A stable prolonged release tablets of sodium valproate and valproic acid

Abstract

A stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising sodium valproate and valprioic acid with no granulating solvent is disclosed, further comprising low viscosity polymer, high viscosity polymer, binder, adsorbent and glidant. A process for the preparation of said orally administrable prolonged release tablet is also disclosed.

Description

[0001] A STABLE PROLONGED RELEASE TABLETS OF SODIUM VALPROATE AND VALPROIC ACID RELATED PATENT APPLICATIONS

[0002] This application claims priority to and benefit of the Indian Patent Application No. 202421052226 filed on July 08, 2024, the disclosures of which are incorporated herein by reference in its entirety as if fully rewritten herein.

[0003] Field of the invention

[0004] The present invention relates generally to a stable oral pharmaceutical composition of sodium valproate and valprioic acid, a process for preparing such composition. The present invention relates particularly to a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising sodium valproate and valprioic acid with no granulating solvent and process of preparing the same.

[0005] Background of the invention

[0006] Valproic acid and sodium valproate are drugs useful for the treatment of epileptic seizures or convulsions. Valproic acid is a liquid at room temperature and thus is not suitable for manufacture of solid pharmaceutical dosage forms such as tablets for oral administration. Sodium valproate is the sodium salt of valproic acid. It is a solid at room temperature and does not melt even at substantially higher temperatures. It is thus more suitable than valproic acid for manufacture of solid dosage forms. However, sodium valproate is highly hygroscopic and readily absorbs water from the atmosphere, which leads to problems of poor stability of compositions made from sodium valproate. US5185159A describes new pharmaceutical composition based on valproic acid and one of the pharmaceutically acceptable salts thereof, obtained by a new galenic preparation process which makes it possible to improve and simplify the galenic production, this composition also contains excipients which favourably modify its kinetics and its bioavailability. US5019398A describes a sustained-release anti-epileptic pharmaceutical composition based on valproic acid. It discloses sodium valproate sustained-release tablets, but the sustained- release time of the sodium valproate sustained-release preparation is only 8 hours, and the release speed is quite fast.

[0007] It is thus desirable to have a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising sodium valproate and valprioic acid, with a stability and bioequivalence comparable to reference product.

[0008] Summary of the invention

[0009] The present inventors have surprisingly found that, the orally administrable prolonged release tablet composition of sodium valproate and valprioic acid which is free of granulating solvent and comprising of low and high viscosity of hypromellose is bioequivalent to reference product and has similar stability like reference product. Notably, said composition is obtained by scalable and reproducible manufacturing process.

[0010] In one of the aspects of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising sodium valproate and valprioic acid with no granulating solvent; wherein the composition further comprises low viscosity polymer, high viscosity polymer, binder, adsorbent and glidant. In one of the aspects of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising the low viscosity polymer, which is hypromellose having viscosity from 2663 to 4970 mPa.s.

[0011] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising the high viscosity polymer, which is hypromellose having viscosity from 75000 to 140000 mPa.s.

[0012] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising the binder, which is ethylcellulose of viscosity from 6 to 8 mPa.s

[0013] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising the adsorbent and glidant, which is hydrated silica.

[0014] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet, wherein the composition further comprises suitable film forming agent.

[0015] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet as stable as marketed product used as reference product.

[0016] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet bioequivalent with marketed product used as reference product. In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet, wherein the composition is manufactured by wet granulation method without using granulating solvent.

[0017] In another aspect of the invention is provided a stable granulating solvent free orally administrable prolonged release tablet pharmaceutical composition comprising:

[0018] (a) Sodium valproate,

[0019] (b) valproic acid,

[0020] (c) Hypromellose of viscosity from 2663 to 4970 mPa.s,

[0021] (d) Hypromellose of viscosity from 75000 to 140000 mPa.s,

[0022] (e) Ethylcellulose of viscosity from 6 to 8 mPa.s , and

[0023] (f) Hydrated silica.

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] Reference will now be made to the exemplary embodiments, and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise.

