IE62643B1

IE62643B1 - Synergistic combination of decarboxylase inhibitors and L-dopa pellets

Info

Publication number: IE62643B1
Application number: IE389488A
Authority: IE
Inventors: Helmut Hettche; Manfred Albring
Original assignee: Asta Medica Ag
Priority date: 1987-12-31
Filing date: 1988-12-30
Publication date: 1995-02-22
Also published as: AU2758288A; ES2052681T3; NO885820L; ES2052681T5; EP0324947B1; NO885820D0; DK730488D0; DK730488A; JPH0296520A; EP0324947A1; GR3006182T3; ATE81971T1; PT89350A; DE3875716D1; GR3024980T3; CA1315690C; AU611512B2; IE883894L; FI886047A; EP0324947B2

Abstract

A synergistic combination of L-dopa pellets and decarboxylase inhibitors as pharmaceuticals for Parkinson's disease.

Description

Decarboxylase inhibitors are pharmaceutically active substances which have the property of blocking peripheral decarboxylases (i.e. decarboxylases occurring in the intestine and blood circulation) . The decarboxylate inhibitors may be benzerazide (DL-serine-2-(2,3,4trihydroxybenzyl)-hydrazide) , carbidopa (-)-L-a-hydrazino3 , 4-dihydroxy-c~methyl"hydrocinnamic acid), L-sarIne~2~ (2,3,4"trihydroxybenzyl)-hydrazide, giveine-2- (2,3,4trihydroxybenzyl)-hydrazide or L-tyrosine-2-(2,3,410 trihydroxybenzyl)-hydrazide, in particular benserazide.

L-Dopa ((S) -2-amino-3» (3,4-dihydroxyphenyl) -propionic acid) is a pharmaceutical agent with a pronounced antiParkinson action.

The combination of the decarboxylase inhibitor benserazide 15 and L-dopa has been known since I960. In this combination, the L-dopa is not present in pellet form. This formulation has the disadvantage that great fluctuations in the plasma level occur when this combination is used in the therapy of Parkinson’s disease, and consequently consider20 able fluctuations in response, for example in the form of tha so-called on-off symptoms (especially in later stages of the disease), in which case the patient is subject to sudden immobility.

There has therefore for a long time been a demand for an improved form of administration with prolonged action in which, for example, the on-off symptoms are reduced (see S.M. Stahl, New Drug delivery systems - a new approach to Parkinson’s disease, Symposium Harlow/GB 8.7.1985).

It is thus an object of the present invention to provide an improved medicament from decarboxylase inhibitors and L-dopa with prolonged and improved action for the treatment of Parkinson's disease.

S It has now surprisingly been found that when a combination of decarboxylase inhibitors and L-dopa pellets is used* in which the pellets may have delayed release of the active ingredient (so-called delayed action)* a prolonged and improved effect in the treatment of Parkinson's disease is observed, in particular in the advanced stages of the disease.

The following improvement, for example* is obtained compared with the hitherto conventional treatment with the combination of decarboxylase inhibitor and L-dopa15 The patients may take the delayed action combinations less frequently than the standard combinations while obtaining the same or an improved anti-Parkinson effect. Due to the delayed resorption, peak concentrations in the serum and the attendant side effects (dyskinesias) are avoided. The delayed action combination causes effective L-dopa serum concentrations to build up over a longer period of time than the standard combination. The therapeutic L-dopa dose may thus b© cumulatively reduced by this effect and due to the lower frequency of ad25 ministration. Since the L-dopa side effect syndrome depends cumulatively on the dose, this long time side effect can also be reduced by using this delayed action combination.

The improvement and prolongation of the action of the combination according to the invention compared with the standard combination can be demonstrated as follows; After administration of the evening dose of the combination to Parkinson patients, the nightly movements of the patients are measured by accelerometry of arms and legs. The Parkinson patients begin their attempts to move the lags at the stage of akinesis. A change of movement from the legs to the arms indicates an improvement in the clinical picture of the patient.

Another parameter for the improved effectiveness of the combination according to the invention compared with the standard combination is the reduced morning akinesis after administration of the combination in the evening.

US Patent Specification 3 557 292 disloses inter alia a combination of L-dopa and benserazide in which, however, the L-dopa is not in pellet form. Compared with this known combination, the combination according to the invention surprisingly has the following advantages: Reduced frequency of administration, reduction in th© rate of side effects and more uniform action.

German Offenlegungsschrift 3 232 873 discloses a combina20 tion of L-dopa and the decarboxylase inhibitors carbidopa and benserazide. Here again L-dopa is not used in pellet form. The disadvantage of this known combination compared with the combination according to the invention is that the known combination is found to have only an inadequate anti-Parkinson action and in particular the dyskinesias of the patients are prolonged.

The present invention relates to medicaments according to the Patent Claims and to the use of decarboxylase inhibitors and their salts with physiologically acceptable acids or bases together with L-dopa pellets, also in separate formulations.

The quantities by weight and parts by weight given in the Patent Claims refer to the pure active ingredients, i.e. not to the salts of these active ingredients. If salts are used, the quantities ar® to be altered in accordance with the different molecular weight of the salts.

Benserazide is preferably used as an acid addition salt, in particular a salt of a hydrohalic acid (for example the hydrochloride or hydrobromide) or of an organic acid (for example embonic acid, maleic acid, citric acid, tartaric acid). Carbidopa and L-dopa are generally not used in the form of a salt. When L-dopa is used as a salt, this may be, for example, a salt of a physiologically. acceptable alkali or alkaline earth metal.

