IE883894L - Synergistic combination of decarboxylase inhibitors and L-dopa pellets - Google Patents

Abstract

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

Description

6 2 6 4 3 Decarboxylase Inhibitors are pharmaceutical^ active substances which have the property of blocking peripheral decarboxylases (i.e. decarboxylases occurring la the intestine and blood circulation) . The decarboxylate 5 inhibitors may be benzerazide (DL-serine-2- (2,3,4-trihydroxybenzyl)-hvdrazide) * carbidopa (-)-L-a-hydrasino-3 , 4-dihydroxy-a~methyl~hydrocinnamic acid), L-serine-2" {2,3,4-trihydroxybenzyl) -hydrazide, glycine-2-(2,3,4-trihydroxybenzyl) -hydrazide or L-tyrosine-2~(2,3,4-10 trihydroxybenzyl)-hydrazide, in particular benserazide.

L-Dopa ((S) -2-amino-3- (3 , 4-dihydroxypheny1) -propionic acid) is a pharmaceutical agent with a pronounced anti-Parkinson action- The combination of the decarboxylase inhibitor benserazide 15 and L-dopa has been known since 1960. 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 consider-20 able fluctuations in response, for example in the fojns of the 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 25 improved form of administration with prolonged action in which, for example, the on-off symptoms are reduced fsee S.M. Stahls New Drug delivery systems - a new approach to Parkinson's disease, Symposium Harlow/GB 8.7. 3.985) . 1 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. 5 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 10 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-dopa- 15 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 20 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 be cumulatively reduced by this effect and due to the lower frequency of ad-25 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 30 combination according to the invention compared with the standard combination can be demonstrated as follows: After 2 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 legs 5 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 10 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 15 combination, the combination according to the invention surprisingly has the following advantages: Reduced frequency of administration, reduction in the rate of side effects and more uniform action.

German Offenlegungsschrift 3 232 873 discloses a combina-20 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 23 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 30 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 are to be altered in accordance with 5 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, 10 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 15 invention may consist, for example, of from 10 to 800 ag, preferably from 20 to 300 mgt, in particular from 75 to 2S0 mg of decarboxylase inhibitor and from 50 to S000 »g, preferably from 100 to 3000 mg, in particular from 300 to 1500 mg of L-dopa- 20 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 dosa 25 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 S 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. 30 According to the invention, the decarboxylase inhibitor 4 and L-dopa may be administered, for example, in the following ratios by weights 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 5 weight of decarboxylase inhibitor with 1 to 50 parts by-weight of L-dopa, in particular 1 part toy weight of decarboxylase inhibitor with 2 to 20 parts by weight of L-dopa.

For example, a pharmaceutical preparation can easily be 10 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 15 invention may, for example, contains 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 lag, preferably from 50 to 500 mg, in particular from 100 to 500 lag 20 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 courset, also be 25 prepared.

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

Pallets are understood to be spherical or cylindrical 5 preparations having a diameter of from 0.1 to 2 nvra.

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 5 or solvents to form a paste and forcing the resulting plastic mass through perforated discs and subdividing the resulting strands, forming them into round pieces and drying.

Alternatively, the pharmaceutical preparations may b© 10 produced by simultaneously or successively applying the active ingredients, with or without binders., to neutral pellets which are free from active ingredients (so-called nonp&reilles).

