NL8203343A - PHARMACEUTICAL PREPARATION. - Google Patents

Description

N.O. 31,316 1 a; .

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Pharmaceutical preparation L-dopa, (-) - 3- (3,4-dihydroxyphenyl) -L-alanine, is a known compound of significance in the therapy of Parkinson's disease.

Decarboxylase inhibitors are also known compounds. For example, the N1-d1-seryl-N2- (2,3,4-trihydroxybenzyl) hydrazine hydrochloride is disclosed in U.S. Pat. No. 3,178,476 as a decarboxylase inhibitor.

5, The use of a combination of L-dopa and a specific carboxylase inhibitor, namely the N-dl-seryl-N2- (2,3,4-trihydroxybenzyl) -hydrazine hydrochloride in the treatment of the disease of

Parkinson is described in U.S. Patent 3,557,292.

The use of L-dopa alone in a rapidly disintegrating tablet is described in U.S. Patent 3,632,778.

15 So far, in the treatment of the disease

Parkinson's use large amounts of L-dopa, because much of the administered L-dopa is metabolised enzymatically, ie by decarboxylase, in the stomach or in bleed, before the L-dopa passes through the blood-brain box, where it is therapeutic activity unfolds.

The amount of the orally administered L-dopa, which passes the blood-brain box intact, can be significantly increased, i.e., the anti-Parkinson's activity is "energized" when L-dopa is administered in combination with a known decarboxylase inhibitor.

Although the usual capsules and tablets containing L-dopa and a decarboxylase inhibitor initially show higher blood levels of L-dopa, these formulations do not maintain such blood levels above an original peak value similar to that of the exclusive administration of L-dopa is achieved.

Conventional sustained-release active ingredient formulations containing L-dopa do not lead to the desired therapeutic success, i.e., high blood levels of L-dopa.

In accordance with the invention, it has been found that a hydrodynamically weighted sustained release active ingredient formulation containing L-dopa and a decarboxylase inhibitor achieves better blood levels of L-dopa. The invention therefore relates to a hydrodynamically balanced delayed active substance pharmaceutical preparation, characterized in that the preparation contains 8203343 f · 2 a) as active active ingredient L-dopa and a dercarboxylase inhibitor, the ratio from L-dopa to decarboxylase inhibitor is about 4: 1 to about 10: 1 and b) about 5 to about 80% by weight of a hydrocolloid or a mixture of hydrocolloids; up to about 60% by weight of a fat or mixture of fats and up to 80% by weight inert, edible pharmaceutical excipients, the preparation being hydrodynamically balanced in capsule or tablet form so that it is in contact with the stomach fluid assumes a total specific gravity of less than 1, so that it floats in the gastric fluid and remains in the stomach until essentially all of the active ingredients are released.

Oral administration of the composition of the invention not only significantly increases L-dopa blood levels, but also results in longer-lasting L-dopa blood levels than those with either regular capsules or tablets containing L-dopa or a decarboxylase inhibitor, or with conventional sustained-release active ingredient formulations, which contain either L-dopa alone or in combination with a decarboxylase inhibitor.

The compositions of the invention, which are present as tablets or capsules, float in the gastric fluid for a period of time during which substantially all of the active ingredients are released into the gastric fluid.

Formulations that remain intact and buoyant in the stomach while releasing the drug contained therein are known. For example, U.S. Patents 4,126,672, 4,140,755, and 4,167,558 disclose sustained-release active agent formulations when administered orally. The capsules and tablets are hydrodynamically weighed so that they assume a specific gravity of less than 1 in total when in contact with gastric juice 30 and consequently float in the gastric juice, which has a specific gravity between 1.004 and 1.010. These sustained-release active ingredient formulations are based on a mixture of the active ingredients with one or more hydrophilic hydrocolloids.

