KR20030056474A - Manufacturing Method & Formulation of Controlled-release Carbidopa/Levodopa Tablets - Google Patents

Abstract

PURPOSE: A new sustained release tablet composition as a matrix type or single drug administration system containing carbidopa and levodopa as an active component is provided. The sustained release tablet composition exhibits an elution rate of about 60% within 1 hour and 90% or more within 2 hour after administration. Therefore, it uniformly and slowly releases an active ingredient. CONSTITUTION: Carbidopa and levodopa are blended with 0.5 to 5% by weight of Eudragit RL-30D or Eudragit RL-100 and the mixture is added with purified water, dried at 50deg.C in a fluidized bed drier for 30min, mixed with a lubricating agent and tabletted. For an example, 16.7% by weight of carbidopa(anhydride) USP is blended with levodopa KP, 13.0% by weight of lactose, 1.6% by weight of Eudragit RL-30D, 1.0% by weight of talc and 1.0% by weight of magnesium stearate and dried at 50deg.C for 30min.

Description

Composition of Carbidopa / Levodopa sustained-release tablet and preparation method thereof {Manufacturing Method & Formulation of Controlled-release Carbidopa / Levodopa Tablets}

The present invention relates to a mixed preparation for the simultaneous release of carbidopa and levodopa used in the treatment of Parkinson's syndrome, and relates to a composition of the sustained-release preparation for minimizing side effects and insufficiency which are commonly caused and a method of preparing the same.

Carbidopa is disclosed in U.S. Pat. Chem. 6. A therapeutic agent for Parkinson's syndrome known from 101 (1963) and the like, and levodopa is also disclosed in US Pat. Nos. 3253023, 3405159 or Chem. Pharm. 10, 693 (1962) and the like is a drug for Parkinson's syndrome.

Parkinson's syndrome has been treated with levodopa alone, without the use of carbidopa. A large amount of levodopa was used to treat Parkinson's syndrome, causing severe side effects such as vomiting. Attempts have been made to release levodopa in sustained release form to mitigate these side effects, but it has not proved that sustained release formulations are advantageous over standard formulations. [Eckstein et al., The Lancet, page 431 (1973)].

The combination administration of carbidopa / levodopa (product name: Cinemet, Sinemet) serves to reduce the side effects of levodopa alone administration. Carbidopa does not penetrate the cerebrovascular barrier and is a peripheral decarboxylase inhibitor that does not exhibit pharmacological effects when administered alone at high doses. Increases the amount of levodopa that can be converted to dopamine in the body and reduces the peripheral side effects of dopamine. In combination with levodopa in the treatment of Parkinson's disease, the dose of levodopa can be reduced, the response appears more quickly and the side effects are alleviated.

"Wearing-off" and "on-off" phenomena have emerged as major problems in long-term treatment of Parkinson's syndrome. This phenomenon translates from motility to loss of motility, which can occur several times a day. Clinical symptoms of "on-off" include the unpredictable fast swing phenomenon from motility to loss of motility. The "on" cycle is usually associated with the fact that the levodopa concentration in the plasma is high or increased and often leads to obvious abnormal involuntary movements (dose-related movement disorders), whereas the "off" cycle Although not certain, it is usually associated with the fact that the levodopa concentration in plasma is low or lower. Sustained release formulations can also help prevent "wear-off" and "on-off" phenomena if the occurrence of such clinical variation is facilitated by variations in levodopa concentration.

The invention is a sustained release formulation of a carbidopa / levodopa mixture designed to eliminate or at least alleviate the problems and side effects of high or low levodopa concentrations in the treatment of standard blend formulations. It may also be more convenient for many patients who need to administer once or more.

The novel sustained release tablets of carbidopa / levodopa of the present invention are matrix type or single drug administration systems containing carbidopa and levodopa as active ingredients. The system consists of two types of drugs, which are uniformly dispersed in a single polymer, ie a water soluble polymer and a less water soluble vehicle.

