COMPOSITION COMPRISING L-DOPA

Abstract: The present invention relates to a multiple-unit-dose compris­ ing L-dopa as pharmaceutically active compound, whereby the composition provides a release of L-dopa in accordance with a test in accordance with US Pharmacopea Standards in an arti­ ficial gastric juice having a pH of at most 1.2 of at most 20 % by weight during 1 hr, and in a phosphate buffer accord­ ing to the same standard a release of at least 35 % by weight during 1 hr, and at least 80 % by weight during 3 hrs.

Description: Technical field The present invention relates to a multiple-unit-dosage compo­ sition comprising as a pharmaceutically active compound L-do­ pa, i.e., L-3,4-dihydroxyphenylalanine. The object of the present invention is to obtain a pharmaceu­ tical composition comprising as a pharmaceutically active com­ pound L-dopa, to obtain by means of this in the form of a mul­ tiple-unit-dosage a useable L-dopa composition, which gives a high bioavailability, i.e., gives good pharmacologically active plasma levels at an administration twice to four times a day. Background of the invention L-dopa, | L-3,4-dihydroxyphenyl alanine, or 3-(3,4-dihydroxy­ phenyl)-L-alanine, or 3-hydroxy-L-tyrosine, alternatively,| is a pharmaceutically active compound, which is active at the inhibition of sympthoms of the Parkinson's disease, particular­ ly at the inhibition of the tremor related to the Parkinson's diease. However, hitherto has no pharmaceutical composition been deve­ loped which gives a satisfactory pharmacological effect, i.e., a pharmaceutically high, even plasma level. This depends on several factors, i.a., that L-dopa is rapidly decomposed by carboxylic elimination. This can, and has been regulated by adding a decarboxylase inhibitor, such as benzerazide or car­ bidopa, the administration of which means that the L-dopa dose can be considerably reduced. Other problems are that L-dopa is resorbed over a restricted part of the gastro-intestinal tract, i.e., shows a so called absorption window. Hitherto it has been necessary to administer known compositions five to eight times per 24 hrs due to the short half life time of L-dopa. In spite of this the treatment has given high top le­ vels in the plasma which in turn leads to troublesome side-­ effects. Description of the present invention. It has now surprisingly been shown possible to solve the abovementioned problem and to obtain a pharmaceutically accep­ table composition, which in vivo gives a balanced plasma level, whereby the invention is characterized in that the com­ position in a test according to US Pharmacopea Standards (USP XXI, apparatus 2, 100 rpm) in an artificial gastric juice without enzymes and having a pH of up to 1.2 gives a release of L-dopa of at most 20 % by weight during 1 hr, and in ac­ cordance with the same standard in a phosphate buffer having a pH of 6.8 releases at least 35 % by weight within 1 hr, and at least 80 % by weight within 3 hrs. By means of the present invention an even level of active com­ pound has thus been able to be obtained at the administration twice to four times per 24 hrs, simultaneously as the side effects have been reduced. The present invention further comprises a process for prepar­ ing the present multiple-unit-dose pharmaceutical composition, whereby cores comprising L-dopa are coated with at least an anionic polymer having a pk a of 5.0-5.5 to give the release rates given above. The term anionic polymer having pk a of 5.0-5.5 includes hydro­ xypropyl methylcellulose phtalate, cellulose acetate phtalate, polyvinyl acetate phtalate, and different Eudragit® qualities, such as S100, whereby these qualities includes methylmethac­ rylate methylesters. The present invention will now be described more in detail in the following with reference to a number of examples which all meet the characteristic above. A couple of comparative examples will be shown. Examples 1, A-C. An uncoated granulate was prepared from 300 g of L-dopa, 470 g of mannitol, 60 g of Avicel PH 101 (microcrystalline cellu­ lose), 70 g of L-HPC (low-substituted hydroxypropyl cellu­ lose), and 100 g of ascorbic acid. The granulate present in the form of small spheres having a diameter of 0.5-1.5 mm was then coated according to the following. Example 1. 