MXPA05003879A - Gastro-retentive levodopa delivery form - Google Patents

Abstract

Gastro-retentive dosage forms for prolonged delivery of levodopa and carbidopa -levodopa combinations are described. The dosage forms comprise a tablet containing the active ingredient and a gas-generating agent sealed within an expandable, hydrophilic, water-permeable and substantially gas-impermeable membrane. Upon contact with gastric fluid, the membrane expands as a result of the release of gas from the gas-generating agent in the tablet. The expanded membrane is retained in the stomach for a prolonged period of time up to 24 hours or more during which period the active ingredient is released from the tablet providing delivery of levodopa to the site of optimum absorption in the upper small intestine.

Description

FORM OF SUPPLY OF LEVODOPA GASTRO RETENTIVA FIELD OF THE INVENTION This invention relates to a gastro-retentive formulation of levodopa which delivers the drug in a controlled release manner to the upper small intestine. It also refers to its method of preparation and a method for the treatment of Parkinson's disease.

BACKGROUND Parkinson's disease is a neurodegenerative, progressive disorder of the extrapyramidal nervous system that affects the mobility and control of the skeletal muscle system. Its characteristic configurations include tremor at rest, rigidity and bradykinetic movements. Current evidence indicates that the symptoms of Parkinson's disease are related to the depletion of dopamine in the corpus striatum. The administration of dopamine is ineffective in the treatment of Parkinson's disease, apparently because it does not cross the blood brain barrier. However, levodopa, the metabolic precursor of dopamine, crosses the blood brain barrier and presumably converts to dopamine in the brain. Levodopa has been and is one of the most commonly prescribed drugs for patients diagnosed with Parkinson's, despite the fact that new therapies have entered the market. Carbidopa is often given in combination with levodopa. When levodopa is administered orally, it rapidly decarboxylates to dopamine in the extracerebral tissues so that only a small portion of a given dose is transported without changes to the central nervous system. Carbidopa inhibits the decarboxylation of peripheral levodopa and does not cross the blood brain barrier or affect the metabolism of levodopa within the central nervous system. Since its decarboxylated inhibitory activity is limited to extracerebral tissues, the administration of carbidopa with levodopa makes levodopa more available for transport to the brain. Carbidopa reduces the amount of levodopa required to produce a given response by approximately 75 percent. Most patients who use levodopa experience an initial improvement in their symptoms. However, more than 50% of patients will develop fluctuations in response (dyskinesias) in the first five years of levodopa therapy, associated with the effect at the end of the dose (exhaustion) and the on-off phenomenon. In the first, the dose of levodopa does not last as long as it originally did. This problem can usually be managed by decreasing the dosing interval or switching to prolonged release forms of the drug. With the on-off phenomenon, the patient experiences wide fluctuations of function. Again, it can be treated by giving more frequent doses of levodopa or by using the extended-release form of the drug. drug. There are several levodopa products currently available. Sinemet® (Dupont) is a combination of levodopa and carbidopa used for the treatment of Parkinson's disease and syndrome. It is available in immediate release ("IR") and controlled release (#CR ") formulations.SEMEMET® is available as a tablet in 3 concentrations: 10 mg carbidopa-100 mg levodopa, 25 mg carbidopa-100 mg levodopa and 25 mg carbidopa-250 mg levodopa SINEMET® CR is a prolonged-release form that is available in two concentrations: either 50 mg carbidopa-200 mg levodopa or 25 mg carbidopa-100 mg levodopa. The SINEMET® CR tablet utilizes a polymer-based drug delivery system in which the release of carbidopa and levodopa is controlled by the erosion of the polymer.The sustained release dosage form is designed to release these ingredients over a period of time. 4 to 6 hours With the prolonged release form, the observed variation in levodopa levels in plasma is lower than that observed with the conventional formulation. Sme of levodopa has proven to be difficult through the use of conventional controlled release technologies. One obstacle to achieving such a prolonged release form of levodopa is that the drug is only absorbed to a greater extent in the upper small intestine. Once the controlled release dosage form travels more beyond the absorption site, no further productive absorption of the levodopa will occur. An oral formulation that would provide a constant supply or prolonged plasma level of levodopa for up to 24 hours or more by the use of SR / CR technologies has not been achieved previously. Accordingly, a need remains for a sustained release form of levodopa or carbidopa-Iedodopa combinations, which provides a constant supply of the active ingredient for a period of 12-24 hours.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a gastro-retentive dosage form of levodopa and combinations of carbidopa-Iedodopa, which provides a dose once a day. The invention relies on gastro-retentive technology (GRS) described herein to carry out the retention of a dosage form in the stomach for a period of time of up to 6-24 hours or more. Such dosage form allows prolonged, controlled delivery of levodopa in the upper small intestine, the optimal site of f + armaco absorption, for up to 24 hours or more, resulting in a reduced frequency or dosage and a flat pharmacokinetic profile of the levodopa In addition, the improved bioavailability, provided by the prolonged retention of the dose form at the site of optimal absorption, can result in a reduced dosage requirement.

