AU611512B2 - Synergistic combination of decarboxylase inhibitors and l- dopa pellets - Google Patents
Synergistic combination of decarboxylase inhibitors and l- dopa pellets Download PDFInfo
- Publication number
- AU611512B2 AU611512B2 AU27582/88A AU2758288A AU611512B2 AU 611512 B2 AU611512 B2 AU 611512B2 AU 27582/88 A AU27582/88 A AU 27582/88A AU 2758288 A AU2758288 A AU 2758288A AU 611512 B2 AU611512 B2 AU 611512B2
- Authority
- AU
- Australia
- Prior art keywords
- dopa
- pellets
- salt
- physiologically acceptable
- base
- 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
Links
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- 239000003954 decarboxylase inhibitor Substances 0.000 title claims abstract description 45
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical compound CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 description 1
- 229940093635 tributyl phosphate Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 150000005691 triesters Chemical class 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229940117958 vinyl acetate Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Abstract
A synergistic combination of L-dopa pellets and decarboxylase inhibitors as pharmaceuticals for Parkinson's disease.
Description
611512 S F Ref: 79253 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE: Class Int Class Complete Specification Lodged: Accepted: Published: Priority: Related Art: Name and Address of Applicant: ASTA-Pharma Aktiengesellschaft Weismullerstrasse D-6000 Frankfurt am Main 1 FEDERAL REPUBLIC OF GERMANY Address for Service: Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Complete Specification for the invention entitled: Synergistic Combination of Decarboxylase Inhibitors and L-dopa Pellets m- The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/3 Abstract: Synergistic combination of L-dopa pellets and decarboxylase inhibitors as a medicament against Parkinson's disease.
00 0 0 0 0 o 0 0 00 0 0 0 0 0 0 00 0 000 0 00 0 0 0 0 00 00 00 0 00 0-000 00 a 0. 00 0.0 0q 0 0 0 .0 Syegsi/obiaino earoyaeihbiosadLdp 0Snrgsi cobntino ecarboxylase inhibitors wihmybusdaeenradeLdp the prerty to block eriphral ecarboxhylrazie] (tat iso 0 00 04 00 -hydrazino-3,4-dihydroxy--O(-methyl-hydrocinnamic acid), 0 O L-serine-2-(2,3,4-trihydroxybenzyl)-hydrazide, 00 00 glycine-2- 4-trihydroxybenzyl -hydrazide, L-tyrosine-2- (2,3,4-trihydroxybenzyl)hydrazide, in particular 0 benserazide.
0 0 ~0 0 q L-dopa ((S)-2-amino-3-(3,4--dihydroxyphenyl)propionic acid] is o 00 a medically active substance with pronounced antiparkinsonian 0 0 00 activity.
0 0 The combination of the decarboxylase inhibitor ben! erazide and T,-dopa has been known since 1980. The L-dopa was no present in pellet form in this case. This formulation has the disadvantage that, when used in the treatment of Parkinson's disease, this combination lead-- to severe fluctuations in plasma level andI thus to considerable response fluctuations, for example to 00 a 0 o0 0 o 0 0 0 0 0 00 o O 00 0 o 0 000 0 0 0 0 0 0 00 0 0 0 0 00 000 0 0o 0 00 o 00 0 o00 0 00 O 0 o o Q 0 0 ao oo o oo o o 0 0 2 so-called on-off symptoms (particularly in later stages 'if the illness), whereby the patient is suddenly overcome by immobility.
For a long time now there has therforea been a need for an improved dosage form with prolonged action with which for example, the on-off symptoms are reduced (see E M, Stahl, New Drug Delivery Systems a new approach to Parkinson's disease, Symposium Harlow/GB 8.7.1985).
The object of the invention is therefore the preparation of an improved medicament composed of decarboxylase inhibitors and L-dopa with prolonged and improved effect for the treatment of Parkinson's disease.
It has now surprisingly beei. found that with the use of a combination of decarboxylase inhibitors and L-dopa pellets, wherein the pellets cin also demonstrate a delayed release (a so-called retardation) of the active substance, a prolonged and improved effect may be observed in the treatment of Parkinson's disease, particularly in its advanced stages.
Thus, for example, the following improvement is achieved as compared to the hitherto conventional treatment with the combination of decarboxylase inhibitors and L-dopa: i A 3- Patients need to take the sustained release combination less frequently than the standard combinations for the same or improved antiparkinsonian efficacy, Thanks to the delayed absorption, peak concentrations in the serum and the side effects connected therewith (dyskinesias) are avoided. Using the sustained release combination, effective L-dopa serum concentrations are built up over a longer period of time than with the standard combination. For this reason, and because of the lower frequency of administration of the sustained release combination, the therapeutic L-dopa dosage can be cumulatively reduced. Since the L-dopa side effects syndrome depends on 00 0° °o cumulative dosage, the sustained release combination also makes 0 00 0oo0 it possible to reduce this long-term side effect.
oo 0 00 00 0 0 00 0 o0. The improvement and prolongation of the effect of the 00 0 0 00 0 oa combination of the invention can be demonstrdted as follows as compared to the standard combination: following the 000 administration of the combination to Parkinson patients in the 0 0 0 0 0 evening, patients' nocturnal movements are measured by 0 000 accelerometry of the arms and legs. In the akinesia sta.te, 0 Parkinson patients commence their attempts at movement with the legs. A change over from movement of the legs to that of the t 0 C O 0 arms indicates an improvement in the clinical picture of the patient.
4 Reduced morning akinesia after administration of the combination in the evening is a further parameter for the improved efficacy of the combination of the invention as compared to the standard combination.
US patent 3 557 292 also describes inter alia a combination of L-dopa and bensera:' Ue in which, however, the L-dopa is also not present in pellet form. ,he combination of the invention has the following surprising advantages as compared to this known combination: lower frequency of administration, reduction in the rate of side effects, more even effect.
to 0 5 0 00 o 00 ooa o o o S0 0 000 0 00 0 00 00 0 0 0 0 0000 0o00 9 5 Furthermore, German published patent 3 232 873 discloses a combination of L-dopa with the decarboxylase inhibitors carbidopa and benserazide. Here, too, the L-dopa is not used in pellet form. The disadvantage of this known combination as compared to the combination of the invention is that the known combination has only insufficient antiparkinsonian efficacy whereby, in particular, the dyskinesias of the patients are prolonged.