100 g of uncoated granulate were coated with 9.3 g of hydroxy­ propyl methylcellulose phtalate (HP55, pk a 5.5) to a granulate ready for administration, which was packed in capsules con­ taining the dose 100 mg L-dopa per capsule. Example A. 100 g of uncoated granulate of above were coated with a lami­ nate consisting of a first inner layer consisting of ethyl cellulose, 3.9 g, and Pharmacoat 603 (hydroxypropyl methylcel­ lulose), 2.0 g, and a second outer layer consisting of 9.1 g of hydroxypropyl methylcellulose phtalate (HP55) to a granu­ late ready for administration, which was packed in capsules (100 mg of L-dopa per capsule; about 700 pieces of small spheres per capsule). Example B. 100 g of uncoated granulate of above were coated for compara­ tive reasons with a laminate consisting of a first inner layer of 4.3 g of ethyl cellulose and 2.2 g of Pharmacoat 603, and a secong outer layer of 7.0 g of hydroxypropyl methylcellulose phtalate (HP55) to a granulate ready for administration which was packed in capsules (100 mg of L-dopa per capsule). Example C. For comparative reasons 100 g of uncoated granulate of above were coated with 6.7 g of Pharmacoat 603 to a granulate ready for administration, which was packed in capsules (100 mg of L-dopa per capsule). The compositions according to Ex. 1 and A-C above were tested by being run in an artificial gastric juice without enzymes, pH 1.2 in accordance with USP Standards (USP XXI, apparatus 2, 100 rpm) and then in a phosphate buffer pH 6.8 according to USP Standard (phosphate buffer: 0.2 M KH₂PO₄ 250 ml, 0.2 M NaOH 112 ml, deionized water to 1000 mls) for the study of the release rates, and in phosphate buffer pH 6.8 alone for the study of the release rates without preexposure in acidic environment. The results are shown in FIG. 1-4 (Fig. 1=Ex. 1; Fig. 2=Ex. A; Fig. 3=Ex. B; Fig. 4=Ex. C). The compositions according to Ex. 1, and A-C where then tested in a single dose study on 10 healthy test persons each. The composition according to Ex. 1 took part in another study us­ ing single dose administration. The results are shown in FIG. 5-9. (Fig. 5,6=Ex.1; Fig. 7=Ex. A; Fig. 8=Ex. B; Fig. 9=Ex. C). As evident from FIG. 3 a composition according to Ex. B has too a slow release in pH 6.8, and as evident from FIG. 4 a composition according to Ex. C has a total release in pH 1.2 within a short time. The results evident from FIG. 2,3 and FIG. 4 are also confirm­ ed by the results according to FIG. 7,8 and FIG. 9. As evident from FIG. 7 low plasma levels are obtained, and thereby too low a bioavailability; as evident from FIG. 8 no considerable plasma level at all; and as evident from FIG. 9 too a high initial concentration is obtained using a composition accord­ ing to Ex. C, a concentration which decreases rapidly. As evident from FIG. 5 and 6 a composition according to Ex. 1 gives a considerably more even plasma level and thereby bio­ availability. In accordance with FIG. 5 and 6 no strong plasma peaks are obtained. Example 2-5. An uncoated granulate comprising a high dose of L-dopa was prepared as follows. 850 g of L-dopa were provided with 100 g of Avicel PH 101 (microcrystalline cellulose), 30 g of Tween 80 (polysorbitane ester), and 20 g of Ac-Di-Sol (cross linked Na-carboxymethyl cellulose). The granulate in the form of small spheres, diameter 0.5-1.5 mm, was coated as follows. Example 2. 