JPH0341447B2 - - Google Patents

Description

[Detailed description of the invention]

L-dopa, (-)-3-(3,4-dihydroxyphenyl)-L-alanine, is a known compound, which is associated with Parkinson's syndrome (Parkinsonian syndrome).
sonism). Furthermore, many of the decarboxylase inhibitors are known compounds. For example, N ¹ -dl-seryl-N ² -(2,
3,4-trihydroxybenzyl)-hydrazine hydrochloride is disclosed in Hegedus et al., US Pat. No. 3,178,476, and is effective as a decarboxylase inhibitor. In the treatment of Parkinson's syndrome, L-dopa and the specific decarboxylase inhibitor ^N1 -dl-
The use of seryl-N ² -(2,3,4-trihydroxybenzyl)-hydrazine hydrochloride in combination is disclosed in the US patent by Bartholini et al.
Described in No. 3557292. The use of L-dopa alone in rapidly disintegrating tablets is disclosed in US Pat. No. 3,632,778 to Sheth et al. Traditionally, large doses of L-dopa have been used to treat Parkinson's syndrome, because much of the administered L-dopa does not penetrate the blood-brain barrier, where its therapeutic activity is exploited. )
This is because it is metabolized by an enzyme, ie, decarboxylase, in the stomach or blood before passing through the body. When L-dopa is administered in combination with known decarboxylase inhibitors, the amount of orally administered L-dopa that crosses the blood-brain barrier intact can be substantially increased. , ie the antiparkinsonian activity is "enhanced". However, conventional capsule and tablet compositions containing L-dopa and decarboxylase inhibitors initially show high blood levels of L-dopa, but the tendency is to obtain when L-dopa is administered alone. It does not sustain blood concentrations above the initial peak as well. Conventional controlled release compositions containing L-dopa do not provide the desired therapeutic response, ie, high blood levels of L-dopa. According to the present invention, a hydrodynamically balanced controlled release composition comprising both L-dopa and a decarboxylase inhibitor provides superior blood levels of L-dopa. It was found that giving. More specifically, L-
Oral administration of hydrodynamically equilibrated, controlled release capsules or tablets containing both DOPA and a decarboxylase inhibitor allows for the administration of either conventional capsules or tablets containing both L-Dopa and decarboxylase. or a conventional controlled release capsule or tablet containing either L-dopa alone or a combination of L-dopa and a decarboxylase inhibitor. The result is not only a significant increase but also a more sustained blood concentration of L-dopa. Oral administration of L-dopa and decarboxylase inhibitors from controlled release compositions is improved by hydrodynamically balanced capsule or tablet dosage forms. In the controlled release compositions used in the practice of this invention, the dosage form, either a capsule or a tablet, remains suspended and floats freely in the gastric juices for an extended period of time, during which time Substantially all of the active ingredients contained in the drug are released into the gastric juices. Compositions have been reported in the art that remain suspended in the gastric juices during which substantially all of the drug is released. For example, US Patent No. 4126672; US Patent No. 4140755;
No. 4,167,558 describes compositions for the preparation of controlled release capsules and tablets for oral administration. Capsules or tablets are hydrodynamically equilibrated to have a bulk density (specific gravity) of less than 1 on contact with gastric fluids and thus remain suspended in gastric fluids with a specific gravity between 1.004 and 1.010. Probably. These controlled release compositions are mixtures of the active ingredient and one or more hydrophilic hydrocolloids. When this controlled release capsule or tablet is taken orally, the shell of the capsule
Or the tablet coating, if present, dissolves and the composition comes into contact with gastric fluids. The outermost hydrocolloid hydrates to effectively form an outer barrier, somewhat expanding the capsule or tablet and preventing water penetration.
