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WO2007113371A1 - Préparation pharmaceutique et méthode d'élaboration de ladite préparation - Google Patents

Préparation pharmaceutique et méthode d'élaboration de ladite préparation Download PDF

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Publication number
WO2007113371A1
WO2007113371A1 PCT/FI2006/050119 FI2006050119W WO2007113371A1 WO 2007113371 A1 WO2007113371 A1 WO 2007113371A1 FI 2006050119 W FI2006050119 W FI 2006050119W WO 2007113371 A1 WO2007113371 A1 WO 2007113371A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
carbidopa
levodopa
entacapone
excipients
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/FI2006/050119
Other languages
English (en)
Inventor
Giovanni Politi
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.)
IPRBOX Oy
Original Assignee
IPRBOX Oy
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 IPRBOX Oy filed Critical IPRBOX Oy
Priority to PCT/FI2006/050119 priority Critical patent/WO2007113371A1/fr
Publication of WO2007113371A1 publication Critical patent/WO2007113371A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/205—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention relates to a new pharmaceutical composition and to a new method for the preparation of such a composition. More particularly, the invention relates to a new oral solid pharmaceutical composition comprising entacapone, levodopa and carbidopa or a pharmaceutically acceptable salt or hydrate thereof.
  • the pharmaceutical compositions of the invention are useful in the therapy of Parkinson's disease.
  • Levodopa and carbidopa are the most commonly used drugs in the treatment of Parkinson's disease.
  • Levodopa and carbidopa are commercially available as a combination tablet, e.g., under the trademarks NACOM ® , ISICOM ® , SINEMET ® and SINEMET ® LP 25, all distributed by DuPont Pharma, UK.
  • WO 01/01984 discloses an oral solid pharmaceutical composition comprising levodopa, carbidopa and entacapone and a pharmaceutically acceptable excipient, wherein carbidopa is separated from entacapone and levodopa. In that way, the bioavailability of carbidopa was reported to increase. It is further stated in the publication that bioavailability of carbidopa is significantly affected by a method of preparing of the composition. Both wet and dry granulations of the three active agents are suggested but the wet granulation is preferred.
  • the publication teaches away from compaction granulation (dry granulation) by stating that when compaction granulation is used, large amounts of excipients are needed to obtain compressible granules and tablets having the desired, fast, dissolution behaviour of an immediate release formulation. Further, it is reported that when compaction granulation is used for preparing a fixed dose combination tablet containing levodopa, carbidopa and en- tacapone, the tablets became too large in size, especially for patients who have difficulties in swallowing. Moreover, the formulations prepared by compaction granulation of said publication are not acceptable because of poor stability.
  • absorption-desorption recessarily occur which are generated when the composition comprises very dry agents, like entacapone and levodopa, and hygroscopic agents, like starch, closed together. These Coopera have a significant negative influence on the stability of the composition.
  • the additional water needed during the wet granulation of the composition as described in the above publication, generates strong bonds be- tween the different substances of the composition.
  • the dissolution of levodopa, carbidopa and entacapone is negatively influenced by the additional water.
  • the Applicant has found that additional water gives rise to moisture balance problems in the pharmaceutical compositions described in WO 01/01984 thus deteriorating the stability of the compositions.
  • the active agents In the treatment of parkinsonism, it is highly desirable that the active agents, entacapone, levodopa and carbidopa or a pharmaceutically acceptable salt or hydrate thereof, are released from the oral composition as soon as possible after the intake. It is also highly desirable that the absorption of the three different active agents from one and the same oral solid composition corresponds to that of a commercial available entacapone tablet and that of a levodopa-carbidopa tablet in gastrointestinal tract. However, it is very challenging to adjust the absorption of three different active agents.
  • compositions of the present invention are their small size, fast disintegration and dissolution, and bioequivalency with the most common commercial compositions of levodopa-carbidopa and entacapone. Moreover, the compositions of the present invention are easy to coat and show good stability characteristics. Advantages of the method of the invention are good stability and velocity of the manufacturing and saving of costs due to the need of smaller amounts of source materials and to the simplicity of the production equipment involved.
  • the invention is based on the idea that by choosing appropriate pharmaceutical acceptable excipients for the pharmaceutical oral solid composition the above mentioned advantages can be achieved.
  • compositions of the present invention are stable on a long-term storage due to the absent of additional water brought to the tablets by manufacturing method thereof.
  • the present invention provides an oral solid pharmaceutical composition
  • an oral solid pharmaceutical composition comprising pharmacologically effective amounts of entacapone, levodopa and carbidopa, or a pharmaceutically acceptable salt or hydrates thereof, and one or more pharmaceutically acceptable excipients, wherein the excipients are long-chain polymers having an equilibrium moisture content of at least 2%.
  • the long-chain polymeric compounds useful in the composition of the present invention include, e.g., microcrystalline cellulose and starch.
  • Starch is preferably maize starch. In a preferred embodiment of the invention, maize starch is used as an excipient. Further, in a preferred embodiment of the invention, the equilibrium moisture content of the excipients is at least 3.5%.
  • the equilibrium moisture content of microcrystalline cellulose and maize starch is in the range of 4 to 5% and 4 to 9%, respectively. Hydrogen bonds necessary to hold the composition of the invention together are mainly formed by the naturally existing water brought to the composition by the excipient(s) used.
  • the equilibrium moisture content of the excipients used in the present invention is measured by a weight-loss method described in Euro- pean Pharmacopoeia, 4 th edition 2002, page 48.
  • the total amount of the excipients in the composition of the invention is at most 40%, preferably 10 to 35%, based on the dry weight of the composition.
