JP3158435B2 - Sustained release formulation - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a drug having a property of decreasing the solubility in a neutral region or an alkaline region as compared with an acidic region as a physicochemical property of the drug, at a constant release rate in the body. A sustained release formulation for retention.

Background Art Sustained-release preparations reduce the number of doses to improve the patient's convenience, maintain effective efficacy by maintaining the effective concentration of the drug for a long time, and maintain the prescribed concentration without impairing the efficacy. Since it has many therapeutic advantages such as suppressing toxicity and side effects, many types have been developed so far.

In general, for example, a preparation in which a hardly soluble substance is coated on the surface of a tablet or granule, a preparation in which the compound is mixed in a tablet or granule, a preparation in which a polymer compound is mixed to control drug release, and the like are known.

However, if the drug has a property that its solubility decreases when it becomes a neutral region or an alkaline region as compared with the acidic region as its physicochemical property, the sustained-release preparation manufactured by the general manufacturing method as described above is The drug exhibits a release property depending on the solubility of the drug in the liquidity. As a result, a phenomenon occurs in which the release rate is high in an acidic region where the solubility of the drug is high, and conversely slow in a neutral to alkaline region where the solubility is low.

In general, it is known that the environmental pH in the gastrointestinal tract indicates an acidic region of about 1 to 3 in the stomach and a neutral to alkaline region of about 5 to 8 in the small intestine. Inevitably, the pH in the gastrointestinal tract is affected, and there are concerns about drug release with individual differences and sometimes irregular drug release even in the same person, resulting in variations in blood concentration,
Alternatively, the bioavailability may be reduced.

Therefore, as a basic condition for making such a drug into a sustained-release preparation, some measures must be taken to ensure a stable release rate that is hardly affected by liquidity.

Regarding the method for improving the release of drugs with different solubilities in the acidic region and the neutral to alkaline region, an organic acid and a water-soluble polymer agent are blended in the lumber, and the eluate penetrating into the formulation is kept in the low pH region and released. A method of making the speed less affected by the pH of the test solution (Japanese Patent Application Laid-Open No. 62-283926) is disclosed.

However, the result obtained by this method is not guaranteed to keep the inside of the preparation in an acidic region while the drug is completely released, and is a method that cannot be applied to substances that are reactive with organic acids, Further, there is a disadvantage that a stable release rate cannot be obtained depending on the dispersion state of the water-soluble polymer.

DISCLOSURE OF THE INVENTION In order to overcome the above-mentioned disadvantages of the prior art, the present inventors have intensively studied. Therefore, it is necessary to create a completely new sustained-release preparation which eliminates the above-mentioned disadvantages for a drug having a property in which the solubility becomes lower in the neutral range to the alkaline range as compared with the acidic range as the physicochemical property of the drug. It is an object of the present invention and a problem to be solved.

The gist of the present invention is to form a double film on the surface of a drug.

Here, the double coating means a coating of a substance which is insoluble in water and whose solubility in water does not change due to liquidity, and a coating of a substance which is soluble at pH 5 or more. Also, it means a film of a substance that does not dissolve at a pH of 7 or less and a film of a substance that dissolves at a pH of 5 or more.

The fact that the drug can be given such a double coat and the desired sustained release can be obtained by such a method,
It has been found for the first time by the present inventors.

 Hereinafter, the configuration of the present invention will be described in detail.

The drug which is a control of the present invention has such a property that its solubility decreases in the neutral region to the alkaline region as compared with the acidic region as its physicochemical property.

In general, such a drug is subjected to only a pH-independent film-forming agent to control the release rate, and the release test is carried out with the first JP liquid (pH 1.2) and the second JP liquid (pH 6.8). When carried out, the amount of drug permeating the coated film thickness differs depending on the liquidity because the solubility of the drug with respect to the liquidity is different, and as a result, the release rate is fast in the JP 1st liquid, and conversely in the JP 2nd liquid It will be slow. This means that it is released quickly in the stomach and, conversely, slowly in the small intestine, making it impossible to obtain a stable sustained release formulation.

The present invention seeks to solve such a problem.

In the composition prepared by the method of the present invention, the film of the substance that dissolves at pH 5 or more in the surface layer has the properties of an enteric coating agent, and therefore does not dissolve in the acidic region.
The film has the same mechanism as that of a film of a substance which is insoluble in water and whose solubility in water does not change due to liquidity, or a film of a substance which does not dissolve at a pH of 7 or less.