100 g of the uncoated granulate of above were coated in a fluidized bed with 12.0 g of hydroxypropyl methylcellulose phtalate (HP55) to a granulate ready to be administered, which was packed in gelatine capsules (100 mg of L-dopa per cap­ sule). Example 3. 100 g of the uncoated granulate of above were coated using a mixture of 9.9 g of hydroxypropyl methylcellulose phtalate (HP55) and 2.1 g of ethyl cellulose to a granulate ready to be administered, which was packed in gelatine capsules (100 mg of L-dopa per capsule). Example 4. 100 g of the uncoated granulate of above were coated with a mixture of 7.2 g of Eudragit® S100 (methyl methacrylate methylesters comprising carboxylic acid groups) and 4.7 g of hydroxypropyl methylcellulose phtalate (HP55) to a granulate ready to be adminsitered, which was packed in capsules (100 mg of L-dopa per capsule). Example 5. 100 g of uncoated granulate of above were coated with a lamin­ ate consisting of a first inner layer of 4.2 g of Pharmacoat 603, and 1.8 g of ethyl cellulose, and a second outer layer of 8.0 g of hydroxypropyl methylcellulose phtalate (HP50, pk a 5.0) to a granulate ready to be administered, which was packed in gelatine capsules (100 mg of L-dopa per capsule). The compositions according to Examples 2-5 were tested with regard to the release rate of L-dopa in artificial gastric juice without enzymes in accordance with USP Standards (USP XXI, apparatus 2, 100 rpm), pH 1.2 for 2 hrs and then in a phosphate buffer pH 6.8. The results are given in FIG. 10-13 (Fig. 10=Ex. 2; Fig. 11=Ex. 3; Fig. 12=Ex. 4; Fig. 13=Ex. 5). The compositions according to Examples 2 and 5 have also been tested in six healthy test persons each in a single dose study. The results are shown in FIG. 14-15. (Fig. 14=Ex. 2; Fig. 15=Ex. 5). As evident from FIG. 10-13 the compositions according to Examples 2-5 meet the demands put forward, and as evident from FIG. 14 and 15 the compositions give even plasma levels, comp­ letely without interfering peak levels, which also gives good bioavailability. The composition according to the invention, Example 5 above, has also been tested in patients suffering from Parkinson's disease. The test was also compared with an L-dopa composition present on the market. Fig. 14a and 14b show the blood plasma levels using a composition of Example 5 in two patients, and Fig. 15a and 15b show the blood plasma levels using the compo­ sition of the market in the same two patients. The composition according to the invention was administered to patient 1, Fig. 14a, in doses containing 200 mg, 300 mg, and 300 mg per day, while the same patient obtained 250 mg of L-dopa three times a day using the marketed composition. Patient 2, Fig. 14b, and 15b, was given 100 mg of L-dopa of the composition of the invention four times a day, while the patient was given 125 mg of L-dopa of the marketed composition three times a day. Administration points are shown with arrows. The term multiple-unit-dose above means a dose present in the form of a number of granules, or the like, which taken toge­ ther give the dose size requested. Thus such a multiple-unit-­ dose can comprise from 100 to 1000 small granules having spherical or another shape. Using a multiple-unit-dose, which is administered by means of a capsule, normally hard, or in a SACHET-bag, or using a measuring spoon or other measuring device, the small units will be distributed in the gastric juice and leak out little by little into the intestinal tract. Using the present compositions, which are given orally, the pharmaceutically active dose of L-dopa divided into two to four doses per 24 hrs should be 100-1000 mg. The compositions above can be completed with decarboxylase inhibitors of the above given type, or the compositions can be administered simultaneously with a decarboxylase inhibitor to obtain a better L-dopa effect.

