Methods for preparing a pharmaceutical composition having improved solubility and uses thereof

Abstract

A method for preparing a pharmaceutical composition having improved solubility, including an active compound selected from the group including pimobendan, the method including the step of preparing co-crystals of the active compound and a coformer component by providing the active compound and coformer component in a ratio based on the molecular weights of each component, wherein the ratio of active compound to coformer component is between 1:1 and 2:1.

Description

[0001] METHODS FOR PREPARING A PHARMACEUTICAL COMPOSITION

[0002] HAVING IMPROVED SOLUBILITY AND USES THEREOF

[0003] FIELD OF THE INVENTION

[0004] This invention relates to methods for improving solubility of a pharmaceutical composition. More particularly, but not exclusively, this invention relates to methods for improving solubility of a pharmaceutical composition including pimobendan.

[0005] BACKGROUND TO THE INVENTION

[0006] In the field of animal health, pimobendan is a known medication for congestive heart failure (CHF) in animals, most often, used for dogs. Pimobendan is characterised by low water solubility, and its solubility is also highly pH- dependent, with an acidic environment being required.

[0007] This poor pH-dependent aqueous solubility of pimobendan necessitates the inclusion of citric acid in oral dosage forms. One such example is found in US Patent No. 5,364,646, where hard gelatine capsules containing pimobendan formulated with citric acid were proposed for improved solubility. However, as this medication is administered orally, and the weight ratio of pimobendan to citric acid being between 1 :10 and 1 :20, the acidic taste of the citric acid is rejected by most animals. This necessitates the force-feeding of these capsules to the animals, alternatively, that the capsules be mixed with food prior to application.

[0008] Current strategies to improve the acceptability of the medication to animals, include the encapsulation of the pimobendan into hard gelatin capsules or making use of granulation techniques. For example, in US 2017 / 0368062, solid formulations of pimobendan, dispersed in a polyvalent acid, are disclosed, including a suitable flavour. Further described is a fluid-bed granulation processes for production of the solid formulations.

[0009] Other known approaches include the incorporation of pimobendan in a molten carrier matrix (US patent application 2022 / 0183987), and the preparation of different crystalline forms of pimobendan (NL patent 1037569). These approaches generally improve the acceptability of the medication to the animal being treated. However, these approaches (US 2017 / 0368062, US 2022 / 0183987 and NL 1037569) make use of fluid-bed granulation and / or spray congealing, which require specialised equipment that uses significant amounts of energy for heating and cooling during the manufacturing process. Another disadvantage is that organic solvents may be required, the reclamation of which adds to the complexity and cost of manufacture. OBJECT OF THE INVENTION

[0010] It is accordingly an object of the present invention to provide a method or methods for the preparation of a pharmaceutical composition having improved solubility, the composition including pimobendan, to address the issues identified above, at least to some extent, or which may provide a useful alternative to existing technologies.

[0011] SUMMARY OF THE INVENTION

[0012] According to the invention, there is provided a method for improving solubility of a pharmaceutical composition including an active compound, the method including the step of preparing active-coformer co-crystals. The method extends to the preparation of a pharmaceutical composition showing this improved solubility when compared to compositions disclosed in the prior art, which composition is useful in treating CHF in animals.

[0013] The active compound may be pimobendan. The coformer may be carboxylic acid based, selected from the group including, but not limited to fumaric acid, oxalic acid, succinic acid, and citric acid.

[0014] The pimobendan-coformer co-crystals may be prepared by providing the pimobendan component and coformer component in a ratio based on the molecular weights of each component. The ratio of pimobendan to carboxylic acid may be between 1 :1 and 2:1 .

[0015] The method may include the further steps of lightly grounding together pimobendan and carboxylic acid with a solvent until a paste is formed, leaving the paste to dry, and grounding the dried paste to produce a fine powder of the co-crystals. The solvent may be ethanol. The grounding may take place in a mortar and pestle.

[0016] Alternatively, the method may include the further steps of forming a mixture of pimobendan and carboxylic acid in a grinding container, closing the mixture in the grinding container, and submerging the container in liquid nitrogen until the liquid nitrogen stops boiling, thereafter allowing the mixture to be co-milled. The mixture may be co-milled for 10-minute intervals with a frequency of 30 Hz per session. Prior to each milling session, the grinding container may be submerged in liquid nitrogen. At least three milling sessions may be required to produce a fine powder of the co-crystals.

