DE3232873A1 - PHARMACEUTICAL PREPARATION - Google Patents

Description

Patent attorneys

Dr. Franz Lederer
Dipl.-Ing. Reiner F. Meyer-Roxlau: **: "*** -""-" - - * "..-.

8000 Munich 80: I. ':'' :: * ": -;": .- "3232873

Ludli-ewHm-Sfr. Z2, TtI. (089) 472947 "* **. ** ~ \,"''" ,.

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Sep 3 1982

RAN 4604/7

Pharmaceutical preparation

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

Decarboxylase inhibitors are also known compounds

1 2

fertilize. For example, this is N -dl-Seryl-N - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride in the U.S. Patent 3,178,476 mentioned as a decarboxylase inhibitor.

The use of a combination of L-Dopa and a specific decarboxylase inhibitor, namely the N -dl-Seryl-

2
N - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride in the treatment of Parkinson's disease is described in US Pat. No. 3,557,292.

The use of L-Dopa alone in a rapidly disintegrating Tablet is used in U.S. U.S. Patent 3,632,778.

So far, large amounts of L-Dopa had to be used in the treatment of Parkinson's disease, because a lot of the administered L-dopa enzymatically, i.e. by

Green / 8/10/82

Decarboxylase, is metabolized in the stomach or in the blood before the L-dopa crosses the blood-brain barrier where it does unfolds its therapeutic activity.

The amount of orally administered L-dopa that crosses the blood-brain barrier intact can be significantly increased i.e. the anti-Parkinson’s effect is "potentiated" when L-Dopa in combination with a known Decarboxylase inhibitor is administered.

Although the ordinary capsules and tablets containing L-dopa and a decarboxylase inhibitor initially show higher blood levels of L-dopa, these formulations will not survive such blood levels an initial peak value similar to that obtained with administration of L-dopa is achieved.

Conventional formulations with delayed active ingredient Releases containing L-Dopa do not lead to the desired therapeutic success, i.e. high blood levels of L-Dopa.

According to the invention it has been found that a hydrodynamic balanced sustained-release formulation containing L-Dopa and a decarboxylase inhibitor, Causes superior blood levels of L-Dopa. The invention thus relates to a hydrodynamically balanced one pharmaceutical preparation with delayed release of active ingredients, which is characterized in that it

a) contains as active ingredient L-Dopa and a decarboxylase inhibitor, the ratio of L-Dopa to Decarboxylase inhibitor is about 3: 1 to about 10: 1, and

b) about 5 to about 80 wt .-% of a hydrocolloid or a mixture of hydrocolloids; up to about 60% by weight a fatty substance or a mixture of fatty substances and

-Λ:

up to 80% by weight of inorten, edible pharmaceutical Contains excipients, the preparation in capsule or tablet form is hydrodynamically balanced so that it is in the Contact with gastric fluid assumes a total specific gravity of less than 1, so that it is in the gastric fluid floats and remains in the stomach until essentially all of the active ingredients have been released are.

Oral administration of the preparation according to the invention not only leads to a significant increase of the L-dopa blood level, but also results in long sustained blood L-dopa levels than this with either ordinary capsules or tablets that contain L-dopa or a decarboxylase inhibitor, or with conventional ones Delayed release formulations that containing either L. dopa alone or in combination with a decarboxylase inhibitor.

The preparations according to the invention, either as Tablets or capsules remain floating in the gastric fluid for a period of time during which essentially all of the active ingredients are released into the gastric fluid.

Formulations that remain intact and floating in the stomach while the drug contained therein is released we are known. For example, in U.S. Patents 4,126,672, 4,140,755 and 4,167,558 Delayed release formulations for oral administration are described. The capsules and tablets are hydrodynamically balanced so that they assume an overall specific gravity of less than 1 when they are in Are in contact with gastric juice and consequently in gastric juice, which has a specific gravity between 1.004 and 1.010, stay floating. These sustained release formulations are based on a mixture of the active ingredients Active ingredients with one or more hydrophilic hydrocolloids.

After oral intake of the preparation according to the invention the capsule shell or tablet coating dissolves and the formulation comes into contact with gastric fluid. The very outer hydrocolloid hydrates, forming an outer layer that causes The capsule or tablet is enlarged a little and prevents water from entering. By that the total volume the formulation increases and the inside remains dry as a result of the above-mentioned outer layer, comes the formulation floats up. The resulting soft gelatinous mass takes on a specific overall Weight less than 1 and maintain it. To the extent that the outer layer slowly dissolves, becomes L-dopa and the decarboxylase inhibitor are released slowly through diffusion and / or erosion. Then hydrated the outermost layer of the newly exposed hydrocolloids, so that an intact outer layer is maintained will. The process is continuous with the formulation being kept floating in the gastric fluid until the drugs have been practically exhausted. The remaining matrix that is still in the gastric juice floats, is slowly dispersed or eliminated.

