CA1315690C - Synergistic combination of decarboxylase inhibitors and l-dopa pellets - Google Patents
Synergistic combination of decarboxylase inhibitors and l-dopa pelletsInfo
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- CA1315690C CA1315690C CA000587316A CA587316A CA1315690C CA 1315690 C CA1315690 C CA 1315690C CA 000587316 A CA000587316 A CA 000587316A CA 587316 A CA587316 A CA 587316A CA 1315690 C CA1315690 C CA 1315690C
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- 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
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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
ABSTRACT OF THE DISCLOSURE
Synergistic combination of L-dopa pellets and decarboxylase inhibitors as a medicament against Parkinson's disease.
Synergistic combination of L-dopa pellets and decarboxylase inhibitors as a medicament against Parkinson's disease.
Description
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The present invention is a Synergistic combination of decarboxylase inhibitors and L-dopa pellets Decarboxylase inhibitors are medically active substances having the proper-ty to block peripheral decarboxylases (that is decarboxylases present in the intes~ine and blood circulation). Decarboxylase inhibitors which may be used are benserazide [DL-serine-2-~2,3,4-trihydroxybenzyl)-hydrazide], carbidopa ( (-)-L-dC-hydrazino-3,4-dihydroxy-d~-methyl-hydrocinnamic acid), L-serine-2-(2,3,4-trihydroxybenzyl)-hydrazide, glycine-2-(2,3,4-trihydroxybenzyl)-hydrazide, L-tyrosine-2-(2,3,4-trihydroxybenzyl)hydrazide, in particular benserazide.
L-dopa [ (S)-2-amino-3-(3,4-dihydroxyphenyl) propionic acid] is a medically active substance with pronounced antiparkinsonian activity.
The comblnation of the decarboxylase inhibitor benserazide and L-dopa has been known since 1960. The L-dopa was not present in pellet form in this case. This formulation has the disadvantage that, when used in the treatment of Parkinson's disease, this combination leads to severe fluctuations in plasma level and thus to considerable response fluctuations, for example to so-called on~off symptoms (particularly in later stages of the illness), whereby the patient is suddenly overcome by immobility.
For a long time now there has therefore been a need for an improved dosage form with prolonged action with which, for example, the on-off symptoms are reduced lsee S.M. Stahl, New Drug Delivery Systems - a new approach to Parkinson's disease, Symposium HarlowJGB 8.7.1985).
The present invention provides an improved medicament composed of decarboxylase inhibitors and L-dopa with prolonged and improved effect or the treatment of Parkinson's disease.
~3~ 913 It has now surprisingly been found that with the use of a combination of decarboxylase inhibitors and L-dopa pellets, wherein the pellets can also demonstrate a delayed release (a so-called retardation) of the active substance, a prolonged andimproved 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:
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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) ar~ avoided~ Using the sustained release combination, effective L-dopa serum concentrations are built up over a longer period of time than with the stnndard combination. For this reason, and because of the lo~er frequency of admini~tration of the sustained relea~e combination, the therapeutic L-dopa dosage can be cumulatively reduced. Since the L-dopa side effects syndrome depends on cumulative dosage, the sustained release combination also makes it possible to reduce this long-term side effect.
The improvement and prolongation of the effect of the combination of the invention can be demonstrated as follows as compared to the standard combination: following the administration of the oombination to Parkinson patients in the evening, patients' nocturnal movements are measured by acaelerometry of the arms and legs. In the akinesia stage, Parkinson patients commence their attempts at mo~ement with the legs. A ahange over from movement of the leg~ to that of the arms indicates an improvement in the clinical picture of the patient.
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Reduced morning akinesia after administration of the combinatlon 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 benserazide in which, ho~ever, the L-dopa is also not present in pellet form. The 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.
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.
The invention relates to medicaments according to the patent claims as well as to the use of decarboxylase inhibitors and their salts with physiologically acceptable acids or bases together with L-dopa p~llets, also in separate formulations in each case.
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The amounts or parts by weight quoted herein 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.
The benserazide is preferably used as a pharmaceutically acceptable acid addition salt, salts with halohydric acids (for example the hydrochloride, hydrobromlde) or also with organic acids (for example embonic acid, maleic acid, citric acid, tartaric acid) being particularly suitable.
Carbidopa and L-dopa are generally not used in the form of pharmaceutically acceptable salt. Should L-dopa be used as a pharmaceutically acceptable salt this is, for example, a salt with physiologically acceptable alkali or alkaline earth metals.
The daily doses of the combination of the invention consist, for example, 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.
The daily doses may be given in the form of a single administration of the total amount or in the form of 1 to 10, in particular 2 to 8 partial doses per day. In general, administration 3 to 6 times, in particular 4 to 5 times daily, 3~
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is preferred. The preferred dose of the combination of decarboxyl`ase 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 times daily.
Decarboxylase inhibitors and L-dopa are, for example, used in the following weight ratios in accordance ~ith the invention: 1 part by weight of decarboxylase inhibitor is for example used or combined with 0.5 to 100 parts by weight of L-dopa, preferably 1 part by weight of dacarboxylase inhibitor with 1 to 50 parts by weight of L-dopa, in particular 1 part by weight of dacarboxylas~ inhibitor with 2 to 20 parts by weight of L-dopa.
For the combination, 50 to 1,000 mg of L-dopa and 10 to 100 mg o decarboxylase inhibitor, preferably 100 to 500 mg of L-dopa and 25 to 50 mg of decarboxylase inhibitor may, for example, easily be formulated into the medication.
The dosage unit of the combination of the invention can for ~xample contain~
10 to 100 mg of deca~boxylase inhibitor, preferably 10 to 50 mg, in particular 25 to 50 mg of decarboxyl~se inhibitor and 50 to 1,000 mg, preferably 50 to 500 mg, in particular 100 to 500 mg ~3~LS6~
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 relate to application in humans are in each case related to the free bases and fr~e acids respectively.
The term pellets should be understood to cover spherical or cylindrical shapes having a diameter between 0.1 and 2 mm. Thay are produced by pressing suitable powder mixtures with tabletting presses, compactors or perforated rubber plates or by pasting through addition of solutions or solvents, pressing the resulting plastic mass through perforated discs, dividing, rounding off and drying the resulting strands.
Another possible mnnner of preparation lies in the simultaneous or successive application of the active substances with or without binding agents onto neutral pellets having no active substance (so-called nonpareils).
' ~3~s~a 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 methacrylic resins with exchangeable proton, i.e.
acid, in particular weakly acid, yroups such as COOe (for example AmberliteR IRP-64);
polystyrene resins with exchangeable Na+, acid groups:
S03e (for example AmherliteR IRP-69).
The ion exchangers are acid ion axchangers. The maximum ratio of L-dopa : ion exchanser is ca. 1:1, the minimum ratio about 1 part by weight of L-Dopa to ~00 parts of ion exchanger resin. Preferably 1 to 400 parts by weight of ion exchanger, quite particularly preferably 1 to 100 parts by weight of ion exchanger are used per 1 part by weight of .L-Dopa.
The binding of the L-dopa is effacted by allowing an L-dopa solution to flow through a bed of the ion exchanger in a column.
The charged ion exchanger is dried at temperatures up to about ~0 C. The chargsd ion exchanger particles are pr~ferably also providQd with a coating such as described, for example, in US-A-4,~21,776 An advantage of th~ additional coating is that the releasQ rate of the~active sub~tance can be changed and influenced by the choice of tha aoating material. Hot air at 13~L5G9O
70 C to 90 C 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.
The preparation of the pellets used according to the invention is effected in the conventional manner.
