A film coated tablet formulation comprising benidipine

Abstract

The present invention relates to a film coated tablet comprises benidipine in the form of the free base or in the form of pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, wherein the tablet has a hardness of between 20 N and 70 N. Furthermore, the formulation is obtained using an effective process.

Description

[0001] A FILM COATED TABLET FORMULATION COMPRISING BENIDIPINE

[0002] Field of the Invention

[0003] The present invention relates to a film coated tablet comprises benidipine in the form of the free base or in the form of pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, wherein the tablet has a hardness of between 20 N and 70 N. Furthermore, the formulation is obtained using an effective process.

[0004] Background of the Invention

[0005] Benidipine has the formula 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine- dicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester hydrochloride. It is a synthetic dihydropyridine derivative that has anti-hypertensive and anti-anginal actions. It is a triple L-, T-, and N-type calcium channel blocker. The only calcium antagonist that can inhibit all the three Ca channels mentioned. Furthermore, benidipine has highly affinity with cell membrane, has vascular selectivity and renal protection effect. Therefore, it is an ideal, safe and effective agent for the treatment of hypertension and renal parenchymal hypertension and angina. Benidipine has the following chemical structure of Formula I.

[0006] Formula I: Benidipine

[0007] Benidipine is a class II drug in the BCS classification, that is, poorly water soluble. For poorly soluble drugs, its dissolution is the rate-limiting process of absorption, and is often the most important factor affecting its bioavailability. It is very soluble in formic acid, freely soluble in dimethylformamide, soluble in methanol or ethanol, slightly soluble in acetic anhydride. Furthermore, benidipine HCI presents in low amounts in the formulation so, excessive use of excipients and incompatibilities between them can adversely affect compressibility. The problem can cause also flowability and content uniformity.

[0008] Benidipine was originally disclosed with the application EP63365 B2. In this invention, to overcome these problems mentioned above, a film coated tablet comprising benidipine in the form of the free base or in the form of pharmaceutically acceptable salts having has a hardness of between 20 N and 70 N. Also, the tablet has been developed by using standard techniques which is simple and cost-effective method.

[0009] Detailed Description of the Invention

[0010] The main object of the present invention is to eliminate problems caused by benidipine and bringing additional advantages to the relevant prior art.

[0011] Another object of the present invention is to provide a film coated tablet having a hardness of between 20 N and 70 N comprising benidipine in the form of the free base or in the form of pharmaceutically acceptable salts which is characterized by the desired compressibility and the desired dissolution rate and short disintegration time.

[0012] Another object of the present invention is to provide a formulation which is characterized by excellent pharmacotechnical properties, such as flowability and content uniformity.

[0013] Another object of the present invention is to obtain an effective process for the preparation of a film coated tablet formulation comprising benidipine which has the desired compressibility and the desired dissolution.

[0014] Hardness test was done with Erweka Tablet Hardness Tester.

[0015] According to one embodiment of the invention, a film coated tablet comprises benidipine in the form of the free base or in the form of pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, wherein the tablet has a hardness of between 20 N and 70 N. This hardness provides the desired compressibility thus it is not brittle easily, but also provides a high dissolution rate and short disintegration time.

[0016] Tablets of lower hardness (<20 N) were observed to dissolve very quickly in the first minutes. It was observed that tablets with higher hardness (>70 N) could not be broken, so there were problems in dissolution. Thereof, It has been found that the specified values create a suitable condition for the tablet comprising benidipine.

[0017] According to this embodiment of the present invention, benidipine is in the form of is present as benidipine hydrochloride. According to one embodiment of the present invention, the amount of benidipine hydrochloride is between 1.0% and 10.0% by weight in the total formulation. Preferably, it is between 1.0% and 6.0% by weight in the total formulation.

[0018] According to one embodiment of the invention, a film coated tablet comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, disintegrants, lubricants / glidants, coating agents or mixtures.

[0019] Suitable fillers are selected from the group comprising lactose monohydrate, microcrystalline cellulose, lactose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.

[0020] According to one embodiment of the present invention, the filler is lactose monohydrate.

[0021] According to one embodiment of the present invention, the amount of fillers is between 70.0% and 88.0% by weight in the total formulation. Preferably, it is between 74.0% and 85.0% or between 77.0% and 83.0% by weight in the total formulation.

[0022] Suitable binders are selected from the group comprising polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, natural gums, sucrose, sodium alginate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, alginate, alginic acid, xanthan gum, hyaluronic acid, polysaccharides, carbomer, poloxamer, polyacrylamide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.