  • the total moisture content of the composition of the invention must be at least 1 wt%, preferably 2 to 3 wt%.
  • the total moisture content T is a theoretical value calculated according to an equation given below:
  • the pharmacologically effective amounts of entacapone, levodopa and carbidopa, or a pharmaceutically acceptable salt or hydrate thereof, in the composition of the present invention can all be in the range of those already existing in the market worldwide.
  • the amounts of said active agents depend on numerous factors known to one skilled in the art, such as the severity of the condition of the patient, the desired duration of use, etc.
  • the amount of entacapone in the composition of the invention can vary in the range of 25 to 400 mg, preferably 25 to 300 mg, more preferably 50 to 200 mg, most preferably 200 mg.
  • the amount of levodopa can vary in the range of 25 to 300 mg, more preferably 50 to 250 mg.
  • the amount of carbidopa can vary in the range of 5 to 75 mg, more preferably 10 to 50 mg.
  • An oral solid composition of the present invention can thus contain, e.g., 200 mg of entacapone, 100 mg of levodopa and 25 mg of carbidopa, or 200 mg of entacapone, 150 mg of levodopa and 37.5 mg of carbidopa.
  • the oral solid compositions of the present invention can con- tain a suitable conventional binder and/or lubricant in amounts known in the art.
  • suitable lubricants useful in the present invention include, e.g. magnesium stearate, calcium stearate, hydrogenated vegetable oil, talc. etc.
  • magnesium stearate is used.
  • the amount of the lubricant can vary in the range of 0.5% to 1.5%.
  • An oral solid pharmaceutical composition of the present invention can exist in variety of shapes, like in tablets and capsules.
  • the composition of the invention is in the form of tablets, preferably in oval form.
  • a solvent-free method method of preparing an oral solid pharmaceutical composition comprising pharmacologically effective amounts of entacapone, levodopa and carbidopa, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable excipients
  • which comprises a) simultaneous mixing of pharmaceutically effective amounts of entacapone, levodopa and carbidopa, or a pharmaceutically acceptable salt or hydrate thereof, together with at least one pharmaceutically acceptable excipi- ent which are ong-chain polymers having an equilibrium moisture content of at least 2% to obtain a first mixture, b) granulating the first mixture to obtain granules, if necessary; c) adding a lubricant to the first mixture of step a) or to the granules of step b) to obtain a second mixture; d) formulating the second mixture into an oral solid composition; and e) if desired, coating the composition obtained in step d
  • the method of the invention is preferably a compaction granulation.
  • the oral solid compositions of the invention are preferably coated in order to improve the stability of the composition and to avoid undesirable discoloration in the mouth. Coating is easy to carry out since no disin- tegrants are needed in the composition of the invention. Coating can be performed by using as coating agents those conventional in the art, like HPMC- coating. [0021]
  • the mixing step before granulation can be conducted, e.g. in a high shear mixter of in a fluiduzed bed, but preferably in a tumbler mixer in a manner known in the art.
  • the method of the present invention it is possible to prepare formulations which are substantially smaller in size than the prior art formulations.
  • the weight of the formulation of the invention usually varies in the range of about 350 mg to 530 mg.
  • Disintegration of the formulations of the present invention was tested by a method described in European Pharmacopoeia, 4 th edition 2002, page 191 by means of a standard Erweka dissolution tester.
  • the formulations 1 to 4 of the present invention are described below.
  • a tablet prepared according to WO 01/01984 and SINEMET ® and COMTAN ® tablets were also tested.
  • Times given for dissolution of the formulations of the present invention are estimated values. Estimation is made taking into account various ingredients included in the compositions, manufacturing method and disintegration times of the composition. Estimation can be regarded as justified, since disintegration time of the formulations of the invention corresponds to that of SINEMET ® and COMTAN ® tablets and the particle size of the active agents are equal in the compositions of the invention and in SINEMET ® and COMTAN ® tablets. [0025] It can be seen that the dissolution and disintegration of the tablets of the present invention is significantly better that those of the prior art formulation.
  • compositions containing entacapone, levodopa and carbidopa were formulated into tablets as follows: Entacapone, levodopa and carbidopa were mixed together with one or more excipients used, compacted and granulated. A lubricant is then added to the granules obtained. After the final mixing, the bulk was pressed into tablets.
  • the above formulation has the following characteristics: weight: 473 mg, moisture content: ca. 2.2 %, hardness: 5.2-7.8 kp, compac- tability: good, tabletability: good, flowability: good.
  • the above formulation has the following characteristics: weight: 533 mg, moisture content: ca. 3.1 %, hardness: 8.9-11.4 kp, compac- tability: good, tabletability: good, flowability: good.
  • the above formulation has the following characteristics: weight: 431 mg, moisture content: ca. 2.0%, hardness: 4.5-6.2 kp, compac- tability: good, tabletability: good, flowability: good.
  • Carbidopa (monohydr. respond. Carbidopa 25.0 mg) 27.00 mg
  • the above formulation has the following characteristics: weight: 452 mg, moisture content: ca. 2.3 %, hardness: 5.6-7.9 kp, compac- tability: good, tabletability: good, flowability: good.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une préparation pharmaceutique solide à administration orale comprenant des quantités pharmacologiquement actives d'entacapone, de lévodopa et de carbidopa, ou un sel ou hydrate de qualité pharmaceutique desdits composés, ainsi qu'un ou plusieurs excipients de qualité pharmaceutique, lesdits excipients étant des polymères à longue chaîne présentant une teneur en humidité à l'équilibre d'au moins 2 %. La présente invention concerne également une méthode d'élaboration de ladite préparation. De telles préparations peuvent être employées dans le traitement de la maladie de Parkinson.
PCT/FI2006/050119 2006-03-31 2006-03-31 Préparation pharmaceutique et méthode d'élaboration de ladite préparation Ceased WO2007113371A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/FI2006/050119 WO2007113371A1 (fr) 2006-03-31 2006-03-31 Préparation pharmaceutique et méthode d'élaboration de ladite préparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/FI2006/050119 WO2007113371A1 (fr) 2006-03-31 2006-03-31 Préparation pharmaceutique et méthode d'élaboration de ladite préparation

