EP1117370A1

EP1117370A1 - CONTROLLED RELEASE FROM COPOLYMERS OF ACRYLIC OR METHACRYLIC ACID/L-DOPA, ACRYLIC OR METHACRYLIC ACID/L-$g(a)-METHYL DOPA, ACRYLIC OR METHACRYLIC ACID/CARBIDOPA AND THEIR COMBINATIONS

Info

Publication number: EP1117370A1
Application number: EP00947704A
Authority: EP
Inventors: Fábio Moysés Lins DANTAS; David Tabak; Cristina Tristao De Andrade
Original assignee: Fundacao Oswaldo Cruz
Current assignee: Fundacao Oswaldo Cruz
Priority date: 1999-08-04
Filing date: 2000-08-02
Publication date: 2001-07-25
Also published as: WO2001010378A2; AU6142600A; WO2001010378A3; CA2346291A1; BR9903382A; GB2384426A; GB0111066D0; DE10082749T1

Abstract

The invention relates to site directed drug delivery systems providing a controlled release of L-dopa, carbidopa or L-alpha-methyldopa and/or their combinations which eliminates or at least reduces the deleterious side effects of these drugs. Biologically active copolymers having directional characteristics to the digestive mucous tissue comprise L-dopa, carbidopa or L-alpha-methyldopa chemically combined with biologically acceptable poly(acrylic acid) or poly(methacrylic acid). The copolymers are obtained by a process comprising the steps of: (a) reacting L-dopa, carbidopa or L-alpha-methyldopa with a chlorination agent; (b) bringing into reaction the product of step (a) and poly(acrylic acid) or poly(methacrylic acid) in the presence of a suitable catalyst; (c) washing the copolymer obtained in step (b) with a suitable organic solvent and drying it until constant weight.

Description

Title: Controlled Release from Copolymers of acrylic or methacrylic acid/L-dopa, acrylic or methacrylic acid/L-α- methyldopa, acrylic or methacrylic acid/carbidopa and their combinations

The present invention relates to pharmaceutical preparations for the controlled release of L-α-methyldopa or L-dopa optionally associated with carbidopa aiming to minimize the adverse reactions and inadequacies often experienced with the administration of commonly used dosage of these known antihypertensive and anti-Parkinsonism agents, respectively. The pharmaceutical preparations are based on new copolymers of acrylic or methacrylic acid/L-α-methyldopa, acrylic or methacrylic acid/ L-dopa and acrylic or methacrylic acid/carbidopa having enhanced adhesion to the gastric mucous membrane which permits a substantial intake medicine reduction. Poly (acrylic acid) is the preferential polymer used to obtain the copolymers of the present invention.

BACKGROUND OF THE INVENTION L-dopa (3-hydroxy-L-tyrosine; 3, -dihydroxy-L- phenylalanine) the immediate biological precursor of dopamine, is a known compound and the most commonly used drug in the therapeutic treatment of Parkinsonism.

Carbidopa (5-α-hydrazino-3, -dihydroxy-α-ylbenzene WO 01/10378 „ PCT BROO/00086

propanoic acid) combined with levodopa (L-dopa) is already used in controlled release formulations with the trade name Sinemet™ to minimize the adverse reactions caused by levodopa . L-α-methyldopa, the L form of α-methyl-β- (3, 4- dihydroxyphenyl) alanine, is an analogue of levodopa and an important drug in the therapeutic treatment of hypertension. The anti-hipertensive activity of the DL racemic form of α- methyldopa was described in US 2 868 818, but it was found latter that the L form, substantially free of the D or rectus spatial configuration, should be more potent and less toxic than the racemic mixture (see US 3 344 023) . From these findings, several trials were made to eliminate or at least minimize the toxicity of α-methyldopa. The first approaches were based on process improvements to remove the undesirable reaction side-products, such as those described in US Patent Application Serial No. 115,903 (filed on 09/06/61), US Patent 3,721,697 and US Patent Application Serial No. 502,467 (filed on 22/10/65) . These attempts were not successful due to the inherent biological harmful characteristics of α-methyldopa and the researchers focused their attention on the development of compositions aiming either to reduce α- methyldopa intake amount or to improve the bioavailability of the drug. Examples of these approaches are described in US 4,321,264, US 4,404,193 and FR 2320738.

