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
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • 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
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • 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
  • A61K9/2009—Inorganic compounds
• • 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
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • 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
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• the present invention relates to a novel stable pharmaceutical composition in the form of a sustained release coated tablet comprising an active ingredient, carbomer and pharmaceutically acceptable excipients with a release profile that is precisely regulated by the parameters of the coating process, the use of carbomer for manufacturing the tablet and the process of coating the tablet using a water-based coating suspension.
• the active ingredient is preferably selected from the group consisting of Indapamide and Tramadol or pharmaceutically acceptable salts thereof.
• Indapamide is a compound indicated for the treatment of hypertension and is used as sole therapy or with other antihypertensive agents. Indapamide and the process for manufacturing thereof was described in GB 1203691.
• Tramadol is an analgesic used as sole therapy or in combination with other active ingredients. Tramadol and the process for manufacturing thereof was described in US 3,652,589.
• Indapamide or Tramadol is direct compression. See, EP 1057479, EP 800384, EP 519820,
• carbomer as a sustained release agent in a formulation prepared by direct compression provides a stable tablet, which release profile can be precisely regulated by the parameters of the coating process employing a water-based coating suspension.
• the present invention provides a process for obtaining a sustained release tablet with a desired release profile, comparable to the reference product.
• the tablet according to the invention comprises an active substance, preferably Indapamide, Tramadol or any pharmaceutically acceptable salt thereof, carbomer as a sustained release agent and pharmaceutically acceptable excipients and is coated with a water-based coating suspension.
• an active substance preferably Indapamide, Tramadol or any pharmaceutically acceptable salt thereof, carbomer as a sustained release agent and pharmaceutically acceptable excipients and is coated with a water-based coating suspension.
• compositions include, but are not limited to, extended release-matrix formers, diluents, glidants and lubricants.
• the present invention provides the use of carbomer for preparing sustained release tablets according to the invention.
• Carbomer is a pharmaceutical excipient used mainly for obtaining semisolid dosage forms. Combining carbomer with an extended release-matrix former in solid state unexpectedly results in obtaining suitable for direct compression tabletting mass with exceptional features.
• Carbomer has a relatively very small particle size (2 - 7 ⁇ m) comparing to high-molecular weight extended release-matrix formers, therefore they suit together well and compose direct compression tabletting mass with flowability much greater than those of tabletting masses comprising polymers typically used for preparing sustained release dosage forms. Compression of the tabletting mass according to the invention results in obtaining a matrix tablet swelling very evenly when contacted with water. Additionally, the release profile of the active ingredient from the tablet is independent of the tablet's hardness, and thus also of the compression force applied due to the small particle size of carbomer, which prevents it from fragmentation during compression.
• Sustained release coated tablet according to the invention comprises carbomer in an amount of 10 to 30% by weight.
• the carbomer is Carbopol 974P NF Polymer (Noveon).
• Extended release-matrix former according to the invention, is present in the composition in an amount of 10 to 40% and is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, povidone, Eudragit NE, Eudragit RS and mixtures thereof.
• the extended release-matrix former is hydroxypropyl cellulose.
• Sustained release coated tablet according to the invention comprises the active ingredient in an amount of 0,6 to 40% by weight.
• a premix of the active ingredient with diluent may be employed to afford dosage content uniformity.
• Diluent is present in the composition in an amount of 10 to 70% and is selected from the group consisting of dedicated for direct compression technology lactose, dibasic calcium phosphate, sucrose and mannitol.
• the diluent is DC lactose, e.g., commercially available DCL-11, Flowlac.
• Sustained release coated tablet according to the invention comprises glidants.
• a mixture of talc and colloidal anhydrous silica is employed as the glidant.
• the use of said mixture of glidants greatly contributes to the flowability of the tabletting mass.
• the coated tablet comprises further pharmaceutically acceptable excipients, for instance lubricants, e.g., magnesium stearate, stearic acid.
• lubricants e.g., magnesium stearate, stearic acid.
• Example 1 Composition of a stable sustained release tablet comprising Indapamide according to the invention is given in Example 1. Manufacturing process for a batch size of 304 kg (1 600 000 tablet cores) is given in Example 2.
• Example 1 Composition of a stable sustained release tablet comprising Indapamide according to the invention.
