JP2665858B2 - Long-acting oxybutynin hydrochloride preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention 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, thereby relieving patients from the complexity of taking them and preventing the effects of the medicine from becoming unstable due to forgetting to take them. In addition, there is an advantage that side effects due to a rapid increase in blood concentration can be avoided. Further, by maintaining the optimal blood concentration of the drug, there is an advantage that the treatment is ensured.

In recent years, as urinary incontinence of the elderly has become a social problem, oxybutynin hydrochloride, which has been developed as a therapeutic drug for urinary incontinence and pollakiuria, has been highly evaluated for its effectiveness. Oxybutynin hydrochloride is absorbed immediately after taking, but must be taken three times a day due to its short elimination half-life. Also, urinary incontinence patients often have difficulty in going out of their symptoms for a long time and have difficulty in social life.

[0004]

For this reason, there has been a strong demand for the development of a long-acting preparation which maintains the effect of oxybutynin hydrochloride which is a therapeutic agent for urinary incontinence and pollakiuria.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies and have found that a pharmaceutical composition containing oxybutynin hydrochloride is added with an organic acid, if necessary, to form a sustained-release coating. Was found to be sustained, and the blood concentration of oxybutynin hydrochloride was maintained in humans, thereby completing the present invention.

Therefore, the long-acting oxybutynin hydrochloride preparation of the present invention is characterized by containing a 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 refers to oxybutynin hydrochloride, corn starch, potato starch, pregelatinized starch, lactose, mannitol, sorbitol, excipients such as sucrose, dextrin, crystalline cellulose, and carboxymethyl cellulose, modified starch. Disintegrating agents such as carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, partially pregelatinized starch, and binders such as gum arabic, sodium alginate, agar, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone. After the addition, a pharmaceutical composition such as fine granules, powders, granules, powders, pills, or tablets is added by a conventional method, and a controlled release film is applied to the pharmaceutical composition. It is intended. Alternatively, oxybutynin hydrochloride powder or oxybutynin hydrochloride dissolved in a solvent such as purified water or alcohol using commercially available spherical granules, nonpareil (Freund Corporation: registered trademark) and Selfia (Asahi Chemical Industry: registered trademark). Is uniformly adhered to the surface of granules by a conventional method to obtain a pharmaceutical composition, which is provided with a sustained-release coating.

[0007] In the present invention, as the sustained-release coating agent, commonly used ethyl cellulose, aminoalkyl methacrylate copolymer, methacrylic acid copolymer S,
Water-insoluble polymers such as ethyl acrylate / methyl methacrylate copolymer, polyvinyl chloride, polyethylene, etc., and polymers such as hydroxyethyl cellulose, maleic anhydride copolymer, styrene acrylic copolymer, cellulose acetate phthalate, cellulose acetate Trimellitate, carboxymethylethylcellulose, methacrylic acid copolymer and enteric substances such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetosuccinate, paraffin,
Fats and oils such as microcrystalline wax, stearyl alcohol, senol, glycerin fatty acid ester, hardened oil, carnauba wax, beeswax, mocro, 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, applied to the pharmaceutical composition by a method such as spray coating, and formed into a film.

As the sustained-release film, a film made of a water-insoluble polymer is particularly preferable, and ethyl cellulose, a combination of ethyl cellulose and a water-insoluble polymer, or a mixture of the above substances alone or in combination is preferred. It can be a release coating. When ethyl cellulose and a water-insoluble polymer are combined, 5 to 100 parts by weight of a water-insoluble polymer can be added to 100 parts by weight of ethyl cellulose. Ethyl cellulose is available in various viscosities from Dow or Hercules. The effect on the release characteristics of the active ingredient differs depending on the viscosity of the ethyl cellulose, and the sustained-release coating of the present invention preferably has a viscosity of 7 to 50 cps.

In order to make ethyl cellulose a coating agent, it is usually dissolved in a solvent at a concentration of 3 to 10 parts, or 5 to 5 parts in purified water.
Suspended in 15 parts by weight, 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 preferably with 5 to 50 parts by weight.

