Controlled release pharmaceutical preparation and method for producing the same.

Background of the Invention

The present invention relates to novel controlled release pharmaceutical compositions and a process for their preparation.

Pharmaceutical compositions wherein the drug-containing cores are coated with compact films of hydrophobic polymeric substances are well known.

Such compositions are advantageous in that they have excellent water resistance, light resistance, moisture resistance, erosion resistance, storage stability, etc.

However, a composition having a compact film of a hydrophobic substance has disadvantages in that the rate of release of the drug contained therein is slow, and because the drug cannot be completely released.

In other words, drug release is due to concentration difference or osmotic pressure difference between

The interior and exterior of the composition, which is created by dissolving the drug to a concentration saturated with suppurative fluids that have penetrated inside through the film. However, since the compact film of a basic hydrophobic substance has few open spaces, fluid penetration through the film is slow and even when it is possible to create a sufficient osmotic pressure difference to release the drug outwards, dissolution rate not sufficient due to the small total open space area contributing to the release.

As a method for solving this problem, a process is known in which the particles of a water-soluble substance are embedded in the film of a hydrophobic polymeric substance so that the film can become porous in the dissolution and elimination digestion organs. said soluble substance.

However, this method remains disadvantageous, as a special device for embedding a water-soluble substance in the film is required, and as it is necessary to use various additives such as dispersing agents, plasticizers, antifouling agents. aggregation, etc., which makes for complicated preparation. Moreover, even if the film becomes porous in the digestive organs, its porosity will be affected by the size of the water-soluble substance particles or the degree of dispersion of said substance in the film, so porosity cannot be accurately controlled. .

Summary of the Invention

The present invention has extensively studied the possibility of providing controlled release while maintaining the advantages of a composition having a compact film of a hydrophobic polymeric substance, such as high physical strength, good storage stability. , etc. As a result, a porous film of a hydrophobic polymeric substance could be obtained on the surface of a core, and it was also found that a controlled release pharmaceutical composition with a desired dissolution rate could be obtained by controlling the porosity. of the film.

Notably according to the present invention there is provided a controlled release pharmaceutical composition comprising a core containing a pharmaceutically active ingredient and a porous film of a hydrophobic polymeric substance, said core being coated with said film. porous. In addition, a method for preparing said composition is provided.

Description of Preferred Aspects

In the present invention, the core to be coated with the porous film is not particularly limited to a force; any suitable form such as plain tablets, pills, granules, grains etc. may be used. All in all, it is preferable to use a granule in the form of granules, grains, etc., preferably in the form of granules of particle size of about 30 µm to about 2000 µm, particularly between about 5 µm and about 850 µm. The nucleus of the present invention need not be hydrophobic, but both water soluble nuclei and water insoluble nuclei can be suitably used.

The core may contain a wide variety of excipients comprising diluents, binders, lubricants, anti-aggregating agents, buffers, which are conventionally used in the art. For example, sugars such as sucrose, lactose, mammal I, glucose, etc., starch, crystalline cellulose, calcium phosphate, calcium sulfate, calcium lactate, etc. may be included as diluents. polyvinylic acid, polycritic acid, tacriylic acid polyvinyl pyrrolidone, glucose, sucrose, lactose, maltose, sorbitol, m-nitol, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene gel, polyethylene gel, polyethylene gel, polyethylene gel, polyethylene gel, agar, starch, etc. As lubricants and as anti-aggregating agents it is possible to include talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hardened oil, p1iethylenoglycols, sodium benzoate, 1auri1-sulphate sodium, 1 to 2 magnesium ril sulfate, etc. Furthermore, it may be possible to include as organic acids such as fumaric acid, succinic acid, citric acid, malic acid and salts thereof.

The hydrophobic polymeric substance constituting the porous film is not particularly limited as long as it is capable of forming a film and is water-insoluble but soluble in a water-miscible organic solvent. Examples of such su

<img file="PT90153B_D0001.tif" />

Hydrophobic polymeric substances may include cellulosic ether, cellulosic ester, polyvinyl ester, acyl-type acrylic polymers having a quaternary ammonium-ammonium group, and the like. Specifically, it may include, for example, ethylcellulose, butylcellulose, cellulose acetate, cellulose propionate, polyvinyl acetate, polyvinyl butyrate; Eudragit Rohm Pharma trade name, chemical name: Ethyl acrylate / methyl methacrylate / trimethylammonium chloride methacrylate copolymer, etc., and among them hydrophobic polymeric substances Preferred may include, for example, ethylcellulose, butylcellulose, cellulose acetate, cellulose propionate or Eudragit RS, etc. Of these, particular preference is given to ethyl cellulose and cellulose acetate, with ethyl cellulose being more preferred. Preferably, the ethylcellulose may be a water-insoluble ethylcellulose having, for example, an ethoxy group content of from about 4% to about 55%, particularly from about 43% to about 51%, with a viscosity / viscosity measured at about 100%. 5% ethylcellulose concentration in a mixture of up to 1% (4: 1 J at 25 ° C / 4 to about 350 cp.