[0026] The invention discloses a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising sodium valproate and valprioic acid with no granulating solvent; wherein the composition further comprises low viscosity polymer, high viscosity polymer, binder, adsorbent and glidant.

[0027] Viscosity is a term used to describe the "thickness" of different liquids. Viscosity of a polymer solution depends on concentration and size (i.e., molecular weight) of the dissolved polymer. In one embodiment, the low viscosity polymer as described herein is hypromellose having viscosity from 2663 to 4970 mPa.s. In another embodiment, the high viscosity polymer as described herein is hypromellose having viscosity from 75000 to 140000 mPa.s.

[0028] The term “binder” as used herein refers to polymeric materials which are included into tablet formulations to improve the cohesion and plasticity of the powder mixture, which enhances the processability of the tablet and reduces the risk of tablet breakage during manufacture. In one embodiment, the binder as described herein is ethylcellulose of viscosity from 6 to 8 mPa.s.

[0029] The term “glidant” as used herein refers to a substance that is added to a powder to improve its flowability and an adsorbent is a solid substance used to collect solute molecules from a liquid or gas. In one embodiment, the adsorbent and glidant as described herein is hydrated silica.

[0030] In one of the aspects of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising sodium valproate and valprioic acid with no granulating solvent; wherein the composition further comprises low viscosity polymer, high viscosity polymer, binder, adsorbent and glidant.

[0031] In one of the aspects of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising the low viscosity polymer, which is hypromellose having viscosity from 2663 to 4970 mPa.s. In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising the high viscosity polymer, which is hypromellose having viscosity from 75000 to 140000 mPa.s.

[0032] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising the binder, which is ethylcellulose of viscosity from 6 to 8 mPa.s

[0033] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising the adsorbent and glidant, which is hydrated silica.

[0034] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet, wherein the composition further comprises suitable film forming agent.

[0035] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet as stable as marketed product used as reference product.

[0036] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet bioequivalent with marketed product used as reference product.

[0037] In another aspect of the invention is provided a stable pharmaceutical composition in the form of orally administrable prolonged release tablet, wherein the composition is manufactured by wet granulation method without using granulating solvent. In another aspect of the invention is provided a stable granulating solvent free orally administrable prolonged release tablet pharmaceutical composition comprising:

[0038] (a) Sodium valproate,

[0039] (b) valproic acid,

[0040] (c) Hypromellose of viscosity from 2663 to 4970 mPa.s,

[0041] (d) Hypromellose of viscosity from 75000 to 140000 mPa.s,

[0042] (e) Ethylcellulose of viscosity from 6 to 8 mPa.s , and

[0043] (f) Hydrated silica.

[0044] While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

[0045] EXAMPLES

[0046] The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.

[0047] The pharmaceutical compositions according to invention are formulated as Prolonged Release Tablets. Table 1 provides the compositions according to the invention. Table 1: Composition details of Prolonged Release Tablets according to present invention.

[0048] Note:

[0049] Quantity based on 100 % assay and nil LOD.

[0050] **Quantity of Silica Colloidal Hydrated (Syloid 244 FP) compensated for the actual quantity of Sodium Valproate taken in order to keep the tablet weight constant.

[0051] $ Evaporates during drying. Does not remain in the finished product except in traces

[0052] Brief Manufacturing process:

[0053] 1) Binder preparation: Ethylcellulose added very slowly into Valproic acid under stirring and continued stirring until it becomes clear.

