WO2012159593A2 - Formulation orale combinée à libération contrôlée d'acide acétylsalicylique et procédé pour la préparation - Google Patents

Formulation orale combinée à libération contrôlée d'acide acétylsalicylique et procédé pour la préparation Download PDF

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Publication number
WO2012159593A2
WO2012159593A2 PCT/CZ2012/000042 CZ2012000042W WO2012159593A2 WO 2012159593 A2 WO2012159593 A2 WO 2012159593A2 CZ 2012000042 W CZ2012000042 W CZ 2012000042W WO 2012159593 A2 WO2012159593 A2 WO 2012159593A2
Authority
WO
WIPO (PCT)
Prior art keywords
starch
weight
formulation according
granulate
acetylsalicylic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CZ2012/000042
Other languages
English (en)
Other versions
WO2012159593A3 (fr
WO2012159593A9 (fr
Inventor
OIga SAKOVA
Beata Vladovicova
Anna KABZANOVA
Viera Kormanova
Stefan ZORICAK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zentiva KS
Original Assignee
Zentiva KS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva KS filed Critical Zentiva KS
Priority to ROA201300838A priority Critical patent/RO130316A2/ro
Priority to UAA201315213A priority patent/UA111743C2/uk
Publication of WO2012159593A2 publication Critical patent/WO2012159593A2/fr
Publication of WO2012159593A3 publication Critical patent/WO2012159593A3/fr
Publication of WO2012159593A9 publication Critical patent/WO2012159593A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2095—Tabletting processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to combined oral formulations with controlled release of acetylsalicylic acid, comprising the active ingredient acetylsalicylic acid, at least one another active ingredient from the group of non-narcotic analgesics and/or natural psychotropic agents, and to a method for the preparation thereof.
  • An oral dosage form comprising the active ingredients acetylsalicylic acid, paracetamol and caffeine, and a method for the manufacture thereof is described in international application WO 95/07082 A [EGIS Gyogyszergyar RT, HU].
  • the above-specified tablet comprises the combination of the above-mentioned active ingredients in admixture with pharmaceutical excipients, which are polyvinyl butyral) as a binder and low-substitution hydroxypropyl cellulose as a disintegrant.
  • pharmaceutical excipients which are polyvinyl butyral) as a binder and low-substitution hydroxypropyl cellulose as a disintegrant.
  • the tablets show a satisfactory long-term stability in heavy conditions.
  • the manufacture described is based on wet granulation of a mixture of the active ingredients acetylsalicylic acid, paracetamol and caffeine.
  • the mixture of the active ingredients is fluid sprayed with a 96% ethanolic solution of polyvinyl butyral) with stearic acid in the selected ratio.
  • the prepared granulate is fluid dried until a moisture content of the granulate of 0.5%. (The moisture content of the granulate is measured at the conditions of 70°C/30 minutes.)
  • Low-substitution hydroxypropyl cellulose and stearic acid are admixed to the dried and sieved (mesh size 1 mm) granulate. Tablets are compressed from the prepared mixture.
  • stable oral tablets with controlled release of acetylsalicylic acid comprise at least one further active ingredient selected from the group consisting of non-narcotic analgesics and natural psychotropic agents, and by a specific ratio of the excipients, preferably of starch and stearic acid, wherein the ratio of acetylic acid to the mixture of stearic acid and starch is preferably from 2:1 to 10:1.
  • the further active ingredient from the group of non-narcotic analgesics is paracetamol or ibuprofen, the natural psychotropic agent is caffeine.
  • Suitable starches include corn, potato or rice starch, the corn starch having a moisture content of 3% to 20%, preferably of 11% to 18%.
  • stearic acid having a particle size of 1 to 20 ⁇ is used; preferably, 90% of stearic acid has a particle size of from 1 to 20 ⁇ .
  • the amount of starch in the formulation is from 2% by weight to 10% by weight, preferably from, 4% by weight to 5% by weight, and the amount of stearic acid is from 1% by weight to 5% by weight, preferably from 1.5% by weight to 3% by weight.
  • the combined oral formulation in a preferred embodiment, comprises acetylsalicylic acid in an amount of from 25% to 40% by weight, preferably from 30% to 40% by weight, paracetamol in an amount of from 25% to 40% by weight, preferably from 30% to 40% by weight, and caffeine from 4% to 15% by weight, preferably from 7% to 8 % by weight.
  • the combined oral formulation is prepared by a simple, not demanding, technological process, not requiring any special manufacturing facilities for granulation, without necessity of enhanced safety modifications of the workspace and equipment.
  • stearic acid the substance responsible for the achieved effect, i.e. prolonged release of acetylsalicylic acid and the pharmaceutical excipients starch and lactose used in various premixes, by their mutual weight ratios and by their technological processing, compression into tablets produces the desired release profile of acetylsalicylic acid and a long-term stable product.
  • the oral tablets prepared by the method of the invention, comply with the stability requirement of a formulation comprising a combination of the active ingredients acetylsalicylic acid, at least one further active ingredient from the group of nonnarcotic analgesics and/or natural psychotropic agents, with the desired release profile of acetylsalicylic acid, without the necessity of any further treatment, e.g., by coating the tablets with a film coat.
  • the manufacture of combined oral tablets substantially consists in preparation of premixes of the individual active ingredients.
  • the manufacture of an acetylsalicylic premix in principle comprises simple mixing of acetylcsalicylic acid and the pharmaceutical excipients, stearic acid and starch, in a specific ratio, moisturizing the mixture during mixing, drying, sieving, and final blending until a visually homogeneous mixture is formed.
  • the manufacture of a paracetamol premix in principle comprises simple mixing of paracetamol and the pharmaceutical excipient (preferably corn starch), moisturizing the mixture with a starch paste until formation of the required structure of the granulation material, drying the same and modification of the particle size of the granulate.
  • the pharmaceutical excipient preferably corn starch
  • the manufacture of a caffeine triturate in principle comprises simple mixing of caffeine and the pharmaceutical excipient, preferably lactose, followed by blending the resulting mixture with starch.