The increased bulk in this dosage form, and the central void that remains dry in the capsule or tablet as a result of the above-mentioned barriers, combine to create buoyancy. A flexible gel-like substance is formed which retains a bulk density of less than unity. As the hydrated outermost layer gradually dissolves, L-dopa and decarboxylase inhibitor are gradually released from it by diffusion and/or erosion. Subsequently, a newly hydrated outer layer develops from the newly exposed hydrocolloid, thus keeping the barrier intact. This process is repeated until all the drug is dissolved, with the drug remaining buoyant in the gastric fluid. The remaining matrix that still remains buoyant in the gastric fluid is gradually dispersed or eliminated. The release patterns and resulting blood concentrations achieved with these controlled release compositions have advantages compared to conventional controlled release drugs. A decarboxylase inhibitor has the effect of suppressing the activity of decarboxylase, thus increasing the concentration of administered L-dopa in plasma. Many such decarboxylase inhibitors are known. These known decarboxylase inhibitors suitable for use in these hydrodynamically balanced controlled release compositions include: ^aN1 -dl-seryl- ^N2- (2 , 3,4-trihydroxybenzyl)-hydrazine hydrochloride, b β-(3,4-dihydroxyphenyl)-α-
hydrazino-α-methylpropionic acid, cm-hydroxybenzylhydrazine, and d α-methyldopa. ^N1 -dl-seryl- ^N2- (2,3,4-trihydroxybenzyl)-hydrazine hydrochloride is a preferred decarboxylase inhibitor of the present invention. Hydrocolloids suitable for use in these controlled release compositions include one or more natural, semi-synthetic or fully synthetic anionic or preferably non-ionic hydrophilic gums, modified cellulosic substances or proteinaceous substances such as gum arabic, gum tragacanth, locust bean gum, guar gum, gum india,
Agar, pectin, carrageen, soluble and insoluble alginic hydrochloride, methylcellulose, sodium carboxymethylcellulose, carboxypolymethylene (Carbopol-Cabot Corporation), gelatin, casein, zein, bentonite,
Includes Veegum (RTVanderbilt Co.).
A preferred hydrocolloid is hydroxypropyl methylcellulose. The use of such materials in pharmaceutical compounds is also known in the art. For example, U.S. Pat. No. 3,555,151 to Kaplan et al.
The use of such hydrocolloids in release antacid formulations is indicated. The hydrocolloid used is in acidic medium, i.e. 0.1N
It must be hydrated in gastric fluid with a PH value corresponding to hydrochloric acid (PH value of approximately 1.2). Furthermore, although the initial bulk specific gravity of certain compositions contained in the controlled release preparations of the present invention, particularly tablets, may be greater than or equal to 1, the bulk specific gravity of the composition may be greater than 1 upon contact with gastric fluids. It is essential that it has a low bulk specific gravity and is hydrodynamically balanced to float. There are many ways in which the rate of drug release from a controlled composition can be adjusted. First, the release rate can be influenced by choosing a particular hydrocolloid or mixture of hydrocolloids, e.g. hydroxypropyl methylcellulose with a high viscosity hydrocolloid, e.g. 4000 cps, or a low viscosity hydrocolloid, e.g. 10 cps. It hydrates more gradually compared to hydroxypropyl methylcellulose and retains the state of soft material for a longer time. Additionally, edible, pharmaceutically inert fatty substances having a specific gravity of less than 1 can be added to the composition to reduce the hydrophilic character of the composition and thus increase its buoyancy. Examples of such materials include refined grades of beeswax; fatty acids; long chain fatty alcohols such as cetyl alcohol, stearyl alcohol; esters of fatty acids such as glyceryl monostearate; hydrogenated castor oil, and the like. Also included in these controlled release compositions are additional edible, non-toxic ingredients recognized in the field of pharmaceutical formulation, such as excipients, i.e. buffers, preservatives,
Stabilizers, tablet lubricants, etc. can be added. The amount of hydrocolloid component present in these controlled release compositions ranges widely, i.e. from about 5 to about
It can be varied within a range of 80% by weight. The amount of hydrocolloid can vary depending on the amount and properties of the active ingredient and the inert pharmaceutical auxiliary used. Generally, the amount of hydrocolloid will be between about 15 and about 60% by weight. When a fatty substance or mixture of fatty substances is present in the controlled release composition, such substance constitutes up to about 60% by weight of the total composition. in general,