Latter, during the 70 and 80 years, L-dopa and α- methyldopa formulations using drug carriers capable of delaying the drug release in the body were developed. Conventional dosage forms, including prolonged-release dosage forms, are based on physical mixtures containing one or more drugs and a carrier, frequently a polymeric material which may be natural as well as partially or totally synthetic polymer. US Patent 4,424,235 describes hydrodynamically balanced controlled release compositions for the preparation of capsules or tablets containing L-dopa and a decarboxylase inhibitor. α-Methyldopa is cited as a decarboxylase inhibitor used in the composition which includes natural as well as partially or totally synthetic hydrocolloids such as guar gum, agar, pectin, carrageen, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, gelatin, etc to provide superior blood levels of L-dopa. Document EP 320 051 describes a controlled release combination of carbidopa/levodopa which is a matrix or monolithic drug delivery system consisting of two drugs uniformly dispersed in a polymer vehicle at a concentration that is greater than the solubility of either drug in the polymer. It is mentioned that this combination permit to maintain a stable levodopa level preventing the emergence of "wearing-off" and "on-off" phenomena which may occur in the long-term treatment of Parkinson's disease. The polymers cited in this document belong to the group of water soluble polymers and less water soluble polymers, preferentially a combination of these types, such as hydroxypropylcellulose and poly (vinyl acetate/crotonic acid). The investigation of new drug delivery systems (DDS) emmerged from the necessity of making possible: (1) to maximize the activity of known efficient drugs while minimizing their side effects; (2) to deliver genetically engineered pharmaceuticals to their sites of action, avoiding significant immunogenecity or biological inactivation; (3) to get better targeting in enzyme deficient diseases treatment and cancer therapies and (4) to optimize the therapeutic efficacy and safety of drugs by reducing both the size and number of doses. DDS can be classified, according to the chemical or physical processes occurring in the body during the drug delivery, as (i) controlled release - a drug is released at a constant rate, i.e. reaction kinetics of zero- order, providing a constant plasmatic concentration; (ii) sustained release - the drug concentration decreases with time, i.e. reaction kinetics of first-order and (iii) site- directed release in which the drug has appropriate molecular structure and physicochemical properties to allow site-drug interaction.

In recent years, a number of DDS forms have been proposed, such as drug complexed to a polymeric membrane or formed as a molded product to be adhered on skin or a mucous membrane for slow release or absorption of the drug through the skin or the mucous membrane, respectively; body implant systems in which a drug complexed to various forms of matrix is left in an organ or subcutaneous tissues for slow release; systems in which the drug is microencapsulated by means of liposome or lipid microspheres or as a prodrug formed by covalently bonding a drug to a polymeric compound which is administered directly in the blood or tissues.

Prodrugs, i.e. drugs that are chemically linked to a polymer, have been proposed to achieve the above mentioned goals. Accordingly, in EP 413 281 it is proposed a drug carrier comprising a temperature-sensitive polymeric compound chemically bound to a drug having lower LCST (Lower Critical Solution Temperature) than the body temperature attempting to achieve an enhancement of administration ease and uniform drug concentration for a long period of time in the tissues. Anti-cancer agents, hormones, antibiotics, narcotic antagonists, analgesics, anti-inflamatory agents, hypotensives, anti-depressants, anti-epileptic agents, anti- malarial agents, anti-helmintics or immunoactivators are cited as drugs to be combined with the drug carrier. In EP 452 179, WO 90/15628, US 5,532,305 and EP 911 039, the same approach was pursued by combining medicines with polymers through covalent bonds, ionic bonds, coordinate bonds and the like. EP 452 179 refers to a compound combined with a medicine and a polymer having an alkylenoxy group, such as polyethylene glycol, the combination having directional characteristics to digestive organs. WO 90/15628 describes a polymer/antibiotic conjugate in which the polymer is conjugated to the antibiotic via a covalent bond to get a greater therapeutic index as compared with that of the free antibiotic but maintaining the same activity of the latter. In US 5,532,305 preparations are proposed in which bioactive substances are introduced in a poly-ion complex of hyaluronic acid and cationic polyacrylic acid derivatives (e.g. EUDRAGIT E, a copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters) . And the EP 911 039 proposal is related with drug-resin complexes stabilized by chelating agents.