[0023] According to one embodiment of the present invention, the binder is polyvinylpyrrolidone.

[0024] According to one embodiment of the present invention, the amount of binders is between 2.0% and 15.0% by weight in the total formulation. Preferably, it is between 2.5% and 10.0% or between 3.0% and 8.0% by weight in the total formulation.

[0025] Suitable disintegrants are selected from the group comprising pregelatinized starch, crospovidone, croscarmellose sodium, starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, low substituted hydroxypropyl cellulose, sodium alginate, corn starch, sodium starch glycolate, sodium glycine carbonate or mixtures thereof.

[0026] According to one embodiment of the present invention, the disintegrant is pregelatinized starch.

[0027] According to one embodiment of the present invention, the amount of disintegrants is between 3.0% and 15.0% by weight in the total formulation. Preferably, it is between 5.0% and 12.0% or between 6.0% and 10.0% by weight in the total formulation.

[0028] Suitable lubricants / glidants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, talc, colloidal silicon dioxide, corn, calcium stearate, zinc stearate, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, stearic acid, fumaric acid, glyceryl palmito sulphate or mixtures thereof.

[0029] According to one embodiment of the present invention, the lubricant / glidant is magnesium stearate.

[0030] According to one embodiment of the present invention, the amount of lubricant / glidant is between 0.1% and 3.0% by weight in the total formulation. Preferably, it is between 0.5% and 2.0% by weight in the total formulation.

[0031] Suitable coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, talc, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, glycerine, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), ponceau, iron oxides, pigments, dyes, titanium dioxide, triacetin, coloring agent or mixtures thereof.

[0032] According to an embodiment of the present invention, the coating agents are hydroxypropyl methylcellulose, talc, titanium dioxide, polyethylene glycol.

[0033] According to an embodiment of the present invention, the coating agents are lactose monohydrate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, yellow iron oxide, triacetin, ponceau, FD&C Blue.

[0034] According to an embodiment of the present invention, the amount of coating agents is 1.0% to 5.0% by weight by weight in the total formulation. Benidipine in the form of the free base or in the form of pharmaceutically acceptable salts having the following particle sizes is important for formulation. Especially, it positively affects the dissolution properties. The obtained tablets have the desired dissolution profile.

[0035] As used here in, ‘particle size’ means the cumulative volume size distrubition as tested by any conventionally accepted method such as the laser diffraction method (i.e. malvern analysis). The term d (0.9) means, the size at which 90% by volume of the particles are finer. The term d (0.5) means, the size at which 50% by volume of the particles are finer.

[0036] According to this embodiment of the present invention, benidipine in the form of the free base or in the form of pharmaceutically acceptable salts has a d (0.5) particle size less than 30 pm, preferably less than 25 pm, preferably less than 20 pm, preferably less than 15 pm, preferably less than 10 pm.

[0037] According to this embodiment of the present invention, benidipine in the form of the free base or in the form of pharmaceutically acceptable salts has a d (0.5) particle size between 1 pm and 10 pm.

[0038] According to this embodiment of the present invention, benidipine in the form of the free base or in the form of pharmaceutically acceptable salts has a d (0.9) particle size less than 50 pm, preferably less than 35 pm, preferably less than 25 pm, preferably less than 18 pm.

[0039] According to this embodiment of the present invention, benidipine in the form of the free base or in the form of pharmaceutically acceptable salts has a d (0.9) particle size between 3 pm and 18 pm.

[0040] According to one embodiment of the present invention, the film coated tablet comprises;

[0041] - Benidipine hydrochloride

[0042] - Lactose mo no hydrate

[0043] - Polyvinylpyrrolidone

[0044] According to one embodiment of the present invention, the film coated tablet comprises;

[0045] - Benidipine hydrochloride

[0046] - Lactose mo no hydrate

[0047] - Pregelatinized starch

[0048] - Polyvinylpyrrolidone

[0049] - Magnesium stearate According to one embodiment of the present invention, the film coated tablet is obtained by using a wet granulation method therefore, a simple and low-cost production method was employed. Wet granulation process efficiently counteracts segregation, so it can achieve good dissolution and disintegration properties. In the process, when a granulation solution is prepared with at least one binder and a solvent (preferably water), it was observed that the desired content uniformity is provided. Especially, the problem caused by the use of small amounts of benidipine has been prevented by the wet granulation comprising suitable excipients and steps.