After oral ingestion of the preparation according to the invention, the capsule shell or the tablet coating dissolves and the formulation comes into contact with gastric fluid. The wholly external hydrocolloid hydrates to form an outer layer which causes the capsule or tablet to slightly expand and prevent water from entering. Because the total volume of the 40 formulation increases and the interior due to the aforementioned 8203343

* V

3 reported outer layer remains dry, the formulation floats to the top. The resulting soft gelatinous mass, in total, has a specific gravity of less than 1 and this maintains this. To the extent that the outer layer slowly dissolves, L-dopa and the decarboxylase inhibitor are slowly released by diffusion and / or erosion. The outer layer of the re-exposed hydrocolloids then hydrates to maintain an intact outer layer. The process is continuous, with the formulation kept buoyant in the gastric fluid until the drugs have been leached practically entirely. The residual matrix, which still floats in the stomach juice, is slowly dispersed or eliminated.

The release characteristic and the resulting blood level achieved with the composition according to the invention are better than the usual delayed release mechanisms.

Decarboxylase inhibitors act by inhibiting the decarboxylase activity and thus lead to an increase in the concentration of L-dopa administered in the plasma. Many such decarboxylase inhibitors are known. Among the known decarboxylase inhibitors suitable for the pharmaceutical composition of the present invention are: a) N 2 -dl-seryl-N 2 - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride b) 8- (3 4-dihydroxyphenyl) -a-hydrazino-a-methyl-propionic acid, c) m-hydroxybenzylhydrazine and d) a-methyl-dopa.

According to the invention, the N 1 -dl-seryl-N 2, 2,3,4-trihydroxy-benzyl) -hydrazine hydrochloride is the preferred decarboxylase inhibitor.

Hydrocolloids suitable for the pharmaceutical preparation according to the invention are natural, particulate or totally synthetic anionic or preferably non-ionic hydrophilic gums, modified cellulose products or protein-containing substances such as, for example, acacia gum, tragacanth, locust bean gum, guar gum, karaya gum, agar , pectin, carrageenan, soluble and insoluble alginates, methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, carboxypolymethylene, gelatin, caselle, zelne, bentonite, VEGDM and the like. A preferred hydrocolloid is hydroxypropylmethyl cellulose. The use of such products in pharmaceutical formulations is known per se, for example, U.S. Pat. No. 3,555,151 discloses the use of such hydrocolloids in antacid preparations with retarded active substance release.

The hydrocolloids used must hydrate in the acidic environment, i.e. in the gastric juice, with a pH approximately corresponding to 0.1 N hydrochloric acid (pH approximately 1.2). Although the specific gravity of the formulation of the invention may initially be greater than 1, especially with tablets, it is required that the formulation be hydrodynamically weighed to assume a specific gravity of less than 1 when it comes into contact with the stomach fluid. There are a number of methods by which the rate of release of the active compound from the pharmaceutical preparation according to the invention can be adjusted. The choice of a particular hydrocolloid or a mixture of hydrocolloids can affect the rate of release. For example, high viscosity hydrocolloids, for example, hydroxypropylmethylcellulose 4000 cP, hydrate more slowly and remain in the soft mass state longer than hydrocolloids of lower viscosity, such as, for example, hydroxypropylmethylcellulose 10 cP. The pharmaceutical composition of the invention may further contain edible, pharmaceutically inert fats which have a density of less than 1 to reduce the hydrophilic properties of the formulation and consequently to increase buoyancy. Examples of such substances are purified qualities of beeswax, fatty acids, long chain fatty alcohols such as, for example, cetyl alcohol and stearyl alcohol, fatty acid esters such as, for example, glyceryl monostearate and hydrogenated castor oil.

The compositions of the invention may additionally contain edible, non-toxic ingredients, such as extenders, buffers, preservatives, stabilizers, and tableting lubricants.

The amount of hydrocolloid present in the compositions of the invention can vary over a wide range, from about 5 wt% to about 80 wt% based on the total weight of the composition. The amount of hydrocolloid used varies depending on the amounts and properties of the active active substance and the inert pharmaceutical auxiliaries used.

Generally, the amount of hydrocolloid is between about 15 wt% and 60 wt%.

