Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients

Definitions

• LDOPA L-3,4-dihydroxyphenylalamine
• the patients in most instances, must consume inordinately large quantities of the drug, i.e. on the average of from 3 to 8 grams daily.
• the quantities of LDOPA which must be consumed remain large even when other compounds, such as decarboxylase inhibitors are utilized to potentiate its action. It is therefore readily apparent that it is advantageous to incorporate large quantities of LDOPA into small convenient dosage forms so that the expense and inconvenience of administering many tablets or capsules each day is avoided. Due to the low bulk density and other physical characteristics of LDOPA, No.
• tablets of suitable size containing large amounts of L- DOPA could be formulated in accordance with the present invention by the wet granulation method utilizing as a binder a combination of amylopectin and polyvinylpyrrolidone.
• pharmaceutically excellent tablets containing large quantities of LDOPA e.g., 500 mg. or more are prepared by the wet granulation method utilizing a formulation comprising LDOPA and no more than 10% of the total tablet weight of a binder composed of amylopectin and polyvinylpyrrolidone.
• tablets containing LDOPA are prepared by the conventioal wet granulation method utilizing a binder material comprising amylopectin and polyvinylpyrrolidone.
• the LDOPA tablets of the present invention contain from 1% to 10% of the total tablet weight of binders and not more than 35% by weight inert ingredients.
• the tablets contain from about 1% to about 2% by weight binders based on the total tablet weight and between about 20% and 25% by Weight of a tablet disintegrant, between from about 1% to about 2% lubricants and the remainder other inert ingredients, such as dyes, and the like.
• LDOPA tablets of the present invention may contain up to 750 mg. It is preferred, however, to produce tablets according to the invention which contain either 250 mg. of 500 mg. of L- DOPA. In any event, LDOPA constitutes from about 60 to about and preferably from about 70% to about 73% by weight of the tablets of the present invention.
• the binder component of the novel LDOPA tablets of the present invention is composed of amylopectin, polyvinylpyrrolidone or mixtures thereof. Although either of these two substances will form an acceptable tablet without the other, it is preferred to have both components present. In the preferred composition the ratio of the two components may vary from 1:9 to 9:1. It is, however, especially preferred to use equal quantities of each.
• the amylopectin utilized in the practice of the present invention is a soluble fraction derived from commercial starches. It has a molecular weight of from one million to about ten million with a preferred mean molecular weight of one million.
• amylopectin is a White powder, water dispersible and of sufficiently low viscosity that a 20% weight to volume dispersion in water is pourable at room temperature.
• the polyvinylpyrrolidone utilized in the practice of the present invention meets the specifications of the National Formulary.
• a suitable commercial product is Plasdone K by the GAP Corporation.
• the tablets of the present invention contain from 0.5 to 3.0% by weight preferably from 1% to 2% by weight of a tabletting lubricant conventional in the art.
• the lubricant is comprised of talc and a substance such as stearic acid, calcium stearate, magnesium stearate or a commercial product consisting of diand tri-glycerides of certain fatty acids such as stearic and palmitic acid, e.g. Sterotex, by Capital City Products, Inc. Of these, magnesium stearate is preferred. While the two lubricant components may generally be used in a ratio of from 1:9 to 9:1 it is preferred to utilize equal quantities of each.
• the function of the talc lubricant component is to promote the fiow of the granulation while at the same time preventing picking when the tablets are removed from the molds.
• the second lubricant component functions to improve the overall flow properties and mold release of the granulation.
• the L-DOPA tablets of the present invention contain a tablet disintegrant.
• This class of substance includes, for example, cellulosic products such as methyl cellulose, hydroxy ethyl cellulose and the like, certain commercially available chemically modified starch fractions such as Sta-Rx 1500 by A. E. Staley and Company, and the like. It is preferred to utilize a disintegrant which possesses some tabletting properties.
• a preferred example of such a substance is microcrystalline cellulose such as that commercially available under the trademark Avicel by the American Viscose Corporation.
• the tablets of the present invention contain from about 1% to about 40% by weight of the disintegrating agent, preferably from about 20% to about 25% by weight.
• the process of tablet making by wet granulation is well known in the pharmaceutical arts. It involves basically the intimate blending of the active ingredient and some or all of the inert ingredients with a suitable solvent, such as water, alcohol, methylene chloride, and the like. The granulation thus formed is then dried, such as, by placing it in shallow lined pans in an oven. The resulting dry mixture, which may be intimately mixed with other tabletting ingredients, is then compressed into tablets.
