JPH05339151A - Sustained release oxybutynin hydrochloride preparation - Google Patents

Abstract

PURPOSE:To obtain oxybutynin hydrochloride preparation providing a rapid rising of concentration in plasma, suppression of maximum concentration in plasma and maintenance for many hours, capable of being orally administered, having prolonged action. CONSTITUTION:A medicine compound of oxybutynin hydrochloride is treated with a sustained release coating agent such as water-insoluble polymer or enteric coating substance to give a sustained release oxybutynin hydrochloride. A given amount of the sustained release oxybutynin hydrochloride is added to a preparation, which is optionally mixed with an oxybutynin hydrochloride having immediate effects to give an oxybutynin hydrochloride preparation having prolonged action.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an orally administrable sustained-release preparation containing oxybutynin hydrochloride.

[0002]

2. Description of the Related Art Sustained-release preparations can reduce the number of times of administration per day, so that the patient can be freed from the trouble of taking the medicine, and further, the effect of the medicine becomes unstable due to forgetting to take the medicine. In addition, it has the advantage that side effects due to a rapid increase in blood concentration can be avoided. Further, by maintaining the optimum blood concentration of the drug, there is an advantage that the treatment can be surely performed.

In recent years, urinary incontinence of elderly people is becoming a social problem, and oxybutynin hydrochloride, which was developed as a drug for treating urinary incontinence and frequent urination, is highly evaluated for its effectiveness. Oxybutynin hydrochloride is promptly absorbed after administration, but its elimination half-life is short, so it must be taken 3 times a day. Further, urinary incontinence patients often have difficulty in going out for a long time due to their symptoms, and often have inconvenience in social life.

[0004]

Therefore, there has been a strong demand for the development of a sustained-release preparation in which the effect of oxybutynin hydrochloride, which is a drug for treating urinary incontinence and frequent urination, lasts.

[0005]

Therefore, as a result of intensive studies, the present inventors have found that oxybutynin hydrochloride can be obtained by adding an organic acid to a pharmaceutical composition containing oxybutynin hydrochloride to form a sustained-release coating. The present invention has been completed based on the finding that the sustained release of oxybutynin was obtained and that the blood concentration of oxybutynin hydrochloride was sustained in humans.

Therefore, the sustained-release oxybutynin hydrochloride preparation of the present invention is characterized by containing sustained-release oxybutynin hydrochloride obtained by applying a sustained-release coating to a pharmaceutical composition of oxybutynin hydrochloride. The sustained-release oxybutynin hydrochloride in the present invention, oxybutynin hydrochloride, corn starch, potato starch, pregelatinized starch, lactose, mannitol, sorbitol, sucrose, dextrin, crystalline cellulose and other excipients, carboxymethyl cellulose, modified starch , Carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, partially pregelatinized starch and other disintegrants, and gum arabic, sodium alginate, agar, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and other binders. After addition, it is made into a pharmaceutical composition in the form of fine particles, powder, granules, powder, pills, tablets, etc. by a conventional method, and this pharmaceutical composition is provided with a sustained-release film. It is intended. Alternatively, non-parel (Freund Industrial Co., Ltd .: registered trademark), which is a commercially available spherical granule, and Sphere (Asahi Kasei: registered trademark) are used as powders of oxybutynin hydrochloride, or oxybutynin hydrochloride dissolved in a solvent such as purified water or alcohol. Is obtained by uniformly adhering to the surface of granules by a conventional method to obtain a pharmaceutical composition, which is then subjected to a sustained-release coating.

In the present invention, as the sustained-release coating agent, ethyl cellulose, aminoalkyl methacrylate copolymer, methacrylic acid copolymer S, which are usually used,
Water-insoluble polymers such as ethyl acrylate / methyl methacrylate copolymer, polyvinyl chloride, polyethylene, and polymers such as hydroxyethyl cellulose, maleic anhydride copolymer, styrene-acryl copolymer, and cellulose acetate phthalate, cellulose acetate Trimellitate, carboxymethyl ethyl cellulose, methacrylic acid copolymer and enteric substances such as hydroxypropyl methyl cellulose phthalate and hydroxypropyl methyl cellulose acetosuccinate, paraffin,
Oils and fats such as microcrystalline wax, stearyl alcohol, cenol, glycerin fatty acid ester, hydrogenated oil, carnauba wax, beeswax, syrup, stearic acid, palmitic acid, myristic acid, behenic acid, and metal salts of higher fatty acids are used. These are usually dissolved in an appropriate solvent to form a solution, which is applied to the pharmaceutical composition by a method such as spray coating to form a film.