The daily dose of the combination according to the invention may consist, for example, of from 10 to 800 mg, preferably from 20 to 300 mg, in particular from 75 to 250 mg of decarboxylase inhibitor and from 50 to 8000 mg, preferably from 100 to 3000 mg, in particular from 300 to 1500 mg of L-dopa.

The daily doses may be administered in th© form of a single dose containing the whole quantity or in the form of l to 10, in particular 2 to 8 part doses per day. It is generally preferred to administer 3 to 6 times daily, In particular 4 to 5 times. For example, the preferred dose for the combination of decarboxylase Inhibitor and L-dopa is from 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 amounts to about 25 mg of decarboxylase inhibitor and about 100 mg of L-dopa 3 to 5 times daily.

According to the invention, the decarboxylase inhibitor and L-dopa may be administered, for example, in the following ratios by weight: 1 Part by weight of decarboxylase inhibitor combined, for example, with from 0.5 to 100 parts by weight of L-dopa, preferably 1 part by weight of decarboxylase inhibitor with 1 to 50 parts by weight of L-dopa, in particular 1 part by weight of decarboxylase inhibitor with 2 to 20 parts by weight of L-dopa.

For example, a pharmaceutical preparation can easily be formulated for the combination of from 50 to 1000 mg of L-dopa and from 10 to 100 mg of decarboxylase inhibitor, preferably from 100 to 500 mg of L-dopa and from 25 to 50 mg of decarboxylase inhibitor.

The unit dose of the combination according to the invention may, for example, contain: From 10 to 100 mg of decarboxylase inhibitor, preferably from 10 to 50 mg, in particular from 25 to 50 mg of decarboxylase inhibitor, and from 50 to 1000 mg, preferably from 50 to 500 mg, in particular from 100 to 500 mg of L-dopa. These doses may be administered, for example, 1 to 8 times, preferably 2 to 6 times, in particular 3 to 5 times daily.

Galenic preparations containing the given dosing units from 2 to. for example, 5 times may, of course, also be prepared.

The doses and parts by weight given in the above pages referring to use in humans are in all cases based on the free bases or free acids.

Pellets are understood to be spherical or cylindrical preparations having a diameter of from 0.1 to 2 mm.

They are prepared by compressing suitable powder mixtures by means of tablet presses, compactors or perforated rubber plates or they may be prepared by adding solutions or solvents to form a paste and forcing the resulting plastic mass through perforated discs and subdividing th® resulting strands, forming them into round pieces and drying.

Alternatively, the pharmaceutical preparations may b® produced by simultaneously or successively applying the active ingredients, with or without binders, to neutral pellets which are free from active ingredients (so-called nonpareilles).

Another possibility lies in binding the active ingredient L-dopa to ion exchangers, for example to physiologically acceptable ion exchangers. The following are examples of suitable ion exchangers of this type: Acrylic and methacrylic resins with exchangeable proton, i.e. acid, in particular weak acid groups sueh as COO® (for example, AmberliteW IRP-64) ; polystyrene resins with exchangeable Na+, acid groups: S03® (for example, Amberlite(R) IRP 69).

The ion exchangers are acid ion exchangers. The maximum ratio of L-dopa to ion exchanger is about 1:1 and th© minimum ratio is about 1 part by weight of L-dopa to 800 parts of ion exchanger resin. From 1 to· 4 00 parts by weight of ion exchanger, most preferably from 1 to 100 parts by weight of ion exchanger, are preferably used for 1 part by weight of L-dopa.

Binding of the L-dopa is carried out by passing an L-dopa solution through a bed of the ion exchanger in a column. Th© charged ion exchanger is dried at temperatures of up to about 50*C. The charged ion exchanger particles are preferably covered with a coating, for example as described in uS-A-4 221 776. One advantage of this additional covering is that it can be used to modify and influence the rate of release of the active substance by suitable choice of the covering material. Drying of the coated charged ion exchanger particles may be carried out with air at 70 to SO’C The charged ion exchangers may then be introduced,, for 10 example, into hard gelatine capsules.

Pellets may also be obtained by dripping molten fatty substances, e.g. cetyl stearyl alcohol or waxes.

The methods of spray solidification or vibration dripping used for this purpose are known in the art.

Preparation of the pellets used according to the invention is carried out by the conventional method.

Pellets with controlled release of the active substance are preferably used. These pellets may contain L-dopa alone or both L-dopa and decarboxylase inhibitor. The pellets with controlled release are preferably obtained by coating the conventionally prepared pellets with th® aforesaid active substances in known manner, using at least one coating substance. The following coating substances may be used: Polymers and copolymers of acrylic acid and/or methacrylic acid and/or asters thereof; copolymers of acrylic and methacrylic acid esters containing a small number of ammonium groups (e.g. Eudragit(^) PS), copolymers of acrylic and methacrylic acid esters and trimethylammonium methacrylate (e.g. Eudragit^) RL) ; polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methyl cellulose phthalate or acetate succinate; cellulose-, starch- or polyvinyl acetate phthalte; carboxymethyl cellulose; methyl cellulose-phthalate, -succinate,phthalatesuccinate or -phthalate acid semiester; zexn; ethvl-cellulose and -succinate; shellac; gluten; ethyl carboxyethylcellulose; ethacrylate/maleic acid anhydride copolymer; maleic aeid anhydride/vinyl methyl ether copolymer; styrene/maleic acid copolymers; 2-ethyl-hexylacry late-maleic acid anhydride; crotonic acid/vinyl acetate copolymer; glutamic acid/glutamie acid ester copolymer; carboxymethvlathy1 cellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine.

