JPWO1991006291A1 - Sustained-release formulations - Google Patents

Abstract

(57) [Abstract] This publication contains application data prior to electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] Sustained-Release Formulation Technical Field The present invention relates to a sustained-release formulation for maintaining a constant release rate in the body of drugs that have physicochemical properties that make them highly soluble in acidic pH regions but less soluble in neutral or alkaline pH regions.

BACKGROUND ART Sustained-release formulations offer many therapeutic advantages, such as reducing the number of doses required for patient convenience, maintaining effective drug concentrations for extended periods of time to maintain effective drug efficacy, and suppressing toxicity and side effects without compromising efficacy by maintaining a predetermined concentration. Therefore, many types of sustained-release formulations have been developed. Generally known formulations include those in which poorly soluble substances are coated on the surface of tablets or granules, those in which they are incorporated into tablets or granules, and those in which molecular compounds are incorporated to control drug release.

However, if a drug has physicochemical properties that make it highly soluble in acidic solutions but less soluble in neutral or alkaline solutions, sustained-release formulations manufactured using the above-described process will exhibit release properties that depend on the drug's solubility in the solution. As a result, the release rate will be faster in acidic solutions where the drug is highly soluble and slower in neutral to alkaline solutions where the drug is less soluble.

It is known that the pH of the gastrointestinal tract typically exhibits an acidic pH of approximately 1-3 in the stomach and a neutral to alkaline pH of approximately 5-8 in the small intestine. However, when such formulations are ingested, they are inevitably affected by the pH of the gastrointestinal tract, raising concerns about individual differences in drug release and even irregular drug release even in the same person, which could lead to variations in blood temperature or reduced bioavailability.

Therefore, when preparing a sustained-release formulation of such a drug, some kind of ingenuity is required to ensure a stable release rate that is not easily affected by the liquid's pH.

Regarding methods for improving the release of drugs with different solubilities in the acidic and neutral to alkaline ranges, one method has been disclosed (JP 62-283926 A), in which an acid and a water-soluble polymer are incorporated into the formulation to maintain the eluate that penetrates the formulation in a low pH range, thereby making the release rate less susceptible to the pH of the test solution.

However, this method has drawbacks, such as no guarantee that the formulation will maintain an acidic pH throughout the entire drug release, the fact that it is not suitable for substances that react with organic acids, and the fact that a stable release rate cannot be achieved depending on the dispersion state of the water-soluble polymer.

DISCLOSURE OF THE INVENTION In order to overcome the above-mentioned drawbacks of the prior art, the inventors have conducted extensive research. Accordingly, the objective of the present invention was to create a completely new sustained-release formulation that eliminates the above-mentioned drawbacks for drugs that, due to their physicochemical properties, exhibit high solubility in the acidic range but low solubility in the neutral to alkaline range.

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

Here, the term "double film" refers to a film of a substance that is water-insoluble and whose solubility in water does not change depending on the pH of the solution, and a film of a substance that dissolves at a pH of 5 or higher. It also refers to a film of a substance that does not dissolve at a pH of 7 or lower, and a film of a substance that dissolves at a pH of 5 or higher.

The fact that such a double coating can be applied to a drug and that the desired sustained release can be obtained by this method was discovered for the first time by the present inventors.

The mIfl of the present invention will be described in detail below.

The drugs that are the subject of this invention have physicochemical properties that make them highly soluble in acidic regions and less soluble in neutral to alkaline regions.

Generally, if such drugs are coated with only a pH-independent coating agent to control the release rate and the release test is conducted in circadian fluid 1 (pH 1.2) and circadian fluid 2 (pH 6.8), the amount of drug that permeates the coating membrane will differ depending on the fluid because of the difference in drug solubility. As a result, the release rate will be faster in circadian fluid 1 and slower in circadian fluid 2. This means that release will be faster in the stomach and slower in the small intestine, making it impossible to obtain a stable sustained-release formulation.

The present invention is intended to solve such problems.

In the composition prepared by the method of the present invention, the surface coating of a substance that dissolves at a pH of 5 or higher retains the properties of an enteric coating agent and therefore does not dissolve in acidic regions. It exhibits the same mechanism of action as a coating of a substance that is water-insoluble and whose solubility in water does not change depending on the pH, or a coating of a substance that does not dissolve at a pH of 7 or lower.