Concerning L-dopa, carbidopa and L-α-methyldopa, there is an additional problem to be solved, which is related with the site where the delivery occurs. The main disadvantages of both drugs are related with their low water solubility, sensitivity to chemical oxidation and peripheral decarboxylation as mentioned in EP 320 051 and US 4,424,235. The drug residence time in the the stomach must be enough to provide a complete drug release but avoiding the side effects associated with the formation of toxic metabolites resulting from a high drug plasmic concentration. To come through in these aims, Zorc et al ( Zorc, B., Ljubic, M., Antolic, S., Filipovic-Grcic, J., Maysinger, D., Alebic-Kolbah, T. and Jalsenjak, I. 1993. "Macroraolecular prodrugs . II. Esters of L-dopa and α-methyldopa" , International Journal of Pharmaceutics, 99:135-143) proposed to attach L-dopa and L-α- WO 01/10378 _ PCT/BROO/00086

methyldopa to α, β-poly (N-hydroxyethyl) -DL-aspartamide, a hydrophilic polymer, by an ester linkage.

Accordingly, there is a great need for an improved drug delivery system for L-dopa, carbidopa and L-α-methyldopa without the disadvantages mentioned above.

SUMMARY OF THE INVENTION

The object of the invention is to provide a site directed drug delivery system providing a controlled release of L-dopa, carbidopa and/or their combinations and L-α- methyldopa which eliminates or at least reduces the deleterious side effects of these drugs.

A first embodiment of the present invention refers to a copolymer of acrylic or methacrylic acid/ L-α-methyldopa.

In a second embodiment, the invention is directed to a copolymer of acrylic or methacrylic acid/ L-dopa.

In a third embodiment, the invention is directed to a copolymer of acrylic or methacrylic acid/ carbidopa.

A fourth embodiment is related with pharmaceutical compositions based on a copolymer of acrylic or methacrylic acid/ L-dopa, on a copolymer of acrylic or methacrylic acid/carbidopa and on their combinations.

A fifth embodiment is related with pharmaceutical compositions based on a copolymer of acrylic acid/L-α- methyldopa, on a copolymer of methacrylic acid/L-α-methyldopa and on their combinations. In a sixth embodiment, the invention is directed to a process for the production of biologically active copolymers of acrylic or methacrylic acid/L-dopa, acrylic or methacrylic acid/carbidopa and acrylic acid/L-α-methyldopa having directional characteristics to the digestive mucous tissue comprising the steps of:

(a) reacting L-dopa, carbidopa or L-α-methyldopa with a chlorination agent;

(b) bringing into reaction the product of step (a) and poly (acrylic acid) or poly (methacrylic acid) in the presence of a suitable catalyst;

(c) washing the copolymer obtained in step (b) with a suitable organic solvent and drying it until constant weight.

BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 illustrates a calibration curve to evaluate the conversion degree of L-α-methyldopa.

FIGURE 2 shows the infrared spectrum of L-α-methyldopa. FIGURE 3 shows the infrared spectrum of poly (acrylic acid) . FIGURE 4 shows the infrared spectrum of copolymer acrylic acid/L-α-methyldopa of the present invention.

FIGURE 5 shows the NMR spectrum of L-α-methyldopa. FIGURE 6 shows the NMR spectrum of poly (acrylic acid). FIGURE 7 shows the NMR spectrum of copolymer acrylic acid/L-α-methyldopa of the present invention. FIGURE 8 illustrates a calibration curve of release kinectics to evaluate the release degree of L-α-methyldopa.