One aspect of the present invention therefore provides a gastro-retentive dosage form of levodopa for oral administration to a patient in need thereof, said dosage form comprising (a) a tablet comprising a therapeutically effective amount of levodopa, a binder and a pharmaceutically acceptable gas generating agent, capable of releasing carbon dioxide after contact with gastric fluid and (b) a membrane that is substantially impermeable to gas and permeable to water, hydrophilic, expandable, surrounding the tablet, where the membrane expands as a result of the release of carbon dioxide from the gas generating agent after making contact with the gastric juice, whereby the dosage form becomes too large to pass into the pyloric sphincter of the gastric patient. Optionally, the dosage form is kept within a shell that disintegrates without delay after making contact with the gastric fluid. In addition to levodopa, the tablet may contain carbidopa in amounts effective to provide improved availability of levodopa, as well as pharmaceutically acceptable excipients, diluents, slip agents, lubricants and the like. Another aspect of the present invention provides a method for the manufacture of a gastro-retentive dosage form of levodopa, wherein said method comprises (a) forming a tablet comprising levodopa, a binder and a pharmaceutically acceptable gas generating agent, (b) surround the tablet with a membrane substantially impermeable to gas and permeable to water, hydrophilic, exudable and (c) sealing the membrane to retract the escape of gas from inside the sealed membrane. A further optional step comprises (d) encapsulating the membrane-sealed tablet within a shell that disintegrates without delay upon contact with gastric fluid. A further aspect of the present invention provides a method for the treatment of a patient in need thereof, with a prolonged release dose of levodopa by oral administration to said patient of a gastro-retentive dosage form of the levodopa. In particular, patients suffering from Parkinson's disease will benefit from the method of treatment of the present invention.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a flowchart for the preparation of certain embodiments of the gastro-retentive dosage forms of the present invention. The formulations contain Samarium Oxide, a radionucleotide, to allow measurement of gastrointestinal transit of dosage forms after administration to human volunteers, by the use of scintigraphy. Figure 2 is an in vitro dissolution profile for bags containing tablets of the Tablet Formulation 19 (Formulation in Granule 9). The percentage of levodopa (diamonds) is shown blacks) or carbidopa (gray squares) released from the sacs is simulated gastric fluid as a function of time. The results shown are for two separate solutions - one measure at time points between 0 and 8 hours and at 24 hours, and the other measure at time points between 10 and 34 hours. The measurements are plotted on the same curve. Figure 3 is an in vitro dissolution profile for bags containing tablets of Tablet Formulation 20 (Formulation in Granule 10). The percentage of levodopa (black diamonds) or carbidopa (gray squares) released from the sacs in simulated gastric fluid as a function of time is shown. The results shown are for two separate solutions - one measure at time points between 0 and 8 hours and at 24 hours, and the other measure at time points between 10 and 34 hours. The measurements are plotted on the same curve. Figure 4 is an in vitro dissolution profile for bags containing tablets of Tablet Formulation 21 (Granule Formulation 1 1). The percentage of levodopa (black diamonds) or carbidopa (gray squares) released from the sacs in simulated gastric fluid as a function of time is shown. The results shown are for two separate solutions - one measure at time points between 0 and 8 hours and at 24 hours, and the other measure at time points between 10 and 34.5 hours. The measurements are plotted on the same curve. Figure 5 is a comparison of the profiles of dissolution, which shows the time course of the levodopa release for four different formulations of the dosage form: gray diamonds - tablet formulation 19; black triangle with solid line - tablet formulation 20; black triangle with dotted line - tablet formulation 21; gray square - granule formulation 12 (tablet). Figure 6 is a similar comparison profile of carbidopa release from four different dosage forms: Open circles - tablet formulation 19; open triangle with solid line - tablet formulation 20; X with dotted line -formulation of tablet 21; gray square - granule formulation 12 (tablet). Figure 7 is a time course of the relative expansion of the sacs containing the tablet formulation, based on visual inspection in simulated gastric fluid on a scale of 0 to 3. A rating of 0 indicates that the sack is not Inflated, 1 indicates that it begins to inflate, 2 indicates almost inflated and 3 indicates completely inflated. Figure 8 is a time course of the volume expansion of sacks containing tablets having Granule Formulation 12.

DETAILED DESCRIPTION AND MODALITY CURRENTLY PREFERRED The present invention provides a dosage form gastro-retentive levodopa for oral administration to a patient in need thereof, said dosage form comprising (a) a tablet comprising a therapeutically effective amount of levodopa, a binder, and a pharmaceutically acceptable gas generating agent, capable of releasing carbon dioxide upon contact with gastric juice, and (b) a hydrophilic, expandable, water-permeable, gas-impermeable membrane surrounding the tablet, wherein the membrane expands as a result of the release of carbon dioxide to starting from the gas generating agent in contact with the gastric juice, causing the dosage form to become too large to pass into the pyloric sphincter of the patient for a period of time. The gastro-referential dosage form is optionally provided with a cover that disintegrates without delay upon contact with gastric fluid. One embodiment of this invention can be seen as a gas-generating inflatable system that is encapsulated in a hard-filled, hard gelatin capsule. When the gastric fluid is contacted, the capsule dissolves to release a membrane sac (for example, approximately 25 mm x 25 mm in size) which contains the active ingredient of levodopa formulated with effervescent excipients and release control. When water or gastric fluid enters the sac, carbon dioxide is released from the tablet and this causes the sac to inflate to a volume of about 20 ml. The bag filled with gas is able to float on the aqueous phase and is retained in the stomach because it is too large to pass into the pyloric sphincter. Bag inflation is a gradual process and carbon dioxide is released during a period of time defined in order to maintain inflation. Typically, the sac remains inflated for a period of about 8-12 hours and can remain inflated for up to 24 hours or more. The period of inflation also reflects the time of gastric retention. During their drying time in the stomach, the levodopa and carbidopa present in the components of the tablet are slowly released into the surrounding body fluid, preferably by diffusion, through the membrane of the sac. Since the gastric juice is also always transported, the active ingredient passes continuously and for a prolonged period into the duodenum, where it is absorbed for a prolonged period of time. Accordingly, the gastro-retentive form according to the invention ensures the continuous release of levodopa and carbidopa in conjunction with uniform absorption. Once the gas generating formulation is exhausted, the sac deflates and flattens, becoming flexible enough to pass through the pylorus and thus empties from the stomach. The gastro-retentive dosage form of the present invention is particularly advantageous for the treatment of patients suffering from Parkinson's disease since it provides a prolonged release of the active levodopa at a relatively constant level, directly at the site of optimal absorption in the upper small intestine.

For the purposes of the present invention, "tablet" includes any form of pharmaceutical dosage, solid, containing drug substances with or without suitable diluents, prepared by granulation, compression or molding methods, and also includes hard or soft gelatin capsules , granules, pills and bowls. The terms "gastric fluid" and "gastric juice" are used interchangeably therethrough and refer to the endogenous fluid medium of the stomach, including water and secretions. "Simulated gastric fluid" means any fluid that is generally recognized as providing a useful substitute for authentic gastric fluid in experiments designed to determine the chemical or biological behavior of substances in the stomach. One such simulated gastric fluid is 0.1 N aqueous HCl, pH 1.2. It will be understood that the term "gastric fluid" or "gastric juice" which is used throughout the disclosure and claims means authentic (i.e., endogenous) gastric fluid or simulated gastric fluid. The term "gastro-retentive form" denotes dosage forms that effect the prolonged release of the active ingredient as compared to conventional dosage forms, such as customary tablets or capsules, while avoiding an undesirably high initial dose, effecting the release in a manner continues for a relatively long period and in a controlled manner at a therapeutically effective level by prolonged retention of the dosage form in the stomach. The tablet component of the gastro-dose form retentive of the present invention comprises levodopa, as an active ingredient, a binder and a pharmaceutically acceptable gas generating agent. The tablet component optionally comprises carbidopa in combination with the active ingredient levodopa. The tablet component may additionally contain suitable diluents, slip aids, lubricants, acidulants, stabilizers, inflammation agents and other pharmaceutically acceptable excipients.

Active The active ingredient in the gastro-retentive dosage forms of the present invention is levodopa, which is variously known, inter alia, as L-dopa; β- (3,4-dihydroxyphenyl) -a-alanine; or 2-amino-3- (3,4-dihydroxyphenyl) propanoic acid. Levodopa can be used alone as the active ingredient or can be combined with carbidopa (S-hydrazino-3 acid monohydrate), 4-dihydroxy-α-methylbenzenopropanoic acid) in a weight ratio of levodopa to carbidopa of from about 20 to 1 to about 2 to 1, preferably from about 10 to 1 to about 2 to 1, more preferably from about 5 to 1 to about 3 to 1, in particular about 4 to 1. Levodopa is commercially available and its synthesis has been described in numerous publications, for example, Yamada et al. , Chem. Pharm. Bull. , 10: 693 (1962) and U.S. Patent. No. 496223 and the references cited herein. The known therapeutic uses of levodopa include the treatment of isiopathic and postencephalic Parkinsonism, various extrapyramidal neuropathies and depression. Carbidopa is commercially available. Combinations of levodopa-carbidopa for the treatment of Parkinson's disease are well known and have been described, for example, in the U.S. Patent. No. 4,900,755, and are commercially available (for example, SINEMET®). The tablet component contains the active ingredient levodopa in a therapeutically effective amount. The therapeutically effective amount per dose of levodopa for the treatment of Parkinson's disease is between 100 and about 400 mg / dose. Typically, the levodopa is present in an amount of between 10% to about 50% or the total weight of the tablet, preferably between about 15% and about 40%. In general, this amount of levodopa will provide between about 15% and about 40%. In general, this amount of levodopa will provide between about 100 mg and 250 mg of levodopa per dosage form, which amount is the preferred unit dose range. Other therapeutically effective doses can be easily determined by a person skilled in the pharmaceutical or medical field. Carbidopa, if present, will be included in accordance with the weight ratios discussed above. Typically, carbidopa will be present in about 3% to about 8% of the total weight of the tablet.