Pellets with controlled release of the active substance are preferably used, whereby khese may be pellets which either only contain L-dopa or pellets which contain both L-dopa and decarboxylase inhibitor. The pellets with controlled release are preferably obtained by coating pellets prepared in the conventional manner with the named active substances in known 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 te.g. EudragitR RS), copolymerisates of acrylic and methacrylic acid esters and trimethylammonium methacrylate le.g. EudragitR ~L);
polyvinylacetate; fats, oils, waxes, fatty alcohols;
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hydroxypropylmethylcellulose phthalate or -acetate succinate;
cellulose-, st~rch- and polyvinylacetate phthalata;
carboxymethyl cellulose; methyl cellulose-phthalate,-succinate, -phthalate succinate 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-maleic acid copolymerisate; 2-ethylhexylacrylate maleic a~id anhy~ride; crotonic acid-vinylacetate copolymer; glutamic acid/glutaminic acid ester copolymer;
carboxymethylethylcellul~se ylycerine 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 pellets.
Saparate coating substances for gastric juice resistance are the conventional ones, ~or example physiologically acceptable polymers with free carboxy groups such as copolymerisates of ~crylic acid and/or methacrylic acid, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, methyl cellulose phthalate à~d other phthalates.
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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 oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalate), D-(2-methoxy or ethoxyethyl)-phthalate, ethylphthalyl, butylphthalylethyl-and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate, di(2.-methoxy- or ethoxyethyladipate)); benzophenonQ; diethyl-and dibutylsebacate, -succinate, -tartrate; diethyleneglycol-dipropionate; ethyleneglycol diacetate, -dibutyra~e, -dipropionate tributylphospha'e, tributyrin; hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethyleneglycol-sorbitane monooleate (polysorbates such as polysorbat 80);
sorbitane monooleate, polyvinylpyrrolidone For the coating layer it is possible to use one or several of the coating substances mentioned as well as one or several of the plasticizing agQntS mentioned. The coating layer can contain additional substances for controlling the release of the L-dopa.
Thesa are water-soluble substances such as polyethylene glycols, polyvinylpyrrolidone, copolymerisates of polyvinylpyrrolidone and polyvinylacetate,~olyvinylacetate and similar. For the same purpose it is, however, also possible to use the already mentioned plasticizing agents hydroxypropyl cellulose and/or :
~ 5~9~ 1 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, wheraby further auxiliary substances may be added to optimize workability ~uch as, for example, surface activa substances, solid substances such as talcum andJor 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 C.
In the preparation of L-dopa pellets through dropping a mslt of L-dopa into fat-like substances or waxes, the following substances can, for example, be used: glycerides of saturated fatty acids C8H162 to C1gH16O2~ hydrated peanut oil, hydrated castor oil, hydrated cottonseed oil, stearic acid, p&lmitic acid, 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 or - . .:
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branched chains) of chain length CgH170H to C30H610H, in particular c12H25oH to ~24H49H
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 (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose), sodium alginate, pectin, tragacanth, polyvinylpyrrolidone, polyvinylacetate, polyvinyl ~lcohol, copolymerisate of vinylpyrrolidone and vinylacetate.
The pellets may~ however, also be prepared by embedding L-dopa into the following substances or mixtures of the following substances:
- digestible fats, for example triglycerides of saturated fatty acids CgH1602 to C1gH3602 and thair mixtures, peanut oil and hydrated peanut oil, castor oil and hydrated castor oil, olive oil, sesame oil, cottonseed oil and hydrated cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, mixtures of mono-, di-, triasters of palmitin and stearic acid with glycerine, glycerine trioleate, diglycolstearate, stearic acid.
- undigestible fats or fat-like substances, for example :.
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esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atom~, 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 C8H17OH to C30H61OH, in particular C12H25OH to C24~49OH.
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- polymers such as polyvinyl alcohol, poly~inyl chloride, polyacrylic acid;
anionic polymerisates of methacrylic acid and methacrylic acid estQrs (EudragitR L, EudragitR S), acrylic and methacrylic acid ester copolymerisates with trimethyl ammonium methacrylate (EudragitR RL, EudragitR RS), copolymerisate of acrylic acid ethyl- and methacrylic acid methyl esters EudragitR NE 30 D), as well as from acrylic acid, methacrylic acid as well as their estera (ratio of free carboxy groups to the ester groups 1:1) (Eudragit~ L
30 DJ, polyethylene, polyglycol acid, polyhydroxybutyric acid, polylactic acid, copolymers of lactic acid and glycolic acid (manufacturer: Boehringer Ingelheim), copolymers of lactic acid and ethylene oxide as well as glycolic acid and ethylene oxide, hydroxypropylmethyl cellulose-phthalate or -acetate succinate; cellulose acetate phthalate, starch acetate phthalate, ns well as polyvinylacetats phthalate; carboxymethyl cellulose;
methylcellulose-phthalate, -succinate, -phthalate succinate, ~s~
me-thylcellulose phthalic acid half ester; zein; ethyl cellulose;
shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydrlde copolymer; maleic acid anhydride-vinylmethylether copolymer; styrol-maleic acid-copolymerisate; 2-e-thylhexyl-acrylate-maleic acid anhydride; crotonic acid-vinylacetate copolymer; glutamic acid/glutaminic acid ester copolymer;
carboxymethylcellulose-glycerine monooctanoate; cellulose acetate succinate; polyarginine.
Swelling agents such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (Pharmacoat, Methocel E
= propyleneglycol ether of methyl cellulose), alginic acid and its salts (Na-Ca-salt, also mixtures of alginic acid and calcium salts, e.g. CaHPO4), starch, carboxymethyl starch, carboxymethyl cellulose and their salts (e.g. Na-salt), galactomannan, gum arabic, karaya gum, ghatti gum, agar agar, carrageen, xanthane rubber, guar rubber and its derivatives, carob bean kernel flour, propylene glycol alginate, pectin, tragacanth.
Particulary, for example, an embedment of L-dopa and, when reqired, of the decarboxylase inhibitor in hydrophilic polymers ~or hydrocolloids, when required, with further processing aids, is also suitable.
These hydrophilic polymers or hydrocoloids are substances that are soluble in water or swelling therein, such as cellulose derivatives and varous types of gum. The hydrocolloid preferably contains cellulose derivatives, namely cellulose alkyl 3~ hydroxylates, such as hydroxy-propyl methyl cellulose, hydroxy-propyl cellulose, hydroxy-methyl cellulose or hydroxy-ethyl cellulose; cellulose alkyl carboxylates such as carboxy-methyl cellulose or carboxy-ethyl sellulose and alkali metal salts of cellulose alkyl carboxylates, such as sodium-carboxy methyl and sodium-carboxy ethyl cellulose or acrylic acid homopolymers or copolymers or their alkali metal salts.
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The molecular weigh-t ancl the degree of other substitution of the cellulose ether are not critical and any of the commercial products can be used in the present invention.
The cellulose ther used usually has a viscosity of 3 to 100 OQ0, preferably 3 to 10 000 and particularly preferred 6 to 6 000 centipoises as determined in an aqueous 2 percent by weight solution at 20C.
Furthermore, the cellulose ether used usually has a degree of ether substitution of 0.1 to 6, preferably 0.4 to 4.6.
The acrylic acid copolymer can be a copolymer from acrylic acid with allyl saccharose, methyl acrylate, methacrylic acid, methyl methacrylate, hydroxy-ethyl methacrylate, styrene or a monomer of vinyl ether, such as methyl-vinyl ether. The proportion of comonomer can be varied within the range in which the copolymer is soluble in water or capable of swelling therein.
The proportion usually is not higher than approximately 20 moles, relative to the copolymer.
A commercial mixture of acrylic acid having homopolymer or copolymer with a small amount (usually not more than 20 % by weight) of anther water-soluble polymer ~for e~ample, a methacrylic acid homo or heteropolymer or its salt or polyethylene glycol) can also be used. Suitable pharmacoligically acceptable salts of acrylic acid homopolymers or copolymers are alkali metal salts, such as sodium or potassium salts and ammonium salts. The degree of neutralization of the salts is not limited.
The acrylic acid homopolymers or copolymers or their pharmacologically acceptable salts can have any molecular weight.