• Indapamide (2,44 kg) was pre-mixed with lactose DCL-I l (151,96 kg) in a 800-litre bin mixer for 1 hour at the speed of 18 rpm. Subsequently, the blended material was placed in a 1200-litre bin mixer. Next, lactose DCL-Il (43,5 kg), Klucel HXF (59,74 kg), Carbopol 974P NF Polymer (38,456 kg), Aerosil 200 (1,52 kg) and talc (1,824 kg) were added and the material was blended for 1 hour at the speed of 12 rpm. Finally, magnesium stearate (4,56 kg) was added and the material was blended for 10 minutes at the speed of 12 rpm. Thus obtained mixture was compressed into 190 mg tablet cores using a rotary tabletting machine equipped with 8 mm diameter biconvex punches.
• composition of a stable sustained release tablet comprising Tramadol according to the invention and process for manufacturing thereof are given respectively in Examples 3 and 4.
• composition of a stable sustained release tablet comprising Tramadol according to the invention.
• Aerosil 200 (0,072 kg), talc (0,108 kg) and dibasic calcium phosphate (3,54 kg) were blended in a 50-litre bin mixer for 1 hour at the speed of 12 rpm.
• magnesium stearate (0,18 kg) was added and the material was blended for 5 minutes at the speed of 12 rpm.
• mixture was compressed into 600 mg tablet cores using a rotary tabletting machine equipped with 15,5 x 8,5 mm elongated punches.
• the invention also relates to the coating process of the sustained release tablet comprising an active ingredient, carbomer and pharmaceutically acceptable excipients using a water-based coating solution.
• the water present in the coating solution penetrates the core of the tablet and causes the matrix composed of carbomer and extended release-matrix former to swell.
• the water evaporates from the tablets forming micropores.
• the release profile of the active ingredient from the tablet is directly dependent on the amount of micropores formed in the tablet core during the coating process.
• variable parameters of the coating process are coating suspension feeding rate, air inlet temperature and air flow rate, and their values depend on the type, size and brand of the perforated coating pan used for the process and the amount of tablet cores placed into the perforated coating pan.
• Coating of the tablet cores employing appropriate parameters of the process according to the invention allows for obtaining a coated tablet with any desirable release profile at the same level or higher than the release profile of the uncoated core.
• the value ranges for the parameters of the coating process that regulate the release profile of the active ingredient from the coated tablet are given below:
• Indapamide SR tablets with a release profile that is comparable to the reference product for a batch size of 304 kg (1 600 000 tablet cores, 190 mg each) performed in a perforated coating pan Glatt GCl 500 using water-based coating solution Opadry 33G24509 are given in Example 5.
• the coating process resulted in obtaining sustained release Indapamide coated tablets characterised by total mass of 195 mg and the release of the active ingredient at 95% within 24 hours.
• the release profile of the tablet, which is comparable to the reference product, and the release profile of the uncoated tablet core (71% within 24 h) are presented in Fig. 1.
• the coating process according to the invention allows for obtaining a coated tablet with any desirable release profile at the same level or higher than the release profile of the uncoated core.
• the parameters of the coating process affording Indapamide SR coated tablets which release 89% of the active ingredient within 24 hours are given in
• the coating process resulted in obtaining sustained release Indapamide coated tablets characterised by total mass of 192,5 mg and the release of the active ingredient at 89% within 24 hours.
• the release profile of the coated tablet and the release profile of the uncoated tablet core (71 % within 24 h) are presented in Fig. 2.
• Stability tests were performed for the sustained release coated tablet comprising Indapamide as presented in Example 1, prepared according to the method described in Example 2 and coated employing the process parameters presented in Example 5. The results of the tests are given below.
• said coated tablet is also characterised by very good physical properties, i.e. friability at 0,00% and hardness in the range from 50 to 150 N.
• the parameters of the coating process of Tramadol SR tablet cores prepared according to the method described in Example 4 using Opadry 33G24509 water-based coating suspension composed of 0,45 kg Opadry 33G24509 and 1,55 kg purified water in a perforated coating pan Glatt GMPC2 are given below.
• sustained release Tramadol HCl coated tablets are stable and have very good physical properties, i.e. friability at 0,00% and hardness in the range from 110 to 120 N.

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• Bioinformatics & Cheminformatics (AREA)
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• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2006
  • 2006-06-02 PL PL379831A patent/PL204780B1/pl unknown
• 2007
  • 2007-06-01 WO PCT/PL2007/000036 patent/WO2007142546A2/en active Application Filing
  • 2007-06-01 EP EP07747745A patent/EP2023904A2/en not_active Withdrawn

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