It is, for example, also suitable to use 2 separate coating layers, one for controlled release (for example on® of those mentioned above, in which case it contains little or no free carboxyl groups) and one for resistance to gastric juice, i.e. a coating which prevents release in the stomach. This is particularly suitable for pure L-dopa pellets. Separate coatings for gastric juice resistance may be those customarily used for this purpose, for example, physiologically acceptable polymers containing free carboxyl groups, such as copolymers of acrylic acid and/or methacrylic acid, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, methyl cellulose phthalate and other phthalates.

The following plasticizing agents may be used fox* these coatings: citric and tartaric acid esters (acetyltriethyl-, acetyltributyl-, tributyl- and triethyl citrate); glycerol and glycerol esters (glycerol diacetate, triacetate, acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl, diarnyl, diethyl, dimethyl, dipropyl phthalate), D-(2-methoxy- or ethoxy,sthy 1) phthalate, ethylphthalyl, butylphthalylethyl and butylglycolate; alcohols (propylene glycol, polyethylene gly8 col of various chain lengths), adipates (diethyladipate, di-(2-methoxy or -ethoxyethyladipate)) ? benzophenone; diethyl- and dibutvlsebac&te, -succinate and -tartrate; diethvleneglycol dipropionate; ethylene glycol diacetate, -dibutyrate and -dipropionate; tributylphosphate, tributyrin; hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol sorbitan monooleate (polysorbates such as Polvsorbate 80) j sorbitan monooleate, polyvinyl pyrrolidone.

One or more of the above-mentioned auxiliary substances and one or more of the above-mentioned plasticizing agents may be used for the coating. The coating may contain additional substances to control the release of L-dopa. These are water-soluble substances such as polyethylene glycols, polyvinyl pyrrolidone, copolymers ot polyvinyl pyrrolidone and polyvinyl acetate, polyvinyl acetate and the like» The plasticizing agents already mentioned, hydroxypropyl cellulose and/or hydroxypropyl methyl cellulose, may also be used for the same purpose. In that case, they may be used, for example, in a quantity of from 0.1 to 5% by weight, preferably from 1 to 3% by weight, based on the coating substance.

The coating layer is applied by spraying solutions of the above-mentioned substances in organic solvents or suspensions of the above-mentioned substances in organic solvents or water, optionally with the addition of further auxiliary substances to optimize the processing properties, tor example, surface-active substances, solids such as talc and/or magnesium stearate and/or pigments.

The spraying may be carried out, for example, in a coating tank or in perforated tanks with- controlled supply of the drying medium or by air suspension processes; temperatures of from 10’C to 80 C are generally employed.

For preparing L-dopa pellets by dripping molten L-dopa into fatty substances or waxes, the following substances of this type, for example, may be used: Glycerides of saturated fatty acids C8H16O2 to C18H16G2, hydrogenated peanut oil, hydrogenated castor oil, hydrogenated cotton seed oil, stearic acid, palmitic acid, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with mono10 hydric aliphatic alcohols (1 to 20 carbon atoms), carnauba wax, beeswax, fatty alcohols (straight chain or branched) of chain lengths C8H17OH to G30HgiOH, in particular from ^12«25θ^ Cj^^gOH.

The following are examples of binders which may be used for the preparation by application to neutral pellets: Gelatine, gum arabic, starch paste, cellulose derivatives (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose) , sodium alginate, pectin, tragacanth, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl alcohol, copolymers of vinyl pyrrolidone and vinyl acetate.

The pellets may also be prepared hy embedding L-dopa in the following substances or mixtures of these substances: - Digestible fats, e.g, triglycerides of saturated fatty acids CgHngO? to C18H3gO2 and mixtures thereof, peanut oil and hydrogenated peanut oil, castor oil and hydrogenated castor oxi, olive oil, sesame seed oil, cotton seed oil and hydrogenated cotton seed oil, corn oil, wheatgerra oil, sunflower seed oil, cod liver oil, mixtures of mono-, di- and triesters of palmitic and stearic acid with glycerol, glycerol trioleate, diglycol stearate, stearic acid.

- Indigestible fats and fat-like substances, e.g. esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, In particular 10 to 18 carbon atoms) with monohydric aliphatic alcohols (1 to 20 carbon atoms), carnauba wax, beeswax, fatty alcohols (straight chain or branched) of chain length CgHiyOH to CjQHg^OH, in particular from to G24H4COK.