They usually have a viscosity of 36O to 165 000, preferably 3600 to 165 000 centipoises. The viscosity is determined in a 2.2 %
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by weight aqueous solution oE the sodium salt having a pH value of 7 to 7.5 at 25C + 0.5C.
The acrylic acid homo or copolymers or their pharmacologically acceptable salts can be used individually or as mixture. In the preparations according to the present invention other known hydrocolloids can also be used, as for example, acacia gum, guar gum, gum tragacanth, gum xanthane, pectin, ammonium or sodium alginate, mlxtures of sodium or ammonium alginate wlth physiologically acceptable calcium salts (for example, calcium gluconate, calcium hdyrogen phosphate, calcium chloride) or their mixtures.
Preferred hydrocolloids are sodium carboxy-methyl cellulose, hydroxy-propyl-methyl cellulose (such as Celacol HPM
or Methocel E or K), polyacrylic acid (such as Carbopol 934P) or the above-mentioned alginates.
In particular ~t 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 auxiliary substances.
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In the case of these sustained release components it is possible for example to use 1 to 800 parts by ~eight 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 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 melt and breaking up into small pieces can also be combined in one step by disper~ing the melt in cold water or subjecting it to a spray hardening or dropp;ng with v;bration.
~hrough mixing of L-dopa with the mentioned fats, polymers or swelling agents or mixtures of these substances, also with the use of heat, And forming of the mixtures, possibly after addition of other auxiliary substancesj into pellets;
through mixing of L-dopa with solutions of the mentioned fats or polymers in WAter or organic solvents suah as, for example, ethanol, ethyl acetate, acetone or isopropanol, possibly mixing with carrier materials such as celluloses, as well as su~sequent evaporation of the solvents and mixing the embedded active l lo -., .
131569~
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 polyvinylpyrrolidone or copolymers of polyvinylpyrrolidone and polyvinylac0tate and subsequent formation of pellets which ar~ subse~uently dried.
The pharmaceutical compositions or medications contain as active substance the combination of the invention in a formulation. The individual active sub~tances of the combination can, however, also be present in each case in separate formulations, whereby the already cited amounts of active substance are used in each case for the corresponding dosage unit. The active substances or the activa substance combination is optionally present in 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 and diluting agents can be used.
For example the pelle~ts can be worked into tablets which disintegrate in the stomach or intestine and release the pellets there.
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Carriers and auxiliary substances which can be used for the pharmaceutical formulations are, for example, those substances which are recommended or quoted in the follo~ing literature references as auxillary substances for pharmacy, cosmetics and related fields: Ullmanns Encyklopaedie der technischen Chemie, Volume 4 (1953), pages 1 to 33; Journal of Pharmaceutical Sciences, Volume 52 (1963), pages 918 et seq., H.v.Czetsch-Lindenwald, Hilfsstoffe fuer Pharmazie und angrenzende Gebiete, Pharm. Ind., Issue 2, 1961, pages 72 et seq.; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fuer Pharmazie, Kosmetik und angrenzende Gebiete Cantor KG. Aulendorf in Wuerttemberg 1981~
Examples hereof are gelatine, natural sugars such as cane sugar or milk sugar, lecithin, pectin, starch (for example corn starch), cyclodextrine and cyclodextrine derivatives, polyvinylpyrrolidone, polyvinylacetate, gelatine, gum arabic, alginic acid, tylose, talcum, lycopodium, silicic acid (for example colloidal), cellulose, cellulose derivatives (for example cellulose ether in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and/or lower saturated aliphatic oxyalcohols, for example methyloxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose hydroxypropylmethyl cellulose phthalate); fatty acids as well as magnesium-, calcium- or aluminium ~nlts of fatty acids with 12 to 22 carbon atoms, in particular the _ 18 ~
.... - --` ~a3~L~6~ 1 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-, dl- and triglycerides of saturated fatty acids C12H242 to C18H362 and their mixtures), pharma-ceutically tolerated mono or multivalent alcohols and polyglycols such as polyethylene glycols as well as derivatives hereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carhon atoms, in particular 10 to 18 carbon atoms) with monovalent aliphatic alcohols (1 to ~0 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 alcohol, polyglycol ether with C1-C12 alcohols, dimethylacetamide, lactamide, lactate, ethyl carbonate, silicons (in particular medium viscous polydimethyl siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and similar.
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Other auxiliary substances which can be considered are substances which bring about disintegration tso called disintegrants), such as: cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose as well as cross-linked or mlcrocrystalline cellulose.
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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, trichloroethane, acetone~ 1,2-propylene glycol, polyglycols and their derivatives, dimethylsulphoxide, fatty alcohols, .
triglyceride~, partial esters of glycerine, paraffins and similar. I
In the preparation of the formulations it is possible to use known and conventional solubilizars 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 ethoxylated fatty acid esters of sorbitane, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolisated oleotriglycerides, polyethylene oxide condensatian products of 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 genarally lies between~2 and 40 and in particular between 10 and 20.
`' ' ~ . ' .
' 31S~9~
Polyoxyethylated substances of this type may, for example, be obtainad 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 oxidQ per Mol of glyceride).
Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil.
See also Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fuer 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 examplQ lecithin, ascorbic acid, phosphoric acid). The use of synergists considerably boosts the antioxygenic action of the tocopherols.
Tha pharmaceutical and galenic treatment of the active substancas is effQcted using the conventional standard methods.
For~example active substance(s) are thoroughly mixed with.
auxiliary or carrier a~ubstances through stirring or homogenizing (for example using conventional mixing apparatus), working generally bQing at temperatures between 20 and 80 C, ' , ' : - ' 5~
preferably 20 to 50 C, in particular at room temperature.
Reference is made here to the following standard work: Sucker, Fuchs, Speiser, Pharmazeutische Technologie, Thieme-Verlag Stuttgart, 1978.
Application may be in the interior of the body, for example oral or enteral.
The ccmbination of the invention may also be present as a product in which the two individual active substances are in each case present in separate formulations so that administration may be separate or at differently graded times.
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 weight ratios in which they may be present in the combined 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`~ecarboxylase inhibitor.
.
~3~ V
The acute toxicity of the combination of the invention, expressed in the LD 50, is for example above 1,700 mg/kg i~ 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 hydrochloride 2,000 g of L-dopa are mixed with 220 g of microcrystallina cellulose and the mixture thoroughly moistened with a solution of 60 g of Polysorbate 80 in 820 g of purified water. The moist mass is fed through an extruder (perforation size 0.8 mm) and the strands obtained divided and rounded off using a spheronizer. The moist pellets obtained are dried in a fluidized air bed dryer to a relative humidity (equilibrium humidity) of 25-35 ~. The dried pellets are sieved. Only the sieve fraction of 0.5 to 1.25 mm is further processed~
1,600 g of the pellets are sprayed with a film suspension which is prepared as follows:
28 g of tri~thylcitrate are emulsified with 0.3 g of Polysorbate 80 ln 110 g of purified water and the emulsion mixed with 460 g o~ a 30 % suspension o~copolymerisates of acrylic and methacrylic acld esters with a purified content of ammonium groups (for example EudragitR RS 30 D). 68 g of talcum are suspended in 515 g of purified water with the aid of a : , . . .
- - . ' ~
,~ : , :.
, 1~1569U
conventional homogenizing apparatus and the suspension i5 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 oE the dried pellets is 1,628 g.
1,500 g of pellets of the sieve fraction below 1.25 mm are then j~
sprayed with the following lacquer suspension (coating ~or 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 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 ~tirred into the above obtained dispersion after addition of a few drops of ~ilicon antifoaming ~il. Coating of the suspension thus obtained onto the pellets is effected as described above.
Suspension is sprayed on until the total weight of the dried pellets is 1,978 g.
`` ~3~5~
570 g of benserazide hydrochloride are mixed wikh 420 g of lactosa and granulated with a solution of 20 g of gelatine in 180 g of purified water in the conventional manner. Eollowing drying and sieving of the granulate through a sieve of mesh size 0.8 mm, 6 g of magnesium stearate and 4 g of highly disperse silicon dioxide are added with mixing.