[0050] According to one embodiment of the present invention, a process for the preparation of the film coated tablet comprising benidipine comprises the following steps: a) Mixing benidipine hydrochloride, at least one filler and at least one disintegrant and then sieving, b) Dissolving at least one binder in water, c) Granulating the mixture at step (a) with the granulation solution at step (b), d) Sieving the wet granule and drying the wet granule at fluid bed dryer, e) Sieving the dry granule, f) Adding at least one lubricant / glidant and then mixing, g) Compressing the prepared mixture to form tablets h) Coating these tablets with coating agents.

[0051] According to one embodiment of the present invention, a process for the preparation of the film coated tablet comprising benidipine comprises the following steps: a) Mixing benidipine hydrochloride, lactose monohydrate and pregelatinized starch and then sieving, b) Dissolving polyvinylpyrrolidone in water, c) Granulating the mixture at step (a) with the granulation solution at step (b), d) Sieving the wet granule and drying the wet granule at fluid bed dryer, e) Sieving the dry granule, f) Adding magnesium stearate and then mixing, g) Compressing the prepared mixture to form tablets h) Coating these tablets with coating agents. Example 1: Film coating tablet

[0052] Example 2: Film coating tablet Example 3: Film coating tablet

[0053] A process for example 2 or 3; a) Mixing benidipine hydrochloride, lactose monohydrate and pregelatinized starch and then sieving, b) Dissolving polyvinylpyrrolidone in water, c) Granulating the mixture at step (a) with the granulation solution at step (b), d) Sieving the wet granule and drying the wet granule at fluid bed dryer, e) Sieving the dry granule, f) Adding magnesium stearate and then mixing, g) Compressing the prepared mixture to form tablets h) Coating these tablets with coating agents.

Claims

9CLAIMS1. A film coated tablet comprising benidipine in the form of the free base or in the form of pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, wherein the tablet has a hardness of between 20 N and 70 N.

2. The film coated tablet according to claim 1, wherein benidipine is in the form of is present as benidipine hydrochloride.

3. The film coated tablet according to claim 1, wherein the amount of benidipine hydrochloride is between 1.0% and 10.0% by weight in the total formulation.

4. The film coated tablet according to claim 1, wherein at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, binders, disintegrants, lubricants / glidants, coating agents or mixtures.

5. The film coated tablet according to claim 4, wherein fillers are selected from the group comprising lactose monohydrate, microcrystalline cellulose, lactose, mannitol, spray- dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.

6. The film coated tablet according to claim 5, wherein the filler is lactose monohydrate.

7. The film coated tablet according to claim 5, wherein the amount of fillers is between 70.0% and 88.0% by weight in the total formulation.

8. The film coated tablet according to claim 4, wherein binders are selected from the group comprising polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, natural gums, sucrose, sodium alginate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, alginate, alginic acid, xanthan gum, hyaluronic acid, polysaccharides, carbomer, poloxamer, polyacrylamide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.

9. The film coated tablet according to claim 4, wherein disintegrants are selected from the group comprising pregelatinized starch, crospovidone, croscarmellose sodium, starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose,calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, low substituted hydroxypropyl cellulose, sodium alginate, corn starch, sodium starch glycolate, sodium glycine carbonate or mixtures thereof. The film coated tablet according to claim 9, wherein the disintegrant is pregelatinized starch. The film coated tablet according to claim 1, wherein benidipine in the form of the free base or in the form of pharmaceutically acceptable salts has a d (0.5) particle size less than 30 pm, preferably less than 25 pm, preferably less than 20 pm, preferably less than 15 pm, preferably less than 10 pm. The film coated tablet according to claim 1, wherein benidipine in the form of the free base or in the form of pharmaceutically acceptable salts has a d (0.9) particle size less than 50 pm, preferably less than 35 pm, preferably less than 25 pm, preferably less than 18 pm. The film coated tablet according to claim 1, wherein the film coated tablet comprising;- Benidipine hydrochloride- Lactose mo no hydrate- Polyvinylpyrrolidone A process for the preparation of the film coated tablet comprising benidipine comprises the following steps: a) Mixing benidipine hydrochloride, at least one filler and at least one disintegrant and then sieving, b) Dissolving at least one binder in water, c) Granulating the mixture at step (a) with the granulation solution at step (b), d) Sieving the wet granule and drying the wet granule at fluid bed dryer, e) Sieving the dry granule, f) Adding at least one lubricant / glidant and then mixing, g) Compressing the prepared mixture to form tablets h) Coating these tablets with coating agents.

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