WO2016101969A1 - Préparation pharmaceutique de lévodopa/carbidopa/entacapone et son procédé de préparation - Google Patents

Préparation pharmaceutique de lévodopa/carbidopa/entacapone et son procédé de préparation Download PDF

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Publication number
WO2016101969A1
WO2016101969A1 PCT/EP2014/003467 EP2014003467W WO2016101969A1 WO 2016101969 A1 WO2016101969 A1 WO 2016101969A1 EP 2014003467 W EP2014003467 W EP 2014003467W WO 2016101969 A1 WO2016101969 A1 WO 2016101969A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
levodopa
carbidopa
entacapone
amount
Prior art date
Application number
PCT/EP2014/003467
Other languages
English (en)
Inventor
Evangelos Karavas
Efthymios Koutris
Vasiliki SAMARA
Ioanna Koutri
Anastasia Kalaskani
Andreas KAKOURIS
George GOTZAMANIS
Original Assignee
Pharmathen S.A.
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 Pharmathen S.A. filed Critical Pharmathen S.A.
Priority to EP14838916.6A priority Critical patent/EP3236957A1/fr
Priority to PCT/EP2014/003467 priority patent/WO2016101969A1/fr
Publication of WO2016101969A1 publication Critical patent/WO2016101969A1/fr