The release characteristics and the resulting blood levels achieved with the preparation according to the invention are superior to conventional delayed drug release mechanisms.

Decarboxylase inhibitors work by inhibiting decarboxylase activity and thus lead to an increase in the concentration of administered L-dopa in the plasma. Lots of them Decarboxylase inhibitors are known. Among the known decarboxylase inhibitors for the pharmaceutical according to the invention The following preparations are suitable:

1 2

a) N -dl-Seryl-N - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride,

b) 3- (3,4-Dihydroxyphenyl) -a-hydrazino-oc-methyl-propionic acid,

c) m-hydroxybenzylhydrazine and
5

d) ct-methyldopa.

1 2

According to the invention, the N -dl-seryl-N - (2,3,4-

trihydroxybenzyl) hydrazine hydrochloride is preferred Decarboxylase inhibitors.

Hydrocolloids suitable for the pharmaceutical preparation according to the invention are natural, partial or totally synthetic anionic or preferably nonionic hydrophilic gums, modified celluloses or Portein-containing substances such as 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, casein, zein, bentonite, VEEGUM and the like. A preferred hydrocolloid is hydroxypropyl methyl cellulose. The use of such materials in pharmaceutical formulations is known per se, for example in U.S. Patent specification 3,555,151 describes the use of such hydrocolloids in antacid preparations with delayed release of active ingredients.

The hydrocolloids used must be in an acidic medium, i.e. in gastric juice with a pH of around 0.1N hydrochloric acid corresponds to (about pH 1.2) hydrate. Although the specific gravity of the formulation according to the invention is initially Can be higher than 1, especially in the case of tablets, the formulation is required to be hydrodynamic is balanced so that it has a specific gravity of less than 1 when in contact with gastric fluids comes. There are a number of methods with which the release rate of the active ingredient from the

pharmaceutical preparation according to the invention set can be. The choice of a particular hydrocolloid or mixture of hydrocolloids can affect the rate of release. For example, hydrati- size hydrocolloids of high viscosity, e.g. hydroxypropylmethyl cellulose 4000 cps, hydrates more slowly and stays in a soft mass longer than hydrocolloids low viscosity, such as hydroxypropyl methyl cellulose 10 cps. The pharmaceutical according to the invention The preparation can also contain edible, pharmaceutically inert fatty substances that have a density of less than 1 to reduce the hydrophilic properties of the formulation and consequently the buoyancy to increase. Examples of such substances are purified qualities of beeswax, fatty acids, long-chain fatty alcohols, such as cetyl alcohol and stearyl alcohol, fatty acid esters such as glyceryl monostearate and hydrogenated castor oil.

The preparations according to the invention can additionally contain edible, non-toxic ingredients such as excipients, Buffers, preservatives, stabilizers and tabletting lubricants.

The amount of hydrocolloid contained in the preparations according to the invention can vary within a wide range, namely from about 5 wt .-% to about 80 wt .-%, based on the total weight of the preparation. The amount of hydrocolloid used varies depending on the amounts and Properties of the active ingredient and the inert pharmaceutical excipients that are used. in the in general, the amount of hydrocolloid is between about 15% and 60% by weight.

If a fatty substance or a mixture of fatty substances is present in the preparations according to the invention, is the amount up to 60 wt .-% based on the total preparation. Generally a fatty substance, if any

-V

is present in amounts of from about 5 to about 30 weight percent. The amount of fatty substances is determined by the amounts and physical characteristics of the active ingredient and the hydrocolloid, under consideration the objective of producing a hydrodynamically balanced formulation, i.e. a formulation which, in contact with gastric fluid, has a specific gravity of less than 1.

The amount of edible inert pharmaceutical excipients, which can be contained in the preparations according to the invention also depends on the amounts and physical properties of the other substances present. Substances which themselves have a specific weight of less than 1, e.g. ethyl cellulose, increase the buoyancy of the preparation. Small amounts of substances that Generating carbon dioxide can also be used in the preparations to increase swimming ability, as long as the density of the preparation is not too high. When such substances produce carbon dioxide, the gas bubbles become retained by the outer hydrate layer and thus increase the buoyancy of the formulation. More important is that it is possible, with the choice of inert pharmaceutical excipients, to reduce the rate of release of the To influence the active ingredient from the formulation. For example, soluble excipients increase, for example Lactose or mannitol, the rate of release, while insoluble excipients, e.g. dicalcium phosphate and terra alba reduce the rate of release.

Such pharmaceutical auxiliaries can optionally be present in the formulations in amounts of up to 80% by weight, based on the entire formulation. In general, such conventional pharmaceutical excipients are present in amounts of 5 to 60 % by weight . The use and selection of such substances is within the range of expert knowledge.