According to a first embodiment of the present invention there is provided a method for the treatment or prophylaxis of Parkinson's Disease in a patient requiring said treatment or prophylaxis, which method comprises coadministering or sequentially Administering to said patient an effective amount of L-dopa or a salt thereof with a physiologically acceptable acid or base, in the form of pellets, and a decarboxylase inhibitor or a salt thereof with a physiologically acceptable acid or base.
According to a second embodiment of this invention there is provided a synergistic pharmaceutical formulation comprising L-dopa or a salt thereof with a physiologically acceptable acid or base, in the form of pellets, and a synergistically effective amount of a decarboxylase inhibitor or a salt thereof with a physiologically acceptable acid or base, together with pharmaceutically acceptable carrier, adjuvant, excipient and/or diluent.
00 00 0 0 0 0 0 C 0 According to a third embodiment of this invention there is provided a single dose unit containing 10 to 100mg of decarboxylase inhibitor or a salt thereof with a physiologically acceptable acid or base thereof and to 1000mg of L-dopa or a salt thereof with a physiologically acceptable 5 acid or base thereof, said L-dopa in the form of pellets.
According to a fourth embodiment of this invention there is provided a single dose unit containing 25 to 50mg of decarboxylase inhibitor or a salt thereof with a physiologically acceptable acid or base and 100 to 500mg of L-dopa or a salt thereof with a physiologically acceptable acid or base, said L-dopa in the form of pellets.
The amounts or parts by weight quoted in the specification and the claims relate in each case to the pure active substances, that is, not to salts of these active substances. Should salts be used, the amounts change according to the altered gram-molecular weight of the salts.
Oo 0 The benserazide is preferably used as an acid addition salt, salts with ooo halohydric acids (for example the hydrochloride, hydrob' ,aide) or also with Oon organic acids (for example embonic acid, maleic acid, citric acid, tartaric acid) being particularly suitable. Carbidopa and L-dopa are generally not Soo used in the form of the salt. Should L-dopa be used as a salt this is, for 00 0 °o °40 example, a salt with physiologically acceptable alkali or alkaline earth metals.
The daily doses of the combination of the invention consist, for example, o of 10 to 800 mg, preferably 20 to 300 mg and in particular 75 to 250 mg of decarboxylase inhibitor and 50 to 8,000 mg, preferably 100 to 3,000 mg, in particular 300 to 1,500 mg of L-dopa.
00 0 0 0 The daily doses may be given in the form of a single administration of the o total amount or in the form of 1 to 10, in particular 2 to 8 partial doses o o per day. In general, administration 3 to 6 times, in particular 4 to o o times daily, 6 is preferred. The preferred dose of the combination of decarboxylase inhibitor and L-dopa is for example 25 to 50 mg of decarboxylase inhibitor and about 100 to 500 mg of L-dopa 2 to 6 times daily. In particular this dose is about 25 mg of decarboxylase inhibitor and about 100 mg of L-dopa 3 to 5 tires daily.
Decarboxylase inhibitors and L-dopa are, for example, used in S00 the following weight ratios in accordance with the invention: 1 0 00 oo00o part by weight of decarboxylase inhibitor is for example used or 0 00 0oo combined with 0.5 to 100 parts by weight of L-dopa, preferably 1 00 S000 part by weight of decarboxylase inhibitor with 1 to 50 parts by 00 0 0 o0o weight of L-dopa, in particular 1 part by weight of decarboxylase inhibitor with 2 to 20 parts by weight of L-dopa.
a 00 0 00 0 00 0 00 For the combination, 50 to 1,000 mg of L-dopa and 10 to 100 mg oo 0 of decarboxylase inhibitor, preferably 100 to 500 mg of L-dopa 0 00 and 25 to 50 mg of decarboxylase inhibitor may, for example, easily be formulated into the medication.
The dosage unit of the ccmbination of the invention can for example contain: to 100 mg of decarboxylase inhibitor, preferably 10 to 50 mg, in particular 25 to 50 mg of decarboxylase inhibitor and 50 to 1,000 mg, preferably 50 to 500 mg, in particular 100 to 500 mg i 7 of L-dopa. These doses can, for example, be administered 1 to 8, preferably 2 to 6, in particular 3 to 5 times daily.
It is, of course, also possible to prepare pharmaceutical formulations which contain the stated dosage units 2 to, for example, 5 times.
The doses and parts by weight given in the preceding pages which o a relate to application in humans are in each case related to the 0 0 0 0 00 0 0"0 free bases and free acids respectively.
0 00 o0 0 00 0, 000 0 So The term pellets should be understood to cover spherical or o ooo 0 000 0o °0 cylindrical shapes having a diameter between 0.1 and 2 mm. They are produced by pressing suitable powder mixtures with 0 00 o "og tabletting presses, compactors or perforated rubber plates or by o000 pasting through addition of solutions or solvents, pressing the o000 resulting plastic mass through perforated discs, dividing, 0 00 ooooeo rounding off and drying the resulting strands.
0000 0 0 0000 og o Another possible manner of preparation lies in the simultaneous 0 A or successive application of the active substances with or without binding agents onto neutral pellets having no active substance (so-called nonpareils).
NI
8 A further possibility lies in binding the active substance L-dopa to ion exchangers, for example through binding of L-dopa to physiologically acceptable ion exchangers. The following may for example be used as ion exchangers of this kind: acrylic and methacerylic resins with exchangeable proton, i.e.
acid, in particular weakly acid, groups such as C0OO (for example AmberliteR IRP-64); polystyrene resins with exchangeable Na+, acid groups: 00 0 0 o S0 3 6 (for example AmberliteR IRP-69).
o o 0 0 0o 00 0 s o The ion exchangers are acid ion exchangers. The maximum ratio of Op 0 0 o. o L-dopa ion exchanger is ca. 1 :1 the minimum ratio about I 0 0 00 part by weight of L-Oopa to 800 parts of ion exchanger 0 0o resin. Preferably 1 to 400 parts by weight of ion exchanger, 0 00 0 oo quite particularly preferably 1 to 100 parts by weight of ion 0 0o exchanger are used per 1 part by weight of .L-Dopa.
