AU2012101682B4 - Formulation - Google Patents

Abstract

There is provided a solid pharmaceutical preparation of Pimobendan and citric acid for oral administration to a mammal, the preparation including one or more physiologically 5 acceptable excipients, and comprising a therapeutically effective amount of Pimobendan relative to the citric acid in a weight ratio of about 1:5 or less, and the citric acid in an amount of at least 1.3% w/w of the preparation, and wherein the preparation is coated with a taste masking coating. Methods for providing the preparation and for administering the preparation to induce vasodilation and/or treat a heart condition in a mammal are also 10 provided.

Description

-1 AUSTRALIA Patents Act 1990 (Cth) COMPLETE SPECIFICATION APPLICANT BETROLA INVESTMENTS PTY LTD TITLE FORMULATION The Invention is described in the following statement including the best method known to US. 5 -2 FORMULATION FIELD OF THE INVENTION 5 The present invention relates to a preparation of Pimobendan for oral administration and to a method for providing the preparation. BACKGROUND TO THE INVENTION 10 Pimobendan (4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl)-5 methyl-3(2H)-pyridazinone) (CAS Registry No. 74150-27-9) is commonly used for the treatment and management of heart disease in dogs due to its vasodilation and anti thrombotic activities. In particular, its ability to cause peripheral vasodilation reduces 15 cardiovascular pressure and thereby the load placed on the heart. It is also a known positive inotrope which acts to increase binding efficiency of cardiac myofibril to calcium ions and increase the strength of heart muscle contractions. Pimobendan is typically administered to dogs with other medications such as a diuretic to reduce pulmonary oedema, an aldosterone antagonist to reduce aldosterone-mediated fibrosis and remodeling 20 of heart tissue, and/or further drugs for promoting balanced vasodilation. Whilst particularly suitable for dogs, Pimobendan may also be used for the management of heart failure in other animals and, for example, is available in Japan for use in humans. Pimobendan has only low solubility in aqueous media and as a result, may have relatively poor resorption and bioavailability depending on the formulation in which it is 25 administered. The solubility of Pimobendan is highly dependent on pH and its solubility in aqueous media is significantly increased at low pH values. However, pH in the gastrointestinal tract can fluctuate widely and so there can be substantial fluctuation in the resorption of the Pimobendan between individuals. A dry preparation of Pimobendan and citric acid is described in United States 30 Patent No. 5,364,646 in which the citric acid is intimately mixed with the Pimobendan to -3 form a powdered or granulated mixture. The citric acid is thought to provide an acidic microsphere around the Pimobendan when the citric acid comes into contact with gastric juices thereby enhancing dissolution of the drug in the gastrointestinal tract for resorption. However, the citric acid adversely impacts on the palatability of the preparation. 5 Flavouring agents have been employed to mask the taste of the Pimobendan and citric acid but largely fail to combat the sour taste imparted by the citric acid. Taste is an important factor as the palatability of an oral medication is a significant factor in dosing compliance in small animals (Payne-Johnston et al., 2007). Indeed, unpalatable oral medication can result in an animal not accepting the medication or suboptimal dosing, 10 especially when the medication must be administered to the animal regularly over an extended period of time. SUMMARY OF THE INVENTION 15 The present invention stems from the combination of two separate features. Firstly the observation that the unpalatable taste of Pimobendan and citric acid in a solid preparation can be masked by coating the preparation with a physiologically acceptable film and secondly, the recognition that by masking the taste of the preparation with the film coating, the amount of excipient(s) in the preparation can be reduced allowing a smaller 20 volume of Pimobendan and citric acid to be administered to a subject. More particularly, by providing the preparation with a film coating so that the preparation is swallowed before the animal is exposed to the Pimobendan and citric acid, the present inventors have recognized that the physical volume of the dosage can be decreased whilst retaining the amounts of Pimobendan and citric acid essentially constant. As such, solid dosage forms 25 of the preparation can be made smaller, assisting administration of the preparation/dosage to small animals and thereby, compliance with dosing regimens. Alternatively, a larger dosage of Pimobendan can be administered to the animal in a smaller physical volume. Accordingly, in an aspect of the invention there is provided a solid pharmaceutical preparation of Pimobendan and citric acid for oral administration to a mammal, the 30 preparation including one or more physiologically acceptable excipients, and comprising a -4 therapeutically effective amount of Pimobendan relative to citric acid in a weight ratio of about 1:5 or less, and the citric acid in an amount of at least 1.3% w/w of the preparation, and wherein the preparation is coated with a taste masking coating. Typically, the Pimobendan is present in a preparation embodied by the invention 5 relative to the citric acid in a weight ratio of about 1:5 or less and more preferably, about 1:7.5 or less, 1:10 or less, 1:15 or less. Most typically, the Pimobendan is present in the preparation in a range of from 1:10 to 1:20. Typically, the citric acid is present in the preparation in an amount of at least 1.