The novel dosage system acts to slow release of both drug components, depending on the particular polymer vehicle, by corrosion or by diffusion-controlling mechanisms. Drug release due to corrosion is caused by the slow disintegration of the tablet surface. Drug release by diffusion occurs through the space between the macromolecular polymer bonds or through a porous network filled with an aqueous medium. Optimum corrosion or diffusion conditions can be achieved by controlling the degree of swelling, polymer type, polymer proportion, and other parameters. The advantage of this system is that it maintains the same sustained release even when taken in any part with a simple process and uniform distribution of ingredients. The polymer vehicle used hydroxyethyl cellulose as the water soluble polymer or polymethyl methacrylate-based Eudragit RL-30D or RL-100 (trade name of the German Rom company) as the less water soluble polymer.

1 is a graph showing the levodopa dissolution rate in the sustained-release tablet according to the present invention,

2 is a graph showing carbidopa dissolution rate in the sustained-release tablet according to the present invention.

The novel sustained-release tablet of carbidopa / levodopa of the present invention has the following configuration.

1) After mixing carbidopa and levodopa with lactose, add 0.5-5% by weight of Eudragit RL-30D or Eudragit RL-100 and purified water, and combine them in a fluid bed drier at a temperature of 50 ° C. Carbidopa / levodopa sustained-release tablets prepared by drying for a minute and then sieving, followed by mixing and tableting with a lubricant;

2) After mixing carbidopa and levodopa with 0.5-5% by weight of lactose and hydroxyethyl cellulose,

It is a carbidopa / levodopa sustained-release tablet prepared by adding purified water to the mixed mixture, drying it to a loss of 2% or less at a temperature of 50 ° C. in a fluidized bed dryer, and then mixing and tableting a lubricant after sizing.

The method for producing a novel sustained release tablet of carbidopa / levodopa of the present invention is as follows.

After mixing the active ingredients with lactose, add 0.5 ~ 5% by weight of Eudragit RL-30D or RL-100 and an appropriate amount of purified water, combine them in a fluidized bed dryer at 50 ° C for 30 minutes, and after sizing, 0.5 to 5% by weight of hydroxyethyl cellulose is used as a sustained-release agent, or all of the active ingredients and lactose are mixed together with an appropriate amount of purified water and then dried in the same manner as before. It is manufactured simply by sizing and tableting. Eudragit RL-30D is a polymethyl methacrylate family, and Eudragit RL-100 is dispersed in an aqueous solution. This is a water insoluble but permeable water excipient, which allows water to penetrate into the pores between the matrix to diffuse the drug and elute, depending on the type of Eudragit, gastric, enteric, water soluble, sustained release, soluble, suspension This characteristic is very different. Hydroxyethyl cellulose used as another sustained-release agent is characterized by the formation of a hydrogel when in contact with water, slowly swelling and then eroding and disintegrating, so that the drug slowly elutes.

As the component content present in the novel formulations of the invention, the corresponding amount of carbidopa to levodopa is 1: 4, and the polymer used as a sustained release agent cannot be zero. In addition, sustained release has a great effect on the absorption of the drug and should be properly adjusted so as not to be too delayed.

When the content of Eudragit RL-30D or RL-100 or hydroxyethyl cellulose is 0.5% by weight or less, the drug is eluted in a short time and does not serve as a sustained-release tablet. It can be a problem for absorption.

Sustained-release tablets according to the present invention are initially taken 200 mg (as levadopa) twice a day, and can be increased according to patient-specific dose control. In general, as a levadopa 400 ~ 1600mg per day is divided every 4 to 8 hours excluding sleep time.

Hereinafter, the present invention will be described with reference to specific examples.

Example 1

Composition water weight% Carbidopa (anhydride) USP levodopa KP milk sugar milk drudge RL-30D tal magnesium stearate 16.766.713.01.61.01.0 Sum 100.0

Method of preparation: After mixing the active ingredients and lactose, add Eudragit RL-30D and an appropriate amount of purified water, and combine for 30 minutes at 50 ℃ in a fluid bed dryer. After sizing, the remaining lubricant is mixed and compressed to prepare.

