gPharmacoat 603) Binder 6.250 12.500 25.000 1.88 . . 1 Granulation Pur'f'ed water 7 P63 liguid, solvent 66.500 133.000 0 — Binder, Starch corn disintegrant 15.000 30.000 60.000 4.51 Lactose monoh drate NF Filler 140.325 280.650 42.20 . . Binder, Stare“ prege'at'mze‘j 1551 disinteorant 15.000 30.000 60.000 4.51 Croscarmellose sodium (Ac—di- Disinteg rant sol 1.250 2.500 5.000 0.38 lron oxide brown Colorin- a-ent 0.500 1.000 2.000 0.15 Coovidone Kollidon VA 64 Binder 6.250 12.500 25.000 Croscarmellose sodium (Ac-di- egrant sol 2.500 5.000 10.000 0.75 Vegetarian flavor2 Flavor 8.000 16.000 32.000 2.41 Silica, colloidal anhydrous Glidant gAerosil 200) 1.075 2.150 4.300 0.32 Magnesium stearate Lubricant 2.600 5.200 10.400 0.78 Total pimobendan layer 217.50 435.00 870.00 65.41 Active Benazepril pellets 5% substance in pellets 50.000 100.000 200.000 15.04 Microcrystalline cellulose (Avicel Filler PH 102) 23.590 47.183 94.360 7.10 Microcrystalline ose (Avicel Filler PH 101) 11.470 22.941 45.880 3.45 e for direct compression Filler, flavor I_(DiPac) 26.760 53.529 107.040 8.05 Crosgovidon (Polyglisdone XL) egrant 1.720 3.441 6.880 0.52 , colloidal anhydrous Glidant Aerosil 200 0.310 0.612 1.240 0.09 Ma-nesium stearate Lubricant 1.150 0.34 Total benazepril layer 115.00 230.00 460.00 34.59 Toatal tablet mass 332.50 665.00 100.00 1 will be removed during the process 2 alternatively, natural or synthetic meat, fish or cheese flavor may be used Examples 5, 6 and 7: Pimobendan granules are prepared by ving a first part of pimobendan, succinic acid and polysorbate 80 in ethanol. A second part of pimobendan is sed in water to obtain ndan suspension. Water dispersion of hypromellose is mixed with ndan suspension to obtain final water suspension of pimobendan and hypromellose. The prepared ethanol solution and water sion are sprayed on the dry mixture of starch, e, croscarmellose sodium and colorant. Granules are sieved after drying and mixed with Copovidone, croscarmellose sodium, flavor, colloidal silica and magnesium stearate to obtain the pimobendan layer.

Benazepril pellets (containing 5% of benazepril), are mixed with microcrystalline cellulose, sucrose for direct compression, Crospovidon, dal silica and magnesium stearate to obtain a benazepril blend.

On the rotary tableting machine, the pimobendan layer is placed in the hopper and the machine is adjusted until the desired weight is achieved, then the second hopper is filled with the benazepril blend, and the same procedure is followed until the correct tablet weight is obtained. Both layers are compressed to form bilayer tablets.

Claims (21)

Claims:

1. A fixed dose combination comprising benazepril hydrochloride and ndan in a ratio of 2:1, in the form of a bilayer tablet, wherein the benazepril layer comprises 2.5, 5 or 10 mg pril hydrochloride which are contained in the form of pellets, and wherein the pimobendan layer comprises 1.25, 2.5 or 5 mg pimobendan.

A fixed dose combination of claim 1 wherein the pellets of the benazepril layer se 5% benazepril.

A fixed dose combination of claim 1 or claim 2 wherein the pril s of the benazepril layer are coated with a tive layer consisting of a butyl methacrylate-Z— dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1 :2:1 ).

A fixed dose combination of any one of claims 1 to 3 wherein the benazepril pellets of the benazepril layer have a particle size of 0.15 to 0.4 mm diameter.

A fixed dose combination of claim 4 wherein the benazepril layer comprises excipients having a particle size of from 200 to 400 pm.

A fixed dose combination of any one of claims 1 to 5 wherein the pimobendan layer is in the form of a granulate.

A fixed dose combination of any one of claims 1 to 6 wherein the ndan layer comprises succinic acid.

A fixed dose combination of any one of claims 1 to 7 which contains 1.25 mg pimobendan and 2.5 mg benazepril, and has a width of 6.5 to 7 mm, a length of 11.5 to 12 mm and a thickness of 4.0 to 4.5 mm.

A fixed dose combination of any one of claims 1 to 7 which contains 5 mg pimobendan and 10 mg benazepril, and has a width of 10 to 10.5 mm, a length of 19 to 19.5 mm and a thickness of 6.5 to 7.5 mm.

10. A fixed dose combination of any one of claims 1 to 9 for use in the treatment of congestive heart failure in dogs.

11. A fixed dose combination for use according to claim 10, wherein the fixed dose combination is administered twice daily.

12. A fixed dose combination for use according to claim 10 or 11, wherein the release teristics of benazepril hydrochloride and pimobendan are equivalent to the release characteristics of benazepril hydrochloride and pimobendan when given as single products.

13. Use of a fixed dose combination of any one of claims 1 to 9 for the cture of a medicament for the treatment of congestive heart e.

14. A process for manufacturing of a fixed dose combination of any one of claims 1 to 9 wherein a) a ndan granulate is obtained, b) benazepril pellets are obtained, c) the benazepril pellets obtained in b) are further mixed with excipients to obtain a blend, and d) the granulate and the blend obtained in a) and c) are compressed together to obtain a bilayer .

15. A method for treating congestive heart failure in dogs comprising administering a fixed dose combination of any one of claims 1 to 9.

16. A method according to claim 15 n the fixed dose combination is administered twice daily.

17. A method according to claim 15 or 16 wherein the release characteristics of benazepril hydrochloride and pimobendan from the fixed dose combination are equivalent to the e characteristics of benazepril hydrochloride and pimobendan when given as single products.

18. A fixed dose ation according to any one of claims 1 to 12, substantially as herein described with reference to any one of the Examples thereof.

19. Use ing to claim 13, substantially as herein described with reference to any one of the Examples thereof.

20. A process according to claim 14, substantially as herein described with reference to any one of the Examples thereof.

21. A method according to any one of claims 15 to 17, substantially as herein described with reference to any one of the Examples thereof.