The porous film of the present invention may be different from a porous film consisting solely of a hydrophobic polymeric substance, may be a porous film composed of a hydrophobic polymeric substance and may be a hydrophobic polymeric substance. In this case, as a hydrophilic polymeric substance, a water-soluble polymeric substance, a buried polymeric substance, a gastric juice-soluble polymeric substance, and a polymeric substance may be suitably used.

-Simultaneously enteric and soluble in gastric juice.

Examples of water-soluble polymeric substances may include polysaccharides optionally bearing a sulfuric acid group such as pullulan, dextrin, alkali metal alginate, etc .; poly saccharides having a hydroxyalkyl group or a carboxyalkyl group such as hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc .; may include methylcellose, polyvinyl pyrridine, polyvinyl alcohol. or polyethylene glycol I, etc. Of these, the most preferably water-soluble polymeric substances may include hydroxypropylcellulose or polyethylene glycol.

As an enteric polymeric substance, a water-soluble polymeric substance of pH 5 or higher may be used, including, for example, (1) carboxyalkylcellulose, (2) cellulose derivatives. Iose having a dibasic acid monoester bond, (3) polyvinyl derivatives having a dibasic acid monoester bond, (4) yinyl / maleic acid copolymer or (5) acrylic acid type polymer, etc. Specific examples of (1) may include carboxymethylcellulose; Specific examples of (2) may include cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate s -cinate hydroxypropylmethylcellulose and the like; specific examples of (3) may include dibasic acid monoesters of vinyl polymers such as polyvinyl alcohol phthalate, polyvinyl butyrate phthalate, polyvinylacetacetal phthalate and the like; Specific examples of (4) may include mallyl vinyl acetate anhydride copolymers, maleic anhydride-vinyl ether copolymers, malonic acid-styrene rhoester ester copolymers; and specific examples of (5) may include methacrylic acid-acrylic acid copolymers, styrene-acrylic acid copolymers, methacrylic acid-acrylate acrylate copolymers, Eudragit L and S (trade names of Rhom-Pharma, methyl methacrylic acid methacrylate copolymers), etc. Among these, the most preferred enteric polymeric substances are carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate or Eudragit

L.

In addition, as a gastric juice-soluble polymeric substance any water-soluble polymeric substance of pH 6 or less and capable of forming a peel may be used, including, for example, (a) cellulose derivatives which have a group. mono- or d) substituted amino, (b) polyvinyl derivatives having a mono- or disubstituted amino group, (c) acrylic acid polymers having a mono-substituted amino group, etc. Specific examples of (a) may include benzylaminomethylcellulose, diethylaminomethylcellulose, piperidylethyl hydroxycellulose, diethylamino cellulose acetate, and the like. Specific examples of (b) may include vinyl-viηΐ-Idiethylamine acetate copolymers, vinyl-vinylbenzylamine acetate copolymers, diethyl acetate-ρ o 1 ivtni 1-acetate! α-ketoacetal acetate copolymers vi ni'-o-vii ni-pi peri-di, polymethylamethyl-styrene, etc., and the specific examples;

(8) of (c) may include Eudragit E (trade name Rohm-Pharma, butyl methacrylate methacrylate methacrylate copolymers, dimethylaminoethyl methacrylate], polydimethylamino methacrylate, etc. Among these, the most preferred gastric juice soluble polymeric substances are dimethyl amino-polyvinyl acetate or Eudragit E.