Therefore, at this stage, a film of a substance that dissolves at pH 5 or higher and a film of a substance that is insoluble in water and whose solubility in water does not change due to liquidity or a film of a substance that does not dissolve at pH 7 or lower are added. Since the drug is released through the thickness, it exhibits an excellent release suppressing effect in an acidic region where the solubility of the drug is high.

In the preparation of the present invention, on a film of a substance which is insoluble in water and whose solubility in water does not change due to liquidity or pH
Since a film of a substance that dissolves at a pH of 5 or more is applied on a film of a substance that does not dissolve at a pH of 7 or less, at neutral to alkaline, the film of a substance that dissolves at a pH of 5 or more at the surface layer immediately dissolves. In addition, only a film of a substance which is applied to the lower layer and is insoluble in water and whose solubility in water does not change due to liquidity, or a film of a substance which does not dissolve at a pH of 7 or less.

As a result, the film thickness for suppressing release is reduced, and in this state, a release form of membrane permeation only through (a) is taken, and release is significantly promoted even in a neutral to alkaline region where the solubility of the drug is low. be able to.

That is, the present invention provides a film of a substance that dissolves at a pH of 5 or more on a film of a substance that is insoluble in water and whose solubility in water does not change due to liquidity, or a film of a substance that does not dissolve at a pH of 7 or less. As a result, the film thickness of the substance that dissolves at pH 5 or higher is different from the acidic region in which the film of the substance that dissolves at pH 5 or higher dissolves in the neutral to alkaline region. By utilizing the difference between the two, a release rate that is hardly affected by the liquid property can be obtained.

Regarding the release control of the formulation of the present invention, since the basic release mechanism is through membrane permeation, it is dissolved at the film thickness or pH of 7 or less of the water-insoluble coating material whose solubility in water does not change due to liquidity. The release rate is determined by the film thickness obtained by adding the film thickness of the material film not to be dissolved and the film thickness of the material film dissolved at pH 5 or more.

Here, the use ratio of the coating of the substance soluble at pH 5 or more is 1 to 10 times the coating of a substance that is water-insoluble and does not change its solubility in water due to liquidity, or a coating of a substance that does not dissolve at pH 7 or less. It is preferably 2 to 5 times, and even if a double membrane having a ratio exceeding this range is applied, the effect of the preparation of the present invention cannot be obtained.

This usage ratio is a film of a substance that dissolves at pH 5 or more,
It defines the ratio of the film thickness of a film of a substance that is insoluble in water and whose solubility in water does not change due to liquidity or a film of a substance that does not dissolve at pH 7 or less. By changing the thickness of the film, the release rate of the drug can be adjusted.

In the practice of the present invention, the object can be achieved by a simple method of merely adjusting the amount of the substance to be coated in the production of the preparation. This is also one of the important effects of the present invention that enhance the convenience of the present invention.

Examples of the material constituting the film that is insoluble in water and whose dissolution is not affected by liquidity according to the present invention include, but are not limited to, the following.

Ethyl cellulose, aminoalkyl methacrylate copolymer (Eudragit RS, RN100L, RSPML, RN100, RSP
M), fats and oils and waxes such as higher fatty acids, higher fatty acid ester derivatives, higher alcohols and higher alcohol ester derivatives.

Examples of the material constituting the film of the substance that does not dissolve at a pH of 7 or less according to the present invention include the following.

Hydroxypropyl methylcellulose acetate succinate (AQOAT H), methacrylic acid copolymer S (E
udragit S).

Examples of the material of the film of the substance that dissolves at a pH of 5 or more according to the present invention include the following.

Hydroxypropyl methylcellulose phthalate (HP
-55, HP-55S, HP-50), cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate (AQOAT L, M, H), carboxymethylethylcellulose, methacrylic acid copolymer (Eudrag
it L30D55, L100).

For these materials, the coating of a substance which is insoluble in water and whose solubility in water does not change due to liquidity or the coating of a substance which does not dissolve at a pH of 7 or less with respect to a drug or 1 part of a composition containing the same is 0.01 part to 0.5%. Parts, preferably 0.05 to 0.3 parts.

Further, the coating of the substance soluble at pH 5 or more is 0.01 part to 5 parts.
Parts, preferably 0.1 to 1.5 parts.

In addition, plasticizers that are usually used pharmaceutically can be added to these to form a uniform and good film. For example, propylene glycol, polyethylene glycol, glycerin, triethyl citrate and the like can be used.