51 mg of the mixture together with in each case 153 mg of the ~bove described lacquered pellets are filled into size 2 hard gelatinQ capsules. I
i' One hard gelatine capsu~le 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 according to the process set out in US Pharmacopoeia, 21st Edition (USP
XXI) using the dissolution test appliance, apparatus 2. The releass of the L-dopa in 900 ml of buffer solution is determined at 37C at a paddle revolution speed of 120 rpm. For the first 2 hours the test solution consists of 0.06 molar salt solution, I
after which the pellets are transferred to a phosphate buffer solution pH 6 . 8 of the European Pharmacopoeia~ The release of the L-dopa from the bùf~er solutions is measured in each case.
The release of the L-dopa is . .
~' ' , ~`
-~ ~3~
.. ' after 1 hour 0.1 - 0.2 % in 0.06 m HCl 2 hours 0.3 - 0.9 %
The present invention is a Synergistic combination of decarboxylase inhibitors and L-dopa pellets Decarboxylase inhibitors are medically active substances having the proper-ty to block peripheral decarboxylases (that is decarboxylases present in the intes~ine and blood circulation). Decarboxylase inhibitors which may be used are benserazide [DL-serine-2-~2,3,4-trihydroxybenzyl)-hydrazide], carbidopa ( (-)-L-dC-hydrazino-3,4-dihydroxy-d~-methyl-hydrocinnamic acid), L-serine-2-(2,3,4-trihydroxybenzyl)-hydrazide, glycine-2-(2,3,4-trihydroxybenzyl)-hydrazide, L-tyrosine-2-(2,3,4-trihydroxybenzyl)hydrazide, in particular benserazide.
L-dopa [ (S)-2-amino-3-(3,4-dihydroxyphenyl) propionic acid] is a medically active substance with pronounced antiparkinsonian activity.
The comblnation of the decarboxylase inhibitor benserazide and L-dopa has been known since 1960. The L-dopa was not present in pellet form in this case. This formulation has the disadvantage that, when used in the treatment of Parkinson's disease, this combination leads to severe fluctuations in plasma level and thus to considerable response fluctuations, for example to so-called on~off symptoms (particularly in later stages of the illness), whereby the patient is suddenly overcome by immobility.
For a long time now there has therefore been a need for an improved dosage form with prolonged action with which, for example, the on-off symptoms are reduced lsee S.M. Stahl, New Drug Delivery Systems - a new approach to Parkinson's disease, Symposium HarlowJGB 8.7.1985).
The present invention provides an improved medicament composed of decarboxylase inhibitors and L-dopa with prolonged and improved effect or the treatment of Parkinson's disease.
~3~ 913 It has now surprisingly been found that with the use of a combination of decarboxylase inhibitors and L-dopa pellets, wherein the pellets can also demonstrate a delayed release (a so-called retardation) of the active substance, a prolonged andimproved 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:
. .
~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) ar~ avoided~ Using the sustained release combination, effective L-dopa serum concentrations are built up over a longer period of time than with the stnndard combination. For this reason, and because of the lo~er frequency of admini~tration of the sustained relea~e combination, the therapeutic L-dopa dosage can be cumulatively reduced. Since the L-dopa side effects syndrome depends on cumulative dosage, the sustained release combination also makes it possible to reduce this long-term side effect.
The improvement and prolongation of the effect of the combination of the invention can be demonstrated as follows as compared to the standard combination: following the administration of the oombination to Parkinson patients in the evening, patients' nocturnal movements are measured by acaelerometry of the arms and legs. In the akinesia stage, Parkinson patients commence their attempts at mo~ement with the legs. A ahange over from movement of the leg~ to that of the arms indicates an improvement in the clinical picture of the patient.
~3~
Reduced morning akinesia after administration of the combinatlon 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 benserazide in which, ho~ever, the L-dopa is also not present in pellet form. The 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.
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.
The invention relates to medicaments according to the patent claims as well as to the use of decarboxylase inhibitors and their salts with physiologically acceptable acids or bases together with L-dopa p~llets, also in separate formulations in each case.
~L3~56~
The amounts or parts by weight quoted herein 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.
The benserazide is preferably used as a pharmaceutically acceptable acid addition salt, salts with halohydric acids (for example the hydrochloride, hydrobromlde) or also with organic acids (for example embonic acid, maleic acid, citric acid, tartaric acid) being particularly suitable.
Carbidopa and L-dopa are generally not used in the form of pharmaceutically acceptable salt. Should L-dopa be used as a pharmaceutically acceptable salt this is, for example, a salt with physiologically acceptable alkali or alkaline earth metals.
The daily doses of the combination of the invention consist, for example, 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.
The daily doses may be given in the form of a single administration of the total amount or in the form of 1 to 10, in particular 2 to 8 partial doses per day. In general, administration 3 to 6 times, in particular 4 to 5 times daily, 3~
.
~3~
is preferred. The preferred dose of the combination of decarboxyl`ase 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 times daily.
Decarboxylase inhibitors and L-dopa are, for example, used in the following weight ratios in accordance ~ith the invention: 1 part by weight of decarboxylase inhibitor is for example used or combined with 0.5 to 100 parts by weight of L-dopa, preferably 1 part by weight of dacarboxylase inhibitor with 1 to 50 parts by weight of L-dopa, in particular 1 part by weight of dacarboxylas~ inhibitor with 2 to 20 parts by weight of L-dopa.
For the combination, 50 to 1,000 mg of L-dopa and 10 to 100 mg o decarboxylase inhibitor, preferably 100 to 500 mg of L-dopa and 25 to 50 mg of decarboxylase inhibitor may, for example, easily be formulated into the medication.
The dosage unit of the combination of the invention can for ~xample contain~
10 to 100 mg of deca~boxylase inhibitor, preferably 10 to 50 mg, in particular 25 to 50 mg of decarboxyl~se inhibitor and 50 to 1,000 mg, preferably 50 to 500 mg, in particular 100 to 500 mg ~3~LS6~
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 relate to application in humans are in each case related to the free bases and fr~e acids respectively.
The term pellets should be understood to cover spherical or cylindrical shapes having a diameter between 0.1 and 2 mm. Thay are produced by pressing suitable powder mixtures with tabletting presses, compactors or perforated rubber plates or by pasting through addition of solutions or solvents, pressing the resulting plastic mass through perforated discs, dividing, rounding off and drying the resulting strands.
Another possible mnnner of preparation lies in the simultaneous or successive application of the active substances with or without binding agents onto neutral pellets having no active substance (so-called nonpareils).
' ~3~s~a 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 methacrylic resins with exchangeable proton, i.e.
acid, in particular weakly acid, yroups such as COOe (for example AmberliteR IRP-64);
polystyrene resins with exchangeable Na+, acid groups:
S03e (for example AmherliteR IRP-69).
The ion exchangers are acid ion axchangers. The maximum ratio of L-dopa : ion exchanser is ca. 1:1, the minimum ratio about 1 part by weight of L-Dopa to ~00 parts of ion exchanger resin. Preferably 1 to 400 parts by weight of ion exchanger, quite particularly preferably 1 to 100 parts by weight of ion exchanger are used per 1 part by weight of .L-Dopa.
The binding of the L-dopa is effacted by allowing an L-dopa solution to flow through a bed of the ion exchanger in a column.
The charged ion exchanger is dried at temperatures up to about ~0 C. The chargsd ion exchanger particles are pr~ferably also providQd with a coating such as described, for example, in US-A-4,~21,776 An advantage of th~ additional coating is that the releasQ rate of the~active sub~tance can be changed and influenced by the choice of tha aoating material. Hot air at 13~L5G9O
70 C to 90 C 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.
The preparation of the pellets used according to the invention is effected in the conventional manner.