[0054] 2) Sifting and mixing: Sifted Sodium Valproate, Silica colloidal hydrated and Hypromellose (Methocel E4M premium CR) through 30# and transferee! into rapid mixer granulator (RMG) and mixed for 5 minutes by keeping impeller at slow speed and chopper off. ) Granulation: Binder solution was added slowly into RMG by keeping impeller at slow speed and chopper off with intermittent raking of the wet mass during binder addition. Continued granulation for further 1 to 2 minutes by keeping both impeller and chopper at fast speed. ) Semi-drying: Dried the wet mass in pre-warmed fluidized bed dryer (FBD) at set inlet temperature of 50°C to 55°C for 5 to 10 minutes. ) Milling: Milled semidried granules through 1.5 mm using Multimill at knives forward direction at 500 to 1500 RPM speed. ) Drying: Dried the milled granules in fluidized bed dryer (FBD) at set inlet temperature of 50°C to 55°C till desired LOD is achieved (LOD: less than 3.5 % w / w at 85°C after 10 minutes using moisture analyser). ) Sifting of extragranular raw materials: Sifted Hypromellose (Methocel E4M premium CR), Hypromellose (Methocel K100M premium DC2) and Silica colloidal hydrated through 30#. ) Sifting of milled granules: Sifted the milled granules through 18# before blending process. ) Blending: Transferred approximately 50% sifted granules of step 8 into double cone blender followed by step 7 sifted materials and then remaining 50% of sifted granules and mixed blend for 10 minutes at 16+1 RPM. 0) Compression: Compress the lubricated blend using suitable size punches. 1) Coating : Isopropyl alcohol was added in Purified water and mixed well with stirring. Added slowly Opadry OY-S-6705 in IPA and water solution with stirring. Continued stirring for at least 1 hour or till the homogeneous dispersion is formed. Coated the core tablets to target weight gain in coating machine using coating solution at inlet temperature 55°C to 75°C and bed temperature 35°C to 55°C. After coating dried the tablets for 15 to 20 minutes at 50°C to 65°C and checked the LOD of coated tablets. (LOD: less than 5.0 % w / w at 85°C after 10 minutes. Table 2: Comparative dissolution of Reference product and test product in 0.1N HCI

[0055] Table 3: Comparative dissolution of Reference product and test product in pH 4.5 Acetate buffer Table 4: Comparative dissolution of Reference product and test product in pH 6.8 Phosphate buffer

[0056] Table 5: Bioequivalence Results of 500 mg Tablets

[0057] Conclusion: Above study results of 500mg strength indicates that the presently claimed prolonged release tablet product is bioequivalent with reference product.

[0058] Stability results:

[0059] The composition according to invention was tested for stability up to 24 months at a temperature of 25°C and at the relative humidity of 60% (± 5 %). The results of the stability studies are provided in Table 6.

[0060]

[0061] Impurity K = 2 -Ethyl-2 -methylpentanoic Acid

[0062] Based on the data presented in Table 6, the composition is stable.

Claims

We Claim:

1. A stable pharmaceutical composition in the form of orally administrable prolonged release tablet comprising sodium valproate and valprioic acid with no granulating solvent; wherein the composition further comprises low viscosity polymer, high viscosity polymer, binder, adsorbent and glidant.

2. The pharmaceutical composition according to claim 1, wherein low viscosity polymer is hypromellose having viscosity from 2663 to 4970 mPa.s.

3. The pharmaceutical composition according to claim 1, wherein the high viscosity polymer is hypromellose having viscosity from 75000 to 140000 mPa.s.

4. The pharmaceutical composition according to claim 1, wherein the binder is used as ethylcellulose of viscosity from 6 to 8 mPa.s5. The pharmaceutical composition according to claim 1, wherein the adsorbent and glidant is hydrated silica.

6. The pharmaceutical composition according to claim 1, wherein the composition further comprises suitable film forming agent.

7. The pharmaceutical composition according to claim 1, wherein the composition is as stable as marketed product used as reference product.

8. The pharmaceutical composition according to claim 1, wherein the composition is bioequivalent with marketed product used as reference product.

9. The pharmaceutical composition according to claim 1, wherein the composition is manufactured by wet granulation method without using granulating solvent.

10. A stable granulating solvent free orally administrable prolonged release tablet pharmaceutical composition comprising:(a) Sodium valproate,(b) valproic acid,(c) Hypromellose of viscosity from 2663 to 4970 mPa.s,(d) Hypromellose of viscosity from 75000 to 140000 mPa.s,(e) Ethylcellulose of viscosity from 6 to 8 mPa.s, and(f) Hydrated silica.

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