  • the pharmaceutical excipient preferably lactose
  • the final tabletting blend is prepared by mixing of the individual active ingredients premixes with addition of a glidant facilitating the flowability of the tabletting blend and formation of pressings having the desired weight, strength and friability, which are chemically and physically stable for a sufficiently long period of time and can be filled into commonly used pharmaceutical packages without any problems.
  • the combined oral formulation with controlled release of acetylsalicylic acid comprises, in addition to the three active ingredients - acetylsalicylic acid, paracetamol and caffeine -, pharmaceutically acceptable excipients, namely:
  • the profile of release of the acetylsalicylic acid active ingredient from a therapeutic composition, prepared according to the present invention can be set up to the requirements by the ratio of stearic acid and starch in the acetylsalicylic premix. Further, it has been surprisingly found that acetylsalicylic acid, which undergoes hydrolysis, can be granulated with purified water without decomposition thereof and, moreover, it has been found that acetylsalicylic acid can be stabilized by mixing with stearic acid.
  • the manufacture of a solid therapeutic formulation according to the present invention substantially consists in mixing, in a high-speed pharmaceutical homogenizer for wet homogenization, paracetamol together with a starch, preferably with a starch having a moisture content of from 3% to 25%, in an amount of from 5% to 20% by weight.
  • the said mixture is gradually moisturized with a starch paste, wherein starch amounts to 10% to 50% by weight of said paste.
  • the mixture is shortly mixed until a granulate is formed.
  • the prepared granulate is dried by the chamber, fluidized, vacuum or microwave radiation method, preferably in fluidized state to obtain a final moisture content between 0.1% and 2.0% by weight. Temperatures of the product during drying should be 35°C to 45°C, preferably 39°C to 41°C.
  • the dried granulate is treated to obtain particle sizes compliant with the tabletting process and homogenized. After complete homogenization the mixture can be used for a tabletting process.
  • a caffeine triturate is admixed to the previously prepared paracetamol granulate, an acetylsalicylic acid granulate and silicon oxide are admixed to the resulting mixture and the final blend is tabletted in rotatory tabletting machines to pressings which have a break resistance of from 20 N to 90 N, preferably from 35 N to 75 N and a disintegration of from 30 seconds to 2 minutes and 30 seconds.
  • the tablets can be of a flat rounded, lens rounded, oval or other shape, with possible presence of a break line or logo on one or both surfaces of the tablet.
  • the thus manufactured tablets can be filled into commonly applicable packages destined for pharmaceutical products, preferably into blister packages constituted by PVC/PVdC combination heat-shapable foil and an aluminum foil coated with an adhesive material.
  • Figure 1 Dissolution profile of acetylsalicylic acid processed in a granulate without stearic acid (acetate buffer pH 4.5; 500 ml; 50 rpm).
  • Figure 2 Dissolution profile of acetylsalicylic acid processed in a granulate with stearic acid (acetate buffer pH 4.5; 500 ml; 50 rpm).
  • Example 1 Tablet composition composition of acetylsalicylic granulate % by weight
  • Acetylsalicylic acid is mixed with corn starch and stearic acid having a particle size up to 100 ⁇ in a pharmaceutical granulator of a suitable type.
  • the resulting mixture is then gradually moisturized with purified water until a granulate forms.
  • the latter is transferred into the receptacle of a fluid dryer and dried under slight fluidization at the temperature of the inlet air of 41°C, until the temperature of the granulate reaches 40°C, which indicates completion of the drying process.
  • the dried granulate is then subjected to sizing through an oscillating screen with mesh of 1.0 mm, followed by homogenizing in a homogenizer.
  • Paracetamol is mixed with corn starch in a pharmaceutical granulator of a suitable type.
  • the resulting mixture is then gradually moisturized with corn paste until a granulate forms.
  • the latter is transferred into the receptacle of a fluid dryer and dried under slight fluidization at the temperature of the inlet air of 55 - 60°C, until the temperature of the granulate reaches 42°C.
  • the dried granulate is then subjected to sizing through an oscillating screen with mesh of 1.25 mm and, subsequently, it is transferred into the receptacle of a fluid dryer and dried until the moisture content of the granulate reaches 1.5 %, measured at 90°C/30 minutes.
  • Caffeine is mixed with lactose in a low-speed homogenizer of a suitable type.
  • the triturate is subjected to sizing through an oscillating screen with mesh of 0.8 mm. Corn starch is added to the sieved triturate.
  • the required amounts of the premixes of the individual active ingredients are homogenized in a low-speed homogenizer by dry homogenization with addition of a glidant, which is silicon oxide.
  • composition is prepared for tabletting in rotatory tabletting machines to pressings containing the desired three active ingredients, having satisfactory content uniformity of caffeine, break resistance and disintegration.
  • the following table shows the values of free salicylic acid, measured during storage in various stress conditions. Free salicylic acid is formed as a degradation product of acetylsalicylic acid by the action of hydrolysis.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention a pour objet une formulation pharmaceutique solide orale combinée à libération contrôlée d'acide acétylsalicylique, qui comprend au moins un autre principe actif choisi dans le groupe des analgésiques non narcotiques et/ou des agents psychotropes naturels, et de l'acide stéarique et de l'amidon en tant qu'excipients dans un rapport spécifique, et un procédé pour sa préparation.
PCT/CZ2012/000042 2011-05-25 2012-05-24 Formulation orale combinée à libération contrôlée d'acide acétylsalicylique et procédé pour la préparation Ceased WO2012159593A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
ROA201300838A RO130316A2 (ro) 2011-05-25 2012-05-24 Formulare orală combinată cu eliberare controlată a acidului acetilsalicilic şi procedeu pentru prepararea acesteia
UAA201315213A UA111743C2 (uk) 2011-05-25 2012-05-24 Комбінована пероральна композиція з контрольованим вивільненням ацетилсаліцилової кислоти і спосіб її одержання