Binder The tablet component of the gastro-retentive dosage form comprises the active ingredient (ie, levodopa or combinations of levodopa and carbidopa), a gas generating agent and a binder. Binders (also called wetting agents) are agents used to improve the cohesiveness of the tablet formulation, ensuring that the tablet will remain intact after formation. Suitable binders for use in the present invention include poloxamers, polyethylene glycols (e.g., PEG 3350), polyethylene glycol fatty acid esters (e.g., Myrj), glyceryl palmitostearate (e.g., Precirol AT05), ethers of polyethylene alkyl, glyceryl behenate (eg, Compritol 888), macrogol-32-stearoyl glyceride (eg, Gelucire), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid derivatives, polyoxyethylene stearates , polyoxyethylene-polyoxypropylene copolymers (eg, Lutrol or Pluronics), starches, gelatin, sugars such as lactose, sucrose, glucose and molasses, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, cellulose ethyl and waxes. Especially preferred binders include Myrj52 (particularly Myrj52P or Myrj52FL), Lutrol F68, Compritol 888, Gelucire 50/13, PEG 3350, Precirol AT05 methylcellulose and polyvinylpyrrolidone. The binder is presented in the tablet component in an amount effective to provide cohesion to the final tablet form. The proper amount of binder can be readily determined by someone of ordinary skill in the pharmaceutical field and will depend, among other things, on the particular binder used and the method of preparing the tablet. Typically, the binder is presented in the tablet in an amount of between about 8% to about 15% of the total weight of the tablet.

Gas Generating Agent A gas generating agent is included in the tablet component to generate the carbon dioxide gas which results in the expansion of the membrane component upon contact with gastric juice. Suitable gas generating agents are, for example, solids which release this gas itself, for example, under the action of the body fluid or the hydrogen ions present therein. Such gas generating agents are, for example, those capable of liberating carbon dioxide and include, but are not limited to, pharmaceutically acceptable mono- and di-basic salts of carbonic acid, for example, alkali metal hydrogen carbonates or alkali metal, alkaline earth metal carbonates or ammonia carbonate. Such mono- or di-basic salts are especially sodium hydrogen carbonate (sodium bicarbonate) or sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium glycine carbonate, or mixtures thereof. In order to increase the evolution of carbon dioxide, the acid component normally used in effervescent mixtures, for example, sodium dihydrogen phosphate or disodium hydrogen phosphate, sodium tartrate, sodium ascorbate or citrate can be added to the aforementioned carbonates. of sodium. Yeasts which are equally capable of generating carbon dioxide gas are also suitable. When yeasts are used, for example, cooking yeast, the necessary nutrients, eg glucose, are added to the formulation. Preferably, in the present invention, the gas generating agent will be sodium hydrogen carbonate. The gas generating agent will typically be present in the tablet component in an amount between about 30% and about 82% of the total weight of the tablet. Preferably, the gas generating agent will be presented at about 40% to about 82% of the total weight of the tablet.

Other Agents In addition to the active ingredient, the binder and the gas generating agent, the tablet component may also include one or more diluents, slip aids, lubricants, acidulants, inflammation agents, surfactants and other excipients. pharmaceutically acceptable A diluent is an added substance for increasing the volume of a mixture to form a practical size tablet for granulation, compression or molding when a small amount of active is present. Suitable diluents include lactose, cellulose, dry starch, powdered sugar, dicalcium phosphate, calcium sulfate, sodium chloride, kaolin, mannitol, sorbitol, sucrose, inositol; the preferred diluents are lactose, sorbitol, mannitol, cellulose and starch. A slip aid (or flow improver) is a substance that improves the flow characteristics of a powder mixture. The commonly used gliding aids include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate and talc. Sliding aids useful in this invention include these commonly used auxiliaries and a preferred slip aid is Aerosil 200, colloidal silicon dioxide. A lubricant is a substance having a number of functions in the preparation of the tablet component of this invention, including prevention of adhesion of the tablet material to the surface of the nozzles and punches, reduction of friction between particles, facilitation of expulsion. of the tablet from the nozzle cavity and, in some cases, improvement of the flow rate of the tablet granulation. Commonly used lubricants include talc, magnesium stearate, zinc stearate, stearic acid, glyceryl monostearate, glyceryl palmito stearate, hydrogenated vegetable oils, castor oil hydrogenated, light mineral oil, sodium benzoate, sodium stearyl fumarate and polyethylene glycol (PEG). Any of the lubricants commonly used are suitable for use in the present invention. Preferably, magnesium stearate is used as a lubricant. An acidulant can be added to increase the release of carbon dioxide from this sodium hydrogen carbonate. Commonly used acidulants include citric acid, fumaric acid, malic acid and tartaric acid. It will be apparent from the foregoing that a single substance can serve more than one of the purposes described above.

