DD301037A7 - Perorally administrable dosage form for the treatment of central dopamine deficiency states - Google Patents

Abstract

The invention relates to a perorally administrable pharmaceutical formulation and to a process for its preparation in which the drugs levodopa and carbidopa are embedded in defined proportions in a hydrophilic base consisting of a mixture of polyvinyl alcohols of different vinyl acetate content and non-toxic adjuvants; it significantly expands the possibilities of treatment of central dopamine deficiency states, in particular Parkinson's disease, by ensuring therapeutically effective blood level values in the flooding phase.

Description

Field of application of the invention

The invention relates to a perorally administrable pharmaceutical form, which includes a combination of the drugs levodopo and carbidopa in defined ratios and a process for their preparation. The invention is applicable in the pharmaceutical industry and serves to provide a medicament useful for the therapy of Parkinson's disease.

Known technical background

Severe disturbances of the automatic movement - the so-called Parklnaon syndrome - come with increasing age

Dorzorobralo deficiency of the extrapyramidal motor neurotransmitter dopamine in the basal ganglia of the brain of the enterocerecton, especially in the corpus striatum, as a result of Nlgrostrialis degeneration of unknown aetiology, leads to an imbalance between the motion-mediating dopaminergic and choMnergen neurotransmitter systems.

Substitution of the missing biogranic amine can be achieved by the introduction of its levodopa precursor, which penetrates the blood-blood barrier, which is taken up in dledopamirating neurons and decarboxylated to dopamine (Birkmayer, Hornkiewicz, Wion KHn. Wochenschrift Ta [1961], 787). , It is known that the peripheral Dopadecarboxylierung of levodopa by the simultaneous peroral application of a suitable decarboxylase, such as Carbidopa (DE-PS 3012602, US Patent 3,769,424) or benserazide (DE-PS 3235093) is largely suppressed, resulting in a significant increase Levodopa serum piogel results in a relevant reduction of the therapeutically necessary dose and a concomitant reduction of gastrointestinal and cardiovascular side effects. The production of levodopa and carbidopa-containing capsules, film-coated tablets and tablets capable of floating in gastric juice is known (GB-PS 1 243474, US Pat. No. 4,424,235, BE-PS 894376). Furthermore, it is known that international standards so far require only a very fast in vitro-Liberation (USP XXI), Also known are methods for the preparation of medicaments from which the drugs levodopa and carbidopa are released slowly and simultaneously. These medicaments can be, for example, polymeric matrices (EP-PS 0253490, EP-PS 0320051 l / pellets (DE-PS 3841955, EP-PS 0260236, EP-PS 0324947) or also multilayer molded articles (EP-PS 0302693, EP-PS 0314206) Furthermore, it is known that the conversion of a drug substance or of a drug mixture into a pharmaceutical form is an important means of influencing the bioavailability and, at the same time, a method for making it possible to handle very low drug doses by means of suitable pharmaceutical-tochnological auxiliaries or to provide drug incompatibility Furthermore, for the manufacture of tablets, a large number of methods are known, the aim of which is to produce powdered araneistophones and / or mixtures of powdered araneistofone and pharmaceutical-technological auxiliaries under technical conditions To translate taboos. It is known that the properties of the compositions, such as stability, electrostatic chargeability, flowability and tableting behavior as well as their bioavailability, can be influenced and changed by adding suitable pharmaceutical-technological auxiliaries to drugs or drug-excipient mixtures. ·,

Likewise, the filling of drug-containing powder mixtures, granules, pellets u. S. described in hard gelatin capsules. Furthermore, it is known that a significant delay of the drug liberating can be achieved by the addition of poly (vinyl alcohol) (U. Meyer, Diss., Berlin 1977) and that polyvinyl alcohol generally fast disintegrating solid tablets are produced (W.Rietschel, "DieTablette"; , Aulendorf, 1966).

-2- 3C1 037

Description ..'·

The considerable variability of the clinical picture of the Parkinson: Parkinson's disease requires a sensitive, individually adjustable

medical therapy.. . ^; ,

On the one hand, the therapist must be provided with a drug formon which compensates for transmitter deficits that have occurred during the course of the day by means of an immediate complete liberation of the drugs Levqdopa and Carbidopa, and thus a rapid one

Improvement of the overall condition of patients can achieve. ',

On the other hand, however, in a not inconsiderable number of patients, as a result of the rapid release of active ingredient, a long-term therapy with subsequently high levodopa plasma levels is undesirable and uncomfortable, the condition is strong

debilitating side effects. , , , ,

The invention has for its object to develop a perorally administrable drug form and a method for their preparation, dom can be prepared from levodopa and carbidopa tablets and capsules, from which the Arznoistoffe controlled in the flooding period of about 30-45min and another desired Period completely and evenly, but not significantly delayed, released.

