Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)

Definitions

• the present invention relates to a film coated tablet formulation 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 benidipine has a d (0.9) particle size less than 50 pm. Furthermore, the formulation is obtained using an effective process.
• 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.
• 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. Benidipine was originally disclosed with the application EP63365 B2.
• a film coated tablet comprising benidipine in the form of the free base or in the form of pharmaceutically acceptable salts having has a d (0.9) particle size less than 50 pm is provided. Also, the tablet has been developed by using standard techniques which is simple and cost-effective method.
• the main object of the present invention is to eliminate problems caused by benidipine and bringing additional advantages to the relevant prior art.
• Another object of the present invention is to a film coated tablet comprising benidipine has a d (0.9) particle size less than 50 pm and at least one pharmaceutically acceptable excipient in a formulation providing the desired dissolution profile.
• Another object of the present invention is to provide a formulation which is characterized by excellent pharmacotechnical properties, such as flowability, compressibility and content uniformity.
• 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 dissolution and the desired stability.
• 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.
• 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).
• d (0.9) means, the size at which 90% by volume of the particles are finer.
• d (0.5) means, the size at which 50% by volume of the particles are finer.
• 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 benidipine has a d (0.9) particle size less than 50 pm.
• 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 35 pm, preferably less than 25 pm, preferably less than 18 pm.
• 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.
• 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.
• 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.
• benidipine is in the form of is present as benidipine hydrochloride.
• 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.
• 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.
• 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. It was surprisingly found that when prepared the film coated tablet with at least one suitable filler, it was observed that the desired flowability, compressibility and content uniformity.
• 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.
• the filler is lactose monohydrate.
• 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.
• the amount provides the desired flowability, compressibility and content uniformity.
• 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.
• the binder is polyvinylpyrrolidone.
• 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.
• 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.
• the disintegrant is pregelatinized starch.
• 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.
• 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.
• the lubricant/glidant is magnesium stearate.
• 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.
• 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.
• the coating agents are hydroxypropyl methylcellulose, talc, titanium dioxide, polyethylene glycol.
• the coating agents are lactose monohydrate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, yellow iron oxide, triacetin, ponceau, FD&C Blue.
• the amount of coating agents is 1.0% to 5.0% by weight by weight in the total formulation.
• the film coated tablet comprising benidipine in the form of the free base or in the form of pharmaceutically acceptable salts has a hardness of between 20 N and 70 N. This provides high chemical and mechanical stability, thus it is not brittle easily, but also provides a high dissolution rate and short disintegration time.
• the film coated tablet comprises;
• the film coated tablet comprises;
• 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.
• 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.
• a solvent preferably water
• a process for the preparation of the film coated tablet comprising benidipine comprises the following steps: a) Mixing benidipine hydrochloride having d90 particle size less than 50 pm, 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.
• 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
• Example 2 Film coating tablet
• Example 3 Film coating tablet
• a process for example 1 or 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.

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• Health & Medical Sciences (AREA)
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• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Medicinal Chemistry (AREA)
• Chemical & Material Sciences (AREA)
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• Medicinal Preparation (AREA)

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• 2022
  • 2022-12-10 EP EP22908123.7A patent/EP4447964A4/de active Pending

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