FIGURE 9 shows graphically the L-α-methyldopa release from a tablet based on the copolymer acrylic acid/L-α- methyldopa of the present invention.

FIGURE 10 shows graphically the L-α-methyldopa release from a tablet based on a mixture of poly (acrylic acid) and L- α-methyldopa .

FIGURE 11 illustrates graphically the comparison between the L-α-methyldopa release rates from tablets based on the physical mixture of poly (acrylic acid) and L-α-methyldopa and that from tablets based on the copolymer acrylic acid/L-α- methyldopa of the present invention (%/hour).

FIGURE 12 illustrates graphically the comparison between the L-α-methyldopa release rates from tablets based on the physical mixture of poly (acrylic acid) and L-α-methyldopa and that from tablets based on the copolymer acrylic acid/L-α- methyldopa of the present invention (mg/hour) .

DETAILED DESCRIPTION OF THE INVENTION L-α-methyldopa was introduced in the market in 1962 in Germany by Merck & Co with the trade name Aldomet . Since then, L-α-methyldopa has been frequently prescribed for individuals suffering from moderate to severe hypertension and depending on the severity of the hypertension (high blood pressure) the daily dosage may range from 0.5 to 3.0 g. The drug effect occurs after 3 to 6 hours from the administration and remains for 24 to 48 hours. The L-α-methyldopa absorption is variable and incomplete. Only about 50% of the oral dose is absorbed by the organism and its elimination half-life is 1.7 hours .

®

Sinemet , a trademark for a combination of carbidopa and levodopa, was introduced in the market in 1975 as an attempt to reduce the deleterious side effects of levodopa (L-dopa) which was already a known substance used to control the Parkinson syndrome (see EP 320 051) . Only 23-30% of the orally administered dose of L-dopa reaches the systemic circulation as intact drug and the plasma level after an oral dose is about 20% of that after an intravenous dose and its half-life is short (45 minutes). As mentioned in the above cited documents representative of the state of the art, the challenge in maximizing drug effectiveness and minimizing deleterious side effects is to increase drug bioavailability and simultaneously reduce the drug amount in the medicine. According to the present invention, this is accomplished by providing a copolymer obtained by reacting L-dopa, carbidopa or L-α-methyldopa with a mucoadhesive polymer, such as poly (acrylic acid) or poly (methacrylic acid).

Mucoadhesion may be defined as the ability of a material to adhere to a mucous tissue for an extended period of time. The mucus is the layer covering the mucosa aiming its protection against mechanical, chemical, microbiological and viral aggressions. Besides its gastric protection role against back diffusion of hydrochloric acid, the mucus provides a diffusion barrier for molecules, and especially against drug absorption. In fact, diffusion through the mucus layer depends largely on the active ingredients physicochemical characteristics and their intimate contact. Smart et al . (Smart, J.D., Kellaway, I.W. and Worthington, H.E.C., 1983, "An in vitro investigation of adhesive materials for use in controlled drug delivery" , International Journal of Pharmacian and Pharmacology, 36:295-299) studied the adhesive properties of several materials. Table 1 shows the bioadhesiveness strength of some materials.

Table 1: BIOADHESIVENESS STRENGTH OF SOME MUCOADHESIVE MATERIALS

The values in Table 1 were obtained by following the methology described by Smart et al . The polymers, from up to down, have a decrease in mucoadhesiveness and in number of carboxylic groups, i.e. polycarboxylic polymers (carboxymethylcellulose and poly (acrylic acid)) have higher adhesive strength.

The choise of an appropriate polymer to be used in controlled release pharmaceutical preparations must take into account several physicochemical properties of the adhesion site. Studies using fluorescence methods (Hui, Ho-Wah, Robinson, J.R. 1985, "Ocular delivery of progesterone using a bioadhesive polymer", International Journal of Pharmaceutics, 26:203-213) showed that (i) cationic and anionic polymers have higher adhesiveness than neutral polymers; (ii) referring to the relation adhesiveness :potential toxicity, polyanions have a better performance than polycations; (iii) the presence of sulfate groups in polymers provide an enhanced adhesiveness as compared with polymers having carboxylic groups; (iv) the adhesive strength is proportional to the charge density of the polymer.