- Polymers such as polyvinyl alcohol, polyvinyl chloride, polyacrylic acid; anionic polymers of methacrylic acid and methacrylic acid esters (EudragitL, Eudragit(R)s), acrylic and methacrylic . acid ester copolymers with trimethylammonium methacrylate (Eudragit(R) RL, EudragitRS) ,, copolymer of acrylic acid ethyl and methacrylic acid methyl esters (EudragitNE 30 D) and of acrylic acid and methacrylic acid and their esters (ratio of the free carboxyl groups to the ester groups 1:1) (Eudragit^ L 30 D) ,, polyethylene, polyglycollic acid, polyhydroxybutyric acid, polylactic acid, copolymers of lactic acid and glycollic acid (Manufacturers: Boehringer Ingelheim), copolymers of lactic acid and ethylene oxide and glycollic acid and ethylene oxide, hydroxypropyl methyl cellulose-phthalate or -acetate succinate; cellulose acetate phthalate, starch acetate phthalate and polyvinyl acetate phthalate; carboxymethylcellulose? methyl cellulose phthalate, succinate and phthalate succinate and methyl cellulose phthalic acid semiesters; zein; ethyl cellulose; shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate/maleic acid anhydride copolymer; maleic acid anhydride/vinyl methyl ether copolymer; styrene/maleic acid copolymers; 2-ethylhexyl-acrylatemaleic acid anhydride; crotonic acid/vinyl acetate copolymer; glutamic acid/glutamic acid ester copolymer; carboxymethylcellulose/glycerol monooctanoate; cellulose acetate succinate; polyarginine.

- Swelling substances such as methyl cellulose, hydroxy5 propyl cellulose, hydroxypropyl methyl cellulose (Pharmacoat, Methocel E = propylene glycol ether of methyl cellulose), alginic acid and its salts (Na and Ca salts and mixtures of. alginic acid and calcium salts, e.g. CaHPO^), starch, carboxymethyl starch, carboxy10 methyl cellulose and its salts (e.g. Na salt), galactomannan, gum arabic, karava gum, ghatti gum, agar-agar, carrageen, xanthane gum, guar gum and its derivatives, earob bean meal, propylene glycol alginate, pectin and tragacanth.

One suitable method is, for example, the embedding of L-dopa and optionally th® decarboxylase inhibitor in hydrophilic polymers or hydrocolloids, optionally together with auxiliary substances.

Such hydrophilic polymers or hydrocolloids are substances which are soluble or capable of swelling in water, such as cellulose derivatives and gums. The hydrocolloid preferably contains cellulose derivatives, I.e. cellulose ethers such as methyl cellulose, cellulose alkyl hydroxylates such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose or hydroxyethyl cellulose; cellulose alkyl carboxylates such as carboxymethyl cellulose or carboxyethyl cellulose and alkali metal salts of cellulose alkyl carboxylates such as sodium carboxymethyl cellulose and sodium carboxyethyl cellulose or acrylic acid homopolymers or copolymers or alkali metal salts thereof.

The molecular weight and the degree of ether substitution t. of the cellulose ether are not critical and all trade products may be used in this invention.

The cellulose ether used generally has a viscosity of from 3 to 100,000, preferably from 3 to 10,000, most preferably from 6 to 6000 centipoises, determined on an aqueous 2% by weight solution at 20BC. Further, the cellulose ether used generally has a degree of ether substitution of from 0.1 to 6, preferably from 0.4 to 4.6.

The degree of ether substitution is a measure of the average number of ether groups for 3 hydroxyl groups per glucose unit of the cellulose.

The acrylic acid copolymer used may be a copolymer of acrylic acid with allyl saccharose, methyl acrylate, methacrylic acid, methyl methacrylate, hydroxyethyl methacrylate, styrene or a monomer of a vinyl ether such as methyl vinyl ether.

The proportion of the comonomer may be varied within the range in which the copolymer is water-soluble or capable of swelling In water. The proportion is generally not greater than about 20 mols-%, based on the copolymer.

A commercial mixture of acrylic acid homopolymer or copolymer with a small quantity (usually not more than 20% by weight) of another water-soluble polymer (for example a methacrylic acid homo- or copolymer or salt thereof or polyethylene glycol) may also be used, suitable pharmacologically acceptable salts of acrylic acid homopolymers or copolymers include alkali metal salts such as sodium or potassium salts and ammonium salts. The degree of neutralization of the salts is not limited.

Th© acrylic acid homopolymers or copolymers or their pharmacologically acceptable salts may have any molecular weights. They generally have a viscosity of from 360 to 165,000, preferably from 3600 to 16,500 centipoises. The viscosity is determined on a 2.2% by weight aqueous solution of the sodium salt at a pH of from 7 to 7.5 and at 25"C ±0.5’C.

The acrylic acid homopolymers or copolymers or their pharmacologically acceptable salts may be used singly or as mixtures. Other known hydrocolloids may also be used in the preparations according to the invention, e.g. acacia gum, guar gum, tragacanth gum, xanthane gun, pectin, ammonium or sodium alginate, mixtures of sodium or ammonium alginate with physiologically acceptable calcium salts (for example, calcium gluconate, hydrogen phosphate or chloride) or mixtures thereof.

Preferred hydrocolloids are: Sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose (such as Celacol HPM or Methocol E or K) , polyacrylic acid (such as Carbopol 934P) or the alginates mentioned above.

This form of preparation may be carried out by dissolving or dispersing L-dopa or its salts in the above-mentioned fats or fat-like substances or mixtures thereof, optional20 ly with melting of the said substances followed by cooling, side reduction, optional addition of further substances, e.g. the above-mentioned substances which are water-soluble or swell in water, and the formation of pellets. Cooling of the melt and size reduction may be combined as a single step by dispersing th© melt in cold water or subjecting it to spray solidification or vibration dripping; by mixing L-dopa with the above mentioned fats, polymers or swelling substances or mixtures of these substances, optionally with the application of heat, and shaping of the mixtures to form, pellets, optionally after the addition of auxiliary substances; by mixing L-dopa with solutions of the above-mentioned fats or polymers in water or organic solvents such as ethanol, ethyl acetate, acetone or isopropanol, optionally with the admixture of carrier materials such se celluloses, and subsequent removal of the solvents by evaporation and mixing of the resulting embedded active substances with other auxiliary substances and working up of the resulting substance to pellets; by moistening a mixture of L-dopa and the above mentioned swelling substances with organic solvents such as ethanol, ethyl acetate, acetone or isopropanol, optionally with the addition of binders such as polyvinyl pyrrolidone or copolymers of polyvinyl pyrrolidone and polyvinyl acetate, followed by shaping to form pellets, which are subsequently dried.

