Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-04-26
2004-02-17
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S464000, C424S465000, C424S468000, C424S494000, C424S495000, C424S497000, C424S498000
Reexamination Certificate
active
06692769
ABSTRACT:
This application is the national phase under 35 U.S.C. § 371 of PCT International Application No. PCT/JP99/05834 which has an International filing date of Oct. 22, 1999, which designated the United States of America.
TECHNICAL FIELD
The present invention relates to sustained release particles for which, together with dissolution of a drug being effectively controlled, there is no occurrence of sticking during compression, and a preparation method therefor. In addition, the present invention also relates to a preparation method for tablets using said sustained release particles.
BACKGROUND ART
An example of a known preparation method of an oral sustained release preparation is a method in which a drug-containing core substance is coated with ethyl cellulose or other water-insoluble polymer. Although this preparation has high controllability of drug release and excellent moisture resistance, humidity resistance, wear resistance, storage stability and so forth, coatings consisting only of water-insoluble polymer generally require an extremely large amount of coating to control drug release in the case of using for drugs having extremely high solubility in water or for fine particles having a mean particle size of 100 &mgr;m or less. In addition, in the case of increasing the amount of coating to delay the dissolution rate, there is the problem in which a phenomenon referred to as so-called upper limitation of dissolution occurs in which the drug does not completely dissolve.
On the other hand, Japanese Patent No. 2518882 (publication date: Jul. 31, 1996) describes a sustained release oral preparation in which pellets of inert materials are coated with a drug-containing layer, and the drug-containing layer is additionally coated with a lipophilic compound such as stearic acid and a curing agent such as ethyl cellulose. However, since the preparation described in this patent contains pellets for the core substance, the mean particle size is about 1 mm or larger. In the case of producing tablets using these large particles, disintegration of the particle-coating layer occurs easily during compression. That makes it difficult to control the dissolution of drug, or makes it necessary to increase the size of the tablets, and these shortcomings cause these particles to lack practicality as raw material particles for tablet production.
DISCLOSURE OF THE INVENTION
The present invention provides sustained release particles that prevent sticking during compression when producing oral sustained release tablets, and a preparation method and so forth thereof.
The inventors of the present invention found that, when producing sustained release tablets, if particles are used in which a drug-containing core substance is coated with a mixed coating of a hydrophobic organic compound-water-insoluble polymer, in addition to effectively controlling the dissolution of drug, sticking during compression molding is prevented thereby without adding a lubricant, and leading to completion of the present invention.
Namely, the present invention relates to sustained release particles having a mean particle size of 300 &mgr;m, or smaller, comprising a drug-containing core substance coated with a mixed coating of a hydrophobic organic compound-water-insoluble polymer, a preparation method of said sustained release particles, and a preparation method of tablets by compression using said sustained release particles.
The following provides a more detailed explanation of the present invention.
Examples of hydrophobic organic compounds used in the present invention include higher fatty acids having 6 to 22 carbons that may or may not have an unsaturated bond, higher alcohols having 6 to 22 carbons that may or may not have an unsaturated bond, and glycerin esters of higher fatty acids having 6 to 22 carbons that may or may not have an unsaturated bond.
Examples of higher fatty acids having 6 to 22 carbons that may or may not have an unsaturated bond include stearic acid, capric acid, lauric acid, myristic acid, palmitic acid, undecanoic acid, caproic acid, caprylic acid, arachidic acid, behenic acid, oleic acid, linoleic acid and linolenic acid.
Examples of higher alcohols having 6 to 22 carbons that may or may not have an unsaturated bond include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol and undecanol.
Examples of glycerin esters of higher fatty acids having 6 to 22 carbons that may or may not have an unsaturated bond include glycerin esters of the above higher fatty acids such as stearin, myristin, palmitin and laurin.
Of these, higher fatty acids having 6 to 22 carbons that may or may not have an unsaturated bond are preferable, and stearic acid is particularly preferable.
Not only one types of the above hydrophobic organic compounds, but also a mixture of two or more types may be used for the hydrophobic organic compound.
In addition, examples of water-insoluble polymer used in the present invention include water-insoluble cellulose derivatives, water-insoluble vinyl derivatives and water-insoluble insoluble acrylic polymers.
Specific examples of the above water-insoluble cellulose derivatives include ethyl cellulose and cellulose acetate.
Specific examples of water-insoluble vinyl derivatives include polyvinyl acetate and polyvinyl chloride.
Specific examples of water-insoluble acrylic polymers include ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymer and methyl methacrylate-ethyl acrylate copolymer.
Of these, water-insoluble cellulose derivatives are preferable, and ethyl cellulose is particularly preferable.
Not only one type of the above water-insoluble polymers, but also a mixture of two or more types may be used for the water-insoluble polymer.
In the mixed coating of a hydrophobic organic compound-water-insoluble polymer, hydrophobic organic compound and water-insoluble polymer can be used by suitably combining each of the above coating agents, and mixtures of one type or two or more types of hydrophobic organic compounds, or mixtures of one type or two or more types of water-insoluble polymers can be used in combination. Of these, a preferable combination is higher fatty acid having 6 to 22 carbons that may or may not contain an unsaturated bond and a water-insoluble cellulose derivative, while a particularly preferable combination is stearic acid and ethyl cellulose.
In the mixed coating as claimed in the present invention, the mixing ratio of hydrophobic organic compound and water-insoluble polymer and the coating ratio of the mixed coating is suitably determined according to the effective dose, and so forth, of the drug used. In this case, the higher the ratio of hydrophobic organic compound to water-insoluble polymer in the mixed coating, the easier it is to control dissolution time. In addition, the greater the coating ratio of the mixed coating to the drug containing core substance, the easier it is to control dissolution time.
The mixing ratio of hydrophobic organic compound and water-insoluble polymer in the mixed coating is normally within the range of 5:95 to 95:5, and particularly preferably within the range of 30:70 to 80:20.
In addition, although the coated amount of mixed coating fluctuates according to the type and size of the core substance, the coating ratio (wt % of mixed coating to core substance) should be within the range of 20 to 200 wt %, and particularly preferably within the range of 40 to 100 wt %.
Moreover, various additives may be blended into the mixed coating as claimed in the present invention, and examples of such additives include colorants, opacifiers, plasticizers and lubricants.
Examples of colorants include food dyes, lake pigment, caramel, carotene, annato, cochenille and iron oxide, as well as opaque colorants consisting mainly of lake pigment and syrup (OPALUX). Specific examples of these colorants include aluminum lake food dyes such as red food dye No. 2 and No. 3, yellow dye No. 4 and No. 5, green dye No. 3, blue dye No. 1 and No. 2 and violet dye No. 1, annato (natural pigment originating in Bixa orel
Ikegami Kengo
Ishibashi Takashi
Mizobe Masakazu
Nagao Keigo
Yoshino Hiroyuki
Birch & Stewart Kolasch & Birch, LLP
Spear James M.
Tanabe Seiyaku Co. Ltd.
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