Poly (acrylic acid) or copolymers based on acrylic acid have been proposed to be used in the gastrointestinal tract due to their good adhesiveness through almost the whole mucous region (see Jabbari, E., Wisniewski, N. and Peppas, N.A., 1993, "Evidence of mucoadhesion by chain interpenetration at a poly (acrylic acid) /mucin interface using ATR-FTIR spectroscopy" , Journal of Controlled Release, 26:99-108) .

The use of a bioadhesive polymers is recommended for (a) drug controlled release; (b) active substances directed to absorption in specific sites; (c) increasing the medicine residence time into the body and (d) prodrugs .

The polymers poly (acrylic acid) (PAA) and poly (methacrylic acid) (PMAA) used in the present invention have a Molecular Weight up to 200,000 and were formed by polymerizing acrylic or methacrylic acid using standard techniques. In a preferred manner, the polymers were prepared from acrylic acid or from methacrylic acid in an aqueous medium.

To prepare the copolymers, in a first step, L-dopa, carbidopa or L-α-methyldopa and a chlorination agent, e.g. tionyl chloride are brought into reaction at a temperature of up to 10°C and under positive pressure of inert gas, such as nitrogen, to avoid hydrolysis of the acid chloride recently formed and to improve reaction yield by stripping off side products such as S0₂ and HCl in a system provided with a neutralization device. The copolymer is obtained by the addition of poly (acrylic acid) or poly (methacrylic acid) to the reaction medium and is preferentially carried out in the presence of a suitable catalyst at a temperature of up to 20°C. Pyridine or its derivatives are preferred catalysts due to their low nucleophilic strength and good solubility in the organic reaction medium.

The reaction conditions facilitate the formation of the copolymer in its anhydride form. Indeed, the excess of the chlorination agent garantees the formation of L-α-methyldopa (or L-dopa or carbidopa) chloride and, consequently, the highly acidic medium leads to a protonic form of the amine group of the L-α-methyldopa (or L-dopa or carbidopa) , inhibiting amide formation which could result from the reaction between L-α-methyldopa (or L-dopa or carbidopa) with PAA (or poly (methacrylic acid)) or with another molecule of L-α-methyldopa (or L-dopa or carbidopa) . Other advantageous reaction characteristics are: excess of chlorination agent which permits the elimination of humidity from PAA or from poly (methacrylic acid); presence of a catalyst which activates the reactant L-α-methyldopa (or L-dopa or carbidopa) chloride and low reaction temperature inhibiting the formation of anhydride cross linkages in the copolymer. The reaction yield was high, i.e. the reaction occured with a high conversion degree. The resulting copolymers acrylic or methacrylic acid/L- α-methyldopa, acrylic or methacrylic acid/L-dopa and acrylic or methacrylic acid/carbidopa are then purified by using standard techniques to remove side products, non-reacted reactants, catalyst and reaction solvent. The final step of the purification process is the dispersion of the obtained product in a suitable medium, e.g. tetrahydrofuran, followed by a filtration step under vacuum and a drying step.

