Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-02-22
2001-05-29
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S482000, C424S468000, C424S462000, C424S472000
Reexamination Certificate
active
06238704
ABSTRACT:
TECHNICAL FIELD
This invention relates to sustained-release preparation which can control release of a highly water-soluble medicinally active ingredient over a long time and process for the production thereof.
BACKGROUND ART
Sustained-releasing methods of highly water-soluble medicinally active ingredients may roughly be classified into the following two types.
The first sustained-releasing method is by forming a matrix (JP-B 60-56122). According to this publication, the sustained-release was attained by the method wherein a water-soluble medicinally ingredient was granulated with hydrophobic substance to form a matrix. However, the control of release over 4 hours or longer is not described in this publication.
The second sustained-releasing method is by film coating (JP-A 63-27424). In this publication, the preparation to be coated with a binder or a film basis by using an organic solvent (the organic solvent method) was described to enable zero-order release over 10 hours or longer.
Though it is easy to control the release by the organic solvent method, its practical application is restricted due to environmental pollution, the remains of organic solvents in the preparation, maintenance of safety, and the like. Therefore, the methods of coating with an aqueous dispersion for sustained-release polymer by using water as a solvent and of coating only with heated and melted wax have recently been attempted.
As an aqueous dispersion for sustained-release polymer, ethylcellulose latex (Aquacoat (trade name), FMC), ethyl acrylate-methyl methacrylate copolymer (Eudragit NE 30D (trade name), Röhm Pharma), aminoalkyl methacrylate (Eudragit RS 30D (trade name), Röhm Pharma), and the like have been developed. However, it is difficult to control the release of highly water-soluble medicinally active ingredients over a long time even by using them. If the ingredient is coated with a very thick controlling layer, zero-order release cannot be achieved. The reasons in the method of controlling the release only with these sustained-release films are exemplified as follows; inconstant crystalinity of formed films, existence of micropores, susceptible to the surface construction of the material to be coated, gradual change of the ability of the releasing control, and the like.
In the method of coating only with heated and melted wax without using any organic solvent (JP-A 5-309314), the control of the initial period release and the sustained-release time are not satisfactory, and the control of release over a long time is difficult by this method.
DISCLOSURE OF INVENTION
In the above situation, the inventors of the present invention have studied sustained-release preparation which can control release of a highly water-soluble medicinally active ingredient over a long time using an aqueous dispersion for sustained-release polymer.
The inventors of the present invention found that the sustained-releasing layer formed by miscibilization of a plasticizer, aqueous ethylcellulose latex, and wax is useful for solving the above problems and accomplished the present invention. The present invention is hereinafter explained in detail.
The present invention relates to sustained-release preparation of a medicinally active ingredient having a sustained-releasing layer formed by miscibilization of a plasticizer, ethylcellulose, and wax.
The present invention further provides the followings; a) the sustained-release preparation wherein an amount of the wax is 20 to 120% by weight to the weight of the ethylcellulose, b) the sustained-release preparation wherein an amount of the plasticizer is 5 to 50% by weight to the weight of the ethylcellulose, c) the sustained-release preparation wherein the sustained-releasing layer is coated with a water soluble polymer, d) the sustained-release preparation wherein the sustained-release preparation of c) is further coated with a layer containing a medicinally active ingredient, e) the sustained-release preparation having a sustained-releasing layer which is formed by heating and melting wax and aqueous ethylcellulose latex containing a plasticizer to miscibilize them, f) a process for preparing sustained-release preparation which comprises miscibilizing a plasticizer, ethylcellulose, and wax in which granules containing a medicinally active gradient are coated with aqueous ethylcellulose latex containing the plasticizer and the wax to form layers, further coated with a water soluble polymer, and then heated, and g) a composition wherein a plasticizer, ethylcellulose, and wax are miscibilized.
When an amount of the wax is 20% by weight or less to the weight of ethylcellulose, the sustained-releasing layer is not formed by miscibilization of the plasticizer, ethylcellulose, and wax with heating. When an amount of the wax is 120% by weight or more to the weight of ethylcellulose, the medicinally active ingredient is slightly released.
When an amount of the plasticizer is 5% by weight or less to the weight of ethylcellulose, the sustained-releasing layer is not formed by miscibilization of the plasticizer, ethylcellulose, and wax with heating. When an amount of the plasticizer is 50% by weight or more to the weight of ethylcellulose, it is difficult to accomplish the sustained-release because the medicinally active ingredient is readily released.
Medicinally active ingredients which are applicable to the present invention ar not restricted to special ones. Highly water soluble medicine such as phenylpropanolamine hydrochloride, potassium chloride, acetaminophen, ephedrine hydrochloride, methylephedrine hydrochloride, caffeine, dihydrocodeine phosphate, oxycodone hydrochloride, water-soluble vitamins such as vitamin B etc., cimetidine, clonazepam, clonidine, isosorbide dinitrate, nitroglycerine, propranolol, scopolamine, morphine, ethenzamide, chlorphenylamine maleate, diphenhydramine hydrochloride, dextromethorphan hydrobromide, noscapine hydrochloride, and the like are especially applicable. The present invention is also applicable to the medical mixture of the above medicine. Especially, phenylpropanolamine hydrochloride is preferable.
The term “plasticizer” herein used means the material that are useful to decrease the modulus of elasticity and the glass transition temperature of high molecular compounds to increase the elasticity of them. For example, triethyl citrate, triacetin, glycerol esters of fatty acids, phthalic acid esters, and the like are exemplified.
The term “aqueous ethylcellulose latex” herein used means the material that ethylcellulose useful as a sustained-release film basis is emulsified and dispersed in water. For example, Aquacoat (trade name, FMC), Surelease (trade name, Colorcon) are exemplified.
The term “wax” herein used means what is known by the person having ordinary skill in the art as useful to control the releasing speed of medicinally active ingredients. For example, higher alcohols such as cetyl alcohol, stearyl alcohol, etc., higher fatty acids such as palmitic acid, stearic acid, etc., glyceroesters such as monoglyceride, triglyceride, etc., fats and oils such as hydrogenated castor oil, hydrogenated beef tallow, etc., wax such as beeswax, carnauba wax, etc., the mixed wax of the above wax at an appropriate ratio, and the like.
Examples of “water soluble polymer” herein used are hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like.
The term “miscibilization” concerning the plasticizer, ethylcellulose, and wax herein used means the phenomenon that the plasticizer accelerates the cohesion and agglutination of ethylcellulose particles and creates a space into which the wax may penetrate. As the result of “miscibilization”, the three components come to be a substantially integrated layer to form a homogeneous layer. As described later, “miscibilization” is caused by heating. In the present invention, if the three components come to be a substantially integrated layer and the preparation shows the sustained-release, it is regarded that “miscibilization” has occurred.
REFERENCES:
patent: 5395626 (1995-03-01), Kotwal et al.
pa
Fujii Toshiro
Kadota Hitoshi
Sakuma Satoshi
Suzuki Yusuke
Tanaka Hiroshi
Birch & Stewart Kolasch & Birch, LLP
Page Thurman K.
Pulliam Amy E
Shionogi & Co. Ltd.
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