Inflammation Agents In addition to the aforementioned gas generating agents, it is also possible to intensify the action of the agent to use inflammation agents, hydrophilic, pharmaceutically acceptable, for example, partially etherified cellulose derivatives, starches, aliphatic or cyclic poly-N-vinylamides, water-soluble, polyvinyl alcohols, polyacrylates, polymethacrylates, polyethylene glycols or mixtures of these auxiliaries. In certain embodiments, the hydrophilic igniting agent may also serve as a binder. The partially etherified, hydrophilic cellulose derivatives are, for example, lower alkyl ethers of cellulose having an average degree of molar substitution (MS) of more than 1. and less than 3 and an average degree of polymerization of about 100-5000. The degree of substitution is a measure of the substitution of hydroxy groups by lower alkoxy groups per glucose unit. The average degree of molar substitution (MS) is a mean value and indicates the number of lower alkoxy groups per glucose unit in the polymer. The average degree of polymerization (DP) is likewise a mean value and indicates the average number of glucose units in the cellulose polymer. The lower alkyl ethers of cellulose are, for example, cellulose derivatives which are substituted in the hydroxymethyl group (primary hydroxy group) of the glucose unit forming the cellulose chains and optionally in the second and third secondary hydroxy groups by groups C1-C4 alkyl, especially methyl or ethyl, or by substituted C --C4 alkyl groups, for example, 2-hydroxyethyl, 3-hydroxy-n-propyl, carboxymethyl or 2-carboxyethyl. Suitable cellulose lower alkyl ethers are especially methylcellulose, ethylcellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose (in the form of a salt, for example, sodium salt form) or methylcarboxymethylcellulose (in the same way as salt, for example, sodium salt form). A suitable starch for use as a hydrophilic igniting agent is, for example, a mixture of about 15-20% amylose (about 50,000 to 200,000 molar mass) and 80-85% amylopectin (about 1,000,000 to 1,000,000 molar mass), for example, rice starch, wheat or potato, and also derivatives of starch, such as partially synthetic amllopectin, for example, sodium carboxymethylammopectin, and alginates of the alginic acid type. The water-soluble aliphatic or cyclic poly-N-vinylamides are, for example, poly-N-vinyl-methylacetamide, poly-N-vinylethylacetamide, poly-N-vinylmethylpropionamide, poly-N-vinylethylpropionamide, poly-N-vinylmethylisobutyramide. , poly-N-vinyl-2-pyrrolidone, poly-N-vinyl-2-piperidone, poly-N-vinyl-e-caprolactam, poly-N-vinyl-5-methyl-2-pyrrolidone or poly-N -vin I-3-methi-2-pyrrolidone, especially poly-N-vinyl pyrrolidone having an average molar mass of about 10,000-360,000, for example, the polyvinylpyrrolidone obtainable under the trademark Kollidon® (BASF). Suitable polyvinyl alcohols have an average molar mass of about 15,000 to 250,000 and a degree of hydrolysis of about 70-99%. Preferred polyvinyl alcohols are those having a degree of hydrolysis of about 70-88% (partially hydrolyzed polyvinyl alcohol), for example, the polyvinyl alcohol obtainable under the Mowiol® brand (Hoechst) denoted by MOWIOL 3-83, 4-80, 4-88, 5-88 or 8-88. The hydrophilic polyacrylates that can be used as Inflammation agents have an average molecular weight of approximately 8.6X105 to 1.0x106. The polyacrylic acid chains carry a greater or lesser number of short side chains and, therefore, the individual commercial forms differ in this respect, as well as in having different molecular weights. Neutralized polyacrylic acid derivatives (for example, with diluted aqueous sodium hydroxide solution) of the commercial form of Carbopol® (Goodrich), for example, CARBOPOL 934 P or CARBOPOL 940, are preferred. Suitable polymethacrylates are likewise expandable and have an average molecular weight of more than 1.0 x 106. Preferred commercial forms that can be used are methacrylic acid polymers and methacrylic acid esters of the Eudragit® type, for example, EUDRA-GIT L or EUDRAGIT S (Rohm GMBH). Suitable polyethylene glycols have an average molecular weight of about 4000 to 6000. Commercial forms of pharmaceutical quality are preferred, for example, polyethylene glycol such as Lutrol® (BASF), Polydlol®, Polywachs® (Hüls), Polyglykol® , Lanogen® (Hoechst), Carbowax® (Union Carbide), Plurocol® (Wyandotte) or Tetronic® (Kuhlmann). Suitable hydrophilic igniting agents are also homopolymers, such as polyhydroxyalkyl methacrylate having a molecular weight of 5,000 to 5,000,000 anionic or cationic hydrogels, mixtures of agar and carboxymethylcellulose, expandable agents consisting of methylcellulose in admixture with weakly degraded agar, or water-swellable polymers which can be produced by dispersion of a finely particulate copolymer of maleic acid anhydride and styrene, or tragacanth, gelatin or swellable ion exchange resins. Inflatable ion exchangers are, for example, copolymer resins having acidic groups, for example, sulfonic acid groups or salt forms thereof based on styrene-divinylbenzene. Such copolymer resins consist of degraded styrene polymers which are obtained by copolymerization of styrene with divinylbenzene as the degradation agent. The customary derivatization reactions, for example, sulfonation reactions, are used to incorporate acidic groups, such as sulfo groups, into the structure. The preparation and properties of these resins are known. Reference is made to the article in Ullmanns Enzyklopádie der Technischen CEIME, 4th Edition, Vol. 13, p. 279 ff and Kirk-Othmer, Encyclopaedia of Chemical Technology, J. Wiley, Vol. 13, pp. 678 ff, and numerous references in the literature cited in the present. Preferred ion exchange resins are those having quaternary ammonia groups or sulphonic acid groups based on styrenedivinylbenzene, which are commercially available and are acceptable for use in pharmaceutical formulations, for example, commercially available resins by the firm Rohm and Haas under the brand Amberlite® IRP-69.

Surfactants The tablet component may also contain the adjuncts to the conventional pharmaceutical formulation, which are currently used for the preparation of oral dosage forms, such as tablets, for example, surface active substances, for example, the so-called surfactants, for example , anionic surfactants of the alkyl sulfate type, for example, n-dodecyl sodium, potassium or magnesium sulfate, n-tetradecyl sulfate, n-hexadecyl sulfate or n-octadecyl sulfate, alkyl ether sulfate, for example, sodium, potassium or magnesium n-dodecyloxyethyl sulfate, n-tetradecyloxyethyl sulfate, n-hexadecyloxyethyl sulfate or n-octadecyloxyethyl sulfate, or alkanesulfonate, for example, sodium, potassium or magnesium n-dodecanesulfonate, n-tetradecanesulfonate, n-hexadecanesulfonate or n-octadecanosulfonate. Suitable surfactants are also nonionic surfactants of the fatty acid / polyoxyhydroxy alcohol ester type, such as sorbitan monolaurate, monooleate, monostearate or monopalmtate, sorbitan tristearate or trioleate, polyoxyethylene fatty acid adducts / polyhydroxy alcohol esters, such as polyoxyethylene sorbitan monolaurate, monooleate, monostearate, monopalmitate, tristearate or trioleate, polyethylene glycol / fatty acid esters, such as stearate polyoxyethylene, polyethylene glycol stearate 400 or polyethylene glycol stearate 2000, especially block copolymers of ethylene oxide / propylene oxide of the type Pluronics® (BWC) or Synperonic® (ICI), miristaios and their condensation products, or ethylene oxide homopolymers having a degree of polymerization of about 2,000 to 100,000, which are known, for example, under the trademark Poiyox® (Union Carbide).