Another possibility lies in binding the active ingredient. 15 L-dopa to ion exchangers, for example to physiologically-acceptable ion exchangers. The following are examples of suitable ion exchangers of this types Acrylic and methacrylic resins with exchangeable proton,, i.e. acid, in particular weak acid groups such as COO® 20 (for example, AmberliteW IRP-64)? polystyrene resins with exchangeable Ha4", acid groups: S03e (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 the 25 minimum ratio is about 1 part by weight of L-dopa. to 300 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. 30 Binding of the L-dopa is carried out by passing an L-dopa solution through a bed of the ion exchanger in a column. The charged ion exchanger is dried at temperatures of yp 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 5 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 90"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 arte 15 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 20 pellets with controlled release are preferably obtained by coating the conventionally prepared pellets with the aforesaid active substances in known manner, using at. least one coating substance. The following coating substances may be used; 25 polymers and copolymers of acrylic acid and/or methacrylic acid and/or esters thereof; copolymers of acrylic and methacrylic acid esters containing a small number of ammonium groups (e.g. EudragitR3), copolymers of acrylic and methacrylic acid esters and trimethy1ammonium 30 methacrylate (e.g. EudragitW RL) ; polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methyl cellulose phthalate or acetate succinate? cellulose-,. 7 starch- or polyvinyl acetate phthalte; carboxyraethyl cellulose; methyl eellulose-phthalate, -succinate,-phthalatesuccinate or -phthalate acid semiester; zein; ethvl-cellulose and -succinate; shellac; gluten? ethyl carboxyethylcellulose; ethacrylate/maleic acid anhydride copolymer; maleic acid anhydride/vinyl methyl ether copolymer? styrene/maleic acid copolymers? 2-ethyl-hescyl-acry late-ma leic acid anhydride; crotonic acid/vinyl acetate copolymer; glutamic acid/glutamie acid ester copolymer; carboxvmethylathy1 cellulose glycerol mono-octanoate; 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 plasticiaing agents may b® used for these coatings; Citric and tartaric acid asters (acetyltri-ethyl-, acetyltributyl-- tributyl- and triethyl citrate); glycerol and glycerol esters (glycerol diacetate, triacetatef acetylated monoglyceridas, castor oil)i phthalic acid esters (dibutyl, diamyl, diethyl, dimethyl, dipropyl phthalate) , D- (2-methoxy- or ethoxyethyl) ~ phthalate, ethylphthalyl, butylphthalylethyl and butyl-glycolate; alcohols (propylene glycol, polyethylene glv~ 3 col of various chain lengths), adipates (diethvladipate, di- (2-xnethoxy or -ethoxyethyladipata)) ; bensophenone• diethyl- and dibutvlsebacatef -succinate and -tartrate; diethvleneglycol dipropionate; ethylene glycol diacetatet, 5 -dibutyrate and -dipropionate; tributylphosphate, tri-butyrin; hydroxypropylcellulose, hydroxypropylmethyl-cellulose, polyethylene glycol sorbitan monooleate (polysorbates such as Polvsorbate 80) ; sorbitan mono-oleate, polyvinyl pyrrolidone. 10 One or more of the above-mentioned auxiliary substances and one or mors 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 15 glycols, polyvinyl pyrrolidone, copolymers of polyvinyl pyrrolidone and polyvinyl acetate, polyvinyl acetate and the like,.

The plasticizing agents already mentioned, hydroxypropvi cellulose and/or hydroxypropyl methyl cellulose, may also 20 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 weighty preferably from 1 to 3% by weight, based on the coating substance.

The coating layer is applied by spraying solutions of the 25 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 optimise the processing properties, for example, surface-active substances, solids such 30 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 r 9 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 C8H1602 to C18H1602^ 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 13 carbon atoms) with mono-hydric aliphatic alcohols (1 to 20 carbon atoms), carnauba wax, beeswax, fatty alcohols (straight chain or branched) of chain lengths CgH17OH to c3QHgiOH, in particular from Cj_2^25®^ to C24H49OH.

The following are examples of binders which may fo® used for the preparation by application to neutral pellets: Gelatine, gum arable, starch past®, cellulose derivatives (methyl cellulose,, carboxymethvl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose), sodium alginate, pectin, tragacanth, polyvinyl pyrrol idone, polyvinyl acetate, polyvinyl alcohol, copolymers of vinyl pyrrol-idone and vinyl acetate.

The pellets may also be prepared by embedding L-dopa in the following substances or mixtures of these substances: - Digestible fats,, e.g. triglycerides of saturated fatty acids CgHig02 to CigH3g02 and mixtures thereof, peanut oil and hydrogenated peanut oilt, castor oil and hydrogenated castor oil, olive oil, sesame seed oil, cotton seed oil and hydrogenated cotton seed oil, corn oil, wheatgerm oil, sunflower seed oil,, cod liver oil, mixtures of mono-, di- and triesters of palmitic and stearic acid with glycerol, glycerol trioleate, diglvcol 10 stearate, stearic acid.

- Indigestible fats and fat-like substances, e.g. asters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) 5 «ith monohvdric aliphatic alcohols (1 to 20 carbon atoms), carnauba wax, beeswax, fatty alcohols (straight chain or branched) of chain length C3H17OE to CjoBgiOH, in particular from <^2^25°® to c24h49ok.