As a gastric juice-soluble enteric polymeric substance a film-forming polymeric substance which is water-soluble at pH 4.5 or below and in water at pH 6 or above may be used. 1 has acrylic acid-vinylpyridine-like copolymers, carboxymethyl polysaccharides having a mono- or disubstituted amino group or a polyvinyl-amino acid-type derivative. Specific examples of acrylic acid vinyl pyridine copolymers may include methacrylic acid / methyl methacrylate / 2-methyl vinyl pyridine copolymers, methacrylic acid / acrylic copolymers. 1-methyl / 2-methyl-5-vinylpyridine act, styrene / methacrylic acid / 2-vinyl-5-ethylpyridine copolymers, methoxy acrylate / methacrylic acid / 2-vinyl-5-ethylpyridine copolymers, methyl acrylate / methacrylic acid copolymers / 2-νιni lpiyridine, acrylonitrile / methacrylic acid / 2-trifluidine acid copolymers, etc. Examples of carboxymethyl polysaccharides having a mono- or disubstituted amino group may include carboxymethylpiperidine starch, carboxymethyl-benzylaminocellose, etc., and specific examples of polyvinyl-amino acid derivatives may include poly (2- (vinylphenyl) glycine, styrene-N-vinylglycine copolymers, etc.

’⁹7

The association of the hydrophobic polymeric substance with the hydrophobic polymeric substance is not particularly limited, but a preferred combination may include an association of a hydrophobic polymeric substance with a water-soluble polymeric substance or an enteric polymeric substance. As a particularly preferred combination, a combination of ethylcellulose and hydroxypropylcellulose acetate succinate, carboxymethylcellulose or hydroxypropylmethylcellulose may be used. The ratio of hydrophobic polymeric substance to hydrophobic polymeric substance should preferably be from 0.05 to 0.5 parts by weight of the hydrophobic polymeric substance to one part by weight of the hydrophobic polymeric substance.

The porous film consisting of the hydrophobic polymeric substance or an association of the hydrophobic polymeric substance and the hydrophobic polymeric substance is generally sponge-like and has regular or irregular pores of microscopic size which communicate with each other.

The porosity of the porous film is represented by the formula (I) J (total weight of the film) / (total volume of the film): -; -: -; _— :( Actual relative density of film)

In general, porosity should have an appropriate value of between 0.4 and 0.9, particularly between 0.5 and 0.85,

The film thickness can be controlled by the amount of hydrophobic polymeric substance relative to the core, it is desirable to use the hydrophobic polymeric substance in a preparation of from about 3 to 100% w / w, particularly from about 5 to 50%. w / w based on core weight. When using the hydrophobic polymeric substance in combination with the hydrophilic polymeric substance, the total amount of both polymeric substances should preferably be within the aforementioned range.

In the composition of the present invention, by properly controlling the thickness and porosity, it is possible to make a composition having a desired dissolution rate. For example, when the pharmaceutically active ingredient contained in the core is a drug which should produce a pharmaceutical effect within a short period after administration, it is preferable to make the thin film and its larger porosity, whereas for this case Of a drug for which persistent release is desired over a prolonged period, it is preferable to make the thicker film and its smaller porosity.

As a pharmaceutically active ingredient contained in said core, any pharmaceutically orally administered drug may be used without any limitations. Examples of such pharmaceutically active ingredients may include vitamins, amino acids, peptides, chemotherapeutic compounds, agents affecting the respiratory organs, antitussive agents, antitumor agents, autonomic drugs, neuropsychotropic agents, relaxants. muscle-, drugs that

-11ί affects digestion organs, antihistamine agents, antidotes, hypnotic sedatives, antiseptics, antipyretic analgesic antipyretic compounds, cardiotonic drugs, antiarrhythmic compounds, hypotensive diuretics, vasodilators, dietary agents, hypolipidemic agents, hypolipidemic agents, anticoagulants, liver compounds, blood sugar lowering agents, hypotensive agents, etc.

The composition of the present invention may be made by spray-spraying a core containing the pharmaceutically active ingredient, a water / organic solvent mixture having a hydrophobic polymeric substance or a hydrophobic polymeric substance and a hydrophilic polymeric substance. to provide a porous film of said polymer substance or substances on the surface of the core.

The preparation of a nucleus may be carried out according to conventional methods as described in Reimngton's Pharmaceuticals 1 Science, 17th ed., Pp 1 603 to 1632, pp 1 633 to 1643 (Mark Publishing Company, published 1985) . For example, the core may be prepared by mixing a pharmaceutical compound with a suitable excipient or excipients (i.e., fluids, binders, lubricants, etc.) and then granulating the mixture according to the wet extrusion granulation method. , rotatiyo granulation method, fluid bed granulation method, etc.). Alternatively, the core may be prepared according to the rotary granulation method, the autoclave coating method, the fluidized bed coating method, etc.,

<img file="PT90153B_D0002.tif" />

wherein the pharmaceutical compound or a mixture of the compound with an excipient or excipients is gradually added to the inert carrier particles while spraying a solution of a binder dissolved in a suitable dissolyte such as water, a lower alcohol (methanol, ethanol, propanol, isopropanol, butanol, etc.), a lower alkanone (acetone, methyl ethyl ketone, etc.), chloroform, dichloromethane, dichloroethane or a mixture of these compounds, on the particle surface of the inert vehicle. In this case, as inert carrier particles, suitably, for example, particles prepared from sucrose, lactose, starch, cellulose, crystalline, etc. may be used. Such carrier particles should preferably have particles of an average size of about 300 µm and about 1500 µm.