The inventive preparations can be about 10 to 70% by weight L-dopa, preferably about 20 to 50% by weight Contains L-Dopa. The amount of decarboxylase inhibitors in the preparations according to the invention depends on the nature of the used inhibitor. It is around 2 to 20% by weight, preferably from about 4 to about 10 weight percent.

The preferred decarboxylase inhibitor is N -dl-seryl-2
N - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride. The amount of this substance in the preparations according to the invention can vary from about 3 to about 15% by weight, preferably it is from about 4 to about 10% by weight.

Factors that determine the amount of the active ingredients in the preparations according to the invention are for example the therapeutic effectiveness, their specific gravity, their hydrophilic or hydrophobic properties or their stability.

The ratio of L-dopa to decarboxylase inhibitors can vary from about 10 parts of L-dopa to about 3 parts of L-dopa to one part by weight of decarboxylase inhibitors.

1 2

The ratio of L-Dopa to N -dl-Seryl-N - (2,3,4-trihydroxybenzyl) -hydrazine hydrochloride can also vary considerably. It can be from about 5 parts to about 3 parts by weight of this decarboxylase inhibitor. That preferred ratio is about 4: 1.

The preparations according to the invention can by means of known techniques. In most cases, the only thing required is thorough Mixing of all components to a homogeneous mixture and grinding or comminution of the mixture to one relatively small particle size, i.e. a particle size of 100 mesh screen size. The grinding of the mixture especially the hydrocolloids on a very small particle size is the effect of the delayed

Active ingredient release is not detrimental and exercises on the contrary have a positive effect on it. In certain circumstances, conventional pharmaceutical techniques can be used such as clumping, wet granulating or extruding required to ensure the correct filling weight in the capsule or to make the tablet. It is However, it is necessary that the hydrocolloids not be incorporated into moist granules in order to avoid difficulties later to avoid hydration in contact with gastric fluid. For the production of capsules the mixture is expediently reduced to a fine particle size crushed and the capsule completely filled.

For the production of tablets, the ingredients are preferably granulated and then pressed into tablets. The tablets can be produced using conventional tableting machines. The tablets should however, they cannot be compressed to such a hardness that they are not capable of a specific gravity of less than 1 in contact with gastric juice. As a result, the tablet hardness is a critical factor and depends on the initial density of the formulation and the size of the tablet.

The following examples further illustrate the invention.

example 1

Formulation A : Hydrodynamically Balanced Delayed Release Capsules are made from the following ingredients:

Ingredient mg / capsule

1 2

N -dl-Seryl-N - (2,3,4-trihydroxybenzyl) -

hydrazine hydrochloride 29.63

L-Dopa '102.00

Monocalcium phosphate 24.37

Hydrogenated cottonseed oil 30.00

Hydroxypropyl cellulose 4.00

Mannitol 20.00

Hydroxypropyl methyl cellulose 115.00

Talk 15.00

340.00

The N ¹ -dl-seryl-N ² - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride, L-dopa, monocalcium phosphate and hydrogenated cottonseed oil were mixed and ground. This powdery mixture was granulated with hydroxypropyl cellulose dissolved in alcohol. Mannitol and hydroxypropylmethyl cellulose were mixed and ground and added to the granules. The resulting mixture was dried, mixed with the talc and filled into capsules.

-Wr-

Formulation B : Common capsules are made from the following ingredients:

ingredient mg / capsule 5
t ^ -dl-Seryl-N ² - (2,3,4-trihydroxy- benzyl) hydrazine hydrochloride 29.91 L-dopa 101.00 Polyvinyl pyrrolidone 1.00 ¹⁰ methylene chloride q. s. Microcrystalline cellulose 13.50 Talk 6.50 Magnesium stearate 6.50

152.41

1 2

The N -dl-Seryl-N - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride and L-dopa were mixed and ground. The powdery mixture was then mixed with polyvinylpyrrolidone granulated in methylene chloride. The granulate was dried and ground. The microcrystalline cellulose that The talc and the magnesium stearate were added, the mixture mixed thoroughly and filled into capsules.

Formulation C : Hydrodynamically Balanced Delayed Release Tablets are made from the following ingredients:

Ingredient mg / tablet

L-Dopa 204.00

Mannitol 23.00

Calcium carbonate 50.00

Carboxymethyl cellulose 50.00

Polyvinyl pyrrolidone 10.00

Hydroxypropyl methyl cellulose 110.00

1 2

N -dl-Seryl-N - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride 58.00

25th , 00 12th , 00 3 , 00

Fumaric acid talc magnesium stearate

545.00 5

L-dopa, mannitol, calcium carbonate and carboxymethyl cellulose were mixed with some of the polyvinylpyrrolidone granulated in alcohol. The hydroxypropyl methyl cellulose was added to the granules, which were then dried overnight became.