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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
    • A61K31/185—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
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • 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; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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 belongs to the technical field of pharmaceutical dosage form preparation.
  • it relates to a pharmaceutical composition comprising a combination of Levodopa / Carbidopa / Entacapone or pharmaceutically acceptable salts or hydrates thereof and manufacturing process for the preparation of the composition above.
  • Levodopa Parkinson's disease (PD) is a chronic and progressive neurodegenerative condition associated with considerable morbidity and social and economic consequences. Levodopa is the most effective treatment for the symptoms of PD. No other medial or surgical intervention has been shown to provide better antiparkinsonian efficacy. Levodopa is chemically designated as (-)-3-(3, 4-dihydroxyphenyl)-L-alanine-3-hydroxy-L-tyrosine and represented by FORMULA (I).
  • Chronic Levodopa therapy is associated with the development of potentially disabling motor complications, such as fluctuations in the motor response, involuntary movements, dyskinesias, which can result in disability and have a significant impact on a patient's quality of life.
  • Levodopa-associated motor complications are a result of high dosage and the non-continuous delivery of Levodopa to the brain.
  • Levodopa is metabolized mainly by two enzymes: dopa decarboxylase (DDC) and catechol O- methyltransferase (COMT).
  • DDC dopa decarboxylase
  • COMP catechol O- methyltransferase
  • a fixed dose combination of Levodopa/Entacapone/Carbidopa is currently marketed under the tradename of Stalevo ® by Novartis Pharmaceuticals Corporation, which is a pharmacokinetically (PK) optimized Levodopa formulation that peripherally inhibits both of the main pathways of Levodopa metabolism.
  • PK profile of Levodopa with dual enzyme inhibition is markedly improved, increasing the half-life of Levodopa by up to 85% and the bioavailability of the drug by 35% in plasma.
  • the active pharmaceutical ingredients in Stalevo ® in addition to Levodopa, are Carbidopa monohydrate, is which is chemically known as (aS)-a-hydrazino-3, 4-dihydroxy-a-methyl benzene propanoic acid monohydrate and represented by FORMULA (II), as a DDC- inhibitor, and
  • Entacapone which is chemically known as (E)-2-cyano-3-(3, 4-dkhydroxy-5-nitrophenyl)-N, N-diethyl-2-propenamide and represented by FORMULA (III), as a COMT-inhibitor.
  • EP 1189608 B 1 provides an oral solid pharmaceutical composition of Levodopa / Carbidopa / Entacapone combination, characterized in that substantial portion of Carbidopa is separated from Entacapone and Levodopa.
  • Said composition comprises at least one pharmaceutically acceptable excipient being a sugar alcohol or starch, or a sugar alcohol and starch, wherein the preferred sugar alcohol is mannitol and the preferred starch is maize starch.
  • an object of the present invention to provide an oral solid pharmaceutical composition comprising a combination of Levodopa / Carbidopa / Entacapone, or pharmaceutically acceptable salts or hydrate thereof, in which the dissolution profile of each active agent is comparable to that of the reference product Stalevo®.
  • Further object of the present invention is to provide an oral solid pharmaceutical composition comprising combination of Levodopa / Carbidopa / Entacapone, or pharmaceutically acceptable salts or hydrate thereof, which is stable under long-term storage.
  • An additional object of the present invention is to provide a method for the preparation of the composition described above.
  • the process for the preparation of a solid pharmaceutical dosage form comprising Levodopa, Entacapone, Carbidopa as active agents comprises the steps of:
  • step (3) processing the mixture obtained in step (3) into the desired dosage form.
  • Parkinsonism medication needs to be taken several times a day to keep the patients without symptoms.
  • the frequent medicament uptake and poor patient compliance let to fixed dose combination film-coated tablets of Levpdopa / Entacapone / Carbidopa as a replace dosage regime of Entacapone and Levovodopa / Carbidopa separate tablets. This is especially important for Parkinsonism patients with tremor and old age.
  • dissolution tests are conventionally used to identify formulation factors that may have an effect on the bioavailability of the drug.
  • the dissolution test can be used to demonstrate bioequivalence by determining the similarity factor ⁇ .
  • An fi value between 50 and 100 suggests that the two dissolution profiles are similar. Therefore, dissolution studies can serve several purposes, including quality control of scale-up and of production batches to ensure batch-to-batch consistency and that the dissolution profiles remain similar to those pivotal clinical trial batches.
  • the inventors of the present application have surprisingly found that effective control of the dissolution profiles of three active agents, namely Levodopa, Entacapone, Carbidopa or pharmaceutically acceptable salts or a hydrate thereof, in a single solid pharmaceutical composition can be achieved with the present invention.
  • dextrates in the pharmaceutical composition of the present invention stabilizes the dosage of form in terms of undesirable impurities that could potentially affect the pharmacological result as well as the health of the patient. Furthermore, dextrates made possible to include in the composition other common pharmaceutically acceptable excipients such as microcrystalline cellulose that prior art considered as causing stability problems and degradation of the active pharmaceutical substances.
  • the amount of dextrates in the composition of the present invention has been found to be effective in an amount of from 10% to 30% w/w of the total weight of the composition.
  • the dry granulation process present herein comprises two main steps of dry mixing. The presence of dextrates allows the mixing of Carbidopa together with Entacapone and Levodopa which was unacceptable so far since the APIs were considered incompatible.
  • the method is characterized in that the active agents are divided in two portions, each portion is granulated separately and subsequently the two granules are mixed together.
  • these two compositions are referred as PART-A and PART-B.
  • PART-A comprises dry granulation of approximately 20% by weight of the total amount of Levodopa in the composition, 90% by weight of the total amount by weight of Entacapone in the composition, 70% to 80% of by weight of the total amount of dextrates in the composition and other optional pharmaceutically acceptable excipients.
  • the granules are micronized to the desired particle size range by conventional methods known in the art, such as milling, grinding, etc.
  • PART-B comprises dry granulation of the remaining amounts of Levodopa, Entacapone, dextrates, the total amount of Carbidopa and other optional pharmaceutically acceptable excipients.
  • the two parts of the composition are dry granulated together with excipients of external phase and then formulated in the desired dosage form.
  • the tablets can be optionally coated with a film coating in a mount of 2% to 5% of the total weight of the composition.
  • Excipients should be chosen carefully in order to provide optimized pharmacotechnical and physicochemical properties but mainly not to promote degradation of the active pharmaceutical ingredients. Sometimes, it is preferred to select excipients that promote stability of the active agents during long-term storage. It is suggested in the literature that thioether compounds, such as methionine, glutathione, thioglycerol, sodium thiosulfate, and metal chelators, such as disodium ethylene-diamine-tetra-acetate (EDTA), deferoxamine mesylate, stabilize the Carbidopa molecule. The inventors of the present application examined the stabilization effect of a number of the above mentioned compounds in composition comprising Carbidopa molecule.
  • EDTA disodium ethylene-diamine-tetra-acetate
  • the current composition comprises dextrates in an amount of from 10% to 30% w/w, crospovidone in an amount of from 0.5% to 4% w/w, povidone in an amount of from 5% to 15% w/w, macrocrystalline cellulose in an amount of from 5% to 25% w/w and magnesium stearate in an amount of from 0.5% to 3% w/w of the total weight of the composition.
  • an improved solid pharmaceutical dosage form comprising Levodopa/Entacapone/Carbidopa, or pharmaceutically acceptable salts or hydrates thereof.
  • a combination of formulating process is also developed for the preparation of solid pharmaceutical dosage form of the present invention.
  • the main advantages of the current formulation are excellent stability of the dosage form during long- term storage and fine-tuned dissolution profiles which provide therapeutic efficacy comparable to those of Stalevo®.
  • Example 1 Solid dosage forms were prepared in accordance with the preferred embodiments of the present invention.
  • the process for manufacturing the dosage forms of tables 1 and 2 below was:
  • Tablets were prepared in all marketed dose strengths, i.e. 50 (75, 100, 125, 150, 175, 200)/12.5 (18.75, 25, 31.25, 37.5, 43.75, 50)/200 of Levodopa/Carbidopa/Entecapone respectively.
  • the dosage forms were prepared in logic of keeping the tablets' total weight below 950mg. This value was considered essential since it could potentially enhance patient compliance.
  • a tablet over lOOOmg would be relatively large in size and could present less appealing to any patient to take.
  • a size over 500mg would result in a tablet of enough tablet size for a patient suffering from Parkinson disease to be able to hold and administer by himself.
  • Table 2 Tablets prepared following a relatively constant amount of excipients
  • compositions are tested for their dissolution profiles.
  • the results of all the above formulations were comparable with the dissolution profile of Stalevo ® . Additionally, all formulation had adequate hardness, disintegration and flowability

