Sustained-release preparation utilizing thermal change and process for the production thereof

A sustained-release preparation which can release a highly water-soluble medicinally active ingredient over a long time and a process for the production thereof are provided. The preparation has a sustained-releasing layer formed by heating and melting a layer composed of both an aqueous ethylcellulose latex containing a plasticizer and a wax to miscibilize them.

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), Rohm Pharma), aminoalkyl
 methacrylate (Eudragit RS 30D (trade name), Rohm 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.

BEST MODE FOR CARRYING OUT THE INVENTION
 The sustained-release preparation of the present invention is produced by
 the method described in the following processes 1) to 5), preferably
 processes 1) to 6), but is not to be construed to be limited thereto. The
 sequence of processes 2) and 3) may be inverted, and the processes 2) and
 3) may be repeated and be carried out simultaneously. The processes 2) and
 3) may be carried out in one step wherein the sustained-release coating
 solution is prepared by heating the aqueous ethylcellulose latex, the wax,
 and the plasticizer and the coating solution is used for the coating.
 1) Preparation of granules containing a medicinally active ingredient: The
 granules containing a medicinally active ingredient are not restricted by
 its shape, size, and the like. Cylindrical granules which are suitable for
 mass-production or spherical granules of which size is uniform is
 preferable. As a production method for the former, the method of extruding
 granulation method in which diluents, binders, and the like which are
 usually used in the ordinary pharmaceutical production are kneaded and
 extruded is exemplified. For example, core particles such as sucrose
 starch spheres, microcrystalline cellulose spheres, etc. are coated with
 diluents, binders, medicinally active ingredients, and the like using
 fluidized-bed coater, centrifugal fluidizing granulator, etc. to give
 spherical granules.
 2) Coating with wax: As the method of coating with the wax, the method
 wherein the granules containing a medicinally active ingredient obtained
 in 1) are coated with the wax by repeating the spraying of a binder such
 as water soluble polymer, etc. and the feeding of fine powder wax is
 exemplified. The method wherein the heated granules are fed and coated
 with powder wax in accordance with the method of hot-melt coating, the
 method wherein the heated and melted wax is added or is sprayed to coat,
 and the like are also exemplified. The amount of the coating varies with
 solubility of medicinally active ingredients and the desired
 sustained-release time. Usually, it is possible to achieve the stable
 controlled release over a long time by coating with the wax of which
 amount is 5 to 80%, preferably 15 to 55%, by weight to the weight of the
 granules containing a medicinally active ingredient. An amount of the wax
 is preferably 20 to 120% by weight to the weight of the ethylcellulose.
 3) Coating with aqueous ethylcellulose latex containing the plasticizer:
 The coating solution is prepared by mixing aqueous ethylcellulose latex
 with the plasticizer of which amount is 5 to 50%, preferably 10 to 30%, by
 weight to the weight of the ethylcellulose. The wax coated granules are
 coated with the coating solution by a fluidized-bed coater, a centrifugal
 fluidizing granulator, and the like.
 4) Coating with a water soluble polymer: The granules obtained in the
 processes 1) to 3) are coated with a water soluble polymer of which amount
 is 1 to 5% by weight to the weight of the coated granules by a
 fluidized-bed coater, a pan coater, a centrifugal fluidizing granulator,
 and the like. They may further be coated with lubricants, colors, and the
 like.
 5) Forming the sustained-releasing layer by miscibilizing the three
 component the plasticizer, ethylcellulose, and wax, with heating and
 melting: The water soluble polymer coated granules are heated at
 50.degree. C. to 90.degree. C., at which the wax are usually melted, for 1
 to 3 hours by a fluidized-bed coater, a side-vented dryer, and the like.
 In this process, "miscibilization" occurs between the ethylcellulose layer
 containing the plasticizer and the wax layer, and the three components
 come to be an integrated layer This integration was surely confirmed by
 the electron microscope observation and the sustained-releasing layer was
 formed.
 This miscibilization phenomenon specifically occurs between the
 ethylcellulose layer containing the plasticizer and the wax layer. The
 formed layer is able to stabilize the release of highly water-soluble
 medicine controlled over a long time. Because the miscibilization
 phenomenon does not occur between the wax and the water soluble polymer
 coated in the above process, different from hydrophobic polymers such as
 ethylcellulose, it is considered that the water soluble polymer prevents
 the wax from oozing out to the surface of the granules.
 6) Optionally forming a fast releasing part of a medicinally active
 ingredient by coating with the medicinally active ingredient on the
 granules having the sustained-releasing layer obtained in the above
 processes: The process is carried out by the method wherein the granules
 having the sustained-releasing layer obtained in the process 5) are coated
 with the aqueous solution of a medicinally active ingredient, a binder,
 etc., the powder coating method wherein powder of a medicinally active
 ingredient is sprayed to them for coating, and the like.