In addition, water-soluble polymers or powders can be added to these materials for the purpose of promoting release.
More than one species can be used in combination. For example, hydroxylpropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, talc, cornstarch, mannitol, lactose and the like can be used.

As the drug used in the present invention, as a general property, the solubility is different between the acidic region and the neutral to alkaline region, and any drug whose release rate is reduced in the neutral to alkaline region compared to the acidic region. This kind of drug can be applied. Typical examples of these are the following various drugs.

1. Frequent urinary treatment agent Flavoxate hydrochloride, oxybutynin hydrochloride, terodiline hydrochloride, 4-diethylamino-1,1-dimethyl-2-butynyl (±) -α-cyclohexyl-α-phenylglycolate hydrochloride monohydrate 2. Arrhythmia treatment Agents Aprindine hydrochloride, mexiletine hydrochloride, procainamide hydrochloride, arotinolol hydrochloride 3.β-blocker Carteolol hydrochloride, propranolol hydrochloride, labetalol hydrochloride, metoprolol tartrate 4.Coronary vasograding agent dilazep hydrochloride, trimetazine hydrochloride, etaphenone hydrochloride 5.Allergic disease treatment Agents Ketotifen fumarate, azelastine hydrochloride 6. Airway lubricating expectorant Ambroxol hydrochloride 7. Parkinson's syndrome treatment amantadyl hydrochloride 8. Circulation enhancer Ethylephrine hydrochloride 9. Cardiac function / tissue circulation enhancer Isoproterenol hydrochloride 10. Cirapide hydrochloride Improves circulation and metabolism 11. Anesthetic Lidocaine hydrochloride 12. Antidepressant Maprotiline hydrochloride 13. Antiemetic diphenidol hydrochloride 14. Central antitussive Clofedanol hydrochloride Best mode for carrying out the invention The present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example 1 A non-parel (Freund Co., Ltd.) 24-g mesh (900 g) was centrifuged flow type coating granulator (Freund Co., Ltd. CF-
360), 5% of hydroxypropylcellulose
While spraying the solution (containing 50% ethanol), a mixture of 100 g of oxybutynin hydrochloride, 600 g of corn starch and 70 g of low-substituted hydroxypropylcellulose was gradually added and granulated, followed by drying to obtain about 1800 g of spherical elementary granules. . Next, 500 g of the spheroidal granules were put into a centrifugal flow type coating granulator, and 750 ml of an ethanol / methylene chloride (1/1) mixed solution containing 25 g of ethylcellulose, 2.5 g of propylene glycol, and 7.5 g of talc was sprayed, and about 530 g of Coated granules were obtained [pre-granules-1].

Further, 500 g of the pregranules-1 is put into a centrifugal flow type coating granulator, and mixed with ethanol / water (6/4) containing 50 g of hydroxypropylmethylcellulose acetate succinate (AQOATL), 10 g of triethyl citrate and 15 g of talc. 1250 ml of the solution was sprayed to obtain about 570 g of double-coated granules [Product 1 of the present invention].

Example 2 500 g of the spherical elementary granules obtained in Example 1 were charged into a centrifugal flow type coating granulator, and ethanol / ethanol containing 50 g of ethyl cellulose, 5 g of propylene glycol, and 15 g of talc was added.
Spray 1500 ml of a mixed solution of methyl chloride (1/1)
g of coated granules were obtained [pre-granules-2].

Further, 500 g of Pregranulate-2 was charged into a centrifugal fluidized coating granulator, and ethanol / water (6/4) containing 100 g of hydroxypropylmethylcellulose acetate succinate (AQOAT L), 20 g of triethyl citrate, and 30 g of talc was used.
2500 ml of the mixed solution was sprayed to obtain about 650 g of a double-coated granule [Product of the present invention-2].

Example 3 After mixing 150 g of flavoxate hydrochloride, 152.5 g of lactose, 152.5 g of corn starch and 25 g of microcrystalline cellulose, 180 ml of an aqueous solution containing 20 g of polyvinyl alcohol was added and kneaded with a kneader. This was extruded by an extrusion granulator (0.5 mm), dried and sized to obtain about 500 g of columnar elementary granules.

Next, 300 g of the columnar elementary granules were added to a fluidized bed granulator (STRE
A), Eudragit RS30D 9g, triethyl citrate
225 ml of an ethanol solution containing 0.9 g and 2.7 g of talc was sprayed to obtain about 310 g of coated granules [Pre-granule-3].