If fatty materials are included in the composition, such materials are present in an amount of about 5% to about 30% by weight. The amount of fatty substance is controlled by the amount and physical properties of both the active ingredient and the hydrocolloid with the aim of obtaining a hydrodynamically balanced composition, i.e. a formulation that obtains a bulk density of less than 1 in the gastric fluid. be done. The edible inert pharmaceutical auxiliary substances that may be present in the controlled release composition will also vary according to the amounts and physical characteristics of the other ingredients. Materials that themselves have a bulk density of less than 1, such as ethylcellulose or other fillers, will increase the buoyancy of the composition. Small amounts of carbon dioxide generators can be used in the composition to increase buoyancy if the dosage is not very dense. As such materials generate carbon dioxide, the foam becomes trapped in the hydrated outer layer, thus increasing the buoyancy of the formulation. More importantly, inert pharmaceutical auxiliaries can be selected to modify the rate of release of the active ingredient from the composition. for example,
Soluble excipients, such as lactose, mannitol, etc., will increase the rate of release, while insoluble excipients, such as dicalcium phosphate, china clay, etc., will decrease the rate of release. If such pharmaceutical auxiliary substances are included in the formulation, they may be present up to about 80% by weight of the final formulation. Generally, such conventional pharmaceutical adjuvants are present in an amount of about 5% to about 60% by weight of the formulation. The inclusion and selection of such materials is considered to be within the skill of the art. Hydrodynamically balanced controlled release capsule or tablet compositions can contain from about 10 to about 70%, preferably from about 20 to about 50%, by weight L-dopa. The amount of decarboxylase inhibitor in a hydrodynamically balanced controlled release capsule or tablet composition will depend on the particular inhibitor used. An effective range is about 2 to about 20% by weight, preferably about 4 to about 10% by weight. A preferred decarboxylase inhibitor in the practice of this invention is ^N1 -dl-seryl- ^N2- (2,3,4-trihydroxybenzyl)-hydrazine hydrochloride.
^N1 -dl-ceryl- ^N2 in hydrodynamically equilibrated controlled release capsule or tablet compositions
The amount of -(2,3,4-trihydroxybenzyl)-hydrazine hydrochloride can range from about 3 to about 15% by weight, preferably from about 4 to about 10% by weight. Factors that influence the amount of active ingredient present in these controlled release compositions include the amount required for sufficient therapeutic dosage, the bulk density of the active ingredient, the hydrophilic or hydrophobic properties of the active ingredient, This includes things like stability. These properties are known and readily ascertained by those skilled in the art. The ratio of L-dopa to decarboxylase inhibitor can vary from about 10 to about 3 parts of L-dopa for each part by weight of decarboxylase inhibitor. Also, L-dopa vs. N ¹ −dl-seryl-N ² −
The ratio of (2,3,4-trihydroxybenzyl)-hydrazine hydrochloride can vary considerably. The ratio is L for each 1 part by weight of decarboxylase inhibitor.
- from about 5 to about 3 parts by weight as dopa. A preferred ratio is about 4:1. Hydrodynamically balanced controlled release compositions are prepared by methods well established in the art. In many cases, all that is required is to mix all the ingredients thoroughly to form a homogeneous mixture, and to have a relatively fine particle size, i.e. all particles are 100%
It is only necessary to knead or grind it so that it passes through a mesh sieve. Grinding the mixture, especially the hydrocolloid, to a very fine particle size does not impair the controlled release mechanism and in fact has a positive effect. Under certain circumstances, conventional pharmaceutical methods of sludging, wet granulation or extrusion may be required to achieve a suitable fill weight in capsules or to prepare tablets. . However, the hydrocolloid should not be incorporated into any granules to avoid difficulties due to subsequent hydration upon contact with gastric fluids. For capsules, it is preferred to mill the mixture to a fine particle size and completely fill the capsule. For tablets, it is preferred to granulate the ingredients and then compress the composition into a tablet. Tablets are manufactured on conventional tabletting equipment. However, the tablets should not be compressed so hard that upon contact with gastric fluids they will no longer have a bulk density of less than 1. Therefore, the hardness of the tablet is critical and depends on the initial density of the formulation and the size of the tablet. The effective dosage of the composition of the present invention is, for example, generally 4 to 8 capsules of Formulation A in Example 1 below.