3 % of the preparation and more preferably, at least about 1.

9 5 %, 2

.

6 % or 5.

2 % w/w of 10 the preparation or greater (e.g., up to 15% w/w of the preparation). Typically, the coating is a film coating. In at least some embodiments the coating is an immediate release coating. If desired, the coating can include one or more flavouring agents. Typically, however, no flavouring agent is included in the coating and/or the preparation. 15 In another aspect of the invention there is provided a method for providing a solid pharmaceutical preparation of Pimobendan and citric acid for oral administration to a mammal, comprising: mixing citric acid and a therapeutically effective amount of Pimobendan with one or more physiologically acceptable excipients to form a mixture comprising the 20 Pimobendan relative to citric acid in a weight ratio of about 1:5 or less, and the citric acid in an amount of at least 1.

3 % w/w of the mixture; and coating the mixture with a taste masking coating. In embodiments described herein, the solid pharmaceutical preparation of Pimobendan can be comprised of essentially solely granules of a substantially 25 homogeneous mixture of the Pimobendan, the citric acid, and the one or more excipients. In another aspect there is provided a method for inducing vasodilation and/or treating a heart condition in a mammal, comprising orally administering to the mammal an effective amount of a solid preparation of Pimobendan and citric acid embodied by the invention. 30 The term "taste masking coating" encompasses a coating that at least partially masks the taste imparted by the Pimobendan and citric acid in the preparation. Typically, the taste of the Pimobendan and citric acid is completely masked by the coating.

-5 By the term "immediate release coating" as used herein is meant a coating which has susbtantially no influence on the rate of release of the pimobendan and citric acid from the preparation in vivo when compared to the preparation in the absence of the coating as may be determined, for example, by statistical assessment of the amount of pimobenden in 5 peripheral blood. Typically, an immediate release coating in the context of the invention has essentially no controlled release, swelling and/or erosion properties which may lead to the non-immediate release of the pimobendan and citric acid from the preparation. Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, 10 integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers, integers or steps. Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the invention. It is not to be taken as an admission that any or all of these matters form part of 15 the prior art base or were common general knowledge in the field relevant to the invention as it existed in Australia or elsewhere before the priority date of this application. The features and advantages of the invention will become further apparent from the following detailed description of exemplary embodiments of the invention. 20 DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS OF THE INVENTION Pimobendan and citric acid in powder form are normally used in the provision of a preparation embodied by the invention to achieve intimate admixing of the two 25 components together to provide a citric acid microenvironment of the desired pH about the Pimobendan when the citric acid is wetted in the gastrointestinal tract of the subject mammal, although any suitable dry form of either Pimobend and or citric acid can be used. The term "excipient" as used herein is to be taken in a broad sense to encompass a component or components forming a vehicle or medium for delivery of the Pimobendan 30 and citric acid. Excipients that can be utilised in a preparation embodied by the invention -6 include binders such as lactose, sucrose, starch (e.g., corn (maize) starch, tapioca starch, wheat starch, potato starch, modified starches, and mixtures thereof), povidone polyvinylpyrrolidone, microcrystalline cellulose (e.g., Avicel