To be used for their therapeutic indications, an effective amount of the copolymers of the present invention may be incorporated into a pharmaceutical composition preferably for oral administration. Suitable forms of solid oral dosage are tablets, troches, capsules and the like. Where necessary, or desirable, common pharmaceutically acceptable compounding ingredients, i.e. diluents, flavorings, stabilizers, tabletting lubricants, preservatives, coloring agents and the like may be used. The amount of the inert pharmaceutical adjunct materials which may be present in the controlled release formulations of the invention will vary in accordance with the amounts and physical properties of the other components. Such conventional pharmaceuticals adjuncts are present in from about 5% to about 60% by weight of the formulation. The inclusion of and choise of such materials depend on several factors and their proportions are known by the skilled in the art. The present invention is described in detail below by referring to examples. It must be understood that the present invention is not limited to these examples but includes variations and modifications in the scope where the invention functions. In addition, it must be emphazised that despite the examples describe the preparation of the copolymer acrylic acid/L-α-methyldopa, the preparation of the copolymers methacrylic acid/L-α-methyldopa, acrylic or methacrylic acid/L-dopa and acrylic or methacrylic acid/carbidopa follow the same procedures as to prepare the copolymer acrylic acid/L-α-methyldopa. Indeed, the reaction of the acrylic acid with L-α-methyldopa is similar to the reactions of the acrylic acid with L-dopa and of the acrylic acid with carbidopa. The homology between methacrylic acid and acrylic acid also facilitates the reactions of methacrylic acid with L-α-methyldopa, methacrylic acid with L-dopa and methacrylic acid with carbidopa.

EXAMPLE 1

Synthesis of poly (acrylic acid) to be used in the preparation of the copolymers of the present invention:

25 g (0.35 mol) of glacial acrylic acid were dissolved in 500 ml of water. Then, 0.0595 g of sodium persulfate was added to the mixture and brought into reaction at 80°C under nitrogen atmosphere with stirring. The polymer was dried and turned into chips.

The resultant polymer was purified by dissolving the chips in a 10% methanol solution. The product was recovered after precipitation by using ethyl ether, the precipitation step being repeated for three times. A further drying step at

50°C was applied until constant weight. The dried polymer was ground to 60 mesh size. EXAMPLE 2

Synthesis of the copolymer acrylic acid/methyldopa (PAA- mDOPA) anhydride of the present invention:

23.824 g (0.1 mol) of L-α-methyldopa were dissolved in 300 ml of dioxane. 20 ml (about 0.28 mol) of tionyl chloride were added and brought into reaction at 4°C under a nitrogen stream. All reactants and the atmosphere inside the reactor must be dry, i.e. no humidity is permitted. A trap system is provided to garantee a dry reaction atmosphere. The reaction proceeded until a yellow brownish color was obtained, when the trap system was closed and 2 ml of pyridine was feeded to the mixture aiming to speed up the reaction. The temperature was then increased to 11°C and 7.206 g (0.1 mol) of dry poly (acrylic acid) obtained according to Example 1, was added and the reaction was allowed to proceed for 24 hours. During the copolymer formation, the reaction was monitored by thin layer chromatography .

To determine the reaction yield a calibration curve of L-α-methyldopa conversion was contructed. Figure 1 shows the absorbance variation, measured at 281 nm, with concentration and was used to determine the conversion degree of the reaction to produce the copolymer acrylic acid/ L-α- methyldopa. The results are presented in Table 2. Table 2 : Determination of the Conversion Degree

The average conversion degree as calculated from the values in the last column of Table 2 is 50.60%. The molecular weight of the repeting unit to which L-α-methyldopa has been incorporated, thus forming the copolymer acrylic acid/ L-α- methyldopa, was estimated as 265.3 g/mol.

An additional purification step was carried out by grinding the copolymer, washing two times with dioxane and drying it until constant weight. The final product is white; hygroscopic; soluble in water, absolute ethanol, acetone and dimethyl formamide; insoluble in tetrahydrofuran, dioxane, ethyl ether and ethyl acetate; has a lower T_g (Glass Transition Temperature) as compared to PAA and has high adhesiveness to human skin. The structure of the copolymers of the present invention were characterized by using infrared spectroscopy and C¹³NMR (nuclear magnetic resonance) techniques. Likewise, PAA and L- α-methyldopa were characterized for comparison purposes.

Figures 2, 3 and 4 show the infrared spectra of L-α- methyldopa, of PAA and of copolymer acrylic acid/ L-α- methyldopa, respectively.