[0017] The co-crystals produced by the above methods may show improved solubility in an aqueous medium.

[0018] DETAILED DESCRIPTION OF THE INVENTION

[0019] The following description is provided as illustrating the principles of the invention and is not intended to limit the scope of the invention. According to the invention, there is provided a method for preparing a pharmaceutical composition having improved solubility useful in treating CHF in animals, including an active compound and a carboxylic acid, the method including the step of preparing active-coformer co-crystals. In this invention, the active compound is pimobendan and the conformer carboxylic acid is citric acid.

[0020] The pimobendan-coformer co-crystals are prepared by providing the pimobendan component and conformer component in a ratio based on the molecular weights of each component. This ratio of pimobendan to citric acid is between 1 :1 and 2:1 . This is a significant reduction in the pimobendan citric acid ratio compared to what is taught in the prior art.

[0021] The method includes the further steps of lightly grounding together pimobendan and citric acid with a solvent until a paste is formed, leaving the paste to dry, and grounding the dried paste to produce a fine powder of the co-crystals. The solvent used in this instance is ethanol. The grounding takes place in a mortar and pestle or similar.

[0022] Alternatively, the method includes the further steps of forming a mixture of pimobendan and citric acid in a grinding container, closing the mixture in the grinding container, and submerging the container in liquid nitrogen until the liquid nitrogen stops boiling, thereafter allowing the mixture to be co-milled. Preferably, the mixture is co-milled for 10-minute intervals at a frequency of

[0023] 30 Hz per session. Prior to each milling session, the grinding container is submerged in liquid nitrogen. At least three milling sessions are required to produce a fine powder of the co-crystals.

[0024] The co-crystals produced by the above methods show improved solubility in an aqueous medium.

[0025] The co-crystals obtained by the method of this invention are as follows: pimobendan-coformer co-crystals in a ratio between 1 :1 and 2:1 . This may be provided in the form of a pharmaceutical composition.

[0026] Further provided is a method of treating congestive heart failure in an animal in need thereof by administering the co-crystals to the animal.

[0027] Further provided is pimobendan-coformer co-crystals in a ratio between 1 :1 and 2:1 for use in the treatment of congestive heart failure in an animal in need.

[0028] Still further is provided the use of pimobendan-coformer co-crystals in a ratio between 1 :1 and 2:1 in the manufacture of a medicament for treating congestive heart failure in an animal.

[0029] The animal may be a dog. Example of the invention

[0030] In this invention, pimobendan-citric acid co-crystals are prepared by either slurry conversion and solvent evaporation or by co-milling.

[0031] In 2016, the revised guidelines of the FDA described co-crystals as “crystalline materials composed of two or more different molecules within the same crystal lattice associated by non-ionic and non-covalent bonds”.

[0032] Slurry conversion and solvent evaporation:

[0033] Co-crystals were prepared by slurry conversion and solvent evaporation. The ratio of compounds / components used was based on the molecular weight of pimobendan and citric acid The active and citric acid were together lightly ground in a mortar and pestle with ethanol. The paste-like mixture was then left to dry. The dried paste was then ground in a mortar and pestle to produce a fine white powder.

[0034] Co-crystal ball milling (BM):

[0035] Pimobendan and citric acid were mixed and co-milled using a Retsch MM400 (Retsch GmbH & Co, Haan, Germany). A 50 ml steel screw top grinding jar was used, containing two steel balls per jar. The jar was filled with roughly 4 g of the mixture. The mixture / powder was closed inside the grinding jar with the two balls and then submerged in liquid nitrogen until the liquid nitrogen stopped boiling. A milling session consisted of grounding / milling for a duration of 10 minutes at a frequency of 30 Hz. The jar was again submerged in liquid nitrogen before continuing the next grinding session. A total average grinding time of 30 minutes was required to produce a fine white powder of the co-crystals. In this example, the powder was milled at varying ratio’s (pimobendan to citric acid) of between 1 :1 and 2:1.