As a coating solvent in combination with ethylcellulose or a water-insoluble polymer, a simple substance or a mixture of ethyl alcohol, methanol, isopropyl alcohol, acetone, methyl cellosolve, halogenated hydrocarbon and the like can be used. Further, when film coating is performed, various additives can be usually added to the coating solution.

Examples of additives 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,
Lubricants such as aluminum hydroxide gel and the like, or butylhydroxyanisole, dibutylhydroxytoluene, propyl gallate, ascorbic acid palmitate, dl-α-tocopherol, cysteine, thioglycerol and the like can be used as antioxidants. Further dyes,
Flavors, flavoring agents and the like can also be added. These are controlled release coating agents, for example, 0.01 to 50 parts by weight per 100 parts by weight of ethyl cellulose.
Parts by weight are preferably used.

It is known that when the thickness of the sustained-release coating agent, for example, the thickness of a coating made of a polymer such as ethyl cellulose, is increased, a lag time occurs before the release of the drug. In order to reduce the lag time and control the release rate, a water-soluble substance may be added to the water-insoluble sustained release coating agent such as ethyl cellulose. For these purposes, for example, sucrose, sorbitol, mannitol, sodium chloride, and 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 diethyl amino acetate, and the like. The amount of the water-soluble substance used depends 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 ethylcellulose, and the release rate can be adjusted by changing the film thickness with these. .

Next, when the sustained release preparation is administered to a human, 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, the pH of the duodenum is 5 to 6, and the pH of the jejunum is 6 to 6.
7. It is said that pH reaches 8 in the ileum, and the effect of pH fluctuations on the release of drugs cannot be ignored. Since the solubility of the drug of the preparation of the present invention in alkaline was reduced, it was expected that it would be difficult to ensure dissolution from the preparation even in the lower intestine. In order to solve this problem, the present inventors have made intensive studies and have completed a sustained-release formulation of oxybutynin hydrochloride which is not affected by pH by adding an acidic substance.

As the acidic substance, hydrochloric acid, phosphoric acid, acetic acid,
Lactic acid, adipic acid, ascorbic acid, erythorbic acid,
Citric acid, gluconic acid, glucono delta 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. Phosphoric acid and its salts, ascorbic acid and its salts, citric acid and its salts, tartaric acid and its salts can be used in combination, and can also be freely combined from the above 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 by weight, it is preferably 1 to 20 parts by weight. These acidic substances may be used as they are in the form of a powder mixed with a pharmaceutical composition of oxybutynin hydrochloride, or may be dissolved in a solvent such as purified water or alcohol and then added to the pharmaceutical composition. , Powders, granules, powders, pills or tablets. It can also be applied in powder form or liquid form to commercially available spherical granules such as nonpareil and selfia. The sustained release agent having improved solubility in this way is
Evaluation was performed 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.

[0015] Next, the preparation of the present invention in which the immediate-release and sustained-release oxybutynin hydrochloride are combined is the above-mentioned sustained-release oxybutynin hydrochloride and the immediate-release preparation obtained by adding an acidic substance to a pharmaceutical composition in the same manner. It is a preparation in combination with a soluble oxybutynin hydrochloride. The combination ratio of the quick release member and the sustained release member is determined so as to obtain a desired blood concentration and duration. Furthermore, the sustained release of oxybutynin hydrochloride can also be controlled by combining several types with different release rates. In the present invention, the compounding ratio of the quick-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 shape of the long-acting oxybutynin hydrochloride preparation thus obtained is in the form of powder, fine granules, granules or pills. Further, a pharmaceutical excipient may be added to these, and processed into a dosage form such as a capsule, a sachet or a tablet by a conventional method.

[0016]

The long-acting oxybutynin hydrochloride preparation of the present invention obtained as described above can rapidly increase the plasma concentration of oxybutynin hydrochloride, suppress the maximum plasma concentration and maintain the same for a long time, Once a day or 2 days a day
It has become possible to obtain a dosage form preparation.

