HU215191B - Process for the production of controlled release medical preparations for the treatment of dopamine-deficiency, containing a combination of levodopa and carbidopa as active substances - Google Patents

Abstract

Method of the Invention The present invention relates to a pharmaceutical composition comprising a medicament containing controlled release release medication for the treatment of postoperative duodenal dysfunction, comprising Levőpapa and Carbaikapa. The process is a) 100 to 250 parts by weight of bleeds and b) 10 to 25 parts by weight of Carbayapa active ingredient, based on the total weight of active ingredients c) 10 to 200% by weight of polyvinyl chloride, i) 0 to 100 parts by weight, 0 to 3% by weight of residual acetate, 60,000 - 80 000 moles of acrylic with a specific surface area of 0.1 to 0.18 m2 / g, fully soap-grown (from vinyl-alk and / or ii) 100 to 0 parts by weight, with a residual acetate content of 10 to 18% by weight, with an average molecular weight of 80 000, 0, It contains 5 to 0.69 m2 / g of superficial surface and contains 0.2 to 0.36 cm3 / g of porosity, partly pans, and is blended into a pharmaceutical composition suitable for use with a galvanic auxiliary coagulant. ŕ

Description

The scope of the description is 6 pages

HU215 191 Β

FIELD OF THE INVENTION The present invention relates to a method for the preparation of Levodopa (3-hydroxy-L-tyrosine) and Carbidopa (L-a- (3,4-dihydroxybenzyl) -α-hydroxy-propionic acid monohydrate) active ingredients in defined proportions. The method provides for simple preparation of the pharmaceutical composition by means of process-technological procedures known per se. The method of the present invention provides a pharmaceutical composition which releases both active ingredients rapidly and over a period of time in defined proportions, thereby ensuring that the bioavailability of peripheral decarboxylase inhibitor Carbidopa and dopamine precursor Levodopa is optimal. The present invention is applicable to the pharmaceutical industry and is useful in the manufacture of a medicament for the treatment of Parkinson's disease.

At an advanced age, severe disturbances in the automatism of locomotor organs, also known as Parkinson's syndrome, are becoming more common. The lack of dopamine in the pituitary ganglion of the diseased in the pituitary gland requires the balance of dopaminergic and cholinergic neurotransmitters that mediate the course of movement to overturn. The missing biogenic amine can be replaced by the introduction of the levodopa precursor, which penetrates the blood-brain barrier, which is absorbed by dopaminergic nerve cells and dopamine-decarboxylated [Birkmayer and Homkiewicz: Wien. Kiin. Wochenschrift 73, 787 (1961)]. It is known that the peripheral decarboxylation of Levodopa by suitable oral decarboxylase inhibitors such as Carbidopa (DE-PS-3 012 602, US-PS 3 769424) or benzerazide (DE-PS-3 235 093) can be maintained at a significantly lower level, from which Levodopa serum levels are maintained. there is a significant increase in the dose required to reduce the therapeutically required dose and, consequently, in the gastrointestinal and cardiovascular system.

Levodopa and Carbidopa are known to contain capsules, film-coated tablets, and tablets for gastric lavage (GB-PS-1243474, US-PS-4 424 235 and BE-PS-894 376).

It is also known that international standards only require very rapid in vitro release (USP XXI). In addition, there are known methods for the preparation of pharmaceutical compositions which deliver slowly and evenly the active ingredients of Levodopa and Carbidopa. These pharmaceutical compositions may include, inter alia, polymer matrices (EP-A-0 147 780, EP-A-0 253 490 and EP-A-0 320 051), pellets (DE-PS-3 841955, EP-A-0260236 and