OO 0 0 0 0 00 000000 The binding of the L-dopa is effected by allowing an L-dopa O0 0 00e,,0 solution to flow through a bed of the ion exchanger in a column.
00 00 0 o0 The charged ion exchanger is dried at temperatures up to about The charged ion exchanger particles are preferably also provided with a coating such as described, for example, in US-A-4,221,776. An advantage of the additional coating is that the release rate of the'active substance can be changed and influenced by the choice of the coating material. Hot air at t 1 I~ ji. 9 OC to 90 OC can be used to dry the charged ion exchanger particles provided with the coating. The charged ion exchangers can then be filled, for example, into hard gelatine capsules.
It is also possible to obtain pellets through the dropping of melts of fatty substances, for example of cetylstearyl alcohol or waxes. The spray hardening or vibration dropping methods used herefor are known in the art.
@o o 0 0 0 00 o 00 o o The preparation of the pellets used according to the invention 000 0 00 is effected in the conventional manner.
0 0 00 0 o 0o 0 0 0 o o Pellets with controlled release of the active substance are 000 preferably used, whereby these may be pellets which either only 0 00 o°o°°o contain L-dopa or pellets which contain both L-dopa and 1 0 0 0 0 decarboxylase inhibitor. The pellets with controlled release are 0 o 0 Q 00 o preferably obtained by coating pellets prepared in the a00000 0 conventional manner with the named active substances in known 4000 manner with at least one coating substance. Coating substances that can be used are: polymerisates as well as copolymerisates of acrylic acid and/or methacrylic acid and/or their esters; copolymerisates of acrylic and methacrylic acid esters with a low content of ammonium groups EudragitR RS), copolymerisates of acrylic and methacrylic acid esters and trimethylammonium methacrylate EudragitR RL); polyvinylacetate; fats, oils, waxes, fatty alcohols; t 00 0 00 0 0 00 0 oo o oo 0 0 0 Sa 0 0 0 0 0 0 0 0 oo o 0 0 000 00 0 0 oo 0 00 0 00 0 0 0 00 0 00 0 0 0 0 00 00 0 0 0 0 0 000000 0 0 00 a t 0 o a i hydroxypropylmethylcellulose phthalate or -acetate succinate; cellulose-, starch- and polyvinylacetate pbhtl.iate; carboxymethyl cellulose; methyl cellulose-phthalate,-succinate, -phthalate suceinate as well as -phthalate acid semiester; zein; ethyl cellulose and -succinate; shellac; gluten; ethylcarboxyethyl cellulose; ethacrylate maleic acid anhydride copolymer; maleic acid anhydride-vinylmethylether copolymer; styrene-malaic acid copolymerisate; 2-ethylhexylacrylate maleic acid anhydride; crotonic acid-vinylacetate copolymer; glutamic acid/glutaminic acid ester copolymer; carboxymethylethylcellulose glycerine monooctanoate; cellulose acetate succinate; polyarginine.
It is, for example, also favourable to use 2 separate coating layers; one for the controlled release (such as the above named, whereby these then contain no, or only few, free carboxy groups) and one for the gastric juice resistance, that is a coating layer which prevents release in the stomach. This is in particular to be considered for the pure L-dopa pelleta, Separate coating substances for gastric juice resistance are the conventional ones, for example physiologically acceptable polymers with free carboxy groups such as copolymerisates of acrylic acid and/or methacrylic acid, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, methyl cellulose phthalate ad other phthalates.
-r Ii 44 4 44 44 ii 4 44 4 44 4 44 44 ~:44 4 44 4 44~ 4 4 44 4 4*~ 4 44 4 4 4 *~4 4 4 4 0 44 44 4 44 4 44 4 444 4 4 4 4 Plasticizing agents that can be used for these coating substances are: citric and tartaric acid ester (acetyltriethyl-, acetyltributyl-, tributyl-, triethylcitrate); glycerine and glycerine esters (glycerine diacetate, -triacetate, acetylated monoglycerides, castor phthalic acid esters (dibutyl-, diamyl-, diethyl-, dirnethyl-, dipropyl-phthalate), D-(2-methoxy or ethoxyethyl)-phthalate, ethylphthalyl, butylphthalylethylan~d butylgly~olate; alcohols (propylene glycol, polyethylene glycoil of various chain lengths), adipates (diethyladipate, di(2-methoxy- or ethoxyethyladipate)); benzophenone; diethyland dibutylsebacate, -sliccinate, -tartrate; die'.hyleneglycoldipropionate; ethyleneglycol diacetate, -dibutyrate, -dipz-opionate; tributylphosphate, tributyrin; hydroxypropyl cellulose, hydroxypropyl methyl1 cellulose, polyethyleneglycolsorbitane monooleate (polysorbates such as polysorbat sorbitpne monooleate, polyvinylpyrrolidone.
Por the coating layer it is possible to use one or several of the coatin~g substances mentioned as well as one or several of the plasticizing agents mentioned. Thq coatina layer can contain additional substLances for contro:lling the release of the L-dopa.
These are water--soluble substances such as polyethylene qilycols, polyvinylpyrrolidone, copolyimeris.ates of polyvinylpyirrolidone and polyvinylacetate, i olyvinylaac- Le and similar. For the same purpose it is, however, also pnssible to use the already mentioned plasticizing agent.si hydroxy'propyl cellulose and/or L 1 0o o o oo o o o 0 00 0 0 0 o oo o oo 0 00 0 0 0 00 o oo 00 0 0 00 Soo oo o 0 00 o oo 0 ooo 0 00 00 0 o oo 0 a00 a a -12 hydroxypropyl methyl cellulose. In this case their amount is, for example, 0.1 to 5 weight%, preferably 1 to 3 weight% related to the coating substance.
The application of the coating layer is effected through spraying of solutions of the mentioned substances in organic solvents or suspensions of the mentioned substances in organic solvents or water, whereby further auxiliary svustances may be added to optimize workability such as, for example, surface active substances, solid substances such as talcum and/or magnesium stearate and/or pigments.