According to the invention this object is achieved in that 100 to 250 parts by weight of levodopa and 10 to 25 parts by weight of carbidopa with a polymer mixture consisting of 0 to 100 parts by mass of a fully saponified polyvinyl alcohols having 0 ^: 3% Vinylacctatgehalt, miUleren molecular weight of 60,000 to 80,000, a total surface of 0.1 m ² / gbis0,18m ² / g and 100 to 0 parts by mass of a partially hydrolyzed polyvinyl alcohol having from 10 to 18% vinyl acetate content, a mean molecular weight of 80,000, a total surface area of 0.5 m '/ g Biso, 69m ² / g anda "specific pore volume of 0.2 cm ³ / g Biso, 36cm '/ g, are combined in proportions of 10 to 200%, based on the amount of drugs. the drug-polymer mixture are added in an amount customary gaienische auxiliaries, which makes it possible to prepare the dosage form in a manner known per se, for example by direct tableting, tabletting after granulation with a suitable binder or by Filling in hard gelatine capsules.

The polyvinyl alcohols used are preferably commercial products whose k values (Fikentscher, Cellulose Chemistry 13 [1932], 58) for fully hydrolyzed polyvinyl alcohols are in the range from 40 to 59 and for partially hydrolyzed polyvinyl alcohols in the range from 50 to 59.

Surprisingly, it has been found that the mixture according to the invention of the additives and pharmaceutical substances and the resulting simple pharmaceutical-technological processing lead to the solution of the problem.

Furthermore, it has surprisingly been found that obtained by the process according to the invention, the use of combinations of polyvinyl alcohol of various residual acetate contents, levodopa / Carbidopa drug formulations that release the drug quickly and completely, but whose Arznoistoffliberation in the flooding phase can be varied or controlled as needed ,

The ororfungsgsmäßo procedure leads to a dosage form, the two "eiMoife releases quickly and over a period of time in dofiniortan conditions and thus ensures optimal bioavailability of the peripheral Dopadecarboxylanshommers carbidopa and dos dopamine precursor levodopa, for different patient groups, this is possible, with minimal effort dosage forms, each with optimal

To provide clearance. ,

With the dosage form described, the requirement of the use of levodopa / carbidopa medicine forms with immediate and complete or initial delayed liberation can thus be fulfilled according to the clinical picture.

Execution Bolspial ©. · '

Example 1-12.

Levodopa is with Carbidopa, a fully saponified polyvinyl alcohol having a vinyl acetate content of 2.5%, an average molecular weight of 70,000, a total surface of 0.14m ² / g and a k value of 55, hereinafter referred to as PVA1, a teilverseifton polyvinyl alcohol with a vinyl acetate content of 15%, an average molecular weight of 80,000, a total surface area of 0.57 m ^s / g, a specific pore volume of 0.3 cm ³ / g and an average k value of 55, hereinafter referred to as PVA2, and may Nesiumstearat mixed and pressed with a pressing force of 10-5OkN directly into tablets. , j ·

Assessed Tablet Formulations: Table 1 In Vitro Drug Liberation: Table 2 '

Example 13. _; , , , ..

250 g of levodopa, 25 g of carbidopa, 25 g of a fully saponified polyvinyl alcohol having a vinyl acetate content of 3%, an average molecular weight of 60,000, a total surface area of 0.104 m ² / g and a k value of 45.100 g of cellulose powder with a grain size of <n <0,16mm> / = 65% and <0.05 m $ n-10 to 30% and 5g Magnösiumstearat are mixed with 100 ml of a 2% "gelatin solution in Wirbolschichtgranulator at 60 ^e C grartuliart and to a residual water content of 3-4 % dried. The granules are brought by subsequent screening on oino maximum) grain size of 1.2 mm and pressed into tablets with a nominal mass of 407mg at a pressing force of 10 ^ 5OkN. -

In Vitro Drug Liberation: Table 2

Example 14 ... '.... · '

250g of levodopa, 25g of carbidopa, 94g of cellulose powder of <0.16mm> / = 65% and <0.05mm-10 to 30%, 3g of silicon dioxide and 51g of PVA1 are mixed in the fluid bed granulator, sprayed with 10ml of a 20% citric acid aqueous solution and granulated with 150 ml einet 5% aqueous solution of PVA1 and dried at the same time at a temperature of 60 ° C to a residual water content of 3 to 4%. .