The sustained-release coating is preferably a coating composed of a water-insoluble polymer, preferably ethyl cellulose or a combination of ethyl cellulose and a water-insoluble polymer, or a single or a combination of the above substances. It can be a release coating. When ethyl cellulose and a water-insoluble polymer are combined, 5 to 100 parts by weight of the water-insoluble polymer can be added to 100 parts by weight of ethyl cellulose. Ethyl cellulose having various viscosities is commercially available from Dow and Hercules. The effect on the release characteristics of the active ingredient varies depending on the viscosity of ethyl cellulose, and a sustained release coating of the present invention preferably has a viscosity of 7 to 50 cps.

To form ethyl cellulose as a film-forming agent, it is usually dissolved in a solvent at a concentration of 3 to 10 parts, or 5 to purified water.
Suspended in 15 parts by weight, and 1 to 100 parts by weight of the pharmaceutical composition
Although 100 parts by weight is applied, the desired sustained release rate can be obtained with 5 to 50 parts by weight being preferred.

As the coating solvent in combination with ethyl cellulose or a water-insoluble polymer, ethyl alcohol, methanol, isopropyl alcohol, acetone, methyl cellosolve, halogenated hydrocarbon, etc., can be used alone or as a mixed solution. Further, when applying a film coating, various additives can be usually added to the coating liquid.

Examples of the additive include sodium dioctyl sulfosuccinate, dibutyl sebacate, polysorbate 80, polyoxyethylene hydrogenated castor oil, Twee
n, isopropyl myristate, sorbitan monostearate, squalane, polyethylene glycols and other surfactants, trimethyl citrate, triacetin, propylene glycol, glycerin, plasticizers such as medium-chain fatty acid glycerides, talc, magnesium stearate, calcium stearate , Light anhydrous silicic acid, hydrous silicic acid,
As a lubricant such as aluminum hydroxide gel or an antioxidant, butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, ascorbyl palmitate, dl-α-tocopherol, cystine, thioglycerol and the like can be used. More dyes,
Flavors, flavoring agents, etc. can also be added. These are sustained-release coating agents, for example 0.01 to 50 per 100 parts by weight of ethyl cellulose.
Parts by weight are preferably used.

Further, it is known that if the thickness of the sustained-release coating agent, for example, the coating of a polymer agent such as ethyl cellulose is increased, a lag time occurs before the start of drug release. A water-soluble substance may be added to the water-insoluble sustained-release coating agent such as ethyl cellulose in order to reduce the lag time and control the release rate. For these purposes, for example, sucrose, sorbitol, mannitol, sodium chloride, the above-mentioned surfactants and polyethylene glycols, or water-soluble coating agents such as hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. , Aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate and the like are used. The amount of the water-soluble substance used varies depending on the sustained-release coating agent, but usually 0.1 to 50 parts by weight is preferably used with respect to 100 parts by weight of ethyl cellulose, and the release rate can be adjusted by changing these and the film thickness. ..

Then, when the sustained release preparation is administered to humans, the preparation gradually moves from the stomach to the lower part of the intestine. At this time, the pH of the stomach is 1 to 3.5, pH 5 to 6 in the duodenum, and pH 6 to 6 in the jejunum.
7. It is said that the ileum reaches pH 8 and the effect on drug release cannot be ignored due to pH fluctuation. It was expected that it would be difficult to secure the dissolution from the preparation even in the lower part of the intestine because the drug of the preparation of the present invention has a low alkaline solubility. In order to solve this problem, the present inventors have conducted diligent research and have completed a sustained-release preparation of oxybutynin hydrochloride that is not affected by pH by adding an acidic substance.

Acidic substances include hydrochloric acid, phosphoric acid, acetic acid,
Lactic acid, adipic acid, ascorbic acid, erythorbic acid,
Citric acid, gluconic acid, gluconodelta lactone, aspartic acid, glutamic acid, succinic acid, tartaric acid, fumaric acid, malic acid and the like can be used. These acidic substances can be used alone or in combination of two or more. Further, phosphoric acid and its salt, ascorbic acid and its salt, citric acid and its salt, tartaric acid and its salt can be used in combination, and further, it can be freely combined from the above-mentioned acids. These acidic substances vary depending on the constituents of the oxybutynin hydrochloride pharmaceutical composition, but usually 0.1 to 40 parts by weight per 1 part by weight of oxybutynin hydrochloride.
Although it can be used in parts by weight, it is preferably 1 to 20 parts by weight. These acidic substances are used as they are by mixing them into a pharmaceutical composition of oxybutynin hydrochloride in a powder state, or are dissolved in a solvent such as purified water or alcohol and then added to the pharmaceutical composition. , Powder, granules, powder, pills or tablets. Further, it can be attached to commercially available spherical granules such as nonpareil or sphere in the same powder or liquid form. In this way, the sustained release agent with improved solubility is adjusted to pH.
It was evaluated by a dissolution test at 1.2, pH 4.0 and pH 6.8, and it was confirmed that the preparation was not affected by pH.