When coating the core with a porous film, an organic solvent which forms a solvent-water mixture may be used, any solvent which may dissolve the hydrophobic polymeric substance without particular limitation, including, for example, the lower alkanols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-propyl alcohol, n-butyl alcohol, etc., lower alkanones such as acetone, methyl ethyl ketone, etc., 1 and similar acetonitri. Of these, the most preferred disulfides are lower alkanols, particularly preferred as solvents are ethyl alcohol and isopropyl alcohol. The ratio of the mixture between water and organic solvent suitably varies within the range of 9 to 5 volumes of organic solvent to a volume of water, and the porosity of the film may be pores.

The hydrophobic polymeric substance or a combination of the hydrophobic polymeric substance and the hydrophilic polymeric substance is easily controlled by varying said portion. As a general rule, the porosity of the porous film increases with the proportion of water in the water / organic solvent mixture and decreases as the proportion of the organic solvent increases.

The concentration of the hydrophobic polymeric substance in the water / organic solvent mixture should preferably be between 2 and 30% w / w. Likewise, when using a hydrophobic polymeric substance in combination with a hydrophilic polymeric substance, the total concentration of both polymeric substances should preferably be within the aforementioned range.

Spray coating may be carried out according to any conventional coating method. For example, it can easily be accomplished by dissolving a hydrophobic polymeric substance or a combination of a hydrophobic polymeric substance and a hydrophilic polymeric substance in a water / organic solvent mixture and spraying the resulting coating solution onto the surface of a polymer core. according to the fluidized bed coating method, the autoclave coating method, etc. For example, the autoclave coating method can be performed by placing the cores in a coating drum, spraying a water / organic solvent mixture containing a hydrophobic polymeric substance or an association of a hydrophobic polymeric substance and a hydrophilic polymeric substance through a nozzle of a spray gun while rotating said casing drum, and then drying the casing.

After this period, if necessary, talc, titanium dioxide and tc may also be added as an anti-aggregating agent.

The pharmaceutical preparation of the present invention thus obtained may be administered as stated or may be administered in capsules filled with said composition when in the form of granules.

The controlled release pharmaceutical composition of this invention is characterized by a rapid onset of release. This is because the film is porous allowing the suppurative fluids to penetrate into the preparation and dissolve the pharmaceutically active ingredient immediately after administration. Moreover, the composition of the present invention is characterized in that the rate of release can be easily controlled by varying the porosity of the film. For example, where it is necessary to reduce the variation of the level of the pharmaceutically active ingredient in the blood by the minimum blood level of said therapeutically effective active ingredient is close to the corresponding toxic level in the blood, It is possible to minimize the variation between the respective maximum and minimum designations in the blood by reducing the porosity of the film to achieve the therapeutic effect of the active ingredient while maintaining the corresponding blood level below the toxic level. in the event that

Since the active pharmaceutical ingredient has a long-lasting action, it is possible to release the active ingredient at a constant rate over a prolonged period by lower porosity of the film. On the other hand, in the event that the active ingredient is intended to perform a rapid action, it is possible to release the active ingredient immediately after administration by greater porosity of the film.

In addition, the porous film pharmaceutical composition consisting of a hydrophobic polymeric substance and a hydrophilic polymeric substance is effective in dissolving and releasing the pharmaceutical ingredient more rapidly and within a short period after administration, since the porosity itself. of the film becomes larger by dissolving the hydrophilic substance that forms a part of the porous film.

On the other hand, the composition of the present invention is not at all inferior with respect to moisture resistance, light shielding property, water resistance, and erosion resistance when matched with known conditions. which have a compact film of a hydrophobic polymeric substance.

As noted above, the preparation of the present invention is excellent with respect to controlled release while maintaining the advantages of the compositions known in the art.