Pellets with controlled release of the active substance are preferably used, whereby khese may be pellets which either only contain L-dopa or pellets which contain both L-dopa and decarboxylase inhibitor. The pellets with controlled release are preferably obtained by coating pellets prepared in the conventional manner with the named active substances in known 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 te.g. EudragitR RS), copolymerisates of acrylic and methacrylic acid esters and trimethylammonium methacrylate le.g. EudragitR ~L);
polyvinylacetate; fats, oils, waxes, fatty alcohols;
_ -"'' .
~3~5~
hydroxypropylmethylcellulose phthalate or -acetate succinate;
cellulose-, st~rch- and polyvinylacetate phthalata;
carboxymethyl cellulose; methyl cellulose-phthalate,-succinate, -phthalate succinate 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-maleic acid copolymerisate; 2-ethylhexylacrylate maleic a~id anhy~ride; crotonic acid-vinylacetate copolymer; glutamic acid/glutaminic acid ester copolymer;
carboxymethylethylcellul~se ylycerine 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 pellets.
Saparate coating substances for gastric juice resistance are the conventional ones, ~or example physiologically acceptable polymers with free carboxy groups such as copolymerisates of ~crylic acid and/or methacrylic acid, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, methyl cellulose phthalate à~d other phthalates.
-- 10 ~
: . :,. ..
~3~5~
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 oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalate), D-(2-methoxy or ethoxyethyl)-phthalate, ethylphthalyl, butylphthalylethyl-and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate, di(2.-methoxy- or ethoxyethyladipate)); benzophenonQ; diethyl-and dibutylsebacate, -succinate, -tartrate; diethyleneglycol-dipropionate; ethyleneglycol diacetate, -dibutyra~e, -dipropionate tributylphospha'e, tributyrin; hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethyleneglycol-sorbitane monooleate (polysorbates such as polysorbat 80);
sorbitane monooleate, polyvinylpyrrolidone For the coating layer it is possible to use one or several of the coating substances mentioned as well as one or several of the plasticizing agQntS mentioned. The coating layer can contain additional substances for controlling the release of the L-dopa.
Thesa are water-soluble substances such as polyethylene glycols, polyvinylpyrrolidone, copolymerisates of polyvinylpyrrolidone and polyvinylacetate,~olyvinylacetate and similar. For the same purpose it is, however, also possible to use the already mentioned plasticizing agents hydroxypropyl cellulose and/or :
~ 5~9~ 1 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, wheraby further auxiliary substances may be added to optimize workability ~uch as, for example, surface activa substances, solid substances such as talcum andJor 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 C.
In the preparation of L-dopa pellets through dropping a mslt of L-dopa into fat-like substances or waxes, the following substances can, for example, be used: glycerides of saturated fatty acids C8H162 to C1gH16O2~ hydrated peanut oil, hydrated castor oil, hydrated cottonseed oil, stearic acid, p&lmitic acid, 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 or - . .:
. .
~3~5~
branched chains) of chain length CgH170H to C30H610H, in particular c12H25oH to ~24H49H
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 (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose), sodium alginate, pectin, tragacanth, polyvinylpyrrolidone, polyvinylacetate, polyvinyl ~lcohol, copolymerisate of vinylpyrrolidone and vinylacetate.
The pellets may~ however, also be prepared by embedding L-dopa into the following substances or mixtures of the following substances:
- digestible fats, for example triglycerides of saturated fatty acids CgH1602 to C1gH3602 and thair mixtures, peanut oil and hydrated peanut oil, castor oil and hydrated castor oil, olive oil, sesame oil, cottonseed oil and hydrated cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, mixtures of mono-, di-, triasters of palmitin and stearic acid with glycerine, glycerine trioleate, diglycolstearate, stearic acid.
- undigestible fats or fat-like substances, for example :.
: . :
,~
6~ ~
esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atom~, 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 C8H17OH to C30H61OH, in particular C12H25OH to C24~49OH.
. .
- polymers such as polyvinyl alcohol, poly~inyl chloride, polyacrylic acid;
anionic polymerisates of methacrylic acid and methacrylic acid estQrs (EudragitR L, EudragitR S), acrylic and methacrylic acid ester copolymerisates with trimethyl ammonium methacrylate (EudragitR RL, EudragitR RS), copolymerisate of acrylic acid ethyl- and methacrylic acid methyl esters EudragitR NE 30 D), as well as from acrylic acid, methacrylic acid as well as their estera (ratio of free carboxy groups to the ester groups 1:1) (Eudragit~ L
30 DJ, polyethylene, polyglycol acid, polyhydroxybutyric acid, polylactic acid, copolymers of lactic acid and glycolic acid (manufacturer: Boehringer Ingelheim), copolymers of lactic acid and ethylene oxide as well as glycolic acid and ethylene oxide, hydroxypropylmethyl cellulose-phthalate or -acetate succinate; cellulose acetate phthalate, starch acetate phthalate, ns well as polyvinylacetats phthalate; carboxymethyl cellulose;
methylcellulose-phthalate, -succinate, -phthalate succinate, ~s~
me-thylcellulose phthalic acid half ester; zein; ethyl cellulose;
shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydrlde copolymer; maleic acid anhydride-vinylmethylether copolymer; styrol-maleic acid-copolymerisate; 2-e-thylhexyl-acrylate-maleic acid anhydride; crotonic acid-vinylacetate copolymer; glutamic acid/glutaminic acid ester copolymer;
carboxymethylcellulose-glycerine monooctanoate; cellulose acetate succinate; polyarginine.
Swelling agents such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (Pharmacoat, Methocel E
= propyleneglycol ether of methyl cellulose), alginic acid and its salts (Na-Ca-salt, also mixtures of alginic acid and calcium salts, e.g. CaHPO4), starch, carboxymethyl starch, carboxymethyl cellulose and their salts (e.g. Na-salt), galactomannan, gum arabic, karaya gum, ghatti gum, agar agar, carrageen, xanthane rubber, guar rubber and its derivatives, carob bean kernel flour, propylene glycol alginate, pectin, tragacanth.
Particulary, for example, an embedment of L-dopa and, when reqired, of the decarboxylase inhibitor in hydrophilic polymers ~or hydrocolloids, when required, with further processing aids, is also suitable.
These hydrophilic polymers or hydrocoloids are substances that are soluble in water or swelling therein, such as cellulose derivatives and varous types of gum. The hydrocolloid preferably contains cellulose derivatives, namely cellulose alkyl 3~ hydroxylates, such as hydroxy-propyl methyl cellulose, hydroxy-propyl cellulose, hydroxy-methyl cellulose or hydroxy-ethyl cellulose; cellulose alkyl carboxylates such as carboxy-methyl cellulose or carboxy-ethyl sellulose and alkali metal salts of cellulose alkyl carboxylates, such as sodium-carboxy methyl and sodium-carboxy ethyl cellulose or acrylic acid homopolymers or copolymers or their alkali metal salts.
-` ~31S6~
The molecular weigh-t ancl the degree of other substitution of the cellulose ether are not critical and any of the commercial products can be used in the present invention.
The cellulose ther used usually has a viscosity of 3 to 100 OQ0, preferably 3 to 10 000 and particularly preferred 6 to 6 000 centipoises as determined in an aqueous 2 percent by weight solution at 20C.
Furthermore, the cellulose ether used usually has a degree of ether substitution of 0.1 to 6, preferably 0.4 to 4.6.
The acrylic acid copolymer can be a copolymer from acrylic acid with allyl saccharose, methyl acrylate, methacrylic acid, methyl methacrylate, hydroxy-ethyl methacrylate, styrene or a monomer of vinyl ether, such as methyl-vinyl ether. The proportion of comonomer can be varied within the range in which the copolymer is soluble in water or capable of swelling therein.
The proportion usually is not higher than approximately 20 moles, relative to the copolymer.
A commercial mixture of acrylic acid having homopolymer or copolymer with a small amount (usually not more than 20 % by weight) of anther water-soluble polymer ~for e~ample, a methacrylic acid homo or heteropolymer or its salt or polyethylene glycol) can also be used. Suitable pharmacoligically acceptable salts of acrylic acid homopolymers or copolymers are alkali metal salts, such as sodium or potassium salts and ammonium salts. The degree of neutralization of the salts is not limited.