The spraying is effected, for example, in a coating drum or in perforated drums with controlled supply of the drying medium or in an air suspension procedure: working generally being at temperatures between 10 °C and 80 oC.
In the preparation of L-dopa pellets through dropping a melt of L-dopa into fat-like substances or waxes, the following substances can, for example, be used: glyceridcs of saturated fatty acids C 8
H
16 0 2 to C 1 8
H
1 602 hydrated peanut oil, hydrated castor oil, hydrated cottonseed oil, stearic acid, palmitic acid, esters of aliphatic satuiated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms), carnauba wax, beeswax, fatty alcohols (straight or 1 a-- ~nmei Earr;l;Da;ur+-~~~li.~LU"~"LIIUXI~- 13 branched chains) of chain length CgH70H to C 3 0
H
6 1 0H. in particular C 12
H
25 0H to C 24
H
4 9 0H.
In the case of preparation through application on neutral pellets, binding agents that may, for example, be used are: gelatine, gum arabic, starch paste, cellulose derivatives (mathyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose), sodium alginate, pectin, 0 0 tragacanth, polyvinylpyrrolidone, polyvinylacetate, polyvinyl 0 0 0 o o alcohol, copolymerisate of vinylpyrrolidone and vinylacetate.
o 0 0
O
0 0 0 0o The pellets may, however, also be prepared by embedding L-dopa 0 000 0o0 into the following substances or mixtures of the following substances: 0 00 o oo o0 0 0 0 digestible fats, for example 00o triglycerides of saturated fatty acids CH01602 to 0 oa
C
18
H
3 6 0 2 and their mixtures, peanut oil and hydrated 0 0 o,.o peanut oil, castor oil and hydrated castor oil, olive oil, a o a sesame oil, cottonseed oil and hydrated cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, mixtures of mono-, di-, triesters of palmitin and stearic acid with glycerine, glycerine trioleate, diglycolsteerate, stearic acid.
undigestible fats or fat-like substances, for example l -LYllai~-~--i~ .nrrcrr-.rmrrr~ 14 esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms), carnauba wax, beeswax, fatty alcohols (straight chain or branched chain) of chain length C 8
H
17 0H to C 30
H
6 1 0H, in particular C 12
H
2 5 0H to C 24
H
4 9 0H.
polymers such as "0 polyvinyl alcohol, polyvinyl chloride, polyacrylic acid; 0 00 Oao anionic polymerisates of methacrylic acid and methacrylic 0 00 o acid esters (EudragitR L, EudragitR acrylic and 00 00 "0 methacrylic acid ester copolymerisates with trimethyl 0O 0 0 0 0 ammonium methacrylate (EudragitR RL, EudragitR RS), 0 oa copolymerisate of acrylic acid ethyl- and methacrylic acid 0 00 °Oa o methyl esters EudragitR NE 30 as well as from acrylic 0 00 acid, methacrylic acid as vell as their esters (ratio of 0 00 o 0 o free carboxy groups to the ester groups 1:1) (EudragitR L oooo polyethylene, polyglycol acid, polyhydroxybutyric o o acid, polylactic acid, copolymers of lactic acid and t glycolic acid (manufacturer: Boehringer Ingelheim), copolymers of lac'ic acid and ethylene oxide as well as glycolic acid and ethylene oxide, hydroxypropylmethyl cellulose-phthalate or -acetate succinate; cellulose acetate phthalate, starch acetate phthalate, as well as polyvinylacetate phthalate; carboxymethyl cellulose; methylcellulose-phthalate, -succinate, -phthalate succinate, *i3urrr;--i -urru~ 15 methylcellulose phthalic acid half ester; zein; ethyl cellulose; shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydride copolymer; maleic acid anhydride-vinylmethylether copolymer; styrol-maleic acid-copolymerisate; 2-ethylhexyl-acrylate-maleic acid anhydride; crotonic acid-vinylacetate copolymer; glutamic acid/glutaminic acid ester copolymer; carboxymethylcellulose-glycerine monoctanoate; cellulose acetate succinate; 0 0 0 0 00 00 polyarginine.
Swelling agents such as 0 methyl cellulose, hydroxypropyl cellulose, hydroxypropyl O0 ga methyl cellulose (Pharmacoat, Methocel E propyleneglycol ether of methyl cellulose), alginic acid and its salts (Na-, 0o Ca-salt, also mixtures of alginic acid and calcium salts, 9 e.g. CaHPO 4 starch, carboxymethyl starch, carboxymethyl 00oo cellulose and their salts Na-salt), galactomannan, gum 0 0 0 arabic, karaya gum, ghatti gum, agar agar, carrageen, xanthane rubber, guar rubber and its derivatives, carob bean 00.0 Good 0 0 000 kernel flour, propylene glycol alginate, pectin, tragacanth.
00 00 0 0 0 O O0 In particular it is, for example, also possible to effect the embedding of L-dopa and optionally the decarboxylase inhibitor in hydrophilic polymers and hydrocolloids respectively, optionally together with other conventional aux-i.liy substances.
i ii-i~ -r- 16 In the case of these sustained release components it is possible for example to use I to 800 parts by weight of sustained release components, preferably 1.5 to 600 parts by weight, quite particularly preferred 2.0 to 400 parts by weight to 1 part by weight of L-dopa. The preparation of these formulations is effected at temperatures between 18 °C and 80 °C.
The preparation of this dosage form can be effected: by dissolving or dispersing L-dopa or its salts in the mentioned 0 o fats or fat-like substances or mixtures thereof, also by melting the mentioned substances and subsequent recooling, breaking up into small pieces, possibly adding other substances such as the above mentioned water soluble substances or substances that swell in water, and forming into pellets. The cooling of the o oo l I 3 o melt and breaking up into small pieces can also be combined in I o one step by dispersing the melt in cold water or subjecting it OOo to a spray hardening or dropping with vibration.