Next, the combination of immediate-release and sustained-release oxybutynin hydrochloride according to the present invention refers to the above-mentioned sustained-release oxybutynin hydrochloride and an immediate-release obtained by adding an acidic substance to a pharmaceutical composition. It is a drug product that is combined with the oxybutynin hydrochloride. The mixing ratio of the immediate release member and the sustained release member is determined so as to obtain the desired blood concentration and duration. Furthermore, sustained-release oxybutynin hydrochloride can control the duration of blood concentration by combining several types with different release rates. In the present invention, the compounding ratio of the fast-acting oxybutynin hydrochloride is 5 to 50 parts by weight, preferably 10 to 40 parts by weight, based on 100 parts by weight of the total oxybutynin hydrochloride.
Parts by weight. The sustained-release oxybutynin hydrochloride preparation thus obtained is in the form of powder, fine particles, granules, or pills. Further, a pharmaceutical excipient can be added to these and processed into dosage forms such as capsules, sachets and tablets by a conventional method.

[0016]

ACTION AND EFFECT The thus obtained sustained-release oxybutynin hydrochloride preparation of the present invention is capable of promptly rising the plasma concentration of oxybutynin hydrochloride, suppressing the maximum plasma concentration and sustaining it for a long time, Once a day or 2 a day
It has become possible to make a reusable formulation.

[0017]

EXAMPLES AND COMPARATIVE EXAMPLES The present invention will be described in more detail with reference to the following examples. Example 1 Production of Pill A 120 g of oxybutynin hydrochloride and 445 g of lactose were weighed and mixed, and then sieved with a 100 mesh sieve. Next, 200 g of crushed tartaric acid and 200 g of powdered sugar are mixed, and then a powder containing the main drug and a powder for mixing and spraying are obtained. CF coater [CF 360 type, Freund Industrial Co., Ltd.] non-pareil 1
Send 600 g of 03 (Freund Industries) and send hot air while rolling. Separately, hydroxypropyl cellulose (HPC-
L Nippon Soda Co., Ltd. 25g, polyethylene glycol 60
00 70 g of purified water: ethanol (2: 8) in 500 g of binder solution is prepared. While spraying this solution, the powder containing the main drug is sprinkled little by little on the surface of non-pareil to make the pill A adhere evenly. obtain. This is designated as immediate release pill A. Production of coating pill A As a coating solution, 60 g of ethyl cellulose, 12 g of purified shellac, 24 g of hydroxypropylmethyl cellulose (TC-5 Shin-Etsu Chemical Co., Ltd.), 552 g of ethanol,
It was dissolved in 552 g of methylene chloride. Pill A 600g is put into a CF coater, and is 10% as ethyl cellulose (W / W)
The coating solution was sprayed to give sustained release coating pill A.

Example 2 Manufacture of Pill B 2620 g of Nonpareil 103 was put into Granurex GR5 type (Freund Sangyo), and hot air was sent while rolling and flowing.
Separately, 120 g of oxybutynin hydrochloride, 200 g of citric acid, 20 g of polyethylene glycol 6000, and 40 g of hydroxypropyl cellulose were mixed with ethanol and water (7: 3) 3400 g.
Dissolve with stirring, and further suspend 76 g of talc. This solution is sprayed on the surface of non-pareil, and oxybutynin hydrochloride is layered on the surface of non-pareil to obtain pill B. This is designated as immediate release pill B. Production of coating pill B Ethylcellulose (Std 10 D
ow) 200 g, glycerin fatty acid ester (MYVACET
9-40T, Koyo Mercantile Company Ltd) 20 g is dissolved in ethanol 1890 g and methine chloride 1890 g. Pill B (2000 g) was put in Granurex and coated on 10% (W / W) pill B as ethyl cellulose to obtain a sustained-release coated pill B.