Therefore, at this stage, release occurs through the combined film thickness of the coating of the substance that dissolves at pH 5 or higher, the coating of the water-insoluble substance whose solubility in water does not change depending on the pH, or the coating of the substance that does not dissolve at pH 7 or lower, and therefore exhibits an excellent release-inhibiting effect in the acidic range where the drug is highly soluble.

In the formulation of the present invention, a coating of a substance that dissolves at pH 5 or higher is applied over a coating of a water-insoluble substance whose solubility in water does not change depending on the pH, or over a coating of a substance that is insoluble at pH 7 or lower. Therefore, in neutral to alkaline solutions, the coating of the substance that dissolves at pH 5 or higher in section N of the table dissolves immediately first, leaving only the coating of the water-insoluble substance whose solubility in water does not change depending on the pH, or the coating of the substance that is insoluble at pH 87 or lower, applied below.

As a result, the membrane thickness required to inhibit release is reduced, and in this state, release occurs via membrane permeation only via (a), which can significantly promote release even in the intermediate to alkaline range where the drug has low solubility.

That is, the present invention applies a coating of a substance that dissolves at pH 5 or above onto a coating of a water-insoluble substance whose solubility in water varies depending on the liquid pH, or onto a coating of a substance that dissolves at pH 7 or below. This results in a difference in the thickness of the membrane through which the drug permeates between the acidic range, where the coating of a substance that dissolves at pH 5 or above does not dissolve, and the neutral to alkaline range, where the coating of a substance that dissolves at pH 5 or above dissolves. By taking advantage of this difference in membrane thickness, a release rate that is less affected by the liquid pH can be achieved.

With regard to the controlled release of the formulation of the present invention, the fundamental mechanism of release is membrane permeation. Therefore, the release rate I is determined by the sum of the coating thickness of the coating for water-insoluble substances whose solubility in water varies depending on the pH, or the coating thickness of substances that are insoluble at pH 7 or below, and the coating thickness of substances that are soluble at pH 5 or above.

The ratio of the coating of a substance that dissolves at a pH of 5 or higher is 1 to 10 times, preferably 2 to 5 times, the ratio of the coating of a water-insoluble substance whose solubility in water varies depending on the pH, or the coating of a substance that does not dissolve at a pH of 7 or lower. Even if a double membrane is applied at a ratio outside this range, the effects of the formulation of the present invention cannot be obtained.

This use ratio defines the ratio of the TxI ratio between a coating of a substance that dissolves at pH 5 or above and a coating of a water-insoluble substance whose solubility in water does not change depending on the pH, or a coating of a substance that does not dissolve at pH 7 or below. By varying the thickness of the two coatings while maintaining this ratio constant, the drug release rate can be adjusted.

In practicing the present invention, the objective can be achieved by a simple method that simply reduces the amount of coating material used in the preparation of the formulation. This is another important advantage of the present invention that enhances the convenience of the present invention.

Examples of materials that can be used to form the water-insoluble coating of the present invention, and whose dissolution is not affected by the liquid, include, but are not limited to, the following:

Ethyl cellulose, aminoalkyl methacrylate copolymer (Eudragit RS, RNlooL, R5PML, RNloo, R3PII), high-grade I! f#B acid, higher fatty acid ester derivatives, higher alcohols, higher alcohol ester derivatives, and other oils and fats, waxes.

Examples of materials constituting the coating 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 (OAT II), methacrylic acid copolymer S (Eudrag +-5).

Examples of materials for the coating of substances that dissolve at pH 5 or higher according to the present invention include the following:

Hydroxypropylmethylcellulose phthalate (Hf'55, HP-55S, HP-50), cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate (L, M, l (), carboxymethylethylcellulose, methacrylic acid copolymer (L30D55, Li00).

These materials may be used in a ratio of 0.01 to 0.5 parts, preferably 0.05 to 0.3 parts, per drug or drug-containing paraformaldehyde product. Coatings of substances that are water-insoluble and whose solubility in water does not change with the application of liquid, or coatings of substances that are insoluble at pH 7 or below, may be used in a ratio of 0.01 to 0.5 parts, preferably 0.05 to 0.3 parts.

Furthermore, coating of substances that dissolve at pH 5 or higher can be applied at a ratio of 0.01B to 5B, preferably 0.1 to 1.5B.

Additionally, plasticizers commonly used in pharmaceuticals can be added to these formulations to form a uniform, high-quality coating. Examples of such plasticizers include polyvinyl glycol, polyethylene glycol, glycerin, and triethyl citrate.

Furthermore, water-soluble polymers or powders can be added to these materials to promote release. These materials can be one or a mixture of two or more commonly used pharmaceutical substances, such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, talc, corn starch, mannitol, and lactose.