Publications (1)

Publication Number Publication Date
WO2007113371A1 true WO2007113371A1 (fr) 2007-10-11

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FI2006/050119 Ceased WO2007113371A1 (fr) 2006-03-31 2006-03-31 Préparation pharmaceutique et méthode d'élaboration de ladite préparation

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Country Link
WO (1) WO2007113371A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2540465C2 (ru) * 2008-08-22 2015-02-10 Вокхардт Рисерч Сентер Фармацевтическая композиция энтакапона или его солей пролонгрированного высвобождения

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253490A1 (fr) * 1986-06-16 1988-01-20 Merck & Co. Inc. Association carbidopa-levodopa à libération contrôlée
WO2000015196A1 (fr) * 1998-09-14 2000-03-23 Orion Corporation Composition pharmaceutique comprenant une entacapone ou nitecapone, de meme qu'un derive de cellulose reticule
WO2001001984A1 (fr) * 1999-06-30 2001-01-11 Orion Corporation Preparation pharmaceutique a base de levodopa/carbidopa/entacapone
US20040166159A1 (en) * 2002-05-29 2004-08-26 Chien-Hsuan Han Pharmaceutical dosage forms having immediate and controlled release properties that contain an aromatic amino acid decarboxylase inhibitor and levodopa

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253490A1 (fr) * 1986-06-16 1988-01-20 Merck & Co. Inc. Association carbidopa-levodopa à libération contrôlée
WO2000015196A1 (fr) * 1998-09-14 2000-03-23 Orion Corporation Composition pharmaceutique comprenant une entacapone ou nitecapone, de meme qu'un derive de cellulose reticule
WO2001001984A1 (fr) * 1999-06-30 2001-01-11 Orion Corporation Preparation pharmaceutique a base de levodopa/carbidopa/entacapone
US20040166159A1 (en) * 2002-05-29 2004-08-26 Chien-Hsuan Han Pharmaceutical dosage forms having immediate and controlled release properties that contain an aromatic amino acid decarboxylase inhibitor and levodopa

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"brochures Direct compression and Wet granulation, Cargill Cerestar BVBA", CERESTAR FOOD & PHARMA SPECIALTIES EUROPE, 2004 *
KIBBE A.H.: "Handbook of Pharmaceutical Excipients", vol. 3RD ED., 2000, AMERICAN PHARMACEUTICAL ASSOCIATION, pages: 103,525 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2540465C2 (ru) * 2008-08-22 2015-02-10 Вокхардт Рисерч Сентер Фармацевтическая композиция энтакапона или его солей пролонгрированного высвобождения

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