Example 3 Production of Elementary Granules C Oxybutynin hydrochloride 180 g, lactose 1010 g, corn starch 700 g, crystalline cellulose (Avicel PH101:
Asahi Kasei Co., Ltd.) 600 g, succinic acid 300 g, carboxymethyl cellulose (NS-300 Gotoku Pharmaceutical Co., Ltd.) 150 g
Were weighed and mixed uniformly. Furthermore, a 5% aqueous solution of hydroxypropylcellulose prepared separately in advance 12
00 g was added to the above powder and mixed, and then granulated by a conventional method to obtain elementary granules C. This is designated as immediate release granule C. Production of coated granules C 200 g of ethyl cellulose, 40 g of triethyl citrate, 20 g of polyethylene glycol 6000 and 1850 g of ethanol
Dissolve by stirring. Further, 40 g of talc is added, and 1850 g of methylene chloride is added with stirring to prepare a coating solution. 2000 g of elementary granules C was put into a flow coater multi (FML-5, manufactured by Freund) and fluidized, and 10% (W / W) of ethyl cellulose was coated to obtain sustained-release coated granules C.

Example 4 Production of elementary granule D 180 g of oxybutynin hydrochloride, 729.8 g of lactose, 900 g of crystalline cellulose, 600 g of partially pregelatinized starch, 300 g of tartaric acid and 230 g of sodium tartrate are uniformly mixed. Separately prepared 1200 g of 5% HPC aqueous solution was added to obtain elementary granules D by a conventional method. This is designated as immediate release granule D. Production of coated granules D 210 g of ethyl cellulose, 90 g of aminoalkyl methacrylate copolymer, glycerin fatty acid ester 3
g is dissolved in 2849 g of ethyl alcohol and 2850 g of methylene chloride to prepare a coating solution. Next, add 3000g of elementary granules to a Spiraflow coater (FFC, SFC-5).
And 10% (W / W) of ethyl cellulose was coated to obtain sustained-release coated granules D.

Comparative Example 1 Rapid Release Tablets 30 g of oxybutynin hydrochloride, 1.572 g of lactose and 180 g of crystalline cellulose are weighed and uniformly mixed. Next, add 18g of magnesium stearate and lubricate, then 1 tablet
Tablets were compressed to 180 mg to give quick release tablets.

Comparative Example 2 Sustained-release preparation containing no acid 120 g of oxybutynin hydrochloride, 840 g of lactose, 600 g of crystalline cellulose, 400 g of corn starch are weighed and uniformly mixed. Next, 800 g of a separately prepared 5% aqueous solution of hydroxypropyl cellulose is added to this powder and kneaded, and then granulated by a conventional method. Sift these particles to remove fines and agglomerated particles and remove particles of a certain size.
g was coated with the following film solution. The formulation of the film solution is 50 g of ethyl cellulose, triethyl citrate.
10g, polyethylene glycol 6000 5g ethanol
Dissolve in 460 g. Furthermore, 10 g of talc and 460 g of methylene chloride are added to this solution to form a coating solution. The particles were coated with 10% (W / W) of ethyl cellulose by a conventional method. Thus, sustained release coating granules containing no acid were obtained.

[0023]

[Test example]

Test Example A sustained-release preparation obtained in Example was subjected to a dissolution test. In addition, a typical pharmaceutical formulation was administered to humans and the blood oxybutynin concentration transition was measured. ． Experimental method Twelfth revised Japanese Pharmacopoeia test method Test by dissolution test The sustained-release preparation was put in a 1 L flask, and the Japanese Pharmacopoeia first liquid (pH
1.2) Alternatively, 900 ml of phosphate buffer (pH 6.8) was added and kept at 37 °. Paddle method 100 revolutions 1, 2,
The test solution was collected at 3, 4, 6, 8, 10, and 12 hours, and the amount of oxybutynin hydrochloride was determined by a high performance liquid chromatography (HPLC) method. Next, in the human administration test, two quick-release tablets containing 3 mg of oxybutynin hydrochloride were administered to volunteers for comparison. The sustained-release preparation was administered to volunteers by combining the sustained-release preparation (corresponding to 5 mg of oxybutynin hydrochloride) obtained in Example 3 and the immediate-release preparation (corresponding to 1 mg of oxybutynin hydrochloride), and compared with the commercially available preparation. Blood 0.5,
Blood was collected at 1, 2, 3, 4, 6, and 8 hours, and after centrifugation, oxybutynin hydrochloride in plasma was quantified by the HPLC-ECD method.