Example 2

Composition water weight% Carbidopa (anhydride) USP levodopa KP milk sugar hydroxyethyl cellulose tals magnesium stearate 16.766.713.51.11.30.7 Sum 100.0

Method of preparation: After mixing the active ingredients with lactose and hydroxyethyl cellulose, add an appropriate amount of purified water and combine them. Dry in a fluidized bed dryer at 50 ℃ to reduce the drying loss to 2% or less. After sizing, the remaining lubricant is mixed and compressed to prepare.

Comparative Example 1

Composition water weight% Carbidopa (anhydride) USP levodopa KP milk sugar PVP K-30 tal magnesium stearate 16.766.713.51.11.01.0 Sum 100.0

Preparation Method: As in Example 1, but using polyvinylpyrrolidone K-30 (PVP K-30) with an appropriate amount of an organic solvent, such as methylene chloride.

Comparative Example 2

Composition water weight% Carbidopa (anhydride) USP levodopa KP milk sugar milk drudge 2-100 tal magnesium stearate 16.766.713.01.61.01.0 Sum 100.0

Preparation Method: As in Example 1, but using Eudragit S-100 with an appropriate amount of organic solvents such as methylene chloride.

(Test example)

The dissolution test of carbidopa / levodopa sustained-release tablets prepared according to Examples 1 and 2 and Comparative Examples 1 and 2 was carried out in a device described in Method 2 of USP 24 with 750 ml of 0.1 N hydrochloric acid solution maintained at 37 ° C (in artificial gastric fluid). Applicable), while maintaining the speed of 50 rpm with stirring throughout the entire test. After 30, 60, 90 and 120 minutes the eluate was sampled and the released active ingredient was analyzed. Subsequently, sodium phosphate solution was added to make the intestinal solution, and after 30 minutes, the eluate was sampled and the active ingredient was analyzed. The measurement was analyzed at a wavelength of 280 mm using liquid chromatography.

The dissolution rate according to the dissolution test results is shown graphically in FIGS. 1 and 2.

From the dissolution test results of FIGS. 1 and 2, Examples 1 and 2 were eluted in the form of emission control more uniformly than Comparative Examples, but Comparative Example 1 was eluted mostly in a short time, and Comparative Example 2 was artificial until 2 hours. Elution is very delayed in gastric juice, and then rapidly eluted in artificial intestinal fluid.

Carbidopa / levodopa sustained-release tablet according to the present invention is a sustained-release tablet having a dissolution rate of about 60% after 1 hour of administration, and starting to show a dissolution rate of 90% or more by 2 hours. This, it can be seen that the invention is very useful commercially.

Claims (4)

After mixing carbidopa and levodopa with lactose, add 0.5-5% by weight of Eudragit RL-30D or Eudragit RL-100 and purified water and dry them for 30 minutes at 50 ° C in a fluid bed dryer. Carbidopa / levodopa sustained-release tablets prepared by mixing, tableting, and lubricating after formulation. Carbidopa and levodopa are mixed with 0.5 to 5% by weight of lactose and hydroxyethyl cellulose, and then purified water is added to the mixture, and the mixture is dried at a temperature of 50 DEG C in a fluidized bed dryer to reduce the drying loss to 2% or less. , Carbidopa / levodopa sustained-release tablet prepared by mixing and tableting the lubricant after formulation. After mixing carbidopa and levodopa with lactose, add 0.5-5% by weight of Eudragit RL-30D or Eudragit RL-100 and purified water and dry them for 30 minutes at 50 ° C in a fluid bed dryer. A method for producing carbidopa / levodopa sustained-release tablets, characterized in that, after formulation, the lubricant is mixed and tableted. Carbidopa and levodopa are mixed with 0.5 to 5% by weight of lactose and hydroxyethyl cellulose, and then purified water is added to the mixture, and the mixture is dried in a fluidized bed drier at a temperature of 50 ° C. to a drying loss of 2% or less. Method for producing carbidopa / levodopa sustained-release tablets, characterized in that after mixing, lubricating agent is mixed and tableted.