-16 Experimental Examples (1) Composition Preparation:

One kilogram of Nonpareil (trade name Freund-prepared sucrose spherical granules) was placed and stirred with particles of dimensions 710 to 840 µm in a fluidising centrifugal granulator (model CF-360 EX, manufactured by Freund) and 1 kg of diltiazem hydrochloride powder was then added gradually while spraying with a water / ethanol solution (3: 1 weight ratio) containing 40 g sucrose to coat Nonpareil. Subsequently the obtained diltiazem hydrochloride granules were sprayed with a 300 g ethoxide-e (eethoxy content)

: 49.6%) dissolved in 2.7 kg of a water / ethanol mixture (weight ratio = 3: 7; 2: 8 or 1.5: 8.5) while blowing hot air . Drying after spraying yields compositions containing diltiazeme hydrochloride having ethylene cellulose films with different porosities.

(2) Release Speed ​​Comparison:

For the respective compositions obtained as described above, the dissolution tests were performed according to the standard Paddle method dissolution test described in Table 11.^The. revised edition of Japanese Pharmacopoeia, /

The percentage dissolution of the active ingredient (diltiazem hydrochloride) is as shown in Table 1.

Table 1 (3) Results:

<td>Preparation</td><td>Porosity</td><td colspan="3">dissolution percentage</td>

<td> (*1)</td><td> (*2)</td><td>4 hours</td><td>10 hours</td><td>24 hours</td>

<td>THE</td><td> 0,83</td><td> 34</td><td> 77</td><td> 100</td>

<td>B</td><td> 0,54</td><td> 20</td><td> 53</td><td> 86</td>

<td>Ç</td><td> 0,42</td><td> 17</td><td> 34</td><td> 52</td>

(note) :

* 1; A - C represent the following compositions:

A: composition obtained by using a water / ethanol mixture (3: 7) as a coating solution solvent;

B: composition obtained by using a water / ethanol mixture (2: 8) as solvent of the coating solution;

C: composition obtained by using a water / ethanol mixture (1.5: 8.5) as solvent of the coating solution;

* 2; porosity was calculated according to formula (I) above.

As is evident from Table I, it can be seen that as the proportion of water in the water / ethanol mixture decreases, the porosity of the film decreases and the time required to dissolve 100% of the active ingredient increases.

Example 1

500 g Nonpareil of particle size 710 to 840 µm was placed and stirred in a fluidising trifluor granulator and 1 kg of theophylline fine powder was added gradually (chemical designation: 3,7-dihydrogen). hydroxy-1,3-dimethyl-1H-purine-2,6-dione) while spraying a solution of 270 g sucrose dissolved in 145 ml water to cover Nonpareil. Thereafter, 1 kg of theophylline granules thus obtained were placed and stirred in a fluidising centrifugal granulator and a solution of 90 g of ethylcellulose and 10 g of hydroxypropylcellulose dissolved in 1.9 kg of a water mixture was sprayed. / ethanol (3: 7) while blowing hot air. As a result, after drying, 1.1 kg of re-coated theophylline granules were obtained with a porous ethyl cellulose / hydroxypropyl cellulose bead.

The composition obtained had a porous film with a porosity of 0.81.

Example 2

1 Kg of Nonpareil with particle size 710 to 840 µm was placed and stirred in a central granulator.

<img file="PT90153B_D0003.tif" />

fluidiser and 1 kg of sodium salicylate powder was added gradually while spraying 800 g of a water / ethanol mixture containing 400 g of sucrose to adhere to Nonpareil. Subsequently, 500 g of the sodium salicylate granules thus obtained were placed in a fluidized ion coater and, under forced rotation with air insufflation, a mixture of 100 g of ethylcellulose dissolved in 900 g of a water / ethanol mixture (2: 8) to which 50 g of talc had been added while blowing hot air. After drying after spraying, 600 g of sodium salicylate granules coated with a porous ethyl cellulose film were obtained. The composition obtained showed a porous film with a porosity of 0.68.

Example 3

1.33 Kg of Nonpareil with particle size 500 to 710 µm was placed and stirred in a fluidising centrifugal granulator and a 1 Kg mixture of (+) - (2 S, 2 ', 2') maleate fine powder was added gradually. 3S) -3-acetoxy-8-chloro-5- [1- (dimethylamino) -ethi-2,3-dihydro-2- (4-methoxyphenyl) -1 , 5-bezodiazepine-4 (5H) -one and 1.67 g succinic acid at the same time a solution of 652 g sucrose dissolved in 1 957 g of a mixture of , water / ethanol (3: 1) to coat Nonpareil. Then 2 kg of granules thus obtained were placed and stirred in a fluidising centrifugal granulator and a solution of 190 g of ethylcellulose and 10 g of hydroxypropylcellulose dissolved in 1.8 kg of a water / ethanol mixture was sprayed ( 3: 7) while blowing hot air. Then after drought-20-

<img file="PT90153B_D0004.tif" />

2.2 kg of granules coated with a pink film of ethylcellulose / hydroxypropylcellulose were obtained.