TM

), modified cellulose(s) (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose and hydroxyethyl cellulose), 5 fillers such as lactose, pre-gelatinised starch and dibasic calcium phosphate, disintegrating agents to aid the break-up and disintegration of the preparation once the preparation has been swallowed, and lubricants such as magnesium stearate and calcium stearate. The coating can be any suitable coating that will breakdown (e.g., be hydrolysed) and/or dissolve when administered for release of the Pimobendan and citric acid in the 10 preparation embodied by the invention, typically primarily in the stomach. Immediate release film coatings that can be employed include polysaccharides, cyclodextrins, cellulose derivatives, waxes and polymeric coatings. Examples of the cellulose derivatives and immediate release coating agents useful for coating a Pimobendan and citric acid preparation embodied by the invention include acrylate derivatives (e.g. aminoalkyl 15 methacrylate copolymer), polyvinyl alcohol - polyethylene glycol, polyethylene glycol, povidone, cellulose derivatives, cellulose ethers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy propyl methyl cellulose, ethyl cellulose, and mixtures of the foregoing. The Pimodendan and citric acid mixture can be granulated by dry, wet or fluid - bed 20 granulation methods to form a freely flowing preparation, and the granules then coated with an immediate release taste masking coating as described herein. Such a coated granule preparation can be sprinkled onto an animal's food in a measured amount for administration of the Pimobendan to the animal. Generally, however, the coated preparation will be provided in solid unit dosage form as a tablet comprising a 25 predetermined amount of the Pimobendan. The Pimobendan and citric acid mixture can be provided either as a powder or in granulated from form for being pressed into tablets. Typically, is these embodiments, a powdered mixture of the Pimobendan and citric acid is dry granulated and the granules then mixed under low shear with a lubricant such as powdered magnesium stearate to coat the granules so as to inhibit sticking of the granules 30 to tableting equipment when being pressed into tablets.

-7 Tablets or granules of the Pimobendan and citric acid preparation embodied by the invention can be covered with the selected coating by any conventionally known coating process. One or more flavouring agents for providing a beef, chicken or other flavour (e.g., oil of Wintergreen) acceptable to the mammal for whom the preparation is intended can be 5 included in the coating composition. Suitable physiologically acceptable compositions and formulations useful for preparations of the present invention may for instance be found in handbooks and texts well known to the skilled addressee, such as "Remington: The Science and Practice of Pharmacy (Mack Publishing Co., 1995)", the contents of which is incorporated herein in its 10 entirety by reference. The coated preparation of the invention can be administered to the subject mammal to effect vasodilation and/or for any condition that may be treated with Pimobendan including, but not limited to cardiovascular diseases and disorders, and heart conditions such as heart failure such as is associated with myxomatous mitral valve disease 15 (endocardiosis). The mammal can, for example, be a companion animal such as a dog or cat, a rodent, such as a mouse, rat or guinea pig, a pig, horse, or camel, or a human being. Typically, however, the mammal is a companion animal. Small to medium breeds of dogs such as King Charles Cavalier Spaniels, Maltese, Chihuahua, Shih Tzu, Yorkshire Terrier, 20 Silky Terrier, Beagle and Dachshund are particularly suitable for treatment with a preparation embodied by the invention. A preparation embodied by the invention can be administered to a mammal in the normal dosage for the particular condition being treated taking into account factors such as the age and weight of the subject, the severity of the condition and the general health of the 25 subject as can be determined by accepted medical or veterinarian practices by the attending medical practitioner or veterinarian. The invention is described further below by way of a number of non-limiting examples. 30 -8 EXAMPLE 1: Solid preparation of Pimobendan and citric acid Table 1: Components Component Suppliers Quantity (g) Function Sino Chemicals Pimobendan Industry Co., 0.6 Active Ltd. Lactose Trans Chem Pty 86.4 Filler Ltd ISP Polyvinylpolypyrrolidone Technologies, 9.0 Binder/Disintegrant Inc. Citric acid anhydrous APS Healthcare 3.0 Buffer Magnesium stearate APS Chemicals 1.0 Lubricant Hydroxypropyl Hangzhou methylcellulose (Cat. # Cheical Co 1.5 Film coating RJ2011-WLHPMC) ltd. , 5 Approximately 100 grams of the preparation is prepared following the steps described below: 1. Using a granulator, mix all ingredients except the cellulose derivative 10 until homogenous. 2. Compress the mixture of step 1 using a tablet press. 3. Using an air mixer, mix the cellulose derivative into a 50 % ethanol solution until homogenous. 4. Coat the compressed form made in Step 2 with the cellulose derivative 15 and ethanol solution of Step 3 using a film coating pan.