EP-A-0 324 947) or may comprise several layers (EP-A-0 302 693 and EP-A-0 314 206). In addition, it is known to produce powder particles of a defined particle size which are slowly and evenly released over a period of 10 hours by spray drying of aqueous systems containing, in addition to a water-soluble active ingredient, a water-soluble polymer resin which undergoes insoluble resin under the selected conditions of drying (US-PS- 3, 584113). It is generally known that converting an active ingredient or drug mixture into a pharmaceutical composition is an important tool for influencing bioavailability. At the same time, it provides a way to allow very low doses of active ingredients with suitable pharmaceutical excipients, or to reduce the incompatibility of the active ingredients in the active ingredient mixtures, or to provide chemical stability of one or more active ingredients. In addition, a number of methods are known for the manufacture of tablets which are intended to convert powdered active ingredients and mixtures of powdered active ingredients and pharmaceutical excipients into tablets in pharmaceutical technological conditions. Suitable pharmaceutical excipients for the addition of pharmaceutical active ingredients or excipients to mixtures of active ingredients are known to influence and alter the properties of the composition, such as stability, electrostatic charge, flow and tableting, and bioavailability. Similarly, the formulation of powder formulations, granules, pellets, and the like containing known active ingredients is contained in hard gelatin capsules. It is further known that the addition of various residual acetate-containing polyvinyl alcohols results in a significant delay in drug release [U. Meyer: Dissertation, Berlin, 1977] and solid tablets generally disintegrating rapidly with polyvinyl alcohol [W. Rietschel: Die Tablette, Aulendorf, 1996, p. 104].

Partially significant differences in the clinical picture of Parkinson's disease require sensitive, individually adjustable drug therapy. Medication physicians, on the one hand, need pharmaceutical formulations which, after the immediate release of Levodopa and Carbidopa active ingredients, can compensate for deficiencies occurring during the day in the transporter, thereby enabling a rapid improvement of the general condition of the patients. However, in a small proportion of patients, undesirable side effects that severely affect the patient's condition are undesirable, due to the rapid release of the active ingredients and the subsequent high plasma levels of levodopa.

It is an object of the present invention to provide a method for the preparation of a medicament for the treatment of central dopamine deficiency containing levodopa and Carbidopa active ingredients, the active ingredients being contained in a specified proportion and the release of the active ingredients in a suitable pharmaceutical excipient at an initial stage of 30 to 45 minutes, and a further step. complete and steady for the desired time, but without significant delay. The method of the invention avoids the drawbacks of the prior art and can be carried out using suitable, readily available, processable and non-toxic excipients.

In view of the foregoing, the present invention provides a controlled release of Levodopa and Carbidopa active ingredients in an initial stage, as needed.

For the manufacture of a medicament for the treatment of central dopamine deficiency, comprising 100 to 250 parts by weight of the active ingredient Levodopa and 10 to 20 parts by weight of Carbidopa, based on the total weight of the active ingredients c) 10-200% by weight of the polymer.

i) 0-100 parts by weight, 0-3% residual acetate, 60,000-80,000 average molecular weight, 0.1-0.18 m ² / g surface area, fully saponified polyvinyl alcohol and ii) Partially saponified poly (vinyl) with 100-0 parts by weight, 10-18% residual acetate content, 80,000 average molecular weight, 0.5-0.69 m ² / g specific surface area and 0.2-0.36 cm ³ / g specific pore volume alcohol) and is converted to a pharmaceutical composition for oral administration with conventional galenic excipients.

In the preparation of the pharmaceutical composition according to the invention, the usual galenic excipients are added to the active ingredient / polymer mixture in an amount that makes it possible to prepare the pharmaceutical compositions in a conventional manner, inter alia, by direct tabletting, granulation followed by granulation with a suitable binder or filling into hard gelatin capsules. Poly (vinyl alcohol) is preferably commercially available (USP XXII). These can be selected based on k-values [Fikentscher: Cellulosechemie 13, 58, (1932); TGL 18 313] which are fully saponified polyvinyl alcohols in the range of 40-59 and partially saponified polyvinyl alcohols in the range 50-59. Particularly suitable are fully saponified polyvinyl alcohols having 0-3% residual acetate content of 60,000 to 80,000 average molecular weight and 0.1-0.18 m ² / g surface area and 10 to 18% residual acetate content. Partially saponified polyvinyl alcohols having an average molecular weight of 80,000, a specific surface area of 0.5-0.69 m ² / g and a specific pore volume of 0.2-0.36 cm ³ / g.