 The term "diluent" herein used means the diluents which are used for the
 ordinary pharmaceutical production, for example, silicic acids such as
 light anhydrous silicic acid, synthetic aluminum silicate, magnesium
 aluminometasilicate, etc., inorganic salts such as calcium phosphate,
 calcium carbonate, calcium sulphate, etc., saccharides such as lactose,
 sucrose, glucose, mannitol, sorbitol, etc., starches such as corn starch,
 alpha starch, carboxymethyl starch, etc., celluloses such as
 microcrystalline cellulose, low substituted hydroxypropylcellulose, etc.,
 Acacia, dextran, pullulan, and the like.
 The term "binder" herein used means the binders which are used for the
 ordinary pharmaceutical production, for example, hydroxypropylcellulose,
 hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, and
 the like.
 The term "lubricant" herein used is exemplified by talc, magnesium
 stearate, and the like.
 The term "colors" herein used is exemplified by lake pigments, and the
 like.
 The sustained-releasing layer of the present invention is not influenced by
 the pH of the dissolution medium, surface active agents, viscosity, bile
 acid, enzymes, and the like. Additionally, under any temperature
 conditions and any humidity conditions, the layer maintains the stable
 sustained-releasing function. Therefore, this invention provides useful
 preparation which solves the problems such as compliance and tiresomeness
 of taking medicine because the release of the medicinally active
 ingredient is controlled over a long time and enough efficacy of medicine
 can be obtained by taking it once a day.
 As the form of the preparation, capsules wherein the sustained-releasing
 granules are filled into capsules and tablets which are made by
 compressing the sustained-releasing granules are applicable.
 The following examples and Comparative examples are provided to further
 illustrate the present invention.
 EXAMPLE
 Example 1
 Using a centrifugal fluidizing granulator (CF granulator, Freund
 Industrial), 1.36 kg of 32 to 42 meshed sucrose starch spheres as core
 particles were sprayed with 680 g of 5% hydroxypropylcellulose as a binder
 and were simultaneously fed and coated with 1.80 kg of phenylpropanolamine
 hydrochloride as a medicinally active ingredient to give spherical
 granules. The obtained spherical granules were sprayed with 800 g of
 aqueous 5% hydroxypropylcellulose solution as a binder and were
 simultaneously coated with 680 g of crushed hydrogenated castor oil to
 give 3.91 kg of hydrogenated castor oil-coated granules. Using
 fluidized-bed coater (Uni-glatt, Okawara), 250 g of the hydrogenated
 castor oil-coated granules were coated by the method of Waster with the
 solution which were separately prepared by mixing 5.62 g of triethyl
 citrate, 13.1 g of fine-ground talc, and 400 g of 15% Aquacoat (Trade
 name, {character pullout}) as aqueous ethylcellulose latex to give 325 g
 of ethylcellulose-coated granules. The obtained ethylcellulose-coated
 granules were coated with the water-soluble polymer solution comprising
 2.5 g of hydroxypropylcellulose, 3 g of talc, and 98 g of purified water
 to give water soluble polymer-coated granules. Using the above equipment,
 the granules were heated and melted at 85.degree. C. for 2 hours with
 fluidizing and allowed to cool to room temperature to give miscibilized
 granules.
 Example 2
 The miscibilized granules (325 g) prepared in Example 1 were charged into a
 fluidized-bed coater (Wurster-type) and coated with the aqueous solution
 comprising 28 g of phenylpropanolamine hydrochloride and 5 g of
 hydroxypropylmethylcellulose by spraying to give miscibilized granules
 having the fast releasing part.
 Example 3
 The phenylpropanolamine hydrochloride-coated spherical granules (400 g)
 prepared midway of Example 1 were charged into a high speed mixer
 (LFS-GS-1, Fukae Powtec) of which revolution of the agitator was set up to
 300 R/M and were coated with 150 g of heated and melted stearyl alcohol at
 65.degree. C. In the same way as in Example 1, the obtained wax-coated
 granules were coated with aqueous ethylcellulose latex and
 hydroxypropylmethylcellulose. The granules were heated and melted at
 80.degree. C. for 2 hours and allowed to cool to room temperature to give
 miscibilized granules.