When a fatty substance or a mixture of fatty substances is present in the preparations according to the invention, the amount is at most 60% by weight, based on the total preparation. Generally, if present, a fat-40 substance is present in amounts of from about 5 to about 8% by weight. The amount of fat is determined by the amounts and physical properties of the active ingredient and the hydrocolloid, taking into account the objective of preparing a hydrodynamically balanced formulation, ie a formulation which, in contact with the gastric fluid, has a specific gravity of less than 1.

The amount of edible inert pharmaceutical excipients which may be present in the compositions of the invention also depends on the amounts and physical properties of the other substances present. Substances which themselves have a specific gravity of less than 1, for example ethyl cellulose, increase the buoyancy of the preparation. Small amounts of carbonic acid substances can also be used in the compositions to increase buoyancy, provided the density of the composition does not become too high. When such substances generate carbon dioxide, the gas bubbles are retained by the outer hydrate layer and thus increase the buoyancy of the formulation. More importantly, it is possible to influence the rate of release of the active agent from the formulation with the selection of the inert pharmaceutical excipients. For example, soluble extenders, such as lactose or mannitol, increase the rate of release, while insoluble extenders, such as dicalcium phosphate and terra alba, decrease the rate of release. Such pharmaceutical excipients may optionally be present in the formulations in amounts of up to 80% by weight based on the total formulation.

In general, such conventional pharmaceutical excipients are present in amounts from 5 to 60% by weight. The application and choice of such substances is within the knowledge of the expert.

The compositions of the invention may contain about 10 to 70% by weight of L-dopa, preferably about 20 to 50% by weight of L-dopa. The amount of decarboxylase inhibitor in the compositions of the invention depends on the nature of the inhibitor used. It is from about 2 to 20% by weight, preferably from about 4 to about 10% by weight.

The preferred decarboxylase inhibitor is N 4 -dl-35 seryl-N 3 (2,3,4-trihydroxybenzyl) hydrazine hydrochloride. The amount of this substance in the compositions of the invention can range from about 3 to about 15 wt%, and is preferably about 4 to about 10 wt%.

Factors determining the amount of the active ingredient in the compositions of the invention are, for example, the therapeutic activity, their specific gravity, their hydrophilic and hydrophobic properties, and their stability.

The ratio of L-dopa to decarboxylase inhibitor can range from about 10 parts L-dopa to about 3 parts L-dopa on 5 Sn weight-5 part decarboxylase inhibitor.

The ratio of L-dopa to N 1 -dl-seryl-N 2- (2,3,4-trihydroxy-benzyl) -hydrazine hydrochloride may vary considerably. It can be from about 5 parts to about 3 parts by weight of this carboxylase inhibitor. The preferred ratio is about 4: 1.

The preparations according to the invention can be prepared by techniques known per se. In most cases, the only requirement is a thorough mixing of all ingredients into a homogeneous mixture and grinding or comminuting the mixture to a relatively small particle size, i.e., on a 100 mesh size particle size. The grinding of the mixture, in particular of the hydrocolloid on a very small particle size, is not harmful to the effect of the delayed release of the active substance and, on the contrary, has a positive effect thereon. Under certain conditions, conventional pharmaceutical techniques such as clumping, wet granulation or extrusion may be required to secure the appropriate fill weight in the capsule or to manufacture the tablets. However, it is required that the hydrocolloids not be incorporated into moist granules to avoid later difficulties in hydrating them in contact with the gastric fluid. For the manufacture of capsules, the mixture is expediently comminuted to a fine particle size and the capsule is completely filled.

For the manufacture of tablets, the ingredients are preferably granulated and then pressed into tablets. The tablets can be manufactured by conventional tableting machines. However, the tablets were not to be pressed to a hardness such that they are unable to reach a specific gravity of less than 1 in contact with the gastric juice. As a result, the hardness of the tablets is a critical factor and depends on the initial density of the formulation and the size of the tablets.

The following examples further illustrate the invention.