Surprisingly, it has been found that the admixture of auxiliary agents according to the invention and the possible simple pharmaceutical technological processing thereby accomplished the intended purpose. It has also surprisingly been found that by using a combination of various residual acetate-containing polyvinyl alcohols according to the present invention, Levodopa / Carbidopa pharmaceutical compositions which release the active ingredients rapidly and which release the active ingredient in the initial stage are obtained. adjustable or adjustable as needed.

The method of the present invention provides a pharmaceutical composition which delivers the two active ingredients in a defined ratio within a short period of time, thereby providing the optimal bioavailability of the active ingredient of Levodopa, the peripheral dopadecarboxylase inhibitor Carbidopa and the dopamine precursor. Thus, it is possible to produce pharmaceutical formulations with the optimum release properties at a minimum cost for different patient groups. The pharmaceutical composition prepared in the manner described above can meet the requirements for the use of the delayed and complete release of Levodopa / Carbidopa pharmaceutical compositions according to the clinical symptoms of the disease.

The following examples illustrate the invention.

1-12. examples

The amounts of Levodopa and Carbidopa active ingredients in Table 1 are 2.5% by weight of residual acetate, 70000 with an average molecular weight of 0.14 m ² / g and 55 k of fully saponified polyvinyl alcohol (hereinafter referred to as "the"). PVA 1), 15% residual acetate content, 80000 average molecular weight, 0.57 m ² / g specific surface area, 0.3 cm ³ / g specific pore volume and 55 average k-partial saponified alcohol) (hereinafter PVA 2) and magnesium stearate in the amount indicated in Table 1, and the resulting mixture is pressed directly into tablets with a compression force of 10-50 kN.

The composition of the tablets tested is shown in Table 1. The in vitro release data are shown in Table 2.

Example 13

250 g of Levodopa and 25 g of Carbidopa active ingredients, 25 g of 3% residual acetate, 60,000 average molecular weight, 0.104 m ² / g surface area and 45 requests of fully saponified polyvinyl alcohol, 100 g (<16 mm>) Cellulose powder with a particle size distribution of 65% to <0.05 mm = 10-30% by weight and 5 g of magnesium stearate are granulated and granulated with a 100% w / w gelatin solution in a rotary bed granulator at 60 ° C and 3-4% by weight dried to residual water content. The granules are then sieved to a particle size of up to 1.2 mm and compressed into tablets having a nominal weight of 407 mg at a compression force of 10-50 kN.

The in vitro release data are shown in Table 2.

Example 14

250 g of Levodopa and 25 g of Carbidopa active ingredients, 94 g (<0.16 mm> 65% and <0.05 mm = 10-30% by weight) of cellulose powder, g of silicon dioxide and 51 g of PVA 1 in a vortex granulator, 10 ml of a 20% aqueous citric acid solution is pelleted and granulated with 150 ml of 5% aqueous PVA solution and simultaneously dried at 60 ° C to 3-4% residual water. By sieving, the granule has a maximum particle size of 1.2 mm, the granules are mixed with 30 g of talc and 5 g of magnesium stearate for 15 minutes, and the resulting granules are then mixed.

It is extruded into tablets having a nominal weight of 440 mg with a compression force of 10-50 kN.

Table 2 summarizes the in vitro release data.

Example 75

100 g of Levodopa and 25 g of Carbidopa active ingredients and 16 g of PVA 1, 5 g of PVA 2 and 3 g of silica components are mixed in a vortex granulator, pelleted with 10 ml of 20% citric acid solution and then 75 ml of 10% w / w aqueous solution. It is granulated with PVA solution 1 and simultaneously dried at 60 ° C to 3-4% residual water. By sieving, the granule has a maximum particle size of 1.00 mm, then 90 g (<0.16 mm> 65 wt% and <0.05 mm = 10-30 wt% particle size distribution) with cellulose powder, 10 g talc and 2 After mixing with magnesium stearate (g) for 15 minutes, 260 mg portions of the resulting mixture are filled into a hard gelatin capsule.

Table 2 shows the in vitro release data.