The pharmaceutical compositions or medicaments may contain the combination according to the invention as active substance in a formulation, but the individual active substances of the combination may also be present in separate formulations. In which case the given quantities of active substance are used for the given unit dose. The active substances or combination of active substances may be present as mixture with other pharmacologically or pharmaceutically active substances. Preparation of the medicaments is carried out in known manner, optionally with the Inclusion of known and conventional pharmaceutical auxiliary substances and other conventional carriers and diluents. The pellets may, for example, be incorporated In tablets which decompose In the stomach or intestine to release the pellets.

The carriers and auxiliary substances for the pharmaceutical preparations may, for example, be substances such as are mentioned or recommended in the following literature references as auxiliary substances for pharmaceutical, IS cosmetic and related fields: Ullmanns Encyklopadie der technischen Chemie, volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 et seq, H. v „ Czetsch-Lindenwaid, Hilfsstoffe fur · Pharmazie und angrenzende Gebiete; Pharm. Ind., Number 2, 1961, page 72 et seq; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und, angrenzende Gehiete Cantor KG, Aulendorf of Wurttemberg 1981.

Examples include gelatine, natural sugars such, as cane sugar or lactose, lecithin, pectin, starch (for example corn starch), cvclodextrins and cyclodextrin derivatives, polyvinyl pyrrolidone, polyvinyl acetate, gelatine, gum arabic, alginic acid, tylose, talc, lycopodium, silica (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers in which the cellulose hydroxyl groups are partly etherified with lower saturated aliphatic alcohols and/or lower saturated aliphatic hydroxy alcohols, e.g. methyloxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate); fatty acids and magnesium, calcium or aluminium salts of fatty acids having 12 to 22 carbon atoms, in particular of saturated fatty acids (for example stearates) , emulsifiers, oils and fats, in particular vegetable fats (for example, peanut oil, castor oil, olive oil, sesame seed oil, cotton seed oil, corn oil, wheatgerm oil, sunflower seed oil and cod liver oil, in each case optionally hydrogenated; mono-, di- and triglycerides of saturated fatty acids from Ci2H24°2 c18h36°2 and mixtures thereof), pharmaceutically accept30 able monohydric or polyhydric alcohols and polyglycels such as polyethylene glycols and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with monohydric aliphatic alcohols (1 to 20 carbon atoms) or polyhydric alcohols such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol, mannitol, etc., which may also be etherified, esters of citric acid with primary alcohols and acetic acid, benzyl benzoate, dioxalanes, glycerol formals, tetrahydrofurfural alcohol, polyglycol ethers with Ch to Cb2 alcohols, dimethylacetamide, lactamides, lactates, ethyl, carbonates, silicones (in particular medium viscosity polydimethylsiloxanes) , calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like.

Substances which bring about decomposition (so called explosives) may also be used as auxiliary substances, for example: transversely cross-linked polyvinyl pyrroiidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose, which may also be transversely cross-linked, and microcrystalline cellulose.

Water or organic solvents, for example, may be used for the preparation of solutions or suspensions- Examples of these solvents include methanol, ethanol, propanol, isopropanol, dichloromethane, trichloroethane, acetone, 1,2propylens glycol, polyglvcols and their derivatives, dimethylsulphoxide, fatty alcohols, triglycerides, partial esters of glycerol, paraffins and the like.

Known and conventional solubilizing agents or emulsifiers may be used for producing the preparations; for example: Polyvinyl pyrrolIdone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyethoxylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyethoxylated fats, polyethoxylated oleotrxglycerides, linolized oleotrxglycerides, polyethylene oxide condensation r. products of fatty alcohols, alkyl phenols or fatty acids or l-methyl-3~ (2-hydroxyethyl)-imidazolidone- (2). Polyethoxylated means in this context that th® compounds contain polyethoxylene chains which generally have a degree of polymerisation of from 2 to 40, in particular from 10 to 20.

Such polyethoxylated substances may be obtained, for example, by the reaction of compounds containing hydroxyl groups (for example, mono- or diglycerides or unsaturated compounds such as compounds containing oleic acid residues) with ethylene oxide (for example 40 mol of ethylene oxide per mol of glyceride).

Examples of oleotriglycerides include olive oil, peanut oil, castor oil, sesame seed oil, cotton seed oil and corn oil. See also Dr. H.P. Fiedler, ’’Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" 1971, pages 191 to 195.

Th© following are examples of antioxidants which may be used: Sodium metabisulphite, ascorbic acid, gallic acid, gallic acid alkylesters, butyl hydroxyanisole, norhyd.roguaiaretic .acid, tocopherols and tocopherols + synergists (substances which bind heavy metals by complex formation, e.g. lecithin, ascorbic acid, phosphoric acid). The addition of synergists considerably increases the anti25 oxygenic action of the tocopherols.