[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 tartaric acid pulverized and 200 g of powdered sugar are mixed and then mixed with a powder containing the main drug to obtain a powder for spraying. Non-pareil for CF coater [CF 360 type, Freund Corporation] 1
Put 600g of 03 (Freund Corporation) and send warm air while rolling. Separately, hydroxypropyl cellulose (HPC-
L Nippon Soda Co., Ltd.) 25 g, polyethylene glycol 60
A solution of a binder in which 70 g was dissolved in 500 g of purified water: ethanol (2: 8) was prepared, and while this solution was sprayed, a powder containing the main drug was sprayed little by little on the surface of the non-pareil to uniformly adhere the pill A, obtain. This is designated as immediate release pill A. Production of coating pill A Ethyl cellulose 60 g, purified shellac 12 g, hydroxypropylmethyl cellulose (TC-5 Shin-Etsu Chemical Co., Ltd.) 24 g as a coating solution, and ethanol 552 g,
Dissolved in 552 g of methylene chloride. Pill A 600 g is put in a CF coater, and is 10% (W / W) as ethyl cellulose.
The coating solution was sprayed to obtain a sustained-release coating pill A.

Example 2 Production of Pill B 2620 g of nonpareil 103 was placed in Granulex GR5 type (Freund Corporation) 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; 3400 g of a water mixture (7: 3)
While stirring, and further suspend 76 g of talc. This solution is sprayed on the surface of the non-pareil, and oxybutynin hydrochloride is layered on the surface of the non-pareil to obtain pill B. This is designated as immediate release pill B. Production of coating pill B Ethyl cellulose (Std 10 D
ow company) 200g, glycerin fatty acid ester (MYVACET
20-40T, Koyo Mercantile Company Ltd) 20 g are dissolved in ethanol 1890 g and methine chloride 1890 g. Granulex was charged with 2000 g of pill B, and coated with 10% (W / W) pill B as ethyl cellulose to obtain a sustained-release coating pill B.

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

Example 4 Preparation of Elementary Granules 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. 1200 g of a 5% aqueous HPC solution prepared separately was added, and elementary granules D were obtained 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 was dissolved in 2849 g of ethyl alcohol and 2850 g of methylene chloride to prepare a coating solution. Next, 3000g of elementary granules D was added to a spiral flow coater (SFC-5, manufactured by Freund).
And coated with 10% (W / W) as ethyl cellulose to obtain sustained-release coated granules D.

Comparative Example 1 Immediate Release Tablet 30 g of oxybutynin hydrochloride, 1.572 g of lactose, and 180 g of crystalline cellulose were weighed and uniformly mixed. Then add 18g of magnesium stearate and lubricate, then 1 tablet
Tablets were compressed to 180 mg to give immediate 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, and 400 g of corn starch were weighed and uniformly mixed. Next, 800 g of a separately prepared 5% aqueous solution of hydroxypropylcellulose is added to this powder, kneaded, and then granulated by a conventional method. These particles are sieved to remove fine powder and agglomerated particles,
g was coated with the following film solution. The formulation of the film liquid is ethyl cellulose 50g, triethyl citrate
10 g, polyethylene glycol 6000 5 g ethanol
Dissolve in 460 g. Further, 10 g of talc and 460 g of methylene chloride are added to this solution to prepare a coating solution. The particles were coated with ethyl cellulose at 10% (W / W) by a conventional method. Thus, sustained-release coatable granules containing no acid were obtained.

[0023]

[Test example]

Test Example The dissolution test of the sustained release preparation obtained in the example was performed. In addition, a representative formulation was administered to humans, and changes in blood oxybutynin concentration were measured. . Experimental method 12th revision Japanese Pharmacopoeia test method Test by dissolution test Put the sustained release preparation into a 1 L flask,
1.2) Alternatively, 900 ml of a phosphate buffer (pH 6.8) was added, and the mixture was kept at 37 °. Paddle method 1, 2, at 100 rotations
Test liquids were collected at 3, 4, 6, 8, 10, and 12 hours, and the amount of oxybutynin hydrochloride was determined by high performance liquid chromatography (HPLC). Next, in a human administration test, two quick-release tablets containing 3 mg of oxybutynin hydrochloride were administered to volunteers to make a comparative example. A long-acting preparation was administered to volunteers in combination with the sustained-release preparation (equivalent to 5 mg of oxybutynin hydrochloride) obtained in Example 3 and an immediate release preparation (equivalent to 1 mg of oxybutynin hydrochloride), and compared with a commercially available preparation. 0.5 blood,
Blood was collected at 1, 2, 3, 4, 6, and 8 hours, and oxybutynin hydrochloride in the plasma was quantified by HPLC-ECD after centrifugation.