Example I

Formulation A: Hydrodynamically balanced delayed-release active ingredient capsules were prepared from the following ingredients: 8203343 7

Components mg / capsule N1-dl-seryl-N2- (2,3,4-trihydroxybenzyl) - hydrazine hydrochloride 29.63 5 L-dopa 102.00 monocalcium phosphate 24.37 hydrogenated cottonseed oil 30.00 hydroxypropyl cellulose 4.00 mannitol 20.00 Hydroxypropylmethylcellulose 115.00.

talc 15.00 340.00 ul-dl-seryl-N2- (2,3,4-trihydroxybenzyl) -hydrazine hydrochloride, 15 L-dopa, monocalcium phosphate and the hydrogenated cottonseed oil were mixed and ground. This powdered mixture was granulated with hydroxypropyl cellulose dissolved in alcohol. Mannitol and hydroxypropylmethylcellulose were mixed and ground and granulated.

The resulting mixture was dried, mixed with the talc and filled into capsules.

Formulation B: Usual capsules were made from the following ingredients:

Components mg / capsule 25 N * dl-seryl-N2- (2,3,4-trihydroxybenzyl) hydrazine hydrochloride 29.91 L-dopa 101.00 polyvinylpyrrolidone 1.00 methylene chloride q.s.

Microcrystalline cellulose 13.50 talc 6.50 magnesium stearate 6.50 152.41 35 N 1 -dl-seryl-N 2 - (2,3,4-trihydroxybenzyl) -hydrazine hydrochloride and L-dopa were mixed and ground. The powdery mixture was then granulated with polyvinylpyrrolidone in methylene chloride.

The granulate was dried and ground. The microcrystalline cellulose, the talc and the magnesium stearate were added, the mixture 40 was mixed thoroughly and filled into capsules.

8203343 δ

Formulation C: Hydrodynamically weighted tablets with delayed active substance release were prepared from the following components: 5 Ingredients mg / tablet L-dopa 204.00 mannitol 23.00 calcium carbonate 50.00 carboxymethyl cellulose 50.00 10 polyvinylpyrrolidone 10.00 hydroxypropylmethylcellulose 110.00 N * - dl-seryl-N ^ - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride 58.00 fumaric acid 25.00 15 talc 12.00 magnesium stearate 3.00 545.00 L-dopa, mannitol , calcium carbonate and carboxymethyl cellulose were granulated with alcohol in part of the polyvinylpyrrolidone. The hydroxypropylmethylcellulose was added to the granulate, which was then dried overnight.

N * -dl -seryl-N2- (2,3,4-trihydroxybenzyl) -hydrazine hydrochloride was mixed with fumaric acid and granulated with the remaining amount of polyvinyl-pyrrolidone in alcohol. The granulate was dried.

The dopa granulate and the N * dl-seryl-N 2 (2,3,4-trihydroxybenzyl) hydrazine hydrochloride granulate were mixed with talc and magnesium stearate. The mass was pressed into tablets with a hardness of 5-8 Strong-Cobb units. Care was taken that the hardness did not exceed 12 30 Strong-Cobb units.

Example 2

In vitro studies

The hydrodynamically weighed preparation of Example I in capsule and tablet form, as well as the regular capsule of Example I, were as described below, upon in vitro release of L-dopa and N-dl-seryl-N2- (2,3 , 4-trihydroxybenzyl) -hydrazine hydrochloride.

Capsules and tablets were placed separately in 60 ml of gastric juice and stirred at 20 revolutions per minute. The liquid used had a pH of 1.2 (the normal pH of gastric juice). Samples were taken at certain 40 time intervals and examined spectrophotometrically for 8203343 9 L-dopa and N 2 -dl-seryl-N 2 (2,3,4-trihydroxybenzyl) -hydrazine hydrochloride.

The table below lists the results of the in vitro release.

5 _% clearance_

Formulation _ Time (hours) L-dopa decarboxylase inhibitor

a

(hydrodynamically weighed 10 capsule) 0.50 37 40 1.00 63 65 2.00 94 95

B

(regular capsule) 0.25 102 89

15 C

(hydrodynamically balanced tablet) 0.50 26 32 1.00 80 91 2.00 105 107 20

In vivo studies

Bioavailability of L-dopa after administration to man, either in a regular capsule (Formulation B of Example I) or a hydrodynamically weighed capsule (Formulation A) of Example I) 25 each containing 100 ml of L-dopa and 25 mg of N --dl-seryl-n2- (2,3,4-trihydroxy-benzyl) -hydrazine hydrochloride was determined.