Th© pharmaceutical and galenic handling of the active substances is carried out by the usual standard methods. For example, active ingredient(s) and auxiliary substances or carriers are thoroughly mixed by homogenization (for example by means of the usual mixing apparatus), generally employing temperatures of from 20 to 80C, preferably from to 50C, in particular room temperature. Reference may be had to the following standard work: Sucker, Fuchs, Speiser, Pharmazeutische Technologie, Thierae-verlag Stuttgart, 1978.

Administration may be. into the interior of the body, for example orally or enterally.

The combination according to the invention may also be in the form of a product in which the two individual active substances are present in separate formulations so that they may be administered separately or at different times.

When such separate formations are provided, they are adjusted to one another and their active ingredients are present in the unit dose in the quantities and ratios toy weight in which they may be present In the combined mixture.

When separate administration is employed* the two components of the combination need not be administered at the same-time. In such cases, L-dopa may be administered from 5 to 300 minutes after administration of the decarboxylase inhibitor.

The acute toxicity of the combination according to the invention, expressed by the LO 50, may, for example, b© above 1700 mg/kg in the case of oral administration (applies to various animals such as mice or rats).

Example 1: Capsules containing 100 mg ox L-dopa in the form of pellets and 28.5 mg of benserazide hydrochloride 2000 g of L-dopa are mixed with 220 g of microcrystalline cellulose and the mixture is thoroughly moistened through with a solution of SO g of polysorbate 80 in 820 g of purified water. The moist mass is passed through an extruder (apertures 0.8 mm) and the strands obtained are subdivided and rounded off by means of a spheronizer. The moist pellets obtained are dried to a relative moisture content (equilibrium moisture) of 25-35% in a fluidized bed drier. The dried pellets are sieved and only the sieve fraction of from 0.5 to 1.25 mm is used for further processing. 1S00 g of the pellets are sprayed with a film suspension which is prepared as follows; g of triethylcitrate are emulsified with 0.3 g of polysorbate 80 in 110 g of purified water and the emulsion is mixed with 4SO g of a 30% suspension of copolymers of acrylic and methacrylic acid esters containing a small amount of ammonium groups (for example Eudragit^ RS 30 D) . g of talc are suspended in 515 g of purified water by means of a conventional homogenizing apparatus and the suspension is stirred into the above obtained dispersion after the addition of a few drops of silicone antifoamant. Application of the resulting suspension (coating for delayed action) to the pellets is carried out In the usual manner, for example using a fluidized bed spray granulator at an air inflow temperature of 40 to 50 C and an air discharge temperature of at most 40’C. Drying ot the *> pellets is carried out under the same conditions. The pellets are sprayed with the above-mentioned suspension until the total weight of the dried pellets Is 1628 g. 1500 g of pellets of the sieve fraction below 1.25 mm are then sprayed with the following lacquer suspension (coating for resistance to gastric juice): 32 g of Triethvlcitrate are emulsified with 0.3 g of polysorbate. 80 in 130 g of purified water and the emulsion is mixed with 1068 g of a suspension of a copolymer which has an anionic character based on poly(meth)acrylic acid and poly (meth) acrylic acid esters (for example EudragitM L30D) . 160 g of talc are suspended in 620 g of purified water by means of a conventional homogenising apparatus and the suspension is stirred Into the above-obtained dispersion after the addition of a few drops of silicone antifoamant. The suspension thus obtained is applied to the pellets by the method described above. The pellets are sprayed .with the suspension until the total weight of th© dried pellets is 1978 g. 570 g of Benserazide hydrochloride are mixed with 420 g of lactose and granulated in the usual manner with a solution of 20 g of gelatine in 180 g of purified water. After the granulate has been dried and sieved through a sieve of mesh 0.8 mm, 6 g of magnesium stearate and 4 g of highly disperse silicon dioxide are added.

The mixture is filled into size 2 hard gelatine capsules in a quantity of 51 mg together with 153 mg of the lacquered pellets obtained as above.

A hard gelatine capsule contains 100 mg of L-dopa in the form of pellets and 28.5 mg of benserazide hydrochloride.

Release of L-dopa from this form of preparation is tested by the process of the US Pharmacopoeia, 21st Edition (USP XXI) , using the apparatus for the dissolution test. Apparatus 2» With the paddle rotating at the rate of 120 revs/min, the release of L-dopa is determined on a 900 ml test solution at 37 C. The test solution consists of 0.06 molar hydrochloric acid for the first 2 hours and the pellets are thereafter transferred to a phosphate buffer solution pH 6.8 of the European Pharmacopoeia. Release of L-dopa is measured on the test solutions. release of L-dopa amounts to after 1 hour 0.1 - 0.2 % ) ) in 0.06 m HC3 2 hours 0.3 - 0.9 % ) 3 hours 32 - 37 % ) ) in phosphate 4 hours 55 - 60 % ) ) buffer 5 hours 72 - 75 % ) ) pH 6.8 6 hours 81 - 84 % ) A similar process may be employed for preparing capsules containing a) unlacquered L-dopa pellets, b) L-dopa pellets which have only been lacquered with one of the above-mentioned suspensions or c) mixtures of unlacquered and lacquered 25 pellets in addition . to the granulate mixture of benserazide hydrochloride.

The process of lacquering must be suitably modified for obtaining these pellets.