The drugs used in the present invention can be any type of drug, as long as they generally have different solubility in the acidic range and in the neutral to alkaline range, and their release rate is slower in the neutral to alkaline range than in the acidic range. Representative examples of such drugs include the following:

1. Antidiarrheic drugs Flavoxa F hydrochloride, oxybutenin hydrochloride, terocillin hydrochloride, 4-diethylamino-1,1-dimethyl-2-butynyl(s)-α-cyclohexyl-α-phenylglycolate hydrochloride monohydrate 2. Antiarrhythmic drugs Abrinidine hydrochloride, mexiletine hydrochloride, procainamide hydrochloride, gamma-prothrombin hydrochloride 3. Beta-blockers Carteolol hydrochloride, propranolol hydrochloride, lapetalol hydrochloride, metoprrolol tartrate 4. Coronary vasodilators Dilazep hydrochloride, trimethacin hydrochloride, nitafenone hydrochloride 5. Allergic Disease Treatment Ketotifen Fumarate, Azelastine Hydrochloride 6. Expectorant, Smoothener Amproxol Hydrochloride 7. Burkison Syndrome Treatment Amaftadil Hydrochloride 8. Circulatory Enhancer Etilefrine Hydrochloride 9. Cardiac Function/Tissue Promoter Isoproterenol Hydrochloride 10. Circulatory/Metabolic Improver Tiapride Hydrochloride 11. Anesthetic Lidocaine Hydrochloride 2. Antidepressant Mavrotelin Hydrochloride 13. Antiemetic Diphenidol Hydrochloride 14. Centrally Acting Cough Agent Chlofedanol Hydrochloride BEST MODE FOR CARRYING OUT THE INVENTION The present invention is further explained below through examples and test examples, but is not limited thereto.

Example 1 900 g of non-barrel (Freund 11M1 24-32 Methane 5) was placed in a centrifugal flow coating granulator (Freund cF-360). A mixture of 100 g of oxybutynin hydrochloride, 680 g of cornstarch, and 70 g of low-substituted hydroxypropyl cellulose was gradually added while spraying a 5% solution of hydroxypropyl cellulose (50% ethanol-containing water). The mixture was granulated and then dried to obtain approximately 1,800 g of spherical S granules. Next, 500 g of these spherical S granules were placed in a centrifugal flow coating granulator and sprayed with 750 ml of an ethanol/methicillin-coated solution containing 25 g of ethyl cellulose, 2.5 g of propylene glycol, and 7.5 g of talc, to obtain approximately 530 g of coated granules.

Furthermore, 500 g of pre-granule-1 was placed in a centrifugal upflow coating granulator and sprayed with 125 kJ of a 6/4 ethanol/water mixture containing 50 g of hydroxypropyl methylcellulose acetate succinate (A-10), 10 g of triethyl citrate, and 15 g of talc, yielding approximately 570 g of double-coated granules [Product-1 of the present invention].

Example 2 500 g of the spherical S granules obtained in Example 1 were placed in a centrifugal fluidized bed coating granulator and sprayed with 1500 ml of an ethanol/methylene chloride (1/1) solution containing 50 g of ethyl cellulose, 5 g of propylene glycol, and 15 g of talc, to obtain approximately 560 g of coated granules (preparation 1L-2).

Furthermore, 500 g of pre-granule-2 was placed in a centrifugal fluidized bed coating machine and sprayed with 2500 ml of an ethanol/water (6/4) mixture containing 100 g of hydroxypropyl methylcellulose acetate succinate (HCL), 20 g of triethyl citrate, and 30 g of talc, to obtain approximately 650 g of double-coated granules [Invention Product-2].

Example 3 150 g of flavoxate hydrochloride, 152.5 g of lactose, 152.5 g of cornstarch, and 25 g of microcrystalline cellulose were mixed, and then 180 ml of an aqueous solution containing 20 g of polyvinyl alcohol was added and kneaded in a kneader. The mixture was extruded through an extrusion granulator (0.5 m), dry-exploded, and sized to yield approximately 500 g of cylindrical granules.

Next, 300 g of these cylindrical granules were placed in a fluidized bed brewer (FSTRE) and sprayed with 225 ml of an ethanol solution containing 9 g of Budragit R530D, 0.9 g of triethyl citrate, and 2.7 g of talc, yielding approximately 310 g of coated granules. (Pre-granules - 35°C, tEIa -3) 30 (1 g, laminar flow FF) 18 g of hydroxypropyl methylcellulose phthalate (HP-55) 1.8 g of propylene glycol, and 5.4 g of talc were sprayed with 450 ml of an ethanol/methylene chloride (1/1) mixture, yielding approximately 320 g of double-coated granules (Product of the Invention - 3).