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

Abstract

La présente invention concerne une forme posologique pharmaceutique solide comprenant un mélange de lévodopa/entacapone/carbidopa, ou des sels ou des hydrates pharmaceutiquement acceptables associés, caractérisée en ce que les agents actifs sont stabilisés avec des dextrates.
PCT/EP2014/003467 2014-12-23 2014-12-23 Préparation pharmaceutique de lévodopa/carbidopa/entacapone et son procédé de préparation WO2016101969A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP14838916.6A EP3236957A1 (fr) 2014-12-23 2014-12-23 Préparation pharmaceutique de lévodopa/carbidopa/entacapone et son procédé de préparation
PCT/EP2014/003467 WO2016101969A1 (fr) 2014-12-23 2014-12-23 Préparation pharmaceutique de lévodopa/carbidopa/entacapone et son procédé de préparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2014/003467 WO2016101969A1 (fr) 2014-12-23 2014-12-23 Préparation pharmaceutique de lévodopa/carbidopa/entacapone et son procédé de préparation

Publications (1)

Publication Number Publication Date
WO2016101969A1 true WO2016101969A1 (fr) 2016-06-30

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PCT/EP2014/003467 WO2016101969A1 (fr) 2014-12-23 2014-12-23 Préparation pharmaceutique de lévodopa/carbidopa/entacapone et son procédé de préparation

Country Status (2)

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EP (1) EP3236957A1 (fr)
WO (1) WO2016101969A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1189608B1 (fr) 1999-06-30 2003-07-23 Orion Corporation Preparation pharmaceutique a base de levodopa/carbidopa/entacapone
US20050112196A1 (en) * 2003-10-07 2005-05-26 Jianbo Xie Rapidly disintegrating formulation
US20060222703A1 (en) 2005-04-01 2006-10-05 Iprbox Oy Pharmaceutical composition and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1189608B1 (fr) 1999-06-30 2003-07-23 Orion Corporation Preparation pharmaceutique a base de levodopa/carbidopa/entacapone
US20050112196A1 (en) * 2003-10-07 2005-05-26 Jianbo Xie Rapidly disintegrating formulation
US20060222703A1 (en) 2005-04-01 2006-10-05 Iprbox Oy Pharmaceutical composition and preparation method thereof

Also Published As

Publication number Publication date
EP3236957A1 (fr) 2017-11-01

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