Example 2 Capsules containing 100 mg of L-dopa in the form of microtablets and 28.5 mg of benserazide hydrochloride kg of L-dopa are homogeneously mixed in a mixer with 5 2.7 kg of methyl hydroxypropyl cellulose (viscosity of a 2% solution: 15,000 cP), 9 kg of sodium alginate, 9 kg of calcium hydrogen phosphate and 0.06 kg of magnesium stearate. The mixture is compressed to form biconvex tablets 2 mm in diameter and 2 mm In thickness.. The tablets are coated with a gastric juice resistant film in the usual manner, for example as follows: 24 g of titanium dioxide and 24 0 g of talc are homogeneously suspended in a solution of 4 5 g of sodium carboxymethyl cellulose in 1000 g of purified water. 54 g of 1,215 propylene glycol and 597 g of water are then added.

This suspension is introduced with stirring into 1500 g of an aqueous suspension of an anionic copolymer (50:50) based on methacrylic acid and methyl acrylate (Eudragit L 30 D).

About 500 g of the lacquer suspension thus prepared are applied to 1 kg of tablets, for example using a fluidised layer apparatus at an inflow air temperature of 40-50"C and an outflow air temperature of at most 40C. 570 g of Benserazide hydrochloride are mixed with 420 g of lactose, 6 g of magnesium stearate and 4 g of highly disperse silicone dioxide. mg portions of this mixture are introduced into size Q hard gelatine capsules together with 369 ag of the previously obtained lacquered tablets.

A hard gelatine capsule contains 100 mg of L-dopa in the form of pelletized microtahlets and 28.5 mg of benserazide hydrochloride.

The release of L-dopa Is tested by the process of USP XXI* 5 as in Example 1 but with the paddle rotating at 50 revs/min.

The release of L-dopa is as follows; after* 1 hour 0.5 - 1.5 «3. ·%» 10 2 hours 2-4 % 3 hours 23 - 27 % 4 hours 50 - 55 a •b 15 5 hours 71 - 76 % 6 hours 82 - 88 % 20 7 hours above 90 % in 0.06 m HCl in phosphate buffer pH 6.8

Claims

1. Patent Claims:

1. Products containing, as active ingredient, L-Dopa in the form of pellets and decarboxylase inhibitors or salts of these compounds with physiologically 5 acceptable acids or bases as combination preparation for simultaneous or separate use.

2. Product according to Claim 1, characterised in that the combination contains from 0.5 to 100 parts by weight of L-Dopa to 1 part by weight of decarb10 oxylase inhibitor.

3. Product according to one or more of the preceding claims, characterised in that from 10 to 100 mg, preferably from 25 to 50 mg of decarboxylase inhibitor and from 50 to 1000 mg, preferably from 15 100 to 500 mg of L-Dopa (in the form of pellets) are used in the dosage unit for the combination

4. Products according to one or more of the preceding claims, characterised in that the decarboxylase inhibitor is benserazide or carbidopa. 20 5. A process for the preparation of a product to be administered orally according to one or more of the preceding claims, characterised in that 1 part by weight of decarboxylase inhibitor and from 0.5 to 100 parts by weight of L-Dopa, which active 25 ingredients may be in the form ot salts of physiologically acceptable acids or bases, are mixed or homogenised together with conventional carriers and/or diluents. or auxiliary substances at temperatures of from 10 to 80”C, the resulting mixture is used for the preparation of pellets which are optionally covered with a coating and the pellets are introduced into capsules or sachets of suitable size so that the dosage unit contains from 10 - 100 mg of decarboxylase inhibitor and from 50 to 1000 mg of L-Dopa. 6. A process for the preparation of a product according to one or more of the preceding claims, characterised in that 1 part by weight of dec&rfa10 oxylase inhibitor and from 0.5 to 100 parts by weight of L-Dopa, which active ingredients may be present in the form of salts of physiologically acceptable acids or bases, are worked up by a) making up the decarboxylase inhibitor into a 15 solid preparation, using conventional auxiliary substances and carriers; b) making up the L-Dopa into pellets, using conventional auxiliary substances and carriers, which pellets are optionally covered with a 20 lacquer film, and the formulations thus obtained are introduced separately or together into capsules or sachets. 7. A process for the preparation of a product according to one or more of the preceding 25 claims, characterised in that 1 part by weight of decarboxylase inhibitor and from 0.5 to 100 parts by weight of L-Dopa, which active ingredients may be in the form of salts of physiologically acceptable acids or bases, are worked up by a) mixing the decarboxylase inhibitor with at least one of the auxiliary substances, mannitol, sorbitol, lactose, starch, cellulose, optionally granulating the mixture with an aqueous gelatine solution or a vinyl acetate/vinyl pyrrolidone copolymer solution or a starch solution, and mixing the mixture or the granulate with magnesium stearate and highly disperse silicon dioxide and optionally also starch and/or cellulose and optionally compressing it into tablets, b) mixing the L-Dopa with at least one of the auxiliary substances, cellulose, cellulose derivatives, lactose, starch, mannitol, sorbitol, polysorbate, saccharose, glucose, optionally with the addition of binders such as polyvinyl pyrrolidone, vinyl acetate/vinyl pyrrolidone copolymer, gelatine or cellulose derivatives in the form of solutions, and shaping the mixture into pellets which are optionally covered with a lacquer film or applying th© L-Dopa, with or without binder, to neutral pellets (so-called nonpareilles) which are then optionally covered with a lacquer film and preparations a) and b) are then combined to form a medicinal package, optionally after they have been introduced, either separately or together, into capsules, or sachets, so that the dosage unit contains from 10 to 100 mg of decarboxylase inhibitor and from 50 to 1000 mg of LDopa. 8» A process for the preparation of a product according to one or more of the preceding Claims, characterised in that the decarboxylase inhibitor is benserazide or carbidopa. 9. The use of decarboxylase inhibitor and L~Dopa in the form of pellets for the preparation of synergistically acting agents for combating Parkinson’s disease. 10. The use of a decarboxylase inhibitor according to Claim 9, characterised in that the decarboxylase inhibitor is benserazide or carbidopa. 11. The use of L-Dopa in the form of pellets containing from 50 to 1000 mg of L-Dopa in combination with the simultaneous or separate administration of a decarboxylase inhibitor for the preparation of a pharmaceutical product for the treatment of Parkinson's disease. 12. The use of L-Dopa in the form of pellets containing from 50 to 1000 mg of L-Dopa in combination with & decarboxylase inhibitor according to one or more of the preceding claims, characterised in that the 1,-Dopa pellets, alone or together with the decarboxylase inhibitor, ar® used in capsules or sachets. 13. A process for the. preparation of L-Dopa in the form of pellets containing from 50 to 1000 mg of L-Dopa and optionally from 10 to 100 mg of decarboxylase inhibitor for th© combination with simultaneous or separate administration of a decarboxylase inhibitor for the treatment ox Parkinson’s disease, characterised in that a) from 50 to 1000 mg of L-Dopa and optionally from 10 to 100 mg of decarboxylase inhibitor are mixed with conventional auxiliary agents