Preparation of the Tablet The tablet component can be formed by any conventional tabletting method, such as mixing, dry granulation, wet granulation, fluid bed granulation, direct compression, molding or extrusion. Preferably, the tablet component is prepared by use of fluid bed granulation, melt granulation or direct compression methods. Typically, for the preparation of tablets for use in the gastro-retentive dosage form of the present invention, suitable amounts of levodopa, carbidopa (if applicable), a gas generating agent (typically sodium bicarbonate) and a binder in a mixer at high shear for a short period of time. The mixture is heated to a temperature that is approximately 5 ° -10 ° C above the melting temperature of the binder. The heated mixture is mixed and granulated and then crushed in order to obtain particles of fairly homogeneous size (approximately 1.0 mm or less). The granules are mixed with a slip aid (preferably Aerosil 200) and a lubricant (preferably magnesium stearate). This mixture is shaped into tablets by conventional tabletting methodology. Alternatively, the gas generating agent and a diluent, such as sorbitol / mannitol, are mixed in a fluid bed machine and a binder solution is sprayed onto the mixture. The material is dried by heating, cooled and mixed with levodopa, carbidopa (if applicable), slip aid and lubricant. Tablets are formed from the granules by the use of conventional tabletting methods. The tablet can be of any convenient shape and size, suitable for oral administration and / or for ease of preparation of the gastro-retentive dosage form. Typically, the tablet will be round, flat, bevelled or oval and will typically be about 5 mm shorter than the larger internal dimension of the bag. Generally, the tablet will not be more than 20 mm in its greatest dimension. The total weight of the tablet will generally vary from about 250 mg to 2500 mg, preferably ranging from about 500 mg to about 1000 mg, more preferably between about 600 mg and about 800 mg, before the addition of the membrane bag and the optional cover .

Expandable Membrane The hydrophilic membrane, which is expandable at the site of use and permeable to body fluid, consists of a plastic or pharmaceutically acceptable polymeric material, similar to wax, which is substantially impervious to gas with respect to the gas generated by the agent gas generator. By "substantially impermeable to gas" it is meant that the luxury of gas through the membrane is prevented sufficiently to allow the expansion of the sachet or membrane sack after generation of gas from the gas generating agent contained in the component. of tablet for a suitable period of time. Due to its hydrophilic properties, the membrane can absorb body fluid, such as gastric fluid, and can effect the delayed and continuous release of controlled amounts of the levodopa contained in the tablet component by diffusion or optionally by the use of osmosis. Suitable polymeric, plastics or wax-like materials for the hydrophilic expandable membrane include, for example, hydrophilic sheets, for example, sheets of cellulose ethers, such as methyl- or ethyl-cellulose, hydroxypropylcellulose, methyl- or ethyl -hydroxyethylcellulose, methyl- or ethyl-hydroxypropylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, polyacrylonitrile, mixtures of polyvinylpyrrolidone with polyvinyl alcohol, resins based on phthalic acid, alcohol anhydride / polyhydroxy, urethanes, polyamides, lacquer, etc. Polyvinyl alcohols having a degree of hydrolysis of more than 92% (fully hydrolyzed polyvinyl alcohol), especially more than 97%, for example, MOWIOL of the series 98, for example, MOWIOL 4-98, are especially preferred. -98, 20-98, 28-99, 56-98 and 66-100, PVAU228-08. MOWIOL 28-99 and PVAU228-08 are particularly preferred. To these materials it is possible to add additional adjuncts, for example, plasticizers, which improve the elasticity of the membrane, for example, glycerol, polyethylene glycol / fatty acid esters, such as polyethylene glycol stearate 400 or polyethylene glycol stearate 2000, citrate of triethyl, diethyl phthalate, diethyl sebacate and the like. The amount of plasticizer added is from about 0.01 to 60% by weight, based on the total weight of the dosage form. Preferably, glycerol at 10-30% w / w is used as the plasticizer, more preferably 20%. In a modality, the expandable membrane is produced by preparing a homogeneous mixture of polyvinyl alcohol and additives, such as plasticizers, for example, glycerol and / or polyethylene glycol stearate 400, by dissolution in water, which is optionally heated, and evaporation to form layers of suitable thickness, for example, 100 mm, or allowing a solution of polyvinyl alcohol to evaporate in water (without additives). The film or sheet that can be obtained after the evaporation of an aqueous solution, which contains about 40-85% polyvinyl alcohol, 0-40% polyethylene glycol stearate and 1 0-30% glycerol, has particularly advantageous properties. This film is distinguished by a particularly good extensibility. This film can be easily cut into bags or sachets to accommodate individual tablet components or used as a sheet to be folded around the tablet component or several sheets of membrane film can be used to sandwich the tablet components.

Optional Cover In certain embodiments, the gastro-retentive form according to the invention may be provided with a cover that surrounds or contains the tablet component and the membrane component t that disintegrates without delay under the action of body fluid at the site of use and which consists of a film cover or, preferably, a cover in the form of a capsule. Suitable film covers delay the release of the active ingredient only slightly or not at all. Water-soluble film covers of about 20 μm to about 150 μm in thickness are preferred. Suitable film coating materials are especially hydrophilic cellulose derivatives, such as cellulose ethers, for example, methylcellulose, hydroxypropylcellulose or especially hydroxypropylmethylcellulose, mixtures of polyvinylpyrrolidone or a copolymer of polyvinylpyrrolidone and polyvinyl acetate with hydroxypropylmethylcellulose, lacquer mixtures with hydroxypropylmethylcellulose, polyvinyl acetate or copolymers thereof with polyvinylpyrrolidone, or mixtures of water-soluble cellulose derivatives, such as hydroxypropylmethylcellulose, and water-soluble ethylcellulose. If desired, these coating agents can be used in admixture with other adjuncts, such as talcum, wetting agents, for example, polysorbates (eg, for ease of application), or pigments (eg, for identification purposes). . Depending on the solubility of the components, these covers are applied in aqueous solution or in organic solution (for example, lacquer solutions or ethylcellulose in organic solvents). It is also possible to use mixtures of acrylates which are insoluble in water per se, for example, the copolymer of ethyl acrylate and methyl methacrylate, which are used in aqueous dispersion, with water-soluble adjuncts, for example, lactose, polyvinylpyrrolidone, polyethylene glycol or hydroxypropylmethylcellulose. Instead of using a film-like cover, the gastro-retentive forms according to the invention may be provided with a capsule-shaped cover. Hard gelatine capsules having high water solubility and / or swelling capacity are preferred. Capsules of size 000, size 00 and size 0 of dry filling are preferred in order to accommodate the membrane-enclosed tablets. When presented, the cover is preferably a dry filling capsule, more preferably a hard gelatin dry filling capsule.