N -dl-Seryl-N ² - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride was mixed with fumaric acid and granulated with the remaining polyvinylpyrrolidone in alcohol. The granulate was dried.

1 2

The dopa granules and the N -dl-Seryl-N - (2,3,4-

trihydroxybenzyl) hydrazine hydrochloride granules mixed with talc and magnesium stearate. The mass became tablets with a hardness of 5-8 Strong-Cobb units pressed. Care was taken that the hardness did not exceed 12 Strong-Cobb units.

Example 2 25

In vitro studies

The hydrodynamically balanced preparation of Example 1 in capsule and tablet form as well as the usual one Capsules from Example 1 were as described below

1 2

on in vitro release of L-dopa and N -dl-seryl-N (2,3,4-trihydroxybenzyl) hydrazine hydrochloride examined.

Capsules and tablets were individually placed in 60 ml gastric juice and stirred at 20 revolutions / minute. the The liquid used had a pH of 1.2 (the normal pH of gastric juice). At certain time intervals were

Samples are taken and spectrophotometrically for L-Dopa and

1 2

N -dl-Seryl-N - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride examined.

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

10 formulation

Time
(Hours)

% release

L-dopa

Decarboxylase inhibitors

(hydrodynamically

weighed capsule) 0.50 37 40 1.00 63 65 2.00 94 95 B. (ordinary capsule) 0.25 102 89 C. (hydrodynamically from weighed tablet) 0.50 26th 32 1.00 80 91 2.00 105 107 In vivo studies

25th

The bioavailability of L-dopa after administration to humans either in common capsule (formulation B from Example 1) or hydrodynamically balanced capsule (formulation A from Example 1) with 100 ml L-Dopa each

1 2

30 and 25 mg of N -dl-Seryl-N - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride was decided.

Five male test persons were used for the determination. The preparations were afterwards with 100 ml of water administered during a nocturnal fasting period.

Blood samples were collected in heparinized tubes immediately prior to administration of the preparation,

five times during the first 2 hours after administration and then every hour for 9-10 hours.

The concentration of L-dopa in the blood was after a modified method of Spiegel und Tonchen (Clin. Chem. 16, 763).

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

Plasma L-dopa

2 χ (100 + 25) mg

Capsules

Usually in accordance with

4 χ (100 + 25) mg

Capsules

Usually invented according to

Peak concentration, µg / inl

0.97

2.6

Time to peak concentration 20 hours

1.1

2.9

2.6

Area under the curve, µg / hr / ml ~

3.2

2.0

10.1

The results for the blood plasma level were compared with a standard preparation. For the 2 χ (110 + 25) mg dosage, a difference was found between the inventive, -mässen and the usual formulation. The high peaks of L-Dopa originating from the usual capsules samples did not occur when the capsule according to the invention was administered. The peak time was delayed by 1.1 hours for ordinary capsules and 2.9 hours for the capsules according to the invention, which indicates a slower absorption rate.

At the higher dose [4 χ (100 + 25) mg] was the Plasma level / time concentration curve disproportionate

- LS- -

larger than that observed with the lower dose It was found that the dose was not tolerated with the usual capsule (stomach upset).

Claims (5)

bs "* 4604/7 claims 1. Hydrodynamically balanced pharmaceutical preparation with delayed release of active ingredients, characterized in that that it a) as the active ingredient L-Dopa and a decarboxylase inhibitor contains, wherein the ratio of L-dopa to decarboxylase inhibitor is about 3: 1 to about 10: 1, and b) about 5 to about 80% by weight of a hydrocolloid or a mixture of hydrocolloids; to about 60 wt -.% of a fatty substance or a mixture of fatty substances and up to 80 wt .-% of inert edible pharmaceutical auxiliary materials, said preparation being balanced hydrodynamically in capsule or tablet form, so that in contact with gastric fluid a total assumes a specific gravity of less than 1, so that it floats in the gastric fluid and remains in the stomach until essentially all active ingredients have been released. 2. Preparation according to claim 1, characterized in that that the decarboxylase inhibitor [N -dl-seryl-N - (2,3,4-trihydroxybenzyl) hydrazine hydrochloride] is and the 1 2 Ratio of L-Dopa to N -dl-Seryl-N - (2,3,4-trihydroxybenzyl) -hydrazine hydrochloride is about 5: 1 to about 3: 1. 3. Preparation according to claim 1, characterized in that it a) about 20-50% by weight L-dopa; b) about 4-10% by weight decarboxylase inhibitors; c) about 15-60% by weight hydrocolloid; m «ι DS 4604/7 d) up to about 30% by weight of fatty substances
and e) 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 claims 1-3, characterized in that that the hydrocolloid methyl cellulose, hydroxypropyl cellulose, Hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose or carboxypolymethylene or a mixture of such substances. 5. Preparation according to claims 1-3, characterized in that the hydrocolloid is hydroxypropyl methylcellulose is.