It is preferable to administer the drug in divided doses. The following examples further illustrate the invention. Example 1 Formulation A Hydrodynamically equilibrated controlled release capsules were prepared from the following composition: mg ingredient /capsule ^N1 -dl-seryl- ^N2- (2,3, 4-trihydroxybenzyl)-hydrazine hydrochloride 29.63 L-Dopa 102.00 Calcium phosphate 24.37 Hydrogenated cottonseed oil 30.00 Hydroxypropylcellulose 4.00 Mannitol 20.00 Hydroxypropylmethylcellulose 115.00 Talc 15.00 340.00 N ¹ −dl-Ceryl-N ² − (2,3,4-trihydroxybenzyl)-hydrazine hydrochloride, L-dopa, calcium phosphate and hydrogenated cottonseed oil were mixed and ground. This powder mixture was then granulated with hydroxypropyl cellulose dissolved in alcohol. Mannitol and hydroxypropyl methylcellulose were then mixed, ground, and this powder mixture was added to the granules. The resulting granular mixture was dried, mixed with talc lubricant, and filled into capsules. Formulation B Conventional capsules were prepared from the following composition: Ingredients mg/capsule N ¹ -dl-seryl-N ² -(2,3,4-trihydroxybenzyl)-hydrazine hydrochloride 29.91 L-dopa 101.00 Polyvinylpyrrolidone 1.00 Methylene chloride qs Microcrystalline cellulose 13.50 Talc 6.50 Magnesium stearate 6.50 152.41 N ¹ -dl-Ceryl-N ² -(2,3,4-trihydroxybenzyl)-hydrazine hydrochloride and L-Dopa mixed and crushed. This powder mixture was then granulated with polyvinylpyrrolidone in methylene chloride. The granules were dried and the granules were ground. Microcrystalline cellulose, talc and magnesium stearate were added. This composition was mixed thoroughly and poured into capsules. Formulation C A hydrodynamically balanced, controlled release tablet was prepared from the following composition: Ingredients mg/tablet L-Dopa 204.00 Mannitol 23.00 Calcium Carbonate 50.00 Carboxymethylcellulose 50.00 Polyvinylpyrrolidone 10.00 Hydroxypropylmethylcellulose 110.00N ¹ -dl-Ceryl-N ² -(2,3,4-trihydroxybenzyl)-hydrazine hydrochloride 58.00 Fumaric acid 25.00 Talc 12.00 Magnesium stearate 3.00 545.00 L-dopa, mannitol, calcium carbonate and carboxymethylcellulose in alcohol It was granulated with a portion of polyvinylpyrrolidone. Hydroxypropyl methylcellulose was added to the granules and then dried overnight. ^N1 -dl-seryl- ^N2- (2,3,4-trihydroxybenzyl)-hydrazine hydrochloride was mixed with fumaric acid and granulated with the remaining polyvinylpyrrolidone in alcohol. The granules were then dried. L-dopa granules and N ¹ -dl-ceryl-N ² -
(2,3,4-trihydroxybenzyl)-hydrazine hydrochloride granules were mixed with talc and magnesium stearate. Each quantitative amount is 1/
Compacted on a 2 S.C. punch to a hardness of 5-8 SCU. Hardness should not exceed 12 SCU. Example 2 In vitro studies The hydrodynamically equilibrated controlled release compositions of Example 1 in the capsule and tablet forms and in the conventional capsules of Example 1 were tested in vitro with L-dopa. and N ¹ -dl-seryl-N ² -(2,3,
The release of 4-trihydroxybenzyl)-hydrazine hydrochloride was evaluated as follows. Capsules and tablets were placed individually in 60 ml of gastric fluid in a bottle and spun at 20 rpm. The liquid used had a PH value of 1.2 (normal PH value for gastric fluid). After a certain period of time, the sample is removed and L-dopa and
^N1 -dl-seryl- ^N2- (2,3,4-trihydroxybenzyl)-hydrazine hydrochloride was analyzed spectrophotometrically. The table below shows the in vitro release results. The letters under the heading "Composition" correspond to the letters used for the particular composition in Example 1.