• a suitable solvent such as water, alcohol, methylene chloride, and the like.
• the granulation thus formed is then dried, such as, by placing it in shallow lined pans in an oven.
• the resulting dry mixture which may be intimately mixed with other tabletting ingredients, is then compressed into tablets.
• tablets containing L-DOPA can be prepared, utilizing the ingredients set forth herein, that are stable, pharmaceutically elegant, and approximately twenty percent smaller than tablets prepared by other tabletting methods known in the art.
• the small tablet is important in the treatment of Parkinsonism as the disease strikes many elderly individuals who ordinarily have some difficulty in swallowing a large tablet.
• the tablets prepared according to the present invention are free from problems such as capping and poor compressibility inherent in other methods of preparation and methods utilizing other binder materials.
• the tablets of the present invention have been found to possess a dissolution rate in the body not only far superior to tablets made by other methods and containing other binders as described herein, but superior to standard gelatin capsules.
• the relative dissolution of the tablet or capsule is critical as it is theorized that high initial blood levels of L-DOPA are required for the drug to be effective. This theory is based on the fact that the drug is metabolized by enzymes in the blood and the drug must be intact to 4 pass the blood brain barrier where its therapeutic action is exerted. Therefore, the L-DOPA tablets of the present invention, due to their rapid dissolution are superior to L-DOPA tablets and capsules made by other methods and with other inert ingredients.
• EXAMPLE 1 One thousand tablets containing 250 mg. L-DOPA were produced as follows. Using a 1% excess in accordance with standard pharmaceutical practices 252.5 grams of L-DOPA were passed through a suitable comminuting mill and admixed with a certified coloring agent. The resulting powder was granulated with an aqueous suspension prepared by suspending 2.5 grams amylopectin and 2.5 grams polyvinylpyrrolidone in 12.5 ml. distilled water. The resulting wet granulation was dried on lined trays at 120 F. The dry powder was milled on a suitable milling machine utilizing a No. 12 screen and medium speed. The granulation was then blended with 84.7 grams microcrystalline cellulose and some additional coloring material.
• a preblended lubricant comprising 2.5 grams talc and 2.5 grams magnesium stearate was intimately admixed with the granulation and tablets having a diameter of 9.6 mm., a thickness of approximately 3.8 mm., and a weight of approximately 348 mg. were produced therefrom on suitable conventional tabletting machinery,
• EXAMPLE 2 One thousand tablets containing 500 mg. L-DOPA were produced as follows. .Using a 1% excess in accordance with standard pharmaceutical practices 505.0 grams of L-DOPA were passed through a suitable comminuting mill and admixed with a certified coloring agent. The resulting powder was granulated with an aqueous suspension prepared by suspending 5.0 grams amylopectin and 5.0 grams polyvinylpyrrolidone in 25.0 ml. distilled water. The resulting wet granulation was dried on lined trays at 120 F. The dry powder was milled on a suitable milling machine utilizing a No. 12 screen and medium speed. The granulation was then blended with 169.5 grams microcrystalline cellulose and some additional coloring material.
• a preblended lubricant comprising 5.0 grams talc and 5 .0 grams magnesium stearate was intimately admixed with the granulation and tablets having a diameter of 18 mm., a thickness of approximately 6 mm., and a weight of approximately 695 mg. were produced therefrom on suitable conventional tabletting machinery.
• a method of producing a stable tablet containing L-DOPA which comprises wet granulating drying and compressing into tablets a formulation comprising:
• binder comprises from about 10% to about by weight amylopectin and from about 90% to about 10% by weight polyvinylpyrrolidone.
• said binder comprises equal quantities of amylopectin and polyvinylpyrrolidone.
• a pharmaceutical tablet compresed from a direct wet granulation comprising.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=21936793

Family Applications (1)

Country Status (8)

Cited By (19)

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Family Cites Families (3)

• 1970
  • 1970-06-10 US US45244A patent/US3632778A/en not_active Expired - Lifetime
• 1971
  • 1971-06-03 NL NL7107643A patent/NL7107643A/xx unknown
  • 1971-06-08 DE DE19712128461 patent/DE2128461A1/de active Pending
  • 1971-06-09 BE BE768269A patent/BE768269A/xx unknown
  • 1971-06-09 DK DK280271AA patent/DK126236B/da unknown
  • 1971-06-09 GB GB1296505D patent/GB1296505A/en not_active Expired
  • 1971-06-09 ES ES392066A patent/ES392066A1/es not_active Expired
  • 1971-06-09 FR FR7120861A patent/FR2100742B1/fr not_active Expired

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