Claims: 1. A multiple-unit-dose composition comprising L-dopa as phar­ maceutically active compound characterized in that the compo­ sition in a release test according to US Pharmacopea Standards (USP XXI, apparatus 2, 100 rpm) in an artificial gastric juice without enzymes and having a pH of at most 1.2 gives a release of L-dopa of at most 20 % by weight during 1 hr, and in ac­ cordance with the same standard release method in a phosphate buffer having pH 6.8 releases at least 35 % by weight of L-dopa within 1 hr, and at least 80 % by weight within 3 hrs. 2. A composition according to claim 1, characterized in that the release in artificial gastric juice is at most 10 % by weight at pH 1.2 during 2 hrs. 3. A composition according to claim 1, characterized in that it comprises a core having a content of L-dopa 25-40 % by weight coated with 7-10 % by weight of hydroxypropyl methyl­ cellulose phtalate having pka of 5.5. 4. A composition according to claim 1, characterized in that it comprises a core comprising 75-85 % by weight of L-dopa, which core is coated with 8.5-11.0 % by weight of hydroxypro­ pyl methylcellulose phtalate having pka 5.5. 5. A composition according to claim 1, characterized in that it comprises a core having 75-85 % by weight of L-dopa coated with a mixture of 7.5-9.5 % by weight hydroxypropyl methylcel­ lulose phtalate having pka 5.5, and 1.5-2.5 % by weight of ethyl cellulose. 6. A composition according to claim 1, characterized in that it comprises a core having 75-85 % by weight of L-dopa coated with a mixture of 6.0-7.0 % by weight of Eudragit® S100 (methyl methacrylate methylesters comprising carboxylic acid groups), and 3.5-4.7 % by weight of hydroxypropyl methylcellu­ lose phtalate having a pka of 5.5. 7. A composition according to claim 1, characterized in that it comprises a core having 75-85 % by weight of L-dopa coated with a laminate comprising an inner layer 3.2-4.5 % by weight Pharmacoat 603 (hydroxypropyl methylcellulose), and 1.2-2.4 % by weight of ethyl cellulose, and an outer layer of 6.0-9.0 % by weight of hydroxypropyl methylcellulose phtalate having a pka of 5.0. 8. A composition according to one or more of the preceeding claims, characterized in that it further comprises a decarbo­ xylase inhibitor in the form of benzerazide and/or carbidopa. Alternative set of claims 1. Process for the preparation of a multiple-unit-dose compo­ sition consisting of a multiple of coated cores comprising L-dopa as pharmaceutically active compound, characterized in that one prepares a core comprising L-dopa, and coats that core with at least one anionic polymer having a pka of 5.0-5.5 in such an amount that the release rate of L-dopa in a stan­ dardized test according to US Pharmacopea Standards (USP XXI, apparatus 2, 100 rpm) in artificial gastric juice containing no enzymes and having a pH of 1.2 is at most 20% by weight during 1 hr, and according to the same test in phosphate buf­ fer of pH 6.8 is at least 35% by weight after 1 hr, and at least 80% by weight after 3 hrs. 2 . Process according to claim 1, characterized in that the release rate in artificial gastric juice is at most 10 % by weight at pH 1.2 during 2 hrs. 3 . Process according to claims 1-2 , characterized in that the one produces a core comprising 25-40 % by weight of L-dopa, and that one coats this core with 7-10 % by weight of hydroxypropyl methylcellulose phtalate having a pka of 5.5. 4 . Process according to claims 1-2 , characterized in that one produces a core comprising 75-85 % by weight of L-dopa, and that one coats this core 8.5-11.0 % by weight of hydroxy­ propyl methylcellulose phtalate having a pka of 5.5. 5 . Process according to claims 1-2, characterized in that one produces a core comprising 75-85 % by weight of L-dopa, and that one coats this core with a mixture of 7.5-9.5 % by weight of hydroxypropyl methyl cellulose phtalate having a pka of 5.5, and 1.5-2.5 % by weight of ethyl cellulose. 6 . Process according to claims 1-2 , characterized in that one produces a core comprising 75-85 % by weight of L-dopa, and that one coats this core with a mixture of 6.0-7.0 % by weight of Eudragit® S100, and 3.5-4.7 % by weight of hydroxy­ propyl methyl cellulose phtalate having a pka of 5.5. 7 . Process according to claims 1-2 , characterized in that one produces a core comprising 75-85 % by weight of L-dopa, and that one coats this core with a laminate consisting of an inner layer consisting of 3.2-4.5 % by weight of Pharmacoat 603 (hydroxypropyl methylcellulose) and 1.2-2.4 % by weight of ethyl cellulose, and an outer layer of 6.0-9.0 % by weight of hydroxypropyl methylcellulose phtalate having a pka of 5.0. 8. Process according to claims 1-7 , characterized in that the composition further comprises a decarboxylase inhibitor in the form of benzerazide and/or carbidopa.

Inventors: APPELGREN, CURT HENRY, ESKILSSON, EVA CHRISTINA
Applicants: ASTA PHARMA AKTIENGESELLSCHAFT
Application year: 1987
Main classification: A61K31
IPC codes: A61K31, A61K9, A61P25, A61K47