Five male subjects were used for the determination. The preparations were administered with 100 ml of water after an overnight fast.

Blood samples were collected in heparinized tubes immediately before administration of the preparation, five times during the first 2 hours after administration and then at one hour intervals for 9-10 hours.

The concentration of L-dopa in the blood was determined by a modified method from Spiegel and Tonchen (Clin. Chem. 16, 763).

The samples were compared with blood plasma standards. The following results were obtained: 8203343

N

10 2x (100 + 25) mg 4x (100 + 25) mg _capsules_ _capsules_

Plasma L-dopa ordinary according to the ordinary according to the invention highest concentration yg / ml 1.9 0.97 - 2.6 time to highest concentration in hours 1.1 2.9 - 2.6 10 area below the curve, yg / h / ml ^ 3.2 2.0-10.1

The blood plasma level results were compared with a standard formulation. For the dose of 2x (110 + 25) mg, a difference was found between the formulation according to the invention and the ordinary formulation. The high peak levels of L-dopa of the samples from ordinary capsules did not occur when the capsule according to the invention was administered. Time to peak was delayed by 1.1 hours in the regular capsules and 2.9 hours in the capsules of the invention, indicating slower absorption rate.

At the higher dose [4x (100 + 25) mg], the plasma level / time concentration curve was invariably greater than that observed at the lower dose. It was found that the dose was not tolerated with the ordinary capsule (gastric disturbance).

8203343

Claims (6)

Hydrodynamically weighed delayed release active ingredient pharmaceutical composition, characterized in that the composition a) contains active ingredient L-dopa and a decarboxylase inhibitor, wherein the ratio of L-dopa to decarboxylase inhibitor is about 4: 1 to about 10: 1, and b) from about 5 to about 80% by weight of a hydrocolloid or a mixture of hydrocolloids, up to about 60% by weight of a fat or mixture of fats and up to 80% by weight of inert, edible pharmaceuticals. Contains 10 excipients, the preparation in capsule or tablet form being hydrodynamically balanced so that in contact with the gastric fluid it assumes a total specific gravity of less than 1, so that it floats in the gastric fluid and remains in the stomach to substantially all active active substances have been released. Preparation according to claim 1, characterized in that the carboxylaser bucket is [Nl-dl-seryl-N2- (2,3,4-trihydroxybenzyl] -hydrazine hydrochloride] and the ratio of L-dopa to Nl-dl -seryl-N 3 - (2,3,4-trihydroxybenzyl) -hydrazine hydrochloride is about 5: 1 to about 3: 1. Preparation according to claim 1, characterized in that the a) about 20-50 wt% L-dopa, b) about 2-20 wt% decarboxylase inhibitor, c) about 15-60 wt% hydrocolloid, d) up to about 30% by weight of fats and e) contains about 5-60% by weight of edible pharmaceutical excipients and that the ratio of L-dopa to decarboxylase inhibitor is about 4: 1 to about 10: 1. 4. Preparation according to claim 2, characterized in that the a) about 20-50 wt% L-dopa, b) about 4-10 wt% [N1-dl-seryl-N2- (2,3, 4-trihydroxybenzyl) hydrazine hydrochloride, c) about 15-60 wt% hydrocolloid, d) up to about 30 wt% fat, and e) about 5-60 wt% edible pharmaceutical excipients and that contains the ratio of L-dopa until N * -dl -seryl-N ^ - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride is about 4: 1. Preparation according to claims 1 to 4, characterized in that it is hydrocolloid methyl cellulose, hydroxypropyl cellulose, hydroxypropyl 8203343 methyl cellulose, sodium carboxymethyl cellulose or carboxypolymethylene or a mixture of such substances. Preparation according to claims 1 to 4, characterized in that the hydrocolloid is hydroxypropylmethylcellulose. ****** 8203343