Table: In Vivo Tests in Humans: Conventional capsules (Composition B of Example 1) or Hydrodynamically Equilibrated Controlled Release Capsules (Composition A of Example 1) The bioavailability of L-dopa can be improved by administering either
At that time, each capsule contained L-dopa.
100 mg and N ¹ -dl-seryl-N ² -(2,3,4-
Contains 25 mg of trihydroxybenzyl)-hydrazine. The relative bioavailability of the composition was determined using five male subjects. After an overnight fast, the composition was administered with 100 ml of water. Subject blood samples were collected in heparinized tubes immediately before dosing, five times during the first two hours after dosing, and then every hour for 9-10 hours. Blood L-dopa concentration was measured by Spiegel and Tonchen.
The method was improved and measured. (Spiegel, HE and
Tonchen, AE [1970]): Semiautomated
method for measurement of dopa in plasma
Clin.Chem.16, 763. Samples were compared to standard blood plasma. The results are as follows:

[Table] Time to, area under the time curve 3.2 2.0 − 10.1
μg/hour/ml ⁻¹
Blood plasma concentration data were compared to standard preparations. For a dosing rate of 2×(100+25) mg, there was a difference between the controlled release and conventional compositions. The high L-dopa concentration peaks in the blood that occur with conventional capsules did not occur with the hydrodynamically balanced controlled release capsules. The time it takes to reach the peak is different from that of regular capsules.
1.1 hours, while the controlled release capsules were slower at 2.9 hours, indicating slower absorption. At high dosage [4 x (100 + 25) mg], the area under the plasma volume/time concentration curve is 2 x (100 + 25) mg
The condition was significantly greater than that observed after administration of the drug. Area under the curve for (200 + 25) mg controlled release capsules 2 ± = 0.2 μg/hr/ml ^-1 (400 + 100)
Area under the curve of mg controlled release capsules 10±
For 1.5 μg/hr/ml ⁻¹ regular capsules, patients could not tolerate the 400 mg dosage (eg upset stomach).

Claims (1)

[Scope of Claims] 1 a. L-Dopa as an active ingredient in an amount effective to provide a desired concentration of L-Dopa in the blood, and an amount effective relative to the amount of L-Dopa in the composition. decarboxylase inhibitor, and the weight ratio of L-dopa to decarboxylase inhibitor is 3:1 to 10:
1 and b in weight percent based on the total weight of the composition, from 5 to 80% of a hydrocolloid or a mixture of hydrocolloids; up to 60% of a fatty substance or a mixture of fatty substances, and 80% an edible inert pharmaceutical auxiliary substance of up to or the tablet acquires and maintains a bulk density of less than 1, thereby becoming suspended in the gastric juices and remaining suspended in the gastric juices of the stomach until substantially all the active ingredient contained therein has been released. CLAIMS 1. A hydrodynamically equilibrated controlled release composition characterized in that retention is maintained. 2 The decarboxylase inhibitor is N ¹ −dl-seryl-N ² −
(2,3,4-trihydroxybenzyl)-hydrazine hydrochloride and L-dopa versus N1 ^- dl
2. A composition according to claim 1, wherein the ratio of -seryl- ^N2- (2,3,4-trihydroxybenzyl)-hydrazine is in the range of 5:1 to 3:1. 3. In weight % based on the total weight of the composition: a 20-50% L-dopa; b 4-10% decarboxylase inhibitor; c 15-60% hydrocolloid; d up to 30% a fatty substance or a mixture of fatty substances, and e 5% to 60% of an edible inert pharmaceutical auxiliary substance, and the ratio of L-dopa to decarboxylase inhibitor is 3:1 to 5: 1. The composition according to claim 1, which is 4 The hydrocolloid or mixture of hydrocolloids is methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,
The composition according to any one of claims 1 to 4, which is selected from the group consisting of sodium carboxymethyl cellulose and carboxypolymethylene. 5. The composition according to any one of claims 1 to 4, wherein the hydroxypropyl is hydroxypropyl methylcellulose.