[0036] Solubility studies

[0037] An excess of powder (i.e., the co-crystal mixture) was placed in various test tubes with screw cap closures. Water was added to each of the test tubes and placed in a water bath at 37SC ± 2SC, fixed to a rotating axis (54 rpm) for a 24 h period while submerged. The subsequent solutions were then filtered through a 0.45 pm Millipore filter and diluted, after which a UV analysis was performed.

[0038] A UV Shimadzu spectrophotometer model 1800 was used for the analyses of the solubility studies. Methanol was used as solvent. Maximum absorbance was obtained at 326.5 nm.

[0039] Solubility results

[0040] Co-crystals prepared by slurry conversion at a 1 :1 ratio resulted in the best solubility results (i.e., 72.4 pg / mL). There is, however, not a statistically significant difference between the pimobendan citric acid co-crystals produced via slurry conversion in the 1 :1 and 2:1 ratio.

[0041] Therefore, in this invention, the solubility of Pimobendan was increased by preparing co-crystals with a ratio of pimobendan to citric acid of between 1 :1 and 2:1 . The 1 :1 (molar ratio) co-crystals presented with the best solubility results.

[0042] This method has the advantage that it is relatively simple to prepare and that the excipients are relatively cheap.

[0043] It will be appreciated that various alternative embodiments are also possible in accordance with the present invention. Furthermore, it will be understood that some advantages of the present invention may be attained by selecting some of the features of the present invention without utilising other features. Accordingly, those skilled in the art will recognise that modifications and adaptations to the present invention may be possible or desirable in certain circumstances and may form part of the present invention.

Claims

CLAIMS1 . A method for preparing a pharmaceutical composition having improved solubility useful in treating CHF in animals, including an active compound selected from the group including pimobendan, the method including the step of preparing co-crystals of the active compound and a coformer component by providing the active compound and coformer component in a ratio based on the molecular weights of each component, wherein the ratio of active compound to coformer component is between 1 :1 and 2:1 .

2. The method of claim 1 , wherein the coformer is carboxylic acid based, selected from the group including, but not limited to fumaric acid, oxalic acid, succinic acid and citric acid.

3. The method of claim 2, including the further steps of lightly grounding together pimobendan and coformer in the presence of a solvent until a paste is formed, leaving the paste to dry, and grounding the dried paste to produce a fine powder of the co-crystals.

4. The method of claim 3, wherein a mortar and pestle or similar is used for the grinding.

5. The method of claim 3, wherein the solvent is selected from the group including ethanol.

6. The method of claim 2, including the further steps of forming a mixture of pimobendan and coformer in a grinding container, enclosing the mixture inthe grinding container, and submerging the container in liquid nitrogen until the liquid nitrogen stops boiling, thereafter allowing the mixture to be co-milled.

7. The method of claim 6, wherein the mixture is co-milled for 10-minute intervals with a frequency of 30 Hz per session.

8. The method of claim 7, wherein, prior to each milling session, the grinding container is submerged in liquid nitrogen.

9. The method of claim 8, wherein at least three milling sessions are required to produce a fine powder of the co-crystals.

10. The method of claim 3 or 9, wherein the solubility of the co-crystals in an aqueous medium range from 27.64 pg / mL to 72.4 pg / mL.1 1. A pharmaceutical composition comprising co-crystals of pimobendan and coformer, wherein the ratio of pimobendan to coformer is 1 :1 and 2:1 .

12. The pharmaceutical composition of claim 1 1 , wherein the coformer is carboxylic acid based, selected from the group including, but not limited to fumaric acid, oxalic acid, succinic acid and citric acid.

13. The pharmaceutical composition of claim 1 1 , wherein the solubility of the co-crystals in an aqueous medium range from 27.64 pg / mL to 72.4 pg / mL14. A method of treating congestive heart failure in an animal in need thereof by administering the pharmaceutical composition of any one of claims 1 1 -13 to the animal.

15. The pharmaceutical composition of any one of claims 11 -13, for use in the treatment of congestive heart failure in an animal in need thereof.

16. Use of the pharmaceutical composition of any one of claims 11 -13, in the manufacture of a medicament for treating congestive heart failure in an animal.

17. The method, pharmaceutical composition or use of any one of claims 14-16, wherein the animal is a dog.

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