Further, 300 g of Pregranulate-3 was charged into a fluidized bed granulator, and hydroxypropyl methylcellulose phthalate (HP-5
5) 450ml of a mixed solution of ethanol / methylene chloride (1/1) containing 18g, 1.8g of propylene glycol and 5.4g of talc
Was sprayed to obtain about 320 g of double-coated granules [product of the present invention-3].

Example 4 900 g of a non-pareil 24-32 mesh was charged into a centrifugal flow type coating granulator and sprayed with a 5% solution of hydroxypropylcellulose (containing 50% ethanol in water).
A mixture of 100 g of diethylamino-1,1-dimethyl-2-butynyl (±) -α-cyclohexyl-α-phenylglycolate hydrochloride monohydrate, 680 g of corn starch and 70 g of low-substituted hydroxypropylcellulose was gradually added. After granulation, it was dried to obtain about 1800 g of spherical elementary granules.

Next, 500 g of the spherical elementary granules are put into a centrifugal flow type coating granulator, and 750 ml of an ethanol / methylene chloride (1/1) mixed solution containing 25 g of ethyl cellulose, 2.5 g of propylene glycol, and 7.5 g of talc is sprayed, and about 530 g [Pre-granule-4] was obtained.

Further, 500 g of Pregranulate-4 is charged into a centrifugal flow type coating granulator, and mixed with ethanol / water (6/4) containing 50 g of hydroxypropyl methylcellulose acetate succinate (AQOAT L), 10 g of triethyl citrate, and 15 g of talc. 1250 ml of the solution was sprayed to obtain about 570 g of double-coated granules [product of the present invention-4].

Example 5 500 g of a non-pareil 24-32 mesh was charged into a centrifugal flow type coating granulator, and while spraying a 5% solution of hydroxypropylcellulose (containing 50% ethanol), 250 g of diphenidol hydrochloride, 315 g of corn starch, and low-substituted hydroxypropyl After a mixture of 60 g of cellulose was gradually added and granulated, it was dried to obtain about 1150 g of spherical elementary granules.

Next, 500 g of the spherical elementary granules are put into a centrifugal flow type coating granulator, and 500 ml of an ethanol / methylene chloride (1/1) mixed solution containing 15 g of ethyl cellulose, 1.5 g of propylene glycol, and 4.5 g of talc is sprayed thereon, and about 520 g [Pre-granule-5] was obtained.

Further, 500 g of Pregranule-5 was charged into a centrifugal flow type coating granulator, and 40 g of hydroxypropylmethylcellulose phthalate (HP-55), 40 g of propylene glycol,
Ethanol / methylene chloride containing 12 g of talc (1 /
1) 1000 ml of the mixed solution was sprayed to obtain about 550 g of double-coated granules [Product of the present invention-5].

Test Example 1 Pre-granules-1 and 2 of the obtained coated granules and inventive products-1 and 2 were each weighed in an amount equivalent to 10 mg of oxybutynin hydrochloride and subjected to a dissolution test by the paddle method. The test solution was JP 1st solution (pH 1.2) and JP 2nd solution (pH 6.8)
Using 900 ml, sampling was performed at each time, and the amount of released oxybutynin hydrochloride was measured by high performance liquid chromatography.

The results are shown in FIGS. Pregranules-1 and 2 (FIG. 1,
FIG. 3) shows the liquid-affected release of JP1 and JP2 liquids, whereas the products of the present invention-1, 2 (FIGS. 2 and 4) did not affect the liquid properties. It is evident that it shows a less likely release.

Furthermore, a comparison with FIGS. 2 and 4 of the product according to the invention shows that different release rates are obtained. This is a result of changing the film thickness of each of the double films, and indicates that the release rate is adjusted by the film thickness.

Test Example 2 Pre-granules-3 of the obtained coated granules and the product of the present invention
3 was weighed in an amount equivalent to 300 mg of flapoxate hydrochloride,
A dissolution test was performed according to Test Example 1. For the measurement, the absorbance at 316 nm was measured with a spectrophotometer (manufactured by Hitachi).

The results are shown in FIGS. Pregranulate-3 (FIG. 5)
It is clear that the product-3 of the present invention (FIG. 6) shows a release that is less affected by the liquid property, while the first liquid and the second liquid show release influenced by the liquid property. It is.