- Polymers such as polyvinyl alcohol, polyvinyl 10 chloride, polyacrylic acid; anionic polymers of methacrylic acid and methacrylic acid asters (Eudragit L, Eudragit (^) S), acrylic and methacrylic . acid ester copolymers with trixnethylammonium methacry-late (EudragitHLf EudragitRS) e copolymer of 15 acrylic acid ethyl and methacrylic acid methyl esters (Eudragit^) NE 30 D) and of acrylic acid and methacrylic acid and their esters (ratio of the free carboxyl groups to the ester groups 1:1) (EudragitL 30 D), polyethylene, polyglycollic acid, po1yhydroxybutyric 20 acid, polylactic acid, copolymers of lactic acid and, glycol lie acid (Manufacturers: Boehringer Ingelheim) r copolymers of lactic acid and ethylene oxide and glycollic acid and ethylene oxide, hydroxypropyl methyl cellulose-phthalate or -acetate succinate; cellulose 25 acetate phthalatee 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 30 cellulose; ethacrylate/maleic acid anhydride copolymer; maleic acid, anhydride/vinyl methyl ether copolymer; styrene/maleic acid copolymers; 2-ethylhexyl-acrylate-maleic acid anhydride; crotonic acid/vinvl acetate 11 copolymer," glutamic acid/glutantic acid ester copolymer? carboxymethvlcellulose/glycerol monooctanoate? cellulose acetate succinate; polyarginine.

- Swelling substances such as methyl cellulose, hydroxy-5 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. CaHP04), starch, carboxymethyl starch, carboxy-10 methyl cellulose and its salts (e.g. Na salt), galacto-mannan, gum arabic, karava gum, ghatti gum, agar-agar, carrageen, xanthane gum, guar gum and its derivatives, carob bean meal, propylene glycol alginate, pectin and tragacanth. 15 One suitable method is, for example, the embedding of L-dopa and optionally the decarboxylase inhibitor in hydrophilic polymers or hydrocolloids, optionally together with auxiliary substances.

Such hydrophilic polymers or hydrocolloids are substances 20 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 hydroxy1ates such as hydroxypropyl methyl cellulose, hydroxypropvl 25 cellulose, hydroxymethy1 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 30 or acrylic acid homopolymers or copolymers or alkali metal salts thereof.

The molecular weight and the degree of ether substitution r. 12 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 5 from 6 to 6000 cantipoises , determined on an aqueous 2% toy weight solution at 20"C. Further, the cellulose ether used generally has a degree of ether substitution of from 0.1 to 6, preferably from 0.4 to 4.5.

The degree of ether substitution is a measure of the 10 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 allvl saccharose, methyl acrylafce, methacrylic acid, methyl methacrylate, hydroxyethyl 15 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 gener-20 ally not greater than about 20 jnols-3, 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 25 methacrylic acid homo- or copolymer or salt thereof or polyethylene glycol) may also be used. Suitable pharmacologically acceptable salts of acrylic acid hoaopolymers or copolymers include alkali metal salts such as sodium or potassium salts and ammonium salts. The degree of 30 neutralisation of the salts is not limited.

The acrylic acid homopolymers or copolymers or their pharmacologically acceptable salts may have any molecular weights. They generally have a viscosity of from 330 to 165,000, preferably from 3600 to 16,500 centipoises. The 13 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 gum,, 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, hydroxvpropyl methyl cellulose (such as Celacol HPM or Methocol E or K) , polvacrylic 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, optionally 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 he combined as a single step by dispersing the 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 14 fats or polymers in water or organic solvents such as ethanol, ethyl acetate, acetone or isopropanol, optionally with the admixture of carrier materials such as celluloses, and subsequent removal of the solvents toy 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 pharmacological Jly or pharmaccut ically 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 Encvklopadie der technischen Chemie, Volume 4 (1953), pages 1 to 39 ~ Journal of Pharmaceutical Sciences, Volume 52 (1963) f, page 918 et seq, H. v. Czetsch-Lindenwald, Hilfsstoffe fur 5 • Pharmasie und angrenzende GebietaPharm. Ind., Number 2, 1961, page 72 et seq,- Dr. K.P. Fiedler,, Lex ikon dar Hilfsstoffe fur Pharmazie, Kosraetik und angrenzende Gebiete Cantor KG, Aulendorf of Wurttemberg 1981.