5. And carriers at a temperature of from 10 to 80 C and the mixture is compressed to form pellets having a diameter of from 0.1 to 2 mm, or in that b) a mixture of from 50 to 1000 mg of L-Dopa and

6. 10 optionally from 10 to 100 mg of decarboxylase inhibitor and conventional auxiliary agents and carriers is made up into a paste with a conventional solvent at a temperature of from 10 to 60°C and the resulting plastic mass is 15 forced through perforated discs and the resulting strands are divided up, rounded off and dried or in that c) from 50 to 1000 mg of L-Dopa and optionally from 10 to 100 mg of decarboxylase inhibitor 2 0 are dripped into a melt of fatty substances or waxes at a temperature ot from 10 to 80C and brought to solidification or In that d) from 50 to 1000 mg of L-Dopa and optionally from 10 to 100 mg of decarboxylase Inhibitor 25 are applied to neutral pellets at a temperature of from 10 to 60 “C with or without binder or in that ®) from 50 to 1000 mg of L-Dopa and optionally from 10 to 100 mg of decarboxylase Inhibitor 30 are bound to acid ion exchanger particles and the pellets obtained according to a) - s) are optionally coated with at least one conventional coating substance.

7. 14. A process for the preparation of L-Dopa pellets 5 according to one or more of the preceding claims* characterised in that from 50 to 1000 mg of L-Dopa and optionally from 10 to 100 mg of decarboxylase inhibitor are mixed with at least one of the auxiliary substances: cellulose, cellulose; 10 derivatives, lactose, starch, mannitol, sorbitol* polvsorbate, saccharose, glucose, sodium alginate* sodium alginate/calcium salts, optionally with th© addition .of binders such as polyvinyl pyrrolidone* vinyl acetate/vinyl pyrrolidone copolymer, gelatine

8. 15 or cellulose derivatives in the form of solutions and the mixture is formed into pellets and these pellets are optionally coated with a conventional coating substance or L~Dopa is applied to neutral pellets with at least one of the above mentioned 20 auxiliary substances and these neutral pellets are optionally thereafter also coated with a conventional coating substance. 15. A process for the preparation of L-Dopa pellets according to one or more of the preceding claims* 25 characterised in that from 50 to 1000 mg of L-Dopa and optionally from 10 to 100 mg of decarboxylase inhibitor are mixed with at least one hydrophilic polymer or hydrocolloid, optionally with th® addition of conventional binders and/or solvents* 30 and shaped into pellets or the L-Dopa mixture is applied to neutral pellets and the pellets obtained are covered with a coating which is resistant to gastric juice.

9. 16. A process according to claim 15, characterised in that at least one of the following substances is used as hydrophilic polymer or hydrocolloid: Cellulose derivatives, acrylic acid homopolymers, acrylic acid copolymers, pectins, hydrophilic gums or alginates and their physiologically acceptable salts.

10. 17. L~Dopa pellets comaining from 50 το 1000 mg L-Dopa and 1 o optionally from 10 to 100 mg of decarboxylase inhibitor, obtainable according to one or more of Claims 13 to 16. IB. A product according to claim 1, substantially as hereinbefore described. 15 19. A process according to any one of claims 5-8 for the preparation of a perorally admirals treble product, substantially as hereinbefore described and exemplified.

11. 20. A perorally administrable product, whenever prepared by a process claimed in any one of claims 5-8 or 19. 20

12. 21. Use according to claim 9, substantially as hereinbefore described.

13. 22. Use according to claim 11, substantially as hereinbefore described.

14. 23. Use according to claim 12, substantially as hereinbefore 25 described™

15. 24. A process according to any one of claims 13-16 for the preparation of L-Dopa, in the form of pellets, substantially as hereinbefore described and exemplified.

16. 25. L-Dopa pellets, whenever prepared by a process claimed * 30 in any on® of claims 13-16 or 24.