EP3236957A1 - Levodopa/carbidopa/entacapone pharmaceutical preparation and method for preparing the same - Google Patents
Levodopa/carbidopa/entacapone pharmaceutical preparation and method for preparing the sameInfo
- Publication number
- EP3236957A1 EP3236957A1 EP14838916.6A EP14838916A EP3236957A1 EP 3236957 A1 EP3236957 A1 EP 3236957A1 EP 14838916 A EP14838916 A EP 14838916A EP 3236957 A1 EP3236957 A1 EP 3236957A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- levodopa
- carbidopa
- entacapone
- amount
- 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.)
- Withdrawn
Links
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 title claims abstract description 30
- 229960003337 entacapone Drugs 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims description 14
- IVTMXOXVAHXCHI-YXLMWLKOSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;(2s)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 IVTMXOXVAHXCHI-YXLMWLKOSA-N 0.000 title claims description 12
- 239000000825 pharmaceutical preparation Substances 0.000 title description 2
- 229960004502 levodopa Drugs 0.000 claims abstract description 31
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims abstract description 30
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims abstract description 30
- QTAOMKOIBXZKND-PPHPATTJSA-N carbidopa Chemical compound O.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 QTAOMKOIBXZKND-PPHPATTJSA-N 0.000 claims abstract description 21
- 229960004205 carbidopa Drugs 0.000 claims abstract description 20
- 229940096516 dextrates Drugs 0.000 claims abstract description 18
- 239000013543 active substance Substances 0.000 claims abstract description 17
- 239000002552 dosage form Substances 0.000 claims abstract description 16
- 239000007787 solid Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 150000004677 hydrates Chemical class 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 50
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 25
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 229960000913 crospovidone Drugs 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 6
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 6
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 238000007908 dry granulation Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 229940069328 povidone Drugs 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 239000007888 film coating Substances 0.000 claims description 3
- 238000009501 film coating Methods 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 239000007941 film coated tablet Substances 0.000 claims description 2
- 238000012545 processing Methods 0.000 claims description 2
- 229940057948 magnesium stearate Drugs 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 23
- 238000009472 formulation Methods 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 9
- 238000003860 storage Methods 0.000 description 8
- 230000007774 longterm Effects 0.000 description 6
- 239000008187 granular material Substances 0.000 description 5
- 229940103422 stalevo Drugs 0.000 description 5
- 238000007580 dry-mixing Methods 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229940126601 medicinal product Drugs 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 150000005846 sugar alcohols Chemical class 0.000 description 3
- 102100038238 Aromatic-L-amino-acid decarboxylase Human genes 0.000 description 2
- 102000006378 Catechol O-methyltransferase Human genes 0.000 description 2
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 235000019759 Maize starch Nutrition 0.000 description 2
- 208000027089 Parkinsonian disease Diseases 0.000 description 2
- 206010034010 Parkinsonism Diseases 0.000 description 2
- 108010035075 Tyrosine decarboxylase Proteins 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 229940000425 combination drug Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 208000015592 Involuntary movements Diseases 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960001425 deferoxamine mesylate Drugs 0.000 description 1
- IDDIJAWJANBQLJ-UHFFFAOYSA-N desferrioxamine B mesylate Chemical compound [H+].CS([O-])(=O)=O.CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN IDDIJAWJANBQLJ-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000012432 intermediate storage Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
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
Landscapes
- 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
Description
Claims
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP2014/003467 WO2016101969A1 (en) | 2014-12-23 | 2014-12-23 | Levodopa/carbidopa/entacapone pharmaceutical preparation and method for preparing the same |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3236957A1 true EP3236957A1 (en) | 2017-11-01 |
Family
ID=52589327
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP14838916.6A Withdrawn EP3236957A1 (en) | 2014-12-23 | 2014-12-23 | Levodopa/carbidopa/entacapone pharmaceutical preparation and method for preparing the same |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP3236957A1 (en) |
WO (1) | WO2016101969A1 (en) |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI109453B (en) | 1999-06-30 | 2002-08-15 | Orion Yhtymae Oyj | Pharmaceutical composition |
CA2540040C (en) * | 2003-10-07 | 2012-09-11 | Andrx Pharmaceuticals Llc | Rapidly disintegrating formulation |
US20060222703A1 (en) | 2005-04-01 | 2006-10-05 | Iprbox Oy | Pharmaceutical composition and preparation method thereof |
-
2014
- 2014-12-23 EP EP14838916.6A patent/EP3236957A1/en not_active Withdrawn
- 2014-12-23 WO PCT/EP2014/003467 patent/WO2016101969A1/en active Application Filing
Non-Patent Citations (2)
Title |
---|
None * |
See also references of WO2016101969A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO2016101969A1 (en) | 2016-06-30 |
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