0 o through mixing of L-dop with the mentioned fats, polymers or oo o o oswelling agents or mixtures of these substances, also with the use of heat, and forming of the mixtures, possibly after addition of other auxiliary substances, into pellets; through mixing of L-dopa with solutions of the mentioned fats or polymers in water or organic solvents such as, for example, ethanol, ethyl acetate, acetone or isopropanol, possibly mixing with carrier materials such as celluloses, as well as subsequent I evaporation of the solvents and mixing the embedded active
S
A
l^jf~f3^^* C L -17 ingredient obtained with other auxiliary substances and working into pellets; by moistening a mixture of L-dopa and the mentioned swelling agents with organic solvents such as ethanol, ethyl acetate, acetone or isopropanol, possibly with addition of binding agents such as polyvinylpyrrolidcne o copolymers of polyvinylpyrrolidone and polyvinylacetate and subsequent Sformation of pellets which are subsequently dried.
o o D 0 o o oo The pharmaceutical compositions or medications contain as active substance the combination of the invention in a formulation. The 0 o o individual active substances of the combination can, however, also be present in each case in separate formulations, whereby O°"00 the already cited amounts of active substance are used in each 0 DO 0 oo case for the corresponding dosage unit. The active substances or Oo o the active substance combination is optionally present in Su o 0 oo mixture with other pharmacologically or pharmaceutically active substances. The preparation of the medications is effected in known manner, whereby the known and conventional pharmaceutical auxiliary substances as well as other conventional carrier ard diluting agents can be used.
For example the pellets can be worked into tablets which disintegrate in the stomach or intestine and release the pellets there.
u- I -I 18 Carriers and auxiliary substances which can be used for the pharmaceutical formulations are, for example, those substances which are recommended or quoted in the following literature references as auxiliary substances for pharmacy, cosmetics and related fields: Ullmanns Encyklopaedie der techniZ'hen Chemie, Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), pages 918 et seq., H.v.Czetsch-Lindenwald, Hilfsstoffe fuer Pharmazie und O0 0 0 Go o0 o angrenzende Gebiete, Pharm. Ind., Issue 2, 1961, pages 72 et 0 6 0 0 0 0 seq.; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fuer Pharmazie, 00 o 0 Kosmetik und angrenzende Gebiete Cantor KG. Aulendorf in 0 40o O0 Wuerttemberg 1981.
p0o 0 o Examples hereof are gelatine, natural sugars such as cane sugar 0 00 00 00 or milk sugar, lecithin, pectin, starch (for example corn o0 q starch), cyclodextrine and cyclodextrine derivatives, 0 o 0 S polyvinylpyrrolidone, polyvinylacetate, gelatine, gum arabic, alginic acid, tylose, talcum, lycopodium, silicic acid (for example colloidal), cellulose, cellulose derivatives (for a i 0 0 example cellulose ether in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and/or lower saturated aliphati" oxyalcohols, for example methyloxypropyl cellulose, methyl cellulose, hydroxypropyl
N
methyl cellulose hydroxypropylmethyl cellulose phthalate); fatty acids as well as magnesium-, calcium- or aluminium salts of fatty acids with 12 to 22 carbon atoms, in particular the i t
I
i -i i i i i 1~ i
I
I!
99 9 o 99 9r '9 *9 9R 9 9 9 59 9 9 19 saturated (for example stearates), emulsifiers, oils and fats, in particular vegetable (for example peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in each case also hydrated; mono-, di- and triglycerides of saturated fatty acids
C
1 2
H
2 4 0 2 to CICH 3 6 0 2 and their mixtures), pharmaceutically tolerated mono or multivalent alcohols and polyglycols such as polyethylene glycols as well as derivatives hereof, eaters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with mcnovalent aliphatic alcohols (1 to 20 carbon atoms) or multivalent alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, sorbitol, mannitol and so on, which may optionally also be etherified, esters of citric acid with primary alcohols and acetic acid, benzylbenzoate, dioxolanes, glycerine formals, tetrahydrofurfuryl aicohol, polyglycol ether with C 1
-C
1 2 alcohols, dimethylacetamide, lactamide, lactate, ethyl -arbonate, silicons (in particular medium viscous polydimethyl siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, m .esium carbonate and similar.
Other auxiliary substances which can be considered are substances which bring about disintegration (so called disintegrants), such as: cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose as well as cross-linked or microcrystalline cellulose.
I
For the preparation of solutions or suspensions it is, for example, possible to use water or organic solvents, for example methanol, ethanol, propanol, isopropanol, dichloromethane, trichloroethlane, acetone, 1,2-propylene glycol, polyglycols and their derivatives, dimethylsulphoxide, fatty alcohols, triglycerides, partial esters of glycerine, paraffins and 0 0e similar.
a In the preparation of the formulations it is possible to use 0 000 known and conventional solubilizers or emulsifiers. Solubilizers and emulsifiers which may, for example, be used are: polyvinylpyrrolidone, sorbitane fatty acid esters such as sorbitane trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitane monooleate and other O 0 a ethoxylated fatty acid esters of sorbitane, polyoxyethylated fate, polyoxyethylated oleotriglycerides, linolisated 1 oleotriglycerides, polyethylene oxide condensation products of oo ea S* fatty alcohols, alkylphenols or fatty acids or also 1-methyl-3-(2-hydroxyethyl)-imidazolidone-(2). Polyoxyethylated means here that the substances in question contain polyoxyethylene chains, the degree of polymerization of which generally lies between 2 and 40 and in particular between 10 and 0 S 21 Polyoxyethylated substances of this type may, for example, be obtained through reaction of hydroxyl group containing compounds (for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals) with ethylene oxide (for example 40 Mol of ethylene oxide per Mol of glyceride).
Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil.
°o °0 See also Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fuer 0 a 0 a a Pharmazie, Kosmetik und angrenzende Gebiete" 1971, pages 191 to 195.
Antioxidants that may, for example, be used are sodium metabisulphite, ascorbic acid, gallic acid, gallic acid alkyl ester, butylhydroxyanisol, nordihydroguaiacic acid, tocopherols as well as tocopherols synergists (substances which form heavy metals through formation of complexes, for example lecithin, ascorbic acid, phosphoric acid). The use of synergists considerably boosts the antioxygenic action of the tocopherols.
The pharmaceutical and galenic treatment of the active substances is effected using the conventional standard methods.