The acrylic acid homopolymers or copolymers or their pharmacologically acceptable salts can have any molecular weight.
They usually have a viscosity of 36O to 165 000, preferably 3600 to 165 000 centipoises. The viscosity is determined in a 2.2 %
- 15a -- ~3~5~9~
by weight aqueous solution oE the sodium salt having a pH value of 7 to 7.5 at 25C + 0.5C.
The acrylic acid homo or copolymers or their pharmacologically acceptable salts can be used individually or as mixture. In the preparations according to the present invention other known hydrocolloids can also be used, as for example, acacia gum, guar gum, gum tragacanth, gum xanthane, pectin, ammonium or sodium alginate, mlxtures of sodium or ammonium alginate wlth physiologically acceptable calcium salts (for example, calcium gluconate, calcium hdyrogen phosphate, calcium chloride) or their mixtures.
Preferred hydrocolloids are sodium carboxy-methyl cellulose, hydroxy-propyl-methyl cellulose (such as Celacol HPM
or Methocel E or K), polyacrylic acid (such as Carbopol 934P) or the above-mentioned alginates.
In particular ~t 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 auxiliary substances.
- 15b --"
-~ ~3:~L5~
In the case of these sustained release components it is possible for example to use 1 to 800 parts by ~eight 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 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 melt and breaking up into small pieces can also be combined in one step by disper~ing the melt in cold water or subjecting it to a spray hardening or dropp;ng with v;bration.
~hrough mixing of L-dopa with the mentioned fats, polymers or swelling agents or mixtures of these substances, also with the use of heat, And forming of the mixtures, possibly after addition of other auxiliary substancesj into pellets;
through mixing of L-dopa with solutions of the mentioned fats or polymers in WAter or organic solvents suah as, for example, ethanol, ethyl acetate, acetone or isopropanol, possibly mixing with carrier materials such as celluloses, as well as su~sequent evaporation of the solvents and mixing the embedded active l lo -., .
131569~
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 polyvinylpyrrolidone or copolymers of polyvinylpyrrolidone and polyvinylac0tate and subsequent formation of pellets which ar~ subse~uently dried.
The pharmaceutical compositions or medications contain as active substance the combination of the invention in a formulation. The individual active sub~tances of the combination can, however, also be present in each case in separate formulations, whereby the already cited amounts of active substance are used in each case for the corresponding dosage unit. The active substances or the activa substance combination is optionally present in 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 and diluting agents can be used.
For example the pelle~ts can be worked into tablets which disintegrate in the stomach or intestine and release the pellets there.
. ~ .
~3~56~
Carriers and auxiliary substances which can be used for the pharmaceutical formulations are, for example, those substances which are recommended or quoted in the follo~ing literature references as auxillary substances for pharmacy, cosmetics and related fields: Ullmanns Encyklopaedie der technischen Chemie, Volume 4 (1953), pages 1 to 33; Journal of Pharmaceutical Sciences, Volume 52 (1963), pages 918 et seq., H.v.Czetsch-Lindenwald, Hilfsstoffe fuer Pharmazie und angrenzende Gebiete, Pharm. Ind., Issue 2, 1961, pages 72 et seq.; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fuer Pharmazie, Kosmetik und angrenzende Gebiete Cantor KG. Aulendorf in Wuerttemberg 1981~
Examples hereof are gelatine, natural sugars such as cane sugar or milk sugar, lecithin, pectin, starch (for example corn starch), cyclodextrine and cyclodextrine derivatives, polyvinylpyrrolidone, polyvinylacetate, gelatine, gum arabic, alginic acid, tylose, talcum, lycopodium, silicic acid (for example colloidal), cellulose, cellulose derivatives (for example cellulose ether in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and/or lower saturated aliphatic oxyalcohols, for example methyloxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose hydroxypropylmethyl cellulose phthalate); fatty acids as well as magnesium-, calcium- or aluminium ~nlts of fatty acids with 12 to 22 carbon atoms, in particular the _ 18 ~
.... - --` ~a3~L~6~ 1 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-, dl- and triglycerides of saturated fatty acids C12H242 to C18H362 and their mixtures), pharma-ceutically tolerated mono or multivalent alcohols and polyglycols such as polyethylene glycols as well as derivatives hereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carhon atoms, in particular 10 to 18 carbon atoms) with monovalent aliphatic alcohols (1 to ~0 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 alcohol, polyglycol ether with C1-C12 alcohols, dimethylacetamide, lactamide, lactate, ethyl carbonate, silicons (in particular medium viscous polydimethyl siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and similar.
.
Other auxiliary substances which can be considered are substances which bring about disintegration tso called disintegrants), such as: cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose as well as cross-linked or mlcrocrystalline cellulose.
: .
, :
:
5Çi~
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, trichloroethane, acetone~ 1,2-propylene glycol, polyglycols and their derivatives, dimethylsulphoxide, fatty alcohols, .
triglyceride~, partial esters of glycerine, paraffins and similar. I
In the preparation of the formulations it is possible to use known and conventional solubilizars 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 ethoxylated fatty acid esters of sorbitane, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolisated oleotriglycerides, polyethylene oxide condensatian products of 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 genarally lies between~2 and 40 and in particular between 10 and 20.
`' ' ~ . ' .
' 31S~9~
Polyoxyethylated substances of this type may, for example, be obtainad 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 oxidQ per Mol of glyceride).
Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil.
See also Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fuer 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 examplQ lecithin, ascorbic acid, phosphoric acid). The use of synergists considerably boosts the antioxygenic action of the tocopherols.
Tha pharmaceutical and galenic treatment of the active substancas is effQcted using the conventional standard methods.
For~example active substance(s) are thoroughly mixed with.
auxiliary or carrier a~ubstances through stirring or homogenizing (for example using conventional mixing apparatus), working generally bQing at temperatures between 20 and 80 C, ' , ' : - ' 5~
preferably 20 to 50 C, in particular at room temperature.
Reference is made here to the following standard work: Sucker, Fuchs, Speiser, Pharmazeutische Technologie, Thieme-Verlag Stuttgart, 1978.
Application may be in the interior of the body, for example oral or enteral.
The ccmbination of the invention may also be present as a product in which the two individual active substances are in each case present in separate formulations so that administration may be separate or at differently graded times.
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 weight ratios in which they may be present in the combined 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`~ecarboxylase inhibitor.
.
~3~ V
The acute toxicity of the combination of the invention, expressed in the LD 50, is for example above 1,700 mg/kg i~ 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 hydrochloride 2,000 g of L-dopa are mixed with 220 g of microcrystallina cellulose and the mixture thoroughly moistened with a solution of 60 g of Polysorbate 80 in 820 g of purified water. The moist mass is fed through an extruder (perforation size 0.8 mm) and the strands obtained divided and rounded off using a spheronizer. The moist pellets obtained are dried in a fluidized air bed dryer to a relative humidity (equilibrium humidity) of 25-35 ~. The dried pellets are sieved. Only the sieve fraction of 0.5 to 1.25 mm is further processed~
1,600 g of the pellets are sprayed with a film suspension which is prepared as follows:
28 g of tri~thylcitrate are emulsified with 0.3 g of Polysorbate 80 ln 110 g of purified water and the emulsion mixed with 460 g o~ a 30 % suspension o~copolymerisates of acrylic and methacrylic acld esters with a purified content of ammonium groups (for example EudragitR RS 30 D). 68 g of talcum are suspended in 515 g of purified water with the aid of a : , . . .
- - . ' ~
,~ : , :.
, 1~1569U
conventional homogenizing apparatus and the suspension i5 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 oE the dried pellets is 1,628 g.
1,500 g of pellets of the sieve fraction below 1.25 mm are then j~
sprayed with the following lacquer suspension (coating ~or 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 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 ~tirred into the above obtained dispersion after addition of a few drops of ~ilicon antifoaming ~il. Coating of the suspension thus obtained onto the pellets is effected as described above.