Preparation of Gastro-Retentive Forms In one aspect, the present invention provides a method for the manufacture of a gastro-retentive dosage form of levodopa, which method comprises: forming a tablet comprising levodopa, a glomerr and a gas generating agent pharmaceutically acceptable, encircling the tablet with a membrane that is substantially impermeable to gas and permeable to water, hydrophilic, expandable, and sealing the membrane to retard the escape of gas from the interior of the sealed membrane. Optionally, the method comprises the additional step of encapsulating the sealed membrane within a shell that disintegrates without delay upon contact with gastric fluid. As described above, the tablet component can be formed by any convenient method of tabletting. Such methods are well known in the art and are described, for example, in Remington: the Science and Practice of Pharmacy 19h Ed. 1995 Mack Publishing Co. Easton Pa. In the gastro-retentive dosage form of the present invention, the tablet component will be surrounded by the expandable membrane component. . The membrane surrounds the tablet on all sides and is sealed in order to delay the escape of gas generated by the gas generating agent contained in the tablet. This rodeo can carried out in various ways. The membrane may be a pre-formed sachet containing an opening large enough for the insertion of the tablet component. After insertion of the tablet, the opening is sealed by suitable means, for example, heat and / or pressure. Alternatively, the membrane can be formed around the tablet, for example, as a cover on the tablet that completely surrounds the tablet, or it can be formed by sandwiching the tablet component between two or more separate layers of membrane material, or a membrane layer bent over the tablet, and sealing the membrane layers together around the tablet by heat and / or pressure. Typically, the membrane bag surrounding the tablet component will be as small as possible, according to the need to accommodate the tablet component and provide sufficient expansion of the dosage form in the stomach. As mentioned, the hydrophilic membrane is typically prepared in the form of a sachet or sac into which the tablet component can be inserted. Such a sachet is easily prepared from the membrane film prepared as described herein. After insertion of the tablet, the pouch can be sealed around the tablet or delay the escape of gas generated by the gas generating agent in the tablet component. The sachet or sack can be of any convenient shape, typically it will be rectangular or circular. Typically, the sachet or sack The non-inflated membrane is approximately 20-25 mm in the longest dimension and may be shorter, depending on the size of the plywood component that must be accommodated. In some embodiments, the membrane film will not be pre-formed into sacks but rather will be used as a film layer to surround the tablet component, either by sandwiching the tablet between two (or more) membrane layers or by fold a single layer on the tablet. The membrane layers will be sealed on all sides surrounding the tablet and cut along the seal to produce the dosage form. The multiple dosage forms can be produced simultaneously in this manner by the use of a membrane layer large enough to accommodate multiple tablets, sealing of the membrane layers between the tablets and cutting in the sealed membrane to produce the dosage forms. It is also possible that the tablet component is surrounded not by one but by several covers of expandable permeable material. With such a multilayer installation, it is also possible that a formulation of levodopa, or constituents of the formulation, for example, the gas generating agent, such as sodium hydrogen carbonate, is located between individual layers. With a multilayer installation it is possible to achieve a drying time of the dosage form at the site of action, for example, in the stomach. In addition, the expandable membrane (b) can, by itself, contain physiologically active substances.

In a preferred form of the process, the expandable membrane surrounding the tablet component is first produced, for example, by preparation of a homogeneous mixture of polyvinyl alcohol and additives, such as plasticizers, for example, glycerol and / or glycol stearate. of polyethylene 400, by dissolving in water, which is optionally heated, and evaporating to form layers of suitable thickness, for example, 100 mm, or by allowing a solution of polyvinyl alcohol in water to evaporate (without additives). The layers are cut into strips of an appropriate size and the active ingredient formulation consisting of the tablet component is applied. This can be done, for example, by filling the still open sachet, which is then closed completely, for example, by sealing, for example, with heat and / or pressure. The sealed sachets can then fill dry fill capsules. The gastro-referential dosage form according to the invention can be of various forms and can be, for example, round, oval, oblong, fibular and so on, and can be of various sizes, depending on the size and shape of the tableware component. In addition, the dosage form can be transparent, colorless or colored, in order to impart to the product an individual appearance and the ability to recognize itself immediately. In some embodiments, the gastro-retentive dosage form can be prepared by the use of microparticles or nanoparticulates comprising the active (ie, levodopa p combinations of levodopa: carbidoa) in place of a tablet. The microparticulates or nanoparticulates will comprise levodopa, a binder and a gas generating agent, optionally carbidopa, and other optional components, as described for the tablets. Microparticulates or nanoparticles are prepared, by the use, for example, of granulation techniques described herein or other well-known methods for the preparation of microparticulates and nanoparticles. Particularly, the preferred gastro-retentive forms and methods for making them are similar to those described in the U.S. Patent. 4,996,058, which is incorporated herein by reference in its entirety.

METHOD OF TREATMENT The present invention provides a method for the treatment of a patient suffering from Parkinson's disease by oral administration to the patient of the dosage form of gastro-retentive levodopa. The prolonged drying time in the stomach, of the gastro-retentive form of the present invention, provides sustained prolonged release of levodopa or combinations of levodopa-carbidopa at the site of optimal absorption for levodopa. The prolonged release of the active ingredient, provided by the gastro-retentive form, reduces the need for frequent dosing. Therefore, gastro-dose dosage forms Retentives of the present invention are typically administered once or twice in a period of 24 hours, preferably once in 24 hours, but may be administered more or less frequently, depending on the requirement of the patent.

Processing Article In another aspect, the present invention provides a processing article comprising a dosage form of gastro-retentive levodopa, packaging material containing the dosage form and optionally a label or insert containing instructions for using the form of dose for the treatment of Parkinson's disease. The dosage form provided in the processing article preferably includes a hard-filled, hard gelatin capsule shell. The processing article preferably comprises a dosage form comprising carbidopa in combination with levodopa at weight ratios described herein, wherever. Most preferred are combinations of 100 mg of levodopa: 25 mg of carbidopa per dose form and 200 mg of levodopa: 50 mg of carbidopa per dosage form. The individual dosage forms may be packaged separately in individual containers or the packaging material may be provided with a plurality of dosage forms. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way.

EXAMPLE 1 Preparation of Granules Levodopa, carbidopa (if applicable to the batch), sodium bicarbonate and a binder (300 g batch size) are mixed at 200 rpm in the mixer at high Rotolab shear for 5 minutes. The heating jacket was ignited and heated until the desired product temperature was reached. The desired temperature was 5 ° -10 ° C above the melting temperature of the binder used. The materials were mixed and granulated for an additional 15 minutes. The molten material was then removed from the granulation bowl and crushed by the use of Comill, initially using a 1/7 mesh screen and finally a 0.7 mm mesh screen. The dose resistances evaluated were: 100 mg of Levodopa, 100: 25 mg of Levodopa: Carbidopa, 200 mg of Levodopa and 200: 50 mg of Levodopa: Carbidopa. In Table 1 a summary of the elaborated granules is shown.

Preparation of Tablets The Levodopa or Levodopa arbidopa granules are placed in a bag and Aerosll 200 is sieved into the bag containing the granules by using a 1 mm mesh. The mixture in the bag occurs for 3 minutes. Once complete, magnesium stearate is screened into the top bag through a 0.5 mm mesh and mixed in the bag for 3 minutes additional The shaping of the table is carried out by using a Piccola 10 station by using a 16x6mm flat bevel punch. Table 2 shows a summary of the processed tablets.

Table 1. Summary of granular compositions Table 2. Summary of elaborate tablet compositions Example 2 Fluid Bed Granulation Sodium bicarbonate, sorbitol (or sorbitohmannitol at a ratio of 60:40) are mixed in the fluid bed machine (Niro Aeromatic, Strea 1). A binder solution of PEG 6000 and water (16% w / w), PVP K25 and water (16% w / w), or water alone is sprayed onto the bicarbonate mixtures. The materials are dried for an additional 30 minutes at 50 ° C and then cooled for an additional 30 minutes. A sample is taken from the granule and analyzed visually by light microscopy and examined for moisture content. The granules are mixed with levodopa and carbidopa, magnesium stearate and Aerosil 200 and formed into a tablet in the Fette Single-Table Tablet Maker using a 12 mm round punch. Tables 3 and 4 show a summary of the granules and tablets prepared, respectively.