 Example 4
 After mixing 434 g of hydrogenated castor oil, 56.2 g of triethyl citrate,
 1.4 kg of purified water, and 131 g of talc, the resulting mixture was
 heated over 85.degree. C. Using a homomixer (Tokusyu Kika), the mixture
 was stirred for 20 min at 3000 R/M and 2.0 kg of Aquacoat was added to the
 mixture. The resulting mixture was stirred for further 10 min and allowed
 to cool to room temperature to prepare the sustained-release coating
 solution. The phenylpropanolamine hydrochloride-coated spherical granules
 (2.5 kg) prepared midway of Example 1 were charged into a fluidized-bed
 coater (FLO 5, Freund Industrial) and coated with the prepared
 sustained-release coating solution to give 3.7 kg of sustained-release
 solution-coated granules. The obtained sustained-release solution-coated
 granules were coated with 2.5% by weight of the water soluble polymer
 solution used in Example 1 to the weight of the sustained-release
 solution-coated granules. The resulting granules were heated and melted at
 85.degree. C. for 2 hours and allowed to cool to room temperature to give
 miscibilized granules.
 The obtained granules controlled the release over a long time in the same
 manner as the granules obtained in Example 1.
 Example 5
 One kg of phenylpropanolamine hydrochloride as a medicinally active
 ingredient, 1.27 kg of mannitol, and 0.06 kg of hydrogenated castor oil
 were charged into 7.5 L Kneader. To the mixture was added 0.3 kg of 7%
 hydroxypropylcellulose aqueous solution and the resulting mixture was
 kneaded for 15 min. Using an extruder of which opening size is 0.53 mm,
 the mixture was granulated and the obtained granules were dried.
 The granules (1.5 kg) sized by a power mill to be about 300 to 700 .mu.m
 were charged into a fluidized-bed coater and were coated with 0.31 kg of
 fine-ground hydrogenated castor oil while simultaneously spraying with 0.4
 kg of 5% hydroxypropylcellulose aqueous solution as a binder.
 In the same way as in Example 1, the obtained hydrogenated castor
 oil-coated granules were coated with Aquacoat by fluidized-bed coater and
 then with hydroxypropylcellulose and talc. The resulting granules were
 heated and melted at 85.degree. C. for 2 hours and allowed to cool to room
 temperature to give sustained-release granules. Additionally, these
 sustained-release granules were coated with the fast releasing part in the
 same way as in Example 2 to give miscibilized granules comprising the
 sustained-releasing and fast releasing parts.
 Comparative Example 1
 The water-soluble polymer-coated granules prepared midway of Example 1 were
 only dried by the usual method until the temperature of the granules
 reaches 50.degree. without melting the wax to give non-miscibilized
 granules.
 Comparative Example 2
 Without wax coating, the phenylpropanolamine hydrochloride-coated spherical
 granules prepared midway of Example 1 were directly coated with Aquacoat
 solution containing the plasticizer of which composition was the same as
 in Example 1, heated at 85.degree. C. for 1 hour, and allowed to cool to
 room temperature to give the granules not including, different from
 Example 1, the wax.
 Comparative Example 3
 The hydrogenated castor oil-coated granules (300 g) prepared midway of
 Example 1 were charged into fluidized-bed coater. The granules were
 sprayed with the mixture containing 9 g of triethyl citrate and 600 g of
 15% aminoalkyl methacrylate (Eudragit RS 30D) instead of Aquacoat to give
 390 g of coated granules. In the same way as in Example 1, these granules
 were coated with hydroxypropylmethylcellulose, heated and melted at
 85.degree. C. for 1 hour, and allowed to cool to room temperature to give
 the same granules as in Example 1 except that aminoalkyl methacrylate was
 used instead of ethylcellulose.
 The results of dissolution tests of the granules obtained in the Examples 1
 to 3 and Comparative examples 1 to 3 are shown in FIGS. 1 and 2. The
 dissolution test was carried out in accordance with the dissolution test
 method 1 described in Japanese pharmacopeia 12th edition using water as a
 dissolution medium.
 FIG. 1 shows that the miscibilized granules produced in Example 1 are able
 to control the release of phenylpropanolamine hydrochloride over a long
 time even though highly water-soluble phenylpropanolamine hydrochloride is
 used as an active ingredient Because the granules produced in Example 2
 have the fast releasing part to be release immediately and the
 sustained-releasing part, it is realized that efficacy of medicine appears
 immediately and is maintained for a long time. Additionally, the
 controlled release of the sustained-releasing part is not degraded by the
 coating with the fast-releasing part. The granules produced in Example 3
 is able to control the release over a long time in a manner similar to
 those produced in Example 1.
 FIG. 2 shows that release of phenylpropanolamine hydrochloride is hardly
 controlled even though the components of the granules produced in
 Comparative example 1 are the same as those of Example 1. The granules
 produced in the Comparative example 2 control the release a little, but
 sufficient control efficiency is not found. The granules produced in
 Comparative example 3 hardly control the release of phenylpropanolamine
 hydrochloride.
 Industrial Applicability
 The sustained-release preparation which can control the release of a highly
 water-soluble medicinally active ingredient over a long time and the
 process for the production thereof are provided.