As showed in Figure 2, the strong absorptions at 3478, 1644 and 1611 cm^"1 are due to the axial vibration of the hydroxyl group in phenolic group, angular vibration of the amine group, axial asymmetric deformation of the C=0 group of the carboxylic acid, respectively, which are present in L-α- methyldopa .

In Figure 3, at 3454 and 1707 cm^"1, there are characteristic peaks of hydroxyl and carbonyl groups of carboxylic acids, respectively.

In Figure 4 it is clearly seen a displacement of the characteristic peaks of the hydroxyl and carbonyl groups of carboxylic acids. Three strong peaks (at 1735, 1610 and 1525 cm^"1) appear in the characteristic absorption region of carbonyl and amine groups. Likewise, the characteristic absorptions of the aromatic ring, C-C axial vibration and C-H angular vibration are present.

Figures 5, 6 and 7 show the C¹³NMR spectra of L-α- methyldopa, of PAA and of copolymer acrylic acid/ L-α- methyldopa, respectively.

In Figure 7, the two carbonyl characteristic peaks, C6 and C7, are displaced as compared to the carbonyl characteristic peaks of the reactants. It may also be noticed the absence of the C5 characteristic peak which is due to the carboxyl group of the repetitive unit of the polymer PAA. EXAMPLE 3

Formulation of pharmaceutical tablets based on the copolymer acrylic acid/methyldopa (PAA-mDOPA) of the present invention: 14.908 g of PAA-mDOPA, 0.3 g of magnesium stearate, 0.3 g of silicium dioxide and 0.451 g of mannitol were mixed and ground to obtain a fine and homogeneous powdered mixture. Tablets were prepared by compressing this mixture using known techniques .

The formulation was made to obtain tablets with a total weight of 800 mg in which 400 mg of L-α- methyldopa are included. The characteristics of this preparation are shown in Table 3.

For comparison purposes, in Example 4, tablets based on physical mixture of linear poly (acrylic acid) and L-α- methyldopa were prepared.

EXAMPLE 4

Formulation of pharmaceutical tablets based on physical mixtures of linear poly (acrylic acid) and L-α-methyldopa:

6.907 g of PAA, 8.0 g of L-α-methyldopa, 0.3 g of magnesium stearate, 0.3 g of silicium dioxide and 0.451 g of mannitol were mixed and ground to obtain a fine and homogeneous powdered mixture. Tablets were prepared by compressing this mixture using known techniques.

As mentioned in Example 3, the formulation was prepared so as to obtain tablets with a total weight of 800 mg in WO 01/10378 _{2 ι} PCT/BROO/00086

which 400 mg of L-α-methyldopa are included. The characteristics of this preparation are shown in Table 4.

The L-α-methyldopa release profile was determined by using the methology described in USP XXIII - Dissolution test - Apparatus 2. Tablets having formulations according to Examples 3 and 4 were placed in separated vessels in a 900 ml thermoregulated (37°C) and mechanically stirred bath of na aqueous solution of HCl (pH = 1.2). 10 ml aliquots were removed every 30 minutes for UV measurements of the absorption at 281 nm and the values used to prepare the calibration curve of the release kinectics as shown in Figure 8. This figure was used to calculate the amount of released L-α-methyldopa. The values obtained are shown in Tables 3 and 4.

Table 3: Tablets based on the copolymer PAA-methyldopa of the present invention

Table 4: Tablets based on a physical mixture of PAA and L-α- methyldopa

The release values in Tables 3 and 4 may be used to determine the average percent release of L-α-methyldopa. Table 6 shows the results obtained.

Table 6: Percent average release determined from Tables 3 and 4

The plots of Figures 9 and 10 were obtained from Tables 3 and 4, respectively. The plots of Figures 11 and 12 were obtained from Table 6.

Claims

1. A biologically active copolymer having directional characteristics to the digestive mucous tissue comprising L- dopa, carbidopa or L-α-methyldopa chemically combined with biologically acceptable poly (acrylic acid) or poly (methacrylic acid).