For example active substance(s) are thoroughly mixed with auxiliary or carrier substances through stirring or homogenizing (for example using conventional mixing apparatus), working generally being at temperatures between 20 and 80 °C, 22 preferably 20 to 50 in particular at room temperature.
Reference is made here to the following standard work: Sucker, Fuchs, Speiser, Pharmazeutische Technologie, Thieme-Verlag SStuttgart, 1978.
Application may be in the interior UF the body, for example oral or enteral.
G
a The combination of the invention may also be present as a a0 product in which the two individual active substances are in o each case present in separate formulations so that administration may be separate or at differently graded times.
S Should such separate formulations be present, these are to be adapted to each other and contain in each case the active substances in the dosage unit in the amounts and corresponding mixture.
In the case of separate administration, it is also possible for the two combination partners not to be given at the same time.
In such cases L-dopa may be given 5 to 300 minutes after administration of the decarboxylase inhibitor.
a _LII_ I -23 The acute toxicity cc the combination of the invention, expressed in the LD 50, is for example above 1,700 mg/kg in the case of oral application (applies for various animals such as, for example, mouse, rat).
ExampLe 1: Capsules containing 100 mg of L-dopa in pellet form and 28.5 mg of benserazide hydrochluride 00 0 0 .0 0o 0 0 0 o 2,000 g of L-dopa are mixed with 220 g of microcrystalline o cellulose and the mixture thoroughly moistened with a solution o of 60 g of Polysorbate 80 in 820 g of purified water. The moist 0 00 mass is fed through an extruder (perforation size 0.8 mm) and S0o the strands obtained divided and rounded off using a S00 0 o 0 0 spheronizer. The moist pellets obtained are dried in a fluidized 0 0 0 0o Sair bed dryer to a relative humidity (equilibrium humidity) of 0 o0 25-35 The dried pellets are sieved. Only the sieve fraction of 0.5 to 1.25 mm is further processed.
04 00 00 S1,600 g of the pellets are sprayed with a film suspension which is prepared as follows: 28 g of triethylcitrate are emulsified with 0.3 g of Polysorbate in 110 g of purified water and the emulsion mixed with 460 g of a 30 suspension ofcopolymerisates of acrylic and methacrylic acid esters with a purified content of ammonium groups (for example EudragitR RS 30 68 g of talcum are suspended in 515 g of purified water with the aid of t ___ri conventional homogenizing apparatus and the suspension is stirred into the above obtained dispersion after addition of a few drops of silicon antifoaming oil. The application of the suspension thereby obtained (coating for the sustained release) onto the pellets is effected in conventional manner, for example using a fluidized air bed granulator at an air inlet temperature of 40 50 °C and a maximum outlet air temperature of 40 °C.
The drying of the pellets is effected under the same conditions.
The above described suspension is sprayed on until the total weight of the dried pellets is 1,628 g.
1,500 g of pellets of the sieve fraction below 1.25 mm are then sprayed with the following lacquer suspension (coating for gastric juice resistance): 32 g of triethyl citrate are emulsified with 0.3 g of polysorbate 80 in 130 g of purified water and the emulsion mixed with 1,068 g of a suspension of a copolymerisate with anionic character on the basis of poly(meth)acrylic acid and S*poly(meth)acrylic acid esters (for example EudragitR L 30 D).
160 g of talcum are suspended in 620 g of purified water using a conventional homogenizing apparatus and the suspension stirred into the above obtained dispersion after addition of a few drops of silicon antifoaming bil. Coating of the suspension thus bt-ained onto the pellets is effected as described above.
Suspension is spra', i on until the total weight of the dried pellets is 1,978 g.
I
I ~ca s~^j 570 g of benserazide hydrochloride are mixed with 420 g of lactose and granulated with a solution of 20 g of gelatine in 180 g of puricied water in the conventional manner. Following drying and sieving of the granulate through a sieve of mesh size 0.8 smi, 6 g of magnesium stearate and 4 g of highly disperse silicon dioxida are added with mixing.
51 my of the mixture together .ith in each case 153 mg of the above described lacquered pellets are filled into size 2 hard gelatine capsules.
One hard gelatine capsule contains 100 mg of L-dopa in the form of pellets and 28,5 mg of benserazide hydrochloride.
The release of L-dopa from this dosage form is tested accoiding to the process set out in US Pharmacopoeia, 21st Edition (USP XXI) using th dissolution test appliance, apparatus 2. The release of the L-dopa in 900 ml of buffer solution is determined at 3 7°C at a paddle revolution speed of 120 rpm, For the first 2 hours the test solution consists of 0.06 molar- alt solution, after which the pellets are transferred to a phosphate buffer solution pH 6.8 of the European Pharmacopoeia. The release of the L-dopa frin the buffer solutions is measured in each case.
The re lase of the L-dopa is
I
i ii 26 after 1 hour 0.1 0.2 in 0.06 M HCi 2 hours 0.3 0.9 3 hours 32 37 4 hours 55 60 in phosphate buffer hours 72 75 pH 6.8 6 hours 81 84 In a similar manner it is possible to prepare capsules which, apart from the benserazide hydrochloride granulate mixture contain unlacquered L-dopa pellets contain L-dopa pellets which were only lacquered with one of the suspensions mentioned contain mixtures of unlacquered and lacquered pellets.
S To obtain these pellets the lacquering process should be changed accordingly.
S EXAMPLE 2 'o 40 A capsule filling mass was prepared in accordance to US-Patent 4 424 235, example 1, formulation A. The mass was filled into capsules of size 0.
The resulting capsules were introduced into simulated gastric fluid (0.1N Hydrochloric Acid, temperature 37 0 The capsules floated on the surface of the simulated gastric fluid. After approx. 5 minutes the capsule shell ruptured and the content of the capsule, a gelatinous mass, kept floating over hours.
EXiP LE 3 The capsule filling mass of Eximple 2 was compressed to form pellets with a ,'3b diameter of 1.5 mm. The pellets were introduced into simulated gastric
S:"
t fluid (composition see Example The pellets did not float, but sank to the bottom of the container and remained there over hours.