[0024]. Results Results are shown in FIGS. 1 to 6. FIG. 1 shows the dissolution curves of the fast-dissolving tablet shown in Comparative Example 1 at pH 1.2 and pH 6.8 and the dissolution curve from the sustained-release preparation containing no organic acid obtained in Comparative Example 2. It shows a marked sustained release property compared to quick-release tablets, but pH
Compared with the elution of 1.2, pH 6.8 has a lower value, suggesting a problem. FIG. 2 shows the elution curves of the preparation obtained in Example 1 at pH 1.2 and pH 6.8. It can be seen that there is no difference in elution and that the preparation has sustained release. 3 shows the dissolution curves of the preparation of Example 2 at pH 1.2 and pH 6.8, FIG. 4 shows the dissolution curves of the preparation of Example 3 at pH 1.2 and pH 6.8, and FIG. 5 shows the preparation of Example 4 at pH 1.2 and pH 6. 8 shows the elution curve of .8. All of them are hardly affected by pH, and sustained release is obtained.
FIG. 6 is a graph showing changes in blood concentration when 6 mg of the quick-release oxybutynin hydrochloride obtained in Comparative Example 1 was administered to 4 fasting volunteers. In addition, immediate release granule C containing 1 mg of oxybutynin hydrochloride obtained in Example 3 and sustained release coated granule C containing 5 mg of oxybutynin hydrochloride.
4 shows changes in blood concentration when administered in a capsule and administered on an empty stomach. As is clear from the figure, the preparations of Examples showed a rapid increase in blood concentration and a sustained effect as compared with the immediate release tablets. When the biological parameters of the preparations of Examples are compared with those of immediate release tablets, Tmax is 4 times, Cmax is about 1/2, MRT is 3.6 times, AUC is not so different, and sustained release also in human. confirmed.

[Brief description of drawings]

FIG. 1 is a graph showing dissolution curves of preparations of Comparative Examples 1 and 2.

FIG. 2 is a graph showing the dissolution curve of the preparation of Example 1.

FIG. 3 is a graph showing the dissolution curve of the preparation of Example 2.

FIG. 4 is a graph showing the dissolution curve of the preparation of Example 3.

FIG. 5 is a graph showing the dissolution curve of the preparation of Example 4.

FIG. 6 is a graph showing blood levels of the preparations of Comparative Example and Example administered.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Takako Igarashi 957-5 Wanagaya, Matsudo-shi, Chiba Kodama Co., Ltd. Institute for Biological Sciences (72) Inventor Katsuyoshi Yasaka 326-3 Obishi Miyazai, Sakai-machi, Ibaraki Pref. Ball Science Research Institute

Claims (8)

[Claims] 1. A sustained-release oxybutynin hydrochloride preparation containing sustained-release oxybutynin hydrochloride obtained by applying a sustained-release coating to a pharmaceutical composition of oxybutynin hydrochloride. 2. A sustained-release oxybutynin hydrochloride preparation containing sustained-release oxybutynin hydrochloride obtained by applying a sustained-release coating to a pharmaceutical composition containing oxybutynin hydrochloride and an acidic substance. 3. The sustained-release oxybutynin hydrochloride preparation according to claim 2, wherein the acidic substance is contained in an amount of 0.1 to 40 parts by weight with respect to 1 part by weight of oxybutynin hydrochloride. 4. The sustained-release oxybutynin hydrochloride preparation according to claim 1 or 2, wherein the sustained-release coating is a water-insoluble polymer. 5. The sustained-release oxybutynin hydrochloride preparation according to claim 1 or 2, wherein the sustained-release coating comprises ethyl cellulose or a combination of ethyl cellulose and another water-insoluble polymer. 6. The sustained-release according to any one of claims 1 to 5, wherein the amount of the sustained-release coating is 1 to 100 parts by weight based on 100 parts by weight of the pharmaceutical composition containing oxybutynin hydrochloride. Oxybutynin hydrochloride formulation. 7. A sustained-release oxybutynin hydrochloride preparation comprising an immediate-release oxybutynin hydrochloride and a sustained-release oxybutynin hydrochloride. 8. The sustained-release preparation according to claim 7, which contains 5 to 50 parts by weight of immediate-release oxybutynin hydrochloride based on 100 parts by weight of sustained-release oxybutynin hydrochloride according to claim 1 or 2. Oxybutynin hydrochloride formulation.