Suspension is sprayed on until the total weight of the dried pellets is 1,978 g.
`` ~3~5~
570 g of benserazide hydrochloride are mixed wikh 420 g of lactosa and granulated with a solution of 20 g of gelatine in 180 g of purified water in the conventional manner. Eollowing drying and sieving of the granulate through a sieve of mesh size 0.8 mm, 6 g of magnesium stearate and 4 g of highly disperse silicon dioxide are added with mixing.
51 mg of the mixture together with in each case 153 mg of the ~bove described lacquered pellets are filled into size 2 hard gelatinQ capsules. I
i' One hard gelatine capsu~le 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 according to the process set out in US Pharmacopoeia, 21st Edition (USP
XXI) using the dissolution test appliance, apparatus 2. The releass of the L-dopa in 900 ml of buffer solution is determined at 37C at a paddle revolution speed of 120 rpm. For the first 2 hours the test solution consists of 0.06 molar salt solution, I
after which the pellets are transferred to a phosphate buffer solution pH 6 . 8 of the European Pharmacopoeia~ The release of the L-dopa from the bùf~er solutions is measured in each case.
The release of the L-dopa is . .
~' ' , ~`
-~ ~3~
.. ' after 1 hour 0.1 - 0.2 % in 0.06 m HCl 2 hours 0.3 - 0.9 %
3 hours 32 - 37 ~
4 hours 55 - 60 ~ in phosphate huffer 5 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 a) contain unlacquered L-dopa pellets b) contain L-dopa pellets which were only lacquered with one of the suspensions mentioned .
` c) contain mixtures of unlacquered and lacquered pellets.
To obtain these pellets the lacquering process should be changed accordingly. I
', ' : I .
,: I
.
,..,..., .
~3:~L5~
Example 2 Capsules containing 100 mg of L-dopa in the form of microtablets and 28.5 mg of benserazide hydrochloride.
In a mixer 9 kg of L-dopa are homogeneously mixed with 2.7 kg of methyl-hdyroxy-propyl cellulose (viscosity of 2%
solution: 15 OOOcP), 9 kg of sodium alginate, 9 ky of calcium hydrogen phosphate and 0.06 kg of magnesium stearate. The mixture is compressed so as to form biconvex -tablets having a diameter of 2 mm and a thickness of 2 mm. The tablets are coated in the usual manner with a film that is resistant to gastric juices. For example, the following procedure can be used: - 24 g of titanium dioxide and 240 g of talc are homogeneously suspended in a solution 45 g of sodium carboxy-methyl cellulose in 1000 g of purified water.
Subsequently 54 g of 1,2-propylene glycol and 597 g of water are added. This suspension is added to 1500 g of an aqueous dispersion of an anionic copolymer (50:50) based on methacrylic acid and acrylic methyl ester (EudragitR L 30 D) while stirring.
Approximately 500 g of the varnish suspension thus produced are required for 1 kg of tabletsO The coating process is carried out, for example, by using a fluidized bed apparatus at an air inlet temperature of 40 to 50C and an air outlet temperature of maximally 40C.
570 g of benserazide hydrochloride are mixed with 420 g of lactose, 6 g of magnesium stearate and 4 g of highly dispersed silicon dioxide.
This mixture ~s drawn off in batches of 50 mg together with 369 mg of the previously obtained varnished tablets into ' .
;, ' 31 ;3~5~
hard gelatin capsules having the size 0.
A hard gelatin capsule contains 100 mg of L-dopa in the form of pellet-like micro-tablets and 2~.5 mg of benserazide hydrochloride~ The liberation of L-dopa is tested as in Example 1 by means of the process of USP XXI, but at a speed of rotation of the paddle of 50 r.p.m.
The liberation of L-dopa is after 1 hour 0.5 - 1.5 % ~ in 0.06 m HCI
2 hours 2 - 4 %
3 hours 23 - 27 %
4 hours 50 - 55 %
5 hours 71 - 76 % ~ in phosphate buffer 6 hours 82 - 88 % ~ pH 6.8 7 hours more than 90 %J
In a similar manner it is possible to prepare capsules which, apart from the benserazide hydrochloride granulate mixture a) contain unlacquered L-dopa pellets b) contain L-dopa pellets which were only lacquered with one of the suspensions mentioned .
` c) contain mixtures of unlacquered and lacquered pellets.
To obtain these pellets the lacquering process should be changed accordingly. I
', ' : I .
,: I
.
,..,..., .
~3:~L5~
Example 2 Capsules containing 100 mg of L-dopa in the form of microtablets and 28.5 mg of benserazide hydrochloride.
In a mixer 9 kg of L-dopa are homogeneously mixed with 2.7 kg of methyl-hdyroxy-propyl cellulose (viscosity of 2%
solution: 15 OOOcP), 9 kg of sodium alginate, 9 ky of calcium hydrogen phosphate and 0.06 kg of magnesium stearate. The mixture is compressed so as to form biconvex -tablets having a diameter of 2 mm and a thickness of 2 mm. The tablets are coated in the usual manner with a film that is resistant to gastric juices. For example, the following procedure can be used: - 24 g of titanium dioxide and 240 g of talc are homogeneously suspended in a solution 45 g of sodium carboxy-methyl cellulose in 1000 g of purified water.
Subsequently 54 g of 1,2-propylene glycol and 597 g of water are added. This suspension is added to 1500 g of an aqueous dispersion of an anionic copolymer (50:50) based on methacrylic acid and acrylic methyl ester (EudragitR L 30 D) while stirring.
Approximately 500 g of the varnish suspension thus produced are required for 1 kg of tabletsO The coating process is carried out, for example, by using a fluidized bed apparatus at an air inlet temperature of 40 to 50C and an air outlet temperature of maximally 40C.
570 g of benserazide hydrochloride are mixed with 420 g of lactose, 6 g of magnesium stearate and 4 g of highly dispersed silicon dioxide.
This mixture ~s drawn off in batches of 50 mg together with 369 mg of the previously obtained varnished tablets into ' .
;, ' 31 ;3~5~
hard gelatin capsules having the size 0.
A hard gelatin capsule contains 100 mg of L-dopa in the form of pellet-like micro-tablets and 2~.5 mg of benserazide hydrochloride~ The liberation of L-dopa is tested as in Example 1 by means of the process of USP XXI, but at a speed of rotation of the paddle of 50 r.p.m.
The liberation of L-dopa is after 1 hour 0.5 - 1.5 % ~ in 0.06 m HCI
2 hours 2 - 4 %
3 hours 23 - 27 %
4 hours 50 - 55 %
5 hours 71 - 76 % ~ in phosphate buffer 6 hours 82 - 88 % ~ pH 6.8 7 hours more than 90 %J
Claims (31)
1. A product containing as active ingredient L-dopa in the form of pellets and decarboxylase inhibitors or salts of these compounds with physiologically acceptable acids or bases as combination preparation for simultaneous or separate administration.
2. A product according to claim 1, in which the combination includes in each case 0.5 to 100 parts by weight of L-dopa to one part by weight of decarboxylase inhibitor.
3. A product according to claim 1, in dosage unit form containing 10 - 100 mg of decarboxylase inhibitor and 50 to 1,000 mg of L-dopa (in the form of pellets).
4. A product according to claim 3, in dosate unit form containing 25 - 50 mg of decarboxylase inhibitor and 100 to 5,00 mg of L-dopa (in form of pellets).
5. A product according to claim 1, 2 or 3, in which the decarboxylase inhibitor is benserazide or carbidopa.
6. A process for the preparation of a perorally administrable product which comprises mixing or homogenizing 1 part by weight of decarboxylase inhibitor and 0.5 to 100 parts by weight of L-dopa, which comprises may be in the form of salts with physiologically acceptable acids or bases, together with conventional carrier and/or dilution or auxiliary substances at temperatures between 10 and 80°C, preparing from the mixture obtained pellets and filling the pellets into capsules or bags so that 10 - 100 mg of decarboxylase inhibitor and 50 to 1,000 mg of L-dopa are contained in a dosage unit.