2. The biologically active copolymer according to claim 1 wherein its repeating unit is formed through a covalent bond between the acrylic acid repeating unit of poly (acrylic acid) and L-dopa.

3. The biologically active copolymer according to claim 1 wherein its repeating unit is formed through a covalent bond between the methacrylic acid repeating unit of poly (methacrylic acid) and L-dopa.

4. The biologically active copolymer according to claim 1 wherein its repeating unit is formed through a covalent bond between the acrylic acid repeating unit of poly (acrylic acid) and L-α-methyldopa.

5. The biologically active copolymer according to claim 1 wherein its repeating unit is formed through a covalent bond between the methacrylic acid repeating unit of poly (methacrylic acid) and L-α-methyldopa.

6. The biologically active copolymer according to claim 1 wherein its repeating unit is formed through a covalent bond between the acrylic acid repeating unit of poly (acrylic acid) and carbidopa.

7. The biologically active copolymer according to claim 1 wherein its repeating unit is formed through a covalent bond between the methacrylic acid repeating unit of poly (methacrylic acid) and carbidopa.

8. Process for the production of a biologically active copolymer having directional characteristics to the digestive mucous tissue comprising the steps of:

(a) reacting L-dopa, carbidopa or L-α-methyldopa with a chlorination agent; (b) bringing into reaction the product of step (a) and poly (acrylic acid) or poly (methacrylic acid) in the presence of a suitable catalyst; (c) washing the copolymer obtained in step (b) with a suitable organic solvent and drying it until constant weight.

9. Process according to claim 8 wherein the chlorination agent used in sep (a) is tionyl chloride and the reaction is carried out at a temperature of up to 10°C under positive pressure inert gas.

10. Process according to claim 8 or 9 wherein the catalyst used in step (b) is pyridine or a derivative thereof and the reaction is carried out at a temperature of up to 20°C.

11. Process according to claim 8, 9 or 10 wherein the suitable organic solvent used in step (c) is dioxane.

12. A controlled release pharmaceutical comprising a biologically active copolymer selected from the group consisting of poly (acrylic acid/L-α-methyldopa), poly (methacrylic acid/ L-α-methyldopa) or combinations thereof and a pharmaceutically acceptable vehicle.

13. The controlled release pharmaceutical according to claim 12 which comprises poly (acrylic acid/L-α-methyldopa) and a pharmaceutically acceptable vehicle.

14. The controlled release pharmaceutical according to claim 12 which comprises poly (acrylic acid/L-α-methyldopa), poly (methacrylic acid/ L-α-methyldopa) and a pharmaceutically acceptable vehicle.

15. The controlled release pharmaceutical according to claim 12 which comprises poly (methacrylic acid/L-α- methyldopa) and a pharmaceutically acceptable vehicle.

16. A controlled release pharmaceutical comprising a biologically active copolymer selected from the group consisting of poly (acrylic acid/L-dopa), poly (methacrylic acid/ L-dopa), poly (acrylic acid/carbidopa), poly (methacrylic acid/carbidopa) or combinations thereof and a pharmaceutically acceptable vehicle.

17. The controlled release pharmaceutical according to claim 16 which comprises poly (acrylic acid/L-dopa) and a pharmaceutically acceptable vehicle.

18. The controlled release pharmaceutical according to claim 16 which comprises poly (acrylic acid/L-dopa), poly (methacrylic acid/ L-dopa) and a pharmaceutically WO 01/10378 _2g PCT/BROO/00086

acceptable vehicle.

19. The controlled release pharmaceutical according to claim 16 which comprises poly (acrylic acid/L-dopa), poly (acrylic acid/ carbidopa) and a pharmaceutically acceptable vehicle.

20. The controlled release pharmaceutical according to claim 16 which comprises poly (acrylic acid/L-dopa), poly (methacrylic acid/carbidopa) and a pharmaceutically acceptable vehicle.

21. The controlled release pharmaceutical according to claim 16 which comprises poly (methacrylic acid/ L-dopa) and a pharmaceutically acceptable vehicle.