Examples include gelatine, natural sugars such, as cane 10 sugar or lactose, lecithin, pectin, starch (for example corn starch) ,■ cvclodextrins and cyclodextrin derivatives,, polyvinyl pyrrol idone, polyvinyl acetate,, gelatine,,, gum arabic, alginic acid, tylose, talc,, lycopodium, silica (for example colloidal) , cellulose, cellulose derivatives 15 (for example cellulose ethers in which the cellulose hydroxy1 groups are partly etherified with lower saturated aliphatic alcohols and/or lower saturated aliphatic hydroxy alcohols, e.g. methyloxypropyl cellulose,, methyl cellulose,, hydroxypropyl methyl cellulos©, hydroxvpropyl 20 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 25 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 £\2^24?2 to c18h36°2 and mixtures thereof), pharmaceutically accept-30 able monohydric or polyhydric alcohols and polyglycols such as polyethylene glycols and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids v (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, pentaervthritolf 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, polyglvcol ethers with C ^ to c12 alcohols, dimethyl-acetamide, lactaraides, lactates, ethyl, carbonates, silicones (in particular medium viscosity polydimethyl-siloxanes) , 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 pyrrolidone, 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, propanoic isopropanol, dichloromethane, trichloroethane, acetone, 1,2™ propylene glycol, polyglycols 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 oleotriglycerides, linolized oleotriglycerides, polyethylene oxide condensation 17 products of fatty alcohols, alkyl phenols or fatty acids or l«methyl-3~ (2-hydroxyethyl)-imidazolidone- (2). Polyethoxylated Beans in this context that the compounds contain polyethoxylene chains -which generally have a 5 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 hydroxy1 groups (for example, mono- or diglycerides or unsaturated 10 compounds such as compounds containing oleic acid residues) with ethylene oxide (for example 40 mol of ethylene oxide per saol of glyceride) » Examples of oleotriglycerides include olive oil, peanut oil, castor oil, sesame seed oil, cotton seed oil and corn 15 oil. See also Dr. H.P. Fiedler,, "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" 1971, pages 191 to 195.

The following are examples of antioxidants which may be used: Sodium metabisulphite, ascorbic acid, gallic acid# 20 gallic acid alkylestersf butyl hydroxyanisole* norhydro-guaiaretic 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 anti-25 oxygenic action of the tocopherols.

The 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 (far 30 example by means of the usual mixing apparatus), generally employing temperatures of from 20 to 80*C, preferably from 18 20 to 50*C, in particular room temperature. Reference may be had to the following standard works Sucker, Fuchs, Speiser, Pharrna zeut ische Technologie, Thieme-Verlag Stuttgart, 1978. 5 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 10 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 by weight in which they may be present in the combined 15 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 b© administered from 5 to 300 minutes after administration of the 20 decarboxylase inhibitor.

The acute toxicity of the combination according to the invention,, expressed by the LD 50, may, for example,, b© above 1700 mg/kg in the case of oral administration (applies to various animals such as mice or rats). 19 Example 1: Capsules containing 100 mg of 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 5 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 10 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 15 which is prepared as follows: 28 g of triethylcitrate are emulsified with 0.3 g of polysorbate 80 in 110 g of purified water and the emulsion is mixed with 460 g of a 30% suspension of copolymers of acrylic and methacrylic acid esters containing a small 20 amount of ammonium groups (for example Eudragit1* KS 30 DJ . 68 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. 25 Application of the resulting suspension (coating for delayed action) to the pellets is carried out in the usual saanner, 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 of the 30 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. 20 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 5 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 (xneth) acrylic acid and poly (meth) acrylic acid esters (for example Eudragit L30D) . 160 g of talc are suspended in 620 g of purified 10 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 silicons antifoamant. The suspension thus obtained is applied to the pellets by the method described above. The pellets are 15 sprayed with the suspension until the total weight of the 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 20 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 25 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 30 XXI) t, using the apparatus for the dissolution test,. Apparatus 2. With the paddle rotating at the rate of 120 21 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» The release of L-dopa amounts to 10 15 after 1 hour 0.1 - 0.2 % ) 2 hours 0.3- 0.9% ) 3 hours 32 - 37 % ) 4 hours 55 - 60 5 hours 72 - 75 % S hours 81 -84 % ) % ) in 0.06 m HC1 j in ohosohate ) ) buffer ) ) pH 6.8 A similar process may be employed for preparing capsules containing 20 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. 22 Example 2 Capsules containing 100 mg of L-dopa in the form of microtablets and 28.5 mg of benserazide hydrochloride 9 kg of L-dopa are homogeneously mixed in a mixer with 2.7 kg of methyl hvdroxypropyl cellulose (■viscosity of a 2% solutions 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 1,2-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 aerylate (Eudragit L 30 D) .