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SK5028-2011A SK50282011A3 (sk) 2011-05-25 2011-05-25 Controlled acetylsalicylic acid release combined peroral preparation and method for the production thereof
SKPP5028-2011 2011-05-25

Publications (3)

Publication Number Publication Date
WO2012159593A2 true WO2012159593A2 (fr) 2012-11-29
WO2012159593A3 WO2012159593A3 (fr) 2013-01-17
WO2012159593A9 WO2012159593A9 (fr) 2013-03-07

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ID=46513601

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2012/000042 Ceased WO2012159593A2 (fr) 2011-05-25 2012-05-24 Formulation orale combinée à libération contrôlée d'acide acétylsalicylique et procédé pour la préparation

Country Status (5)

Country Link
CZ (1) CZ20131028A3 (fr)
RO (1) RO130316A2 (fr)
SK (1) SK50282011A3 (fr)
UA (1) UA111743C2 (fr)
WO (1) WO2012159593A2 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007082A1 (fr) 1993-09-10 1995-03-16 EGIS Gyógyszergyár Rt. Comprime comprenant plusieurs ingredients dont l'acide acteylsalicylique, et son procede de preparation

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3239506A (en) * 1964-10-16 1966-03-08 Eastman Kodak Co 3-azabicyclo[3.2.2]nonane sulfonamide compounds
US4505862A (en) * 1981-04-14 1985-03-19 Bristol-Myers Company Diphenydramine dihydrogencitrate
WO2009022821A2 (fr) * 2007-08-13 2009-02-19 Hanall Pharmaceutical Company. Ltd Préparation combinée contenant un inhibiteur de hmg-coa reductase et aspirine et son procédé d'élaboration
WO2010081722A2 (fr) * 2009-01-16 2010-07-22 Add Technologies Ltd. Comprimés à désintégration orale pour traiter la douleur

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007082A1 (fr) 1993-09-10 1995-03-16 EGIS Gyógyszergyár Rt. Comprime comprenant plusieurs ingredients dont l'acide acteylsalicylique, et son procede de preparation

Also Published As

Publication number Publication date
CZ20131028A3 (cs) 2014-01-29
UA111743C2 (uk) 2016-06-10
WO2012159593A3 (fr) 2013-01-17
SK50282011A3 (sk) 2013-02-04
RO130316A2 (ro) 2015-06-30
WO2012159593A9 (fr) 2013-03-07

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