[0024] Results The results are shown in FIGS. FIG. 1 shows the dissolution curves at pH 1.2 and pH 6.8 of the fast-dissolving tablet shown in Comparative Example 1 and the dissolution curve from the sustained-release preparation containing no organic acid obtained in Comparative Example 2. It shows marked sustained release compared to immediate release tablets, but pH
Compared to the elution of 1.2, the value was lower at pH 6.8, indicating a problem. FIG. 2 is an elution curve of the preparation obtained in Example 1 at pH 1.2 and pH 6.8, which shows that there is no difference in elution and that the preparation is sustained release. 3 is an elution curve of the preparation of Example 2 at pH 1.2 and pH 6.8, FIG. 4 is an elution curve of the preparation of Example 3 at pH 1.2 and pH 6.8, and FIG. 8 shows the elution curve of .8. All of them are hardly affected by pH and have sustained release.
FIG. 6 is a graph showing changes in blood concentration when 6 mg of fast-release oxybutynin hydrochloride obtained in Comparative Example 1 was administered to four fasting volunteers. Further, immediate-release granules C containing 1 mg of oxybutynin hydrochloride obtained in Example 3 and sustained-release coated granules C containing 5 mg of oxybutynin hydrochloride obtained in Example 3
Shows the time course of blood concentration when was administered in a capsule and fasted. As is clear from the figure, the preparations of the examples showed a rapid increase in blood concentration compared to the immediate release tablets, and showed sustained action. Comparing the immediate release tablet with the biological parameters, the formulations of the examples show a Tmax of 4 times, a Cmax of about 1/2, an MRT of 3.6 times, a small difference in AUC, and a sustained release in humans. confirmed.

[Brief description of the drawings]

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

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

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

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

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

FIG. 6 is a graph showing blood levels after administration of preparations of Comparative Examples and Examples.

Continuing from the front page (72) Inventor Takako Igarashi 957-5 Wagaya, Matsudo-shi, Chiba Kodama Co., Ltd. Inside the Biological Sciences Research Institute (72) Inventor Katsuyoshi Yasaka 326-3, Oki, Sakaicho, Sarushima-gun, Ibaraki Prefecture Kodama Corporation In Bioscience Research Institute (56) References JP-A-60-4120 (JP, A) Pharmaceutical Excipients Study Group “Practical Pharmaceutical Additives” (49.3.5) published by Kagaku Kogyo Co., pp. 108-112 ( (Coating agent)

Claims (7)

(57) [Claims] 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. 2. The long-acting oxybutynin hydrochloride preparation according to claim 1, wherein the acidic substance is contained in an amount of 0.1 to 40 parts by weight per 1 part by weight of oxybutynin hydrochloride. 3. A sustained release oxybutynin formulation of the first Kouki mounting claims a sustained release coating is a water-insoluble polymer. 4. A sustained release coating is ethyl cellulose or ethyl cellulose and other depot oxybutynin formulations as in claim 1 Kouki mounting consisting of a combination of a water-insoluble polymer. 5. The long-acting effect according to any one of claims 1 to 4, 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 preparation. 6. The immediate release oxybutynin hydrochloride and the claims
A sustained-release oxybutynin hydrochloride preparation, comprising the sustained-release oxybutynin hydrochloride according to claim 1 . 7. A sustained release oxybutynin formulation of claim 6 wherein wherein the containing 5-50 parts by weight of immediate release oxybutynin against sustained-release oxybutynin hydrochloride 100 parts by weight of the first Kouki mounting claims .