Table 3. Summary of granule compositions Table 4. Summary of tablet compositions Example 3 - Preparation of Levodopa granules: Carbidopa (Lutrol F68 and PEG3350 Prototype) for Biological Experimentation. Weigh and mix at 200 rpm levodopa, carbidopa, sodium bicarbonate, samarium oxide (SmO3) and either Lutrol F68 or PEG 3350 ( batch size of 300 g) in the Rotolab for 5 minutes, in the proportions set forth in Table 5. Samarium oxide was used in these preparations as a radioactive tracer for analysis of the gastrointestinal transit of the dosage form. The heating jacket lit up. When the desired product temperature was reached, the materials were mixed and granulated for an additional 15 minutes. The molten material was then removed from the granulation bowl and crushed by the use of Comill, initially using a 1/7 mesh screen and finally a 0.7 mm mesh screen. The resistances of the elaborated dose were 100: 25 mg of Levodopa: Carbldopa and 200: 50 mg of Levodopa: Carbidopa. The granules of Levodopa: Carbidopa were mixed in bags by hand in several batches. Equal amounts of the granules made from each batch were placed in a polyethylene bag of suitable size after weighting and mixed for 15 minutes by gentle agitation. Once completed, the samples of the granule mixtures were analyzed.

TABLE 5 The required weight of Levodopa granule mixtures: Carbidopa was placed in a bag and Aerosil 200 was screened into the bag containing the granules by using a 1 mm mesh. The bag mixture was then carried out for 3 minutes. Once complete, the magnesium stearate was screened into the top bag through a 0.5 mm mesh and mixed in a bag for an additional 3 minutes. Tableting was carried out by using a Piccola 10 station using a 16x6 mm flat bevel punch. The tablets contained 98.5% mixed granules from granule formulations 9, 10 or 1 1, 0.5%) of Aerosil 200 and 1.0% magnesium stearate, producing tablets having table formulations 19, 20 or 21, respectively. A bag making machine was used to seal the tablet in the film sacks. Two rolls of PVA film, produced as described in Example 5, were fed into the machine (upper and lower roller). The levodopa or carbidopa / levodopa tablet was placed on the lower film roller and the The upper film roller was fed onto the tablet, vacuum-attracted heat was applied and a sealed pouch was formed. The sack was then cut from the film, rolled up or folded and filled with a gelatin capsule. The sealed bags (25x25 mm) were obtained by cutting them with scissors.

Example 4 - Preparation of Levodopa granules: Carbidopa (prototype MYRJ 52P) A water bath was heated to 60 ° C. The required amounts of levodopa, carbidopa, sodium bicarbonate and samarium oxide set out in Table 6 were weighed in separate containers. The Myrj 52 was weighed in a stainless steel container. Once completed, the levodopa, carbidopa, samarium oxide and sodium bicarbonate were added to the stainless steel container containing the Myrj and mixed for 10 minutes at room temperature. The stainless steel container was then placed in the water bath (temperature taken with a thermometer) and mixed for an additional 20 minutes to melt the Myrj 52. Once completed, the granules were cooled and sieved through a screen of 2.0 mm mesh followed by a mesh screen of 1.0 mm in polyethylene bags, respectively. TABLE 6 Composition of Granule Formulation 12 (% w / w) 14.5% Myrj 52 45.5% NaHCOs 6.7% SmO3 26.7% Levodopa The tablets of Levodopa: Carbidopa were prepared by using the Enerpac Single-Station Press with flat rectangular punches of 16 x 12 mm. The compression force used was 100 bar. In summary, 750 mg of Levodopa granules: Carbldopa were weighed and transferred to the mouthpiece. The granules were then compressed into tablets one at a time. The tablets were removed from the punch and placed in a stainless steel tray for storage with desiccant before placement in bags. PVA bags containing the tablets were prepared, as described in Example 3.

Example 5 - Preparation of PVA Expandable Membrane Suitable amounts of glyceron and USP were mixed in a mixer drum and PVA was added. The mixture was de-aerated for 20 minutes and gradually heated, with mixing increased for 5-6 hours to a temperature of 95 ° C. The mixture was allowed to cool slowly over a period of about eight hours. The PVA film is made by covering the solution on a PET screen. The web is then passed through an oven at temperatures above 100 ° C to allow the PVA solution to dry on a film. After the After drying, the film was rewound to a main roller, which is then cut to the required size and sealed in aluminum foil bags with desiccant. By using the above procedure, a 150 μm thick membrane is produced from 20% glycerol and 80% PVA (MOWIOL 28-99) and used to prepare dosage forms as described in Example 3.

Example 6 - Simulated Gastric Release The release of levodopa and carbidopa from non-encapsulated sacs in a simulated gastric fluid (Mesh II USP, Dissolution Medium - pH 1.2, 0.1 N HCl) was measured over time. The sacks were placed in 900 ml at 37.5 ° C with shaking at 50 rpm for up to 40 hours. The samples of 3 mis were removed by syringe at various time points for analysis. The samples were filtered through a Miliipore Millex hydrophilic PVDF filter of 0.45 μm and the amount of levodopa or carbidopa was determined by HPLC with a UV detector at a wavelength of 280 nm. Figure 2 shows the dissolution profile for levodopa arbidopa dosage forms of 100: 25 mg of PEG 3350 (Granule Formulation 9 / Tablet Formulation 19). Figure 3 shows the dissolution profile for the dosage forms of 1 00:25 mg of levodopa: carbidopa of Lutrol F68 (Granule Formulation 10 / Formulation of Tablet 20). Figure 4 shows the dissolution profile for the dosage forms of 200: 50 mg of levodopa: carbidopa of Lutrol F68 (Formulation of Granule 1 1 / Formulation of Tablet 21). Figure 5 shows the dissolution profiles for the release of levodopa from 4 different dosage forms. Figure 6 shows the dissolution profiles for the release of carbidopa from 4 different dosage forms.

Example 7 - Inflation Time Course for Sacks The inflation of the various dosage forms in the simulated gastric fluid, described in Examples 3-5 was observed and scored on a semi-quantitative scale from 0 to 3, with 0 not being inflated , being 1 starting to inflate, being 2 almost inflated and 3 being fully inflated. The results over an 8-hour time course are shown in Figure 7. Figure 8 shows additional time courses of inflation-deflation of the dosage forms in simulated gastric fluid, measuring the volume of gas retained in the bags. The volume of gas generated was measured by placing the bag in a 1 liter, customizable sealable Duran bottle with a graduated pipette protruding from the cap to measure changes in the height of the meniscus due to the expansion of the bag. Duplicate samples of each dose form were measured every 1 -5 minutes for 4 hours.