Test Example 3 Pre-granules-4 of the obtained granules of the coating and product-4 of the present invention were each treated with 4-diethylamino-1,1-dimethyl-
An amount equivalent to 10 mg of 2-butynyl (±) -α-cyclohexyl-α-phenylglycolate hydrochloride monohydrate was weighed, and a dissolution test was carried out according to Test Example 1. Measurements were taken at each time interval, and 4-diethylamino-1,1-dimethyl-2-butynyl (±) -α-cyclohexyl-α- was sampled by high performance liquid chromatography.
The release amount of phenylglycolate hydrochloride monohydrate was measured.

The results are shown in FIGS. Pregranulate-4 (FIG. 7)
It is apparent that the product of the present invention-4 (FIG. 8) shows a release less affected by the liquidity, whereas the release of the first liquid and the second liquid of the Japanese Pharmacopoeia are affected by the liquidity. It is.

BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1 and 3 show pregranules obtained in Example 1, respectively.
1 shows the dissolution test results of oxybutynin hydrochloride of Pregranule-2 obtained in Example 2. Δ represents the elution curve of the first liquid of JP, and Δ represents the elution curve of the second liquid of JP. The horizontal axis represents time (minutes), and the vertical axis represents the elution rate (%).

2 and 4 show the products of the present invention obtained in Example 1, respectively.
1 shows the results of the dissolution test of oxybutynin hydrochloride of product-2 of the present invention obtained in Example 2. Δ represents the elution curve of the first liquid of JP, and Δ represents the elution curve of the second liquid of JP. The horizontal axis represents time (minutes), and the vertical axis represents the elution rate (%).

FIG. 5 shows the dissolution test results of flavoxate hydrochloride of Pregranulate-3 obtained in Example 3. Δ represents the elution curve of the first liquid of JP, and Δ represents the elution curve of the second liquid of JP. The horizontal axis represents time (minutes), the vertical axis represents dissolution rate (%),
Respectively.

FIG. 6 shows the results of the dissolution test of flavoxate hydrochloride of product-3 of the present invention obtained in Example 3. Δ represents the elution curve of the first liquid of JP, and Δ represents the elution curve of the second liquid of JP. The horizontal axis represents time (minutes), the vertical axis represents dissolution rate (%),
Respectively.

FIG. 7 shows the dissolution test results of 4-diethylamino-1,1-dimethyl-2-butynyl (±) -α-cyclohexyl-α-phenylglycolate hydrochloride monohydrate of pregranulate-4 obtained in Example 4. Is shown. △
Indicates the elution curve of the first liquid of JP, and ▲ indicates the elution curve of the second liquid of JP. The horizontal axis represents time (minutes), and the vertical axis represents the elution rate (%).

FIG. 8 shows the 4-diethylamino-1,1-dimethyl-2-butynyl (±) -α-α of the product-4 of the present invention obtained in Example 4.
The dissolution test result of cyclohexyl-α-phenylglycolate hydrochloride monohydrate is shown.
Δ represents the elution curve of the first liquid of JP, and Δ represents the elution curve of the second liquid of JP. The horizontal axis is time (minutes),
The vertical axis represents the elution rate (%), respectively.

INDUSTRIAL APPLICABILITY As described above, the sustained-release preparation according to the present invention can be a useful device for a drug having a property of lower solubility in a neutral region to an alkaline region than in an acidic region. .

Claims (2)

(57) [Claims] (1) The physicochemical properties of a drug are as follows: the solubility of a drug (except for amphetamine sulfate) is lower in a neutral region or an alkaline region than in an acidic region (except for amphetamine sulfate); a) water-insoluble substances whose solubility in water does not change with pH, and (b) substances that dissolve at pH 5 or higher.
(B) from the inside in the order of (a) and (b), characterized in that the (b) substance has a ratio of 1 to 10 times that of the (a) substance 1, and has a pH-independent release characteristic. Controlled release drug formulation. 2. The physicochemical properties of a drug are as follows: a drug (except for amphetamine sulfate) having a lower solubility in a neutral or alkaline region than in an acidic region, or a composition containing these, a) a substance that does not dissolve at pH 7 or lower, and (b) a substance that dissolves at pH 5 or higher.
(B) from the inside in the order of (a) and (b), characterized in that the (b) substance has a ratio of 1 to 10 times that of the (a) substance 1, and has a pH-independent release characteristic. Controlled release drug formulation.