Suppositories

Details Suppositories Suppositories

2001-04-26

2002-12-10

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S422000, C424S423000, C424S451000, C424S480000, C514S772400, C514S778000

Reexamination Certificate

active

06491942

ABSTRACT:

TECHNICAL FIELD
The present invention relates to suppositories, and more particularly, relates to suppositories which are excellently retainable between the anus and the lower region of the rectum.
BACKGROUND ART
It is known that a suppository, after administered rectally, is disadvantageously spread in the rectum so that the drug is diluted around the affected site. There are reported a number of techniques for inhibition of such spreading, for example, a technique combining metal salts of polyacrylic acid in JP-A-54-26325, a technique combining a mixture of polyacrylic acid and polyvinylpyrrolidone in JP-A-6-40889, a technique combining carboxyvinyl polymers in JP-A-63-280016 and JP-A-1-143825, a technique combining a gel-forming agent such as alkali metal salts of polygum in JP-A-59-55817, a technique combining polyvinyl alcohol, pectin and pullulan in JP-A-61-109710, a technique combining water-swelling clay minerals such as Laponite in JP-A-2-15024, a technique combining water-insoluble absorptive resins such as starch grafted acrylate in JP-A-4-164023, etc.
However, in order to use a suppository as a pharmaceutical preparation, it is necessary to satisfy not only retainability but also many other requirements such as safety, stability and the like. For this reason, acrylate polymers, especially carboxyvinyl polymers, are actually used in many cases.
Carboxyvinyl polymers, when used as a suppository base, have an excellent retainability around the affected site, but are liable to cause an interaction with the main drug and, therefore, they have a drawback of lowering the stability of the main drug at times. For example, mixing a certain basic drug with carboxyvinyl polymers causes coloring, precipitating or lowering the release of the main drug at times. Furthermore, in order to enhance the retainability of the suppository, it is necessary to elevate the viscosity of the gel by combining a base component for neutralization of the carboxyvinyl polymers and in this case, some of the drugs are reacted with the base component to cause coloring or precipitating.
Thus, use of carboxyvinyl polymers as a suppository base has a problem that only a limited number of drugs can be applied. An object of the present invention is to provide a novel suppository base which has little interaction with the drug, and has an excellent retainability.
DISCLOSURE OF THE INVENTION
As a result of various studies in order to solve the above problem, the present inventors have found that a suppository that can contain various kinds of drugs and has a high retainability can be obtained by combining a suppository base with a hydrophobic hydroxypropyl methylcellulose in place of conventional carboxyvinyl polymers.
That is, the present invention is directed to a suppository comprising a hydrophobic hydroxypropyl methylcellulose.
It is known that hydrophobic hydroxypropyl methylcellulose can be used as a base of external preparations for skin use or gel preparations for periodontal use as described in JP-A-4-74108, JP-A-3-223301 and JP-A-6-166614, but it has not been known that hydrophobic hydroxypropyl methylcellulose can be combined in suppositories.
The hydrophobic hydroxypropyl methylcellulose in the present invention refers to hydroxypropyl methylcellulose (HPMC) into which a small amount of a long chain alkyloxyhydroxypropoxyl group has been introduced to impart a hydrophobic property to the HPMC. Here, the long chain alkyl group as a part of the alkyloxyhydroxypropoxyl group refers to a straight or branched chain alkyl group having 6 to 26 carbon atoms, and specific examples thereof are a stearyl group, a palmityl group, a myristyl group and a lauryl group. The most preferred long chain alkyloxyhydroxypropoxyl group in such hydrophobic hydroxypropyl methylcellulose is a stearyloxyhydroxypropoxyl group.
The properties of the hydrophobic hydroxypropyl methylcellulose in the present invention vary largely depending on the amount and molecular weight of the long chain alkyloxyhydroxypropoxyl group introduced. Preferred are hydrophobic hydroxypropyl methylcelluloses having a viscosity of 70-250 mm
2
/s (determined with Ubbelohde viscometer, at 25° C., 0.5 W/W %, a mixture of water and isopropanol (6:4 W/W)). When the viscosity is less than 70 mm
2
/s, the retainability of the suppository may be insufficient, and when the viscosity exceeds 250 mm
2
/s, it may be difficult to formulate the hydrophobic hydroxypropyl methylcellulose into a preparation.
The hydrophobic hydroxypropyl methylcellulose comprises preferably 0.1-20% by mass, and especially preferably 0.5-5% by mass of the preparation. In case the hydrophobic hydroxypropyl methylcellulose comprises less than 0.1% by mass, since sufficient viscosity cannot be obtained, the retainability is insufficient. In case the hydrophobic hydroxypropyl methylcellulose comprises more than 20% by mass, it will be difficult to produce the preparation because the workability is bad due to the high viscosity.
Introduction of a long chain alkyloxyhydroxypropoxyl group into HPMC can be made by a method of reacting an alkyloxyhydroxypropoxylating agent (e.g., a halide, an epoxide or an isocyanate) with the BPMC.
The thus-obtained hydrophobic hydroxypropyl methylcellulose is dispersed into an ordinary suppository base to form a gelling base.
The ordinary suppository base to be used includes oleophilic bases and water-soluble bases, and they can be used in combination. The oleophilic bases include cacao butter, lanolin fat and hard fats. The hard fats include, for example, Witepsol (tradename, manufactured by Huls Inc.), Suppocire (tradename, manufactured by Gattefosse Inc.), Isocacao (tradename, manufactured by Kao Corp.), Pharmasol (tradename, manufactured by NOF Corp.), etc. The water-soluble bases include Macrogol.
The suppository of the present invention can be prepared by a method comprising melt-mixing an ordinary suppository base with a hydrophobic hydroxypropyl methylcellulose, uniformly mixing this mixture with a drug and additives, and filling the resulting mixture into a container, a mold or the like, and cold-solidifying the filling. The method for mixing to be used is any conventional method.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is illustrated in more detail by the following examples and experiments. The hydrophobic hydroxypropyl methylcellulose used in the Examples is Sangelose 60L (tradename, manufactured by Sankyo Chemicals Co.), i.e., a hydroxypropyl methylcellulose into which a stearyloxyhydroxypropoxyl group has been introduced.


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patent: 1-143825 (1989-06-01), None
patent: 3-223301 (1991-10-01), None
patent: 4-74108 (1992-03-01), None
patent: 6-166614 (1994-06-01), None
patent: 6-227965 (1994-08-01), None
Ermis, Dilek et al.; Ketoprofen sustained-release suppositories containing hydroxypropylmethylcellulose phthalate in polyethylene glycol bases; 1995 vol. 13 No. 1. pp. 65-71.*
Ermis Dilek et al. Int. J. Pharm., 1995 vol. 13 No. 1, pp. 65-71.

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