-9 Rather than compressing the mixture of step 1 above, the mixture can be dry granulated and the resulting granules coated with the cellulose derivative and ethanol solution of Step 3. 5 EXAMPLE 2: Solid preparation of Pimobendan and citric acid A further solid preparation (approx. 1 00g) of Pimobendan and citric acid was prepared as described in Example 1, but containing pregelatinised starch instead of lactose and double the amount of citric acid. The preparation was also coated with a greater 10 amount of the immediate release cellulose derivative. Table 2: Components Component Suppliers Quantity (g) Function Sino Chemicals Pimobendan Industry Co., 0.6 Active Ltd. Pregelatinised starch J L Stewart and 83.4 Filler Sons ISP Polyvinylpolypyrrolidone Technologies, 9.0 Binder/Disintegrant Inc. Citric acid APS Healthcare 6.0 Buffer Magnesium stearate APS Chemicals 1.0 Lubricant Ltd.an Hydroypropyl Hangzhou methylcellulose (Cat. # Ruijiang 8.0 Film coating RJ201 1-WLHPMC) Ltd. , 15 As in Example 1, rather than compressing the mixture of step 1 above to form tablets, the mixture can be granulated and the resulting granules coated with the cellulose derivative.

-10 EXAMPLE 3: Solid preparation of Pimobendan and citric acid A further solid preparation (approx. 1 00g) of Pimobendan and citric acid was prepared as described in Example 1 but containing calcium phosphate dibasic instead of 5 lactose. In this Example, the preparation was coated with aminoalkyl methacrylate copolymer. Table 3: Components Component Suppliers Quantity (g) Function Pimobendan Sino Chemicals 0.6 Active _________________Industry Co., Ltd. Calcium phosphate J L Stewart and 86.4 Filler dibasic Sons ISP Polyvinylpolypyrrolidone Technologies, 9 Binder/Disintegrant Inc. Citric acid APS Healthcare 3 Buffer Magnesium stearate APS Chemicals 1 Lubricant ____________________Ltd. Aminoalkyl methacrylate Evonik Industries 1.5 Film coating copolymer 10 As in Example 1, rather than compressing the Pimobendan and citric acid mixture to form tablets, the mixture can be granulated and the resulting granules coated with the aminoalkyl methacrylate copolymer. 15 EXAMPLE 4: Solid preparation of Pimobendan and citric acid A further solid preparation (approx. 1 00g) of Pimobendan and citric acid was prepared as described in Example 3 but containing microcrystalline cellulose instead of calcium phosphate dibasic and double the amount of citric acid. 20 -11 Table 4: Components Component Suppliers Quantity (g) Function Pimobendan Sino Chemicals 0.6 Active _____ ____ _____ ____ Industry Co. Ltd._ _ _ _ _ _ _ _ _ _ Microcrystalline APS Healthcare 83.4 Filler cellulose ISP Polyvinylpolypyrrolidone Technologies, 9.0 Binder/Disintegrant Inc. Citric acid APS Healthcare 6.0 Buffer Magnesium stearate APS Chemicals 1.0 Lubricant ____________________Ltd. Aminoalkyl methacrylate Evonik Industries 8.0 Film coating copolymer As in Example 1, rather than compressing the Pimobendan and citric acid mixture 5 to form tablets, the mixture can be granulated and the resulting granules coated with the aminoalkyl methacrylate copolymer. EXAMPLE 5: Solid preparation of Pimobendan and citric acid 10 A further solid preparation (approx. 1 00g) of Pimobendan and citric acid was prepared as described in Example 1 but containing calcium phosphate dibasic instead of lactose. In this Example, the preparation was coated with polyvinyl alcohol-polyethylene glycol. 