7. A process according to claim 6, in which the pellets are coated.
8. A process as claimed in claim 6, in which 1 part by weight of decarboxylase inhibitor and 0.5 to 100 parts by weight of L-dopa, or salts thereof with physiologically acceptable acids or bases, are processed as follows: a) the decarboxylase inhibitor is processed with conventional auxiliary and carrier substances to a solid formulation; and b) L-dopa is processed with conventional auxiliary and carrier substances into pellets, the formulations obtained by separately or together filled into capsules or bags.
9. A process according to claim 8, in which the pellets are provided with a lacquer film.
10. A process as claimed in claim 6, in which 1 parts by weight of decarboxylase inhibitor and 0.5 to 100 parts by weight of L-dopa or salts thereof with physiologically acceptable acids or bases are processed by: a) mixing the decarboxylase inhibitor with at least one of the auxiliary substances mannitol, sorbitol, lactose, starch, and cellulose, mixing the mixture with magnesium stearate and highly disperse silicon dioxide; b) mixing L-dopa with at least one of the auxiliary substances cellulose, cellulose derivatives, lactose, starch, mannitol, sorbitol, polysorbate, saccharose, and glucose, forming the mixture into pellets or applying L-dopa onto neutral pellets which are subsequently provided with a lacquer film and subsequently combining the formulations of steps a) and b), into a medicinal packing so that the dosage unit contains 10 to 100 mg of decarboxylase inhibitor and 50 to 1,000 mg of L-dopa.
11. A process according to claim 10, in which in step (a) the mixture is granulated before mixing with magnesium stearate and highly disperse dioxide.
12. A process according to claim 11, in which in step (a) the mixture is also mixed with starch or cellulose or both.
13. A process according to claim 10, 11 or 12, in which the mixture is tabletted.
14. A process according to claim 10, in which the L-dopa in step (b) is also mixed with binding agents.
15. A process according to claim 14, in which the binding agents are selected for polyvinylpyrrolidone, vinylacetate-vinyl-pyrrolidone-copolymer, gelatine,and cellulose derivatives in the form of solutions.
16. A process according to claim 14 or 15, in which the pellets are provided with a lacquer film.
17. A process according to claim 10, in which the formulations of steps (a) and (b) are firstly filled into capsules or bags.
18. A process according to claim 10, 11 or 12, in which the decarboxylase inhibitor is benserazide or carbidopa.
19. A process for preparation of L-dopa in the form of pellets which contain 50 to 1,000 mg of L-dopa for combination with simultaneous or separate administration of a decarboxylase inhibitor for the treatment of Parkinson's disease, which comprises a) mixing 50 to 1,000 mg of L-dopa at a temperature between 10 and 80°C with conventional auxiliary and carrier substances and pressing the mixture into pellets having a diameter between 0.1 and 2 mm, or b) form of a mixture of 50 to 1,000 mg of L-dopa and conventional auxiliary and carrier substances at a temperature between 10 and 60°C with a conventional solvent into a paste and pressing the resultant plastic mass through perforated discs, dividing, rounding off and drying the resultant strands, or c) droping and causing to solidify 50 to 1,000 mg of L-dopa and at a temperature between 10 and 80°C in a melt of fat-like substances or waxes, or d) applying 50 to 1,000 mg L-dopa at a temperature between 10 and 60°C onto neutral pellets, or e) binding 50 to 1,000 mg L-dopa to particles of an acid ion exchanger.
20. A process according to claim 19, in which in steps (a) to (e) the L-dopa is in combination with 10 to 100 mg of decarboxylase inhibitor.
21. A process according to claim 19 or 20, in which the pellets obtained according to e) are coated with at least a conventional coating substance.
22. A process according to claim 19, which comprises mixing L-dopa with at least one of the auxiliary substances cellulose, cellulose derivatives, lactose, starch, mannitol, sorbitol, polysorbate, saccharose, glucose, sodium alginate, sodium alginate/calcium salts and forming the mixture into pellets, or applying L-dopa with at least one of the above named auxiliary substances onto neutral pellets.
23. A process according to claim 22, in which the pellets are coated with at least one conventional coating substance.
24. A process according to claim 22, in which the L-dopa is also mixed with a binding agent.
25. A process according to claim 24, in which the binding agent is selected from polyvinylpyrrolidine, inylacetate-vinylpyrrolidone copolymer, gelatine and cellulose derivatives in the form of solutions.
26. A process according to claim 19, in which comprises mixing 50 to 1000 mg of L-dopa and, with at least one hydrophilic polymer or hydrocolloid molding the mixture into pellets or applying mixture to the neutral pellets and providing the pellet thus obtained with a coating that is resistant to gastric juices.
27. A process as claimed in claim 26, wherein at least one of the following substances is used as hydrophilic polymers or hydrocolloid: cellulose derivatives, acrylic acid homopolymers, acrylic acid copolymers, pectins, hydrophilic gum types or alginates, and their physiologically acceptable salts.
28. A process according to claim 26, in which the L-dopa is in combination with 10 to 100 mg of decarboxylase inhibitor.
29. A process according to claim 26, 27 or 28, in which the L-dopa is also mixed with at least one of conventional binders and/or solvents.
30. L-dopa pellets containing 50 to 1,000 mg of L-dopa produced by the process of claim 10, 11 or 12.
31. L-dopa pellets containing 50 to 1000 mg of L-dopa and 10 to 100 mg of decarboxylase inhibitor which produced the process of claim 26 or 27.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3744646.0 | 1987-12-31 | ||
| DE3744646 | 1987-12-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1315690C true CA1315690C (en) | 1993-04-06 |
Family
ID=6343914
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000587316A Expired - Fee Related CA1315690C (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) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140154328A1 (en) * | 2011-04-06 | 2014-06-05 | Cvjetko Brkicic | Pharmaceutical Composition |
Families Citing this family (3)
| 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 |
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 ES ES88120859T patent/ES2052681T5/en not_active Expired - Lifetime
- 1988-12-14 DE DE8888120859T patent/DE3875716D1/en not_active Expired - Lifetime
- 1988-12-14 EP EP88120859A patent/EP0324947B2/en not_active Expired - Lifetime
- 1988-12-14 AT AT88120859T patent/ATE81971T1/en not_active IP Right Cessation
- 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 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
- 1988-12-30 IE IE389488A patent/IE62643B1/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
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140154328A1 (en) * | 2011-04-06 | 2014-06-05 | Cvjetko Brkicic | Pharmaceutical Composition |
| AU2017203939B2 (en) * | 2011-04-06 | 2019-05-30 | BRKICIC, Cvjetko | Pharmaceutical composition |
| US11103891B2 (en) * | 2011-04-06 | 2021-08-31 | Cvjetko Brkicic | Pharmaceutical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0296520A (en) | 1990-04-09 |
| NO885820D0 (en) | 1988-12-30 |
| PT89350B (en) | 1993-09-30 |
| ES2052681T5 (en) | 1997-12-01 |
| NO885820L (en) | 1989-07-03 |
| DK730488A (en) | 1989-07-01 |
| PT89350A (en) | 1989-12-29 |
| IE62643B1 (en) | 1995-02-22 |
| FI886047A (en) | 1989-07-01 |
| ATE81971T1 (en) | 1992-11-15 |
| EP0324947B1 (en) | 1992-11-04 |
| EP0324947B2 (en) | 1997-08-20 |
| IE883894L (en) | 1989-06-30 |
| AU2758288A (en) | 1989-07-06 |
| AU611512B2 (en) | 1991-06-13 |
| GR3006182T3 (en) | 1993-06-21 |
| DE3875716D1 (en) | 1992-12-10 |
| GR3024980T3 (en) | 1998-01-30 |
| ES2052681T3 (en) | 1994-07-16 |
| DK730488D0 (en) | 1988-12-30 |
| EP0324947A1 (en) | 1989-07-26 |
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