The granules are brought to a maximum grain size of 1.2 mm by sieving, mixed with 3OgTaIk and 5 g of magnesium stearet for 15 min and compressed at a pressing force of 10-50 kN into tablets having a nominal mass of 440 mg. In Vitro Drug Detection: Table 2

Bclr.piol 15 "

100g Lovodopa, 25g Carbidopa, 16g PVA1, 5g PVA2 and 3g silica are mixed in the Wii'oelschichtgranulator, sprayed with 10ml of a 20% "Zitronenf HLiralösung and granulated with 75 ml of a 10% aqueous solution of PVA1 and .gloic'i. dried early at a temperature of 6O ⁰ C to a residual water content of 3-4%.

The granules are sieved to a maximum grain size of 1.00 mm, mixed with 90 g of cellulose powder having a particle size range of <0.16 mm> / = 65% and <0.05 mm -10 to 30%, 10 g talc and 2 g magnesium stearate for 15 min and each filled to 260mg in a hard gelatin capsule.

In Vitro Drug Liberation: Table 2

table 1 levodopa 2 levodopa 30 carbidopa 60 PVA 1 carbidopa 101.0 carbidopa 120min 81.4 PVA 2 45 Mg stearate 60 example mg 15 ν ^: mg mg 15   - 90 min _. 83.2 mg mg ' 100 95.4 10 WHERE Drug% - 100.0 102.2 84.7 10 99.2 5 100.0 1 / 100 82.3 93.1 25 100 -. · ' 86.3 98.6 85.3 25 98.7 5 - 2 , '150 85.2 94.4 15 150 100.2 '84.5 33.6 15 99.0 5 - 3 250 83.6 97.7 25 · 250 .. -.: 86.7 25 100.4 5 - · 4 250 89.6 69.2 25 25 82.9 34.9 100 91.2 5 98.0 5 250 42.1 98.1 25 125 103.0 74.2 0 103.0 5 - 6 250 07.3 45.4 25 0 98.3 42.9 125 69.2 5 80.1 7 250 3-3.2 86.3 25 100 - 40.2 25 98.4 5 - 8th 100 74.7 75.5 25 2.5 68.3 30.7 10 92.8 5 98.4 9 100 47.2 73.5 25 12.5 64.8 28.6 50 92.9 5 98.7 10 100 43.6 44.2 25 25 - 87.0 100 53.6 5 61.4 11 100 32.4 38.6 25 50 94.2 85.2 200 51.1 5 65.8 12 27.7 98.6 99.7 84.8 - - table 74.3 92.1 ' 12, the drug release was over 60 Minutes out 92.6 95.4 Time 89.2 94.1 ' 45 30 98.1 100.1 min 85.4 120 min example Examples 7, 11 and 99.0 _ 93.5 1 levodopa 100.3 99.1 91.5 2 90 min 100.1 100.0 86.4 3 103.0 100.5 97.6 4 85.6 86.9 70.4 5 86.4 100.0 87.2 6 70.9 46.6 7 95.1 83.3 8th .. 93.7 75.1 9 100.0 73.0 10 59.4 40.3 11 53.1 37.4 12 102.0 100.0 13 93.0. 90.4 14 98.9 92.3 15 checked: Both example 7 11 · 12 "

Claims (2)

Claim ©: <; -. 1. Peroral a'ppiizierbäre dosage form for the treatment of central dopamine deficiency states, characterized in that the dosage form 100 to 250 parts by weight Levodöpa, 10 to 25 parts by weight Carbidopä, a polymer mixture consisting of 0 to 100 parts by weight of a fully saponified Polyvinylaikohols (PVA 1) with 0 to 3 % Vinyl acetate content, an average molecular weight of 60,000 to 80,000 / a total surface area of 0.1 mm ² / g to 0.18 m ² / g and 100 to 0 parts by weight of a , tei saponified Polyvinylaikohols! (PVA 2) from 10 to 18% Vinylacetetgehalt, an average molecular weight of 80,000, a Gosamtohcrflächo of 0.5m ² / g to 0,69m ² / g and a specific Porenvclumen of 0,2CmVg to 0,36cm ³ / g, in proportions of 10-200%, based on the amount of drug extract, as well as a suitable amount of common galonic excipients. : 2. A process for preparing the medicament form according to claim 1, characterized in that up to 250 parts by weight of levodopa, 10 to 25 parts by weight of carbidopa, a polymer mixture consisting of 10 to 10 parts by weight of a polyvinyl alcohols (PVA 1) having 0 to 3% vinylacotate content, an average molecular weight of 60,000 to 80,000, a total surface area of 0.1 to about 0.18m ² / g and 100 to 0 parts by weight of a saponified polyvinyl alcohol (PVA2) having 10 to 18% vinyl acetate content, an average molecular weight of 80,000, a total surface area of 0.5m ² / g to 0.69 m ² / g and a specific pore volume of 0.2 cm ³ / g to 0.36 cm ³ / g, in proportions of 10 to 200%, based on the "amount of drugs, and a suitable amount of conventional Gatenjscher excipients united.