15 20 -12 Table 5: Components Component Suppliers Quantity (g) Function Pimobendan Sino Chemicals 0.6 Active _________________Industry Co., Ltd. Calcium phosphate J L Stewart and 86.4 Filler dibasic Sons Polyvinylpolypyrrolidone ISP Technologies, 9.0 Binder/Disintegrant ____ ____ ____ ____ ___Inc. Citric acid APS Healthcare 3.0 Buffer Magnesium stearate APS Chemicals 1.0 Lubricant ____________________Ltd. ABO Polyvntyl alcohol- Biopharmaceutical 1.5 Film coating Poytyen lclCo., Ltd. III As in Example 1, rather than compressing the Pimobendan and citric acid mixture 5 to form tablets, the mixture can be granulated and the resulting granules coated with the polyvinyl-alcohol-polyethylene glycol. EXAMPLE 6: Solid preparation of Pimobendan and citric acid 10 A further solid preparation (approx. 1 00g) of Pimobendan and citric acid was prepared as described in Example 5 but containing microcrystalline cellulose rather than calcium phosphate dibasic and double the amount of citric acid. The preparation was also coated with a greater amount of polyvinyl alcohol-polyethylene glycol. 15 20 -13 Table 6: Components Component Suppliers Quantity (g) Function Pimobendan Sino Chemicals 0.6 Active _________________Industry Co. Ltd. Microcrystalline APS Healthcare 83.4 Filler Cellulose Polyvinylpolypyrrolidone ISP Technologies, 9 Binder/Disintegrant ____ ____ ____ ____ ___Inc. Citric acid APS Healthcare 6 Buffer Magnesium stearate APS Chemicals 1 Lubricant ____________________Ltd. ABO Polyvntyl alcohol- Biopharmaceutical 8 Film Coating Polythylne gycolCo., Ltd. As in Example 1, rather than compressing the Pimobendan and citric acid mixture 5 to form tablets, the mixture can be granulated and the resulting granules coated with the polyvinyl-alcohol-polyethylene glycol. Although the invention has been described with reference to a number of embodiments, it will be apparent to those skilled in the art that numerous variations and/or modifications can be made. The present embodiments are, therefore, to be considered in 10 all respects as illustrative and not restrictive 15

Claims (5)

1. A solid pharmaceutical preparation of Pimobendan and citric acid for oral administration to a mammal, the preparation including one or more physiologically 5 acceptable excipients, and comprising a therapeutically effective amount of Pimobendan relative to the citric acid in a weight ratio of about 1:5 or less, the citric acid being in an amount of from 1.3% to 15% w/w of the preparation, and wherein the preparation comprises essentially solely granules of a substantially homogeneous mixture of the Pimobendan, the citric acid and the one or more excipients, and the 10 preparation is coated with a taste masking coating.

2. A preparation according to claim 1 wherein the coating is an immediate release coating.

3. A preparation according to claim 1 or 2 wherein the Pimobendan is present in the preparation relative to the citric acid in a weight ratio of 1:7.5 or less, and the citric 15 acid is present in the preparation in an amount of at least 1. 9 5 % w/w of the preparation.

4. A preparation according to claim 3 wherein the Pimobendan is present in the preparation relative to citric acid in a weight ratio in a range of from 1:10 to 1:20, and the citric acid is present in the preparation in an amount of at least 5. 2 % w/w of the preparation, and the preparation is in the form of a tablet. 20

5. A method for inducing vasodilation and/or treating a heart condition in a mammal, comprising orally administering to the mammal an effective amount of a solid preparation of Pimobendan and citric acid as defined in any one of claims I to 4.