Example 8 - Additional Formulations The granules and tablets were prepared as described in Example 3-4 having the formulations shown in Tables 7-22. Table 7 • Levodopa Granules: Carbidopa 166: 42 mg / g without samarium oxide 'Moisturizing agent is Lutrol F68, Myrj 52P or PEG 3350 Table 8 Levodopa granules: Carbidopa 166: 42 mg / g without samapoxide Table 9 Levodopa granules: Carbidopa 166: 42 mg / g with samapoxide Carbidopa I 4.16 12.48 166.40 * Moisturizing agent is Lutrol F68, Myrj 52P or PEG 3350 Table 10 • Levodopa granules: Carbidopa 166: 42 mg / g with samarium oxide Table 11 Levodopa granules: Carbidopa 333: 83 mg / g without samapoxide Table 12 • Levodopa Granules: Carbidopa 333: 83 mg / g without samarium oxide Table 13 Levodopa Granules: Carbidopa 333: 83 mg / g with samapoxide Table 14 Levodopa granules: Carbidopa 333: 83 mg / g with samapoxide "Wetting agent is Lu rol F68, Myrj 52 or PEG 3350 Table 15 Levodopa Tablets: Carbdopa 100: 25 mg without samapoxide 'Wetting agent is Lutrol F68, Myrj 52P or PEG 3350 Table 16 Levodopa Tablets: Carbidopa 100: 25 mg without samapoxide * Moisturizing agent is Lutrol F68, Myrj 52P or PEG 3350 Table 17 Levodopa Tablets: Carbidopa 100: 25 mg with samapoxide "Wetting agent is Lutrol F68, Myrj 52P or PEG 3350 Table 18 Levodopa Tablets: Carbidopa 100: 25 mg / g with samapoxide Table 19 Levodopa Tablets: Carbidopa 200: 50 mg without samapoxide * Moisturizing agent is Lutrol F68, Myrj 52P or PEG 3350 Table 20 • Levodopa Tablets: Carbidopa 200: 50 mg without samarium oxide * Moisturizing agent is Lutrol F68, Myrj 52P or PEG 3350 Table 21 Levodopa Tablets: Carbidopa 200: 50 mg with samapoxide Table 22 Levodopa Tablets: Carbidopa 200: 50 mg with samapoxide "Wetting agent is Lutrol F68, Myrj 52P or PEG 3350

Claims (28)

1. CLAIMS 1. A gastro-retentive dosage form of levodopa, for oral administration to a patient in need thereof, said dosage form comprising: (a) a tablet comprising a therapeutically effective amount of levodopa, a binder and a gas generating agent pharmaceutically acceptable, capable of liberating carbon dioxide upon contact with gastric juice, and (b) a water permeable and substantially gas-impermeable, hydrophilic, expandable membrane surrounding the tablet, wherein the membrane expands as a result of the release of carbon dioxide from the gas generating agent in contact with the gastric juice, whereby the dosage form becomes too large to pass into the patient's sphincter.
2. 2. The dosage form according to claim 1, characterized in that it further comprises a cover for containing the dosage form, wherein the cover disintegrates upon contac- tion with the gastric fluid.
3. 3. The dosage form according to claim 2, characterized in that the cover is a dry filling capsule.
4. 4. The dosage form according to claim 1, characterized in that the levodopa is present in an amount of about 10% up to about 50% of the total weight of the tablet.
5. 5. The dosage form according to claim 1, characterized in that the tablet also comprises carbidopa.
6. 6. The dosage form according to claim 1, characterized in that the membrane comprises polyvinyl alcohol.
7. 7. The dosage form according to claim 6, characterized in that the polyvinyl alcohol is present in the membrane between 40% and 85%.
8. 8. The dosage form according to claim 1, characterized in that the tablet comprises levodopa and carbidopa in a weight ratio of between about 4 to 1 and about 10 to 1 of levodopa relative to carbidopa.
9. The dosage form according to claim 1, characterized in that the gas generating agent is selected from the group consisting of sodium bicarbonate, sodium carbonate, sodium glycine carbonate, potassium carbonate, calcium carbonate, carbonate of magnesium and mixtures thereof.
10. 10. The dosage form according to claim 9, characterized in that the gas generating agent is sodium bicarbonate. eleven .
11. The dosage form according to claim 1, characterized in that the binder is selected from the group consisting of a polyoxyethylene stearate, a poloxamer, a polyethylene glycol, a glycerol aplitol stearate, a glyceryl monoestearate, a methylcellulose and a polyvinylpyrrolidone .
12. 12. The dosage form according to claim 1, characterized in that the binder is selected from the group consisting of Myrj 52, Lutrol F68, PEG 3350, a methylcellulose and a polyvinylpyrrolidone.
13. 13. A method for making a gastro-retentive dosage form of levodopa, which method comprises (a) forming a tablet comprising levodopa, a binder and a pharmaceutically acceptable gas generating agent, (b) surrounding the tablet with a water-permeable and substantially gas-impermeable, hydrophilic, expandable membrane; and (c) sealing the membrane to retard the escape of gas from the interior of the sealed membrane.
14. The method according to claim 13, characterized in that it further comprises the step of encapsulating the sealed membrane inside a cover that disintegrates without delay on contact with gastric fluid.
15. The method according to claim 14, characterized in that said cover is a dry filling capsule.
16. 16. The method according to claim 13, characterized in that the tablet formed in (a) also comprises carbidopa.
17. The method according to claim 13, characterized in that the levodopa is present in an amount of about 10% or up to about 50% of the total weight of the tablet formed in (a).
18. 18. The method according to claim 13, characterized in that the membrane comprises polyvinyl alcohol.
19. The method according to claim 18, characterized in that the polyvinyl alcohol is present in the membrane between 40% and 85%.
20. The method according to claim 13, characterized in that the tablet formed in (a) comprises levodopa and carbidopa in a weight ratio of between about 4 to 1 and about 10 to 1 of levodopa relative to carbidopa. twenty-one .
21. The method according to claim 13, characterized in that the gas generating agent is selected from the group consisting of sodium bicarbonate, sodium carbonate, sodium glycine carbonate, potassium carbonate, calcium carbonate, magnesium carbonate and mixtures thereof.
22. 22. The method according to claim 21, characterized in that the gas generating agent is sodium bicarbonate.
23. The method according to claim 13, characterized in that the binder is selected from the group consisting of a polyoxyethylene stearate, a poloxamer, a polyethylene glycol, a glycerol palmitostearate, a glyceryl monostearate, a methylcellulose and a polyvinylpyrrolidone .
24. The method according to claim 23, characterized in that the binder is selected from the group consisting of Myrj52, Lutrol F68, PEG 3350, Precirol ATO5, a methylcellulose and a polyvinyl pyrrolidone.
25. The method according to claim 24, characterized in that the binder is selected from the group consisting of Myrj52, Lutrol F68 and PEG 3350.
26. 26. The method according to claim 13, characterized in that the forming step comprises fluid bed granulation. or melt granulation.
27. 27. A method for the treatment of a patient suffering from Parkinson's disease, comprising the oral administration to said patient of the gastro-retentive dosage form according to any of claims 1 to 12.
28. 28. An article of manufacture comprising the dosage form according to any of claims 1 to 12, packaging material containing the dosage form and a label or insert indicating directions for use of the dose form for Parkinson's disease.