In an additional experiment the pellets were filled into capsules of size 0 and such capsule was introduced into the simulated gastreic fluid. Within the first 10 minutes the capsule floated on the surface of the fluid.
After rupture of the capsule shell the pellets were released and sank down -1thke bottom of the container.
Claims (22)
1. A method for the treatment or prophylaxis of Parkinson's Disease in a patient requiring said treatment or prophylaxis, which method comprises coadministering or sequentially administering to said patient an effective amount of L-dopa or a salt thereof with a physiologically acceptable acid or base, in the form of pellets, and a decarboxylase inhibitor or a salt thereof with a physiologically acceptable acid or base.
2. A method according to claim 1, comprising administering to said patient 0.5 to 100 parts by weight of L-dopa per one part by weight of decarboxylase inhibitor.
3. A method according to claim 1 or claim 2, comprising administering to said patient a dose unit containing 10 to 100mg of decarboxylase inhibitor and 50 to 1000mg of L-dopa.
4. A method according to claim 3 comprising administering to said patient a dose unit containing 25 to 50mg of decarboxylase inhibitor and 100 to 500mg of L-dopa. oo
5. A method according to any one of claims 1 to 4 wherein the decarboxylase inhibitor is benserazide or carbidopa.
6. A method according to any one of claims 1 to 5, wherein the pellets are prepared by mixing L-dopa or a salt thereof with a physiologically acceptable acid or base with at least one of the auxiliary substances cellulose, cellulose derivatives, lactose, starch, mannitol, sorbitol, polysorbate, saccharose, glucose, sodium alginate, sodium alginate/calcium salts optionally with addition of binding agents, forming the mixture into pellets, optionally coating the pellets with a conventional coating substance, or, alternatively, (ii) applying L-dopa or a salt thereof with a physiologically acceptable acid or base with at least one of the above named auxiliary substances onto neutral pellets and subsequently optionally also coating these with at least a conventional coating substance.
7. A method according to claim 6, wherein the binding agent is selected from polyvinylpyrrolidone, vinylacetate-vinylpyrrolidone, copolymer, gelatine or cellulose derivatives in the form of solutions.
8. A synergistic pharmaceutical formulation comprising L-dopa or a salt thereof with a physiologically acceptable acid or base, in the form of pellets, and a synergistically effective amount of a decarboxylase .inhibitor or a salt thereof with a physiologically acceptable acid or base, /1158y 28 together with pharmaceutically acceptable carrier, adjuvant, excipient and/or diluent.
9. A formulation according to claim 7 containing 0.5 to 100 parts by weight of L-dopa per part by weight of decarboxylase inhibitor.
A formulation according to claim 8 or claim 9, wherein the decarboxylase inhibitor is benserazide or carbidopa.
11. A formulation according to any one of claims 8 to 10, wherein pellets are prepared by mixing L-dopa or a salt thereof with a physiologically acceptable acid or base thereof with at least one of the auxiliary substances cellulose, cellulose derivatives, lactose, starch, mannitol, sorbitol, polysorbate, saccharose, glucose, sodium alginate, sodium alginate/calcium salts optionally with addition of binding agents forming the mixture into pellets, optionally coating the pellets with a conventional coating substance, or, alternatively, (ii) applying L-dopa or a salt thereof with a physiologically acceptable acid or base thereof with oo a at least one of the above named auxiliary substances onto neutral pellets 2 u and subsequently optionally also coating these with at least a conventional S coating substance.
12. A formulation according to claim 11, wherein the binding agent is selected from polyvinylpyrrolidone, vinylacetate-vinylpyrrolidone copolymer, gelatine or cellulose derivatives in the form of solutions.
13. A single dose unit containing 10 to 100mg of decarboxylase .inhibitor or a salt thereof with a physiologically acceptable acid or base thereof and 50 to 1000mg of L-dopa or a salt thereof with a physiologically acceptable acid or base thereof, said L-dopa in the form of pellets.
14. A single dose unit containing 25 to 50mg of decarboxylase inhibitor or a salt thereof with a physiologically acceptable acid or base and 100 to 500mg of L-dopa or a salt thereof with a physiologically acceptable acid or base, said L-dopa in the form of pellets.
A dose unit according to claim 13 or claim 14, wherein the decarboxylase inhibitor is benserazide or carbidopa.
16. A method of preparing a formulation according to claim 8 for peroral administration comprising mixing or homogenising 1 part by weight of decarboxylase inhibitor or a salt thereof with a physiologically acceptable acid or base and 0.5 to 100 parts by weight of L-dopa or a salt thereof with a physiologically acceptable acid or base, together with a conventional carrier, diluent, excipient and/or adjuvant at a temperature S between 10 and 80*C, forming the resulting mixture into pellets, optionally LM/1158y 11 i -laaa 29 providing the pellets with a coating, and pouring the pellets into capsules or bags of appropriate size such that 10 to 100mg of decarboxylase inhibitor and 50 to 1000mg of L-dopa are contained in the final dosage unit.
17. A method of preparing a formulation according to claim 8, comprising mixing or homogenizing 1 part by weight of decarboxylase inhibitor or a salt thereof with a physiologically acceptable acid or base and 0.5 to 100 parts by weight of L-dopa or a salt thereof with a physiologically acceptable acid or base, by mixing the decarboxylase inhibitor with conventional auxiliary and carrier substances to a solid formulation; mixing L-dopa using conventional auxiliary and carrier substances into pellets which are optionally provided with a lacquer film; and pouring formulations and obtained together into capsules or oo bags. o
18. A method of preparing a formulation according to claim 8, S comprising mixing 1 part by weight of a decarboxylase inhibitor or a salt S thereof with a physiologically acceptable acid or base and 0.5 to 100 parts by weight of L-dopa or a salt thereof with a physiologically acceptable I acid or base, by mixing the decarboxylase inhibitor with at least one of the auxiliary substances mannitol, sorbitol, lactose, starch or cellulose, optionally granulating the mixture with an aqueous gelatine solution or a S vinylacetate-vinylpyrrolidone copolymerate solution or a starch solution, S and mixing the mixture or the granulate with magnesium stearate and highly dispersed silicon dioxide as well as, optionally, also starch and/or cellulose and optionally pressing the mixture into tablets; mixing L-dopa with at least one of the auxiliary substances cellulose, cellulose derivatives, lactose, starch, mannitol, sorbitol, S polysorbate, saccharose, glucose, optionally with addition of binding agents and forming this into pellets which are optionally provided with a lacquer film or applying L-dopa with or without binding agents onto neutral pellets (so-called nonpareils) which are subsequently provided with a lacquer film; and subsequently combining the formulations and optionally after filling into capsules or bags, whereby the filling of and may also be together, into a medicinal packing so that the dosage unit contains 10 to 100mg of decarboxylase inhibitor and 50 to 1000mg of L-dopa.