About 500 g of the lacquer suspension thus prepared are applied to l kg of tablets, for example using & fluidized layer apparatus at an inflow air temperature of 40-50*c and an outflow air temperature of at most 40 "C. 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. 50 mg portions of this mixture are introduced into size o hard gelatine capsules together with 369 mg of the previously obtained lacquered tablets. 23 A hard gelatine capsule contains 100 mg of L-dopa in the form of palletised microtablets 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 in 0-06 a HC1 10 2 hours 2 - 4 % 3 hours 23 - 27 % 4 hours 50 - 55 a •b t in phosphate 15 5 hours 71 - 76 % buffer pH 6.8 6 hours 82 - 88 % 20 7 hours above 90 % 24

Claims (5)

1. Patent Claims: 1. Products containing, as active ingredient, L-Dopa in the for® of pellets and decarboxylase inhibitors or salts of these compounds with physiologically-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 decarb- 10 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 of 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 25 mixture is used for the preparation of pallets 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. 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 decarboxylase 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 solid preparation, using conventional auxiliary substances and carriers; b) snaking up the L-Dopa into pellets, using conventional auxiliary substances and carriers, which pellets are optionally covered with a lacquer film, and the formulations thus obtained are introduced separately or together into capsules or sachets. 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 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 26 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 pvrrolidone 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 the L-Dopa„ with or without binder, to neutral pellets (so-called nonpa re i11es) 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 L-Dopa. 27 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. The use of decarboxylase inhibitor and L-Dopa in the form of pellets for the preparation of synergistically acting agents for combating Parkinsonus disease. The use of a decarboxylase inhibitor according to Claim 9, characterised in that the decarboxylase inhibitor is benserazide or carbidopa. 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. The use of L-Dopa in the form of pellets containing from 50 to 1000 mg of L-Dopa in combination with a decarboxylase inhibitor according to one or mors of the preceding claims, characterised in that the L-Dopa pellets, alone or together with the decarboxylase inhibitor, are used in capsules or sachets. 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 the combination with simultaneous or separate administration of a decarboxylase inhibitor for the treatment of Parkinson1® disease, 28 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 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 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 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 are dripped into a melt of fatty substances or waxes at a temperature of from 10 to 80"C 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 are applied to neutral pellets at a tempera-fare 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 are bound to acid ion exchanger particles and the pellets obtained according to a) - e) are optionally coated with at least one conventional coating substance. A process for the preparation of L-Dopa pellets 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 nig of decarboxylase inhibitor are mixed with at least one of the auxiliary substances: cellulose,, cellulose? derivatives, lactose, starch, mannitol, sorbitol,, polysorbate, saccharose, glucose, sodium alginate, sodium alginate/calcium salts, optionally with the addition .of binders such as polyvinyl pyrrol idone t5 vinyl acetate/vinyl pyrrolidone copolymer, gelatine 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 auxiliary substances and these neutral pellets are optionally thereafter also coated with a conventional coating substance. A process for the preparation of L-Dopa pellets 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 hydrophilic polymer or hydrocolloid, optionally with the addition of conventional binders and/or solvents, 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 30 gastric juice. 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 guas or alginates and their physiologically acceptable salts. L-Dopa pellets owratimsng from 50 to 1000 mg L-Dopa arid optionally froa 10 to 100 sag of decarboxylase inhibitor, obtainable according to one or snore of Claims 13 to 16. 13. A product according to claim 1, substantially as hereinbefore described. 15 19. A process according t© any one of claims 5-8 for the preparation of a perorally administrable product, substantially as hereinbefore described and exemplified. 20. A perorally admin is tr able product, whenever prepared by a process claimed in any one of claims 5-8 or 19. 20 21. use according to claim 9, substantially as hereinbefore described. 22. Use according to claim 11,„ substantially as hereinbefore described. 23. Use according to claim 12, substantially as hereinbefore 25 described - 24. A process according to any one of claims 13-16 for the preparation of L-Dopa, is the form of pellets, substantially as hereinbefore described and exemplified™ 2

5. L-Dopa pellets, whenever prepared by a process claimed 30 in any one of claims 13—16 or 24. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS. 17. 1 0 31