The composition obtained had a porous film with a porosity of 0.85.

Example 4

A mixture of 300 g of diltiazem hydrochloride, 611 g of lactose and 150 g of cornstarch was kneaded with 30 g of polyvinylpyrridone and 100 ml of water and then the particles obtained were classified for pellet granules are obtained. Then 8 g of magnesium stearate was added to the pellets and the pellet mixture was pre-prepared on a rotary pelletizing machine (model RT F-9-2 manufactured by Kikusui Seisakusho) and obtained. 8 mm diameter inserts. The obtained tablets (500 g) containing diltiazem hydrochloride were placed in a coating autoclave and a water / ethanol mixture (3: 7) containing 5% w / w ethylcellulose was sprayed at room temperature. Then, after drying, the Sprinkles coated with a porous ethyl cellulose film were obtained.

The composition obtained had a porous film with a porosity of 0.67.

Example 5

500 g of theophylline granules (cores) obtained by the same procedure as Example 1 were placed in a fluidising centrifugal granulator and a solution of 50 g of ethylcellulose dissolved in a water / isopropanol mixture (4: 6) was sprayed onto them. while blowing hot air. Then, after drying, 500 g of granules coated with a porous ethyl cellulose film were obtained.

The composition obtained had a porous film with a porosity of 0.78.

Example 6

500 g of sodium salicylate granules (cores) obtained by a similar process as in Example 2 were placed in a fluidized bed coating device. 50 g of talc was added to the solution of 100 g of cellulose acetate in 900 g. of a water / acetone mixture (2: 8) and the mixture was sprayed onto the surface of the granules while blowing hot air. Drying after spraying afforded 600 g of granules coated with a porous cellulose acetate film.

The obtained granules had a porous film with a porosity of 0.74.

Example 7

Example 1 was repeated except that 100 g of cellulose acetate butyrate instead of cellulose acetate was used to provide 600 g of granules coated with

<img file="PT90153B_D0005.tif" />

a porous film of cellulose acetate buttrate.

The preparation obtained had a porous film with a porosity of 0.78.

Example 8

1 kg of granules (nuclei) obtained by a similar process as in Example 3 were placed and stirred in a fluidizing centrifugal granulator and a solution of 95 g of ethylcellulose and 5 g of polyvinylpyrrolidone dissolved in 900 g was sprayed onto them. of a water / ethanol mixture (3: 7) while inflating thereafter. Drying after spraying yielded 1.1 kg of granules coated with a porous ethylcellulose / pyrrolidone porous film.

The composition obtained had a porous film with a porosity of 0.81.

Example 9

Example 8 was repeated except 95 g of ethylcellulose and 5 g of polyethylene glycol were used to provide 1.1 kg of granules coated with a porous ethyl cellulose / polyethylene glycol film.

The composition obtained had a porous film with a porosity of 0.79.

<img file="PT90153B_D0006.tif" />

Example 10

Example 8 was repeated except that 95 g of ethylcellulose and 5 g of methylcellulose were used to provide 1.1 kg of granules coated with a porous ethylcellulose / methylcellulose film.

The composition obtained had a porous film with a porosity of 0.82.

Example 11

Example 8 was repeated except that 95 g of ethylcellulose and 5 g of hydroxypropyl methylcellulose were used to provide 1.1 kg of granules coated with a porous ethyl ether / hydroxymethylcellulose film.

The composition obtained had a porous film with a porosity of 0.76.

Example 12

Example 8 was removed except 95 g ethylcellulose and 5 g hydroxypropylcellulose acetate succinate were used to provide 1.1 kg of granules coated with a porous ethyl cellulose / succinate film. hydroxypropylcellulose acetate,

The composition showed a porous film with a pore size

<img file="PT90153B_D0007.tif" />

0.84.

Example 13

Example 8 was repeated except 95 g of ethylcellulose and 5 g of Eudragit L were used to provide 1.1 kg of granules coated with a porous ethyl cellulose / E. dragi L. film.

The composition obtained had a porous film with a porosity of 0.79.