19. A method according to claim 18, wherein the binding agents are I LMM/1158y f- i) i- e 1. 30 selected from polyvinylpyrrolidone, vinylacetate-vinylpyrrolidone copolymer, gelatine or cellulose derivatives in the form of solutions.
A method for the preparation of a formulation according to any one of claims 16 to 19, wherein the decarboxylase inhibitor is benserazide or carbidopa.
21. A pharmaceutical formulation, substantially as hereinbefore described with reference to Example 1.
22. A method for the treatment or prophylaxis of Parkinson's Disease in a patient requiring said treatment or prophylaxis, which method comprises administering to said patient an effective amount of a formulation according to claim 21. DATED this FIFTEENTH day of MARCH 1991 a o 4 a ASTA-Pharma Aktiengesellschaft Patent Attorneys for the Applicants SPRUSON FERGUSON 0 i,, r r I G .i 1158y
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3744646 | 1987-12-31 | ||
DE3744646 | 1987-12-31 |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2758288A AU2758288A (en) | 1989-07-06 |
AU611512B2 true AU611512B2 (en) | 1991-06-13 |
Family
ID=6343914
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU27582/88A Ceased AU611512B2 (en) | 1987-12-31 | 1988-12-30 | Synergistic combination of decarboxylase inhibitors and l- dopa pellets |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0324947B2 (en) |
JP (1) | JPH0296520A (en) |
AT (1) | ATE81971T1 (en) |
AU (1) | AU611512B2 (en) |
CA (1) | CA1315690C (en) |
DE (1) | DE3875716D1 (en) |
DK (1) | DK730488A (en) |
ES (1) | ES2052681T5 (en) |
FI (1) | FI886047A (en) |
GR (2) | GR3006182T3 (en) |
IE (1) | IE62643B1 (en) |
NO (1) | NO885820L (en) |
PT (1) | PT89350B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4983400A (en) * | 1986-06-16 | 1991-01-08 | Merck & Co., Inc. | Controlled release combination of carbidopa/levodopa |
DE4101873C2 (en) * | 1991-01-23 | 1993-12-09 | Isis Pharma Gmbh | Orally administrable drug form for the treatment of central dopamine deficiency states |
US8815950B2 (en) | 2003-08-29 | 2014-08-26 | Janssen Biotech, Inc. | Pharmaceutical compositions and method of using levodopa and carbidopa |
EP2508174A1 (en) * | 2011-04-06 | 2012-10-10 | Ljiljana Sovic Brkicic | Pharmaceutical composition |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3557292A (en) * | 1968-08-16 | 1971-01-19 | Hoffmann La Roche | Compositions and methods for treating parkinson's disease with combinations of l-3,4-dihydroxyphenylalanine and a hydrazine |
US3769424A (en) * | 1970-10-01 | 1973-10-30 | Merck & Co Inc | Composition and method of treating dopamine deficiency in brain tissue |
CH652025A5 (en) * | 1981-09-14 | 1985-10-31 | Hoffmann La Roche | Pharmaceutical preparation. |
-
1988
- 1988-12-14 AT AT88120859T patent/ATE81971T1/en not_active IP Right Cessation
- 1988-12-14 EP EP88120859A patent/EP0324947B2/en not_active Expired - Lifetime
- 1988-12-14 DE DE8888120859T patent/DE3875716D1/en not_active Expired - Lifetime
- 1988-12-14 ES ES88120859T patent/ES2052681T5/en not_active Expired - Lifetime
- 1988-12-26 JP JP63326407A patent/JPH0296520A/en active Pending
- 1988-12-28 PT PT89350A patent/PT89350B/en not_active IP Right Cessation
- 1988-12-30 IE IE389488A patent/IE62643B1/en not_active IP Right Cessation
- 1988-12-30 NO NO88885820A patent/NO885820L/en unknown
- 1988-12-30 CA CA000587316A patent/CA1315690C/en not_active Expired - Fee Related
- 1988-12-30 AU AU27582/88A patent/AU611512B2/en not_active Ceased
- 1988-12-30 DK DK730488A patent/DK730488A/en not_active Application Discontinuation
- 1988-12-30 FI FI886047A patent/FI886047A/en not_active IP Right Cessation
-
1992
- 1992-11-05 GR GR920402503T patent/GR3006182T3/en unknown
-
1997
- 1997-10-09 GR GR970402622T patent/GR3024980T3/en unknown
Also Published As
Publication number | Publication date |
---|---|
FI886047A (en) | 1989-07-01 |
ES2052681T5 (en) | 1997-12-01 |
PT89350A (en) | 1989-12-29 |
AU2758288A (en) | 1989-07-06 |
NO885820L (en) | 1989-07-03 |
DK730488D0 (en) | 1988-12-30 |
NO885820D0 (en) | 1988-12-30 |
IE62643B1 (en) | 1995-02-22 |
PT89350B (en) | 1993-09-30 |
DK730488A (en) | 1989-07-01 |
EP0324947A1 (en) | 1989-07-26 |
CA1315690C (en) | 1993-04-06 |
ES2052681T3 (en) | 1994-07-16 |
EP0324947B2 (en) | 1997-08-20 |
DE3875716D1 (en) | 1992-12-10 |
GR3024980T3 (en) | 1998-01-30 |
ATE81971T1 (en) | 1992-11-15 |
IE883894L (en) | 1989-06-30 |
EP0324947B1 (en) | 1992-11-04 |
JPH0296520A (en) | 1990-04-09 |
GR3006182T3 (en) | 1993-06-21 |
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