Example 16

As described in Example 13, tablets were prepared which were sprayed with an aqueous suspension in a suitable coating apparatus with a perforated drum at an inlet air temperature of 48 ° C consisting of the following components: 5.5 g of hydroxypropylmethylcellulose, 5.5. g talc, 1.7 g titanium dioxide, 0.3 g 6000 polyethylene glycol and 80 g water.

The resulting film tablets have a nominal weight of 420 mg.

Table 2 shows the in vitro release data.

Table 7

Composition of the tablet tested

example levodopa (Mg) Carbidopa (Mg) PVA 1 (mg) PVA 1 (mg) Magnesium Stearate (Mg) First 100.0 10.0 100.0 10.0 5.0 Second 100.0 25.0 100.0 25.0 5.0 Third 150.0 15.0 150.0 15.0 5.0 4th 250.0 25.0 250.0 25.0 5.0 5th 250.0 25.0 25.0 100.0 5.0 6th 250.0 25.0 125.0 0.0 5.0 7th 250.0 25.0 0.0 125.0 5.0 8th 250.0 25.0 100.0 25.0 5.0 9th 100.0 25.0 2.5 10.0 5.0 10th 100.0 25.0 12.5 50.0 5.0 11th 100.0 25.0 25.0 100.0 5.0 12th 100.0 25.0 50.0 200.0 5.0

Table 2

In vitro release

Time (minute) levodopa Carbidopa 15 30 45 60 15 30 45 60 example active ingredient (%) First 82.3 95.4 99.0 101.0 81.4 93.5 99.2 100.0 Second 85.2 93.1 100.3 - 83.2 91.5 98.7 - Third 83.6 94.4 100.1 - 84.7 86.4 99.0 - 4th 89.6 97.7 100.5 - 85.3 97.6 100.4 - 5th 42.1 69.2 86.9 100.2 33.6 70.4 91.2 98.0 6th 87.3 98.1 100.0 - 86.7 87.2 103.0 - 7th 35.2 45.4 70.9 82.9 34.9 46.6 69.2 80.1 8th 74.7 86.3 95.1 103.0 74.2 83.3 98.4 - 9th 47.2 75.5 93.7 98.3 42.9 75.1 92.8 98.4

EN 215 191

Table 2 (continued)

Time (minute) levodopa Carbidopa 15 30 45 60 15 30 45 60 example active ingredient (%) 10th 43.6 73.5 100.0 - 40.2 73.0 92.9 98.7 11th 32.4 44.2 59.4 68.3 30.7 40.3 53.6 61.4 12th 27.7 38.6 53.1 64.8 28.6 37.4 51.1 65.8 13th 74.3 98.6 102.0 - 87.0 100.0 - - 14th 89.2 92.1 93.0 94.2 85.2 90.4 92.6 95.4 15th 86.4 94.1 98.9 99.7 84.8 92.3 98.1 100.1 16th 73.5 98.4 101.7 - 87.3 99.8 - -

In Examples 7, 11, and 12, the release of the active ingredient is tested for over 60 minutes:

example Levodopa (%) Carbidopa (%) 90 minutes 120 minutes 90 minutes 120 minutes 7th 103.0 - 100.0 - 11th 85.6 99.1 86.3 102.2 12th 86.4 100.0 84.5 98.6

Claims (1)

PATIENT PERSONALITY A method for the preparation of a controlled release oral dosage form comprising the active ingredients of Levodopa and Carbidopa for the treatment of centralized dopamine deficiency, characterized in that it comprises: a) 100-250 parts by weight of Levodopa and b) 10-25 parts by weight of the active ingredient Carbidopa, based on the total weight of the active ingredients c) 10-200% by weight of a polymer blend i) 0 to 100 parts by weight, 0-3% residual acetate in 40, 60000-80000 moleku30 latömegű average, from 0.1 to 0.18 m ² / g surface area, completely saponified poly (vinyl alcohol), and / or ii) 100-0 parts by weight, 10-18% residual acetate content, 80000 average molecular weight, 0.5-0.69 m ² / g specific surface area and 0.2-0.36 cm ³ / g specific pore volume, Partially saponified polyvinyl alcohol is mixed and the mixture is converted into a pharmaceutical composition for oral administration with conventional galenic excipients.