Example 4 900 g of non-barrel 24-32 mesh was placed in a centrifugal 1M coating granulator, and a 5% solution of hydroxypropyl cellulose (containing 50% ethanol) was sprayed onto it. A mixture of 100 g of 4-diethylamino-1,1-dimethyl-2-butynyl (Hydrate), 680 g of corn starch, and 70 g of hydroxypropyl cellulose was gradually added from the spray nozzle. The mixture was granulated and then dried to obtain approximately 100 g of spherical granules.

Next, 500 g of these spherical granules were placed in a centrifugal fluidized bed coating granulator, and 750 ml of an ethanol/methylene chloride (MHCl) mixed solution containing 25 g of ethyl cellulose, 2.5 g of propylene glycol, and 7.5 g of talc was sprayed onto the granules to obtain approximately 331 g of coated granules [pre-granule-4].

Furthermore, 500 g of Pre-Granule-4 was placed in a centrifugal fluidized bed coating granulator and sprayed with 1,250 ml of an ethanol/water (674) mixture containing 50 g of hydroxypropyl methylcellulose acetate succinate (HQM), 10 g of triethyl citrate, and 15 g of talc, yielding approximately 570 g of double-coated footing granules (Product C-4).

Example 5 500 g of non-barrel 24-32 Metnko was placed in a centrifugal fluidized bed coating granulator. While spraying a 0.5% solution of hydroxypropyl cellulose (50% ethanol in water), a mixture of 250 g of diphenidol hydrochloride, 315 g of cornstarch, and 60 g of low-substituted hydroxypropyl cellulose was gradually added. The mixture was granulated and then dried to obtain approximately 1,150 g of spherical S granules.

Next, 500 g of these spherical granules were placed in a centrifugal fluidized bed coating granulator and sprayed with 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, to obtain approximately 520 g of coated granules [Pre-H Granules-5].

Furthermore, 500 g of Pre-Granule-5 was placed in a continuous flow type coating maker and sprayed with 1000 ml of an ethanol/methylene chloride (1:1) mixed solution containing 40 g of hydroxypropyl methylcellulose phthalate (HP-55), 4 g of propylene glycol, and 12 g of talc, to obtain approximately 550 g of double-coated granules [Invention Product-5].

Test Example 1 Pre-Granules-1 and -2 of the resulting coated granules and Invention Products-1 and -2 were weighed out in an amount equivalent to 210 mg of oxybutynin hydrochloride, and a dissolution test was performed using the paddle method. 900 ml of JP Fluid 1 (pH 1 and 2) and JP Fluid 2 (pH 6 and 8) were used as test fluids. Sampling was performed at regular intervals, and the amount of oxybutynin hydrochloride released was measured using high-speed liquid fluorography.

The results are shown in Figures 1 to 4. It is clear that Pre-Granules-1 and 2 (Figures 1 and 3) exhibited release that was affected by the fluids in the 1st and 2nd circadian fluids, whereas Products-1 and 2 of the Invention (Figures 2 and 4) exhibited release that was less affected by the fluids.

Furthermore, comparing Figures 2 and 4 for the present invention, different release rates were obtained. This is the result of varying the thickness of each of the double coatings, and indicates that the release rate can be adjusted by the coating thickness.

Test Example 2 Pre-Granule-3 and Product-3 of the resulting coated granules were weighed out in an amount equivalent to 300 mg of flavoxal hydrochloride, and a dissolution test was conducted in accordance with Test Example 1. The absorbance was measured at 316r++n using a spectrophotometer (Hitachi).

The results are shown in Figures 5 and 6. It is clear that Pre-Granule-3 (Figure 5) exhibited release that was affected by the fluids of JP 1st Liquid and JP 2nd Liquid, whereas Inventive Product-3 (Figure 6) exhibited release that was less affected by the fluids.

Test Example 3 Amounts equivalent to 10 mg of 4-diethylamino-1,1-dimethyl-2-butenyl (±)-α-cyclohexyl-α-phenyl glycolate hydrochloride monohydrate were weighed out from each of the resulting coated granules, Pre-Granule-4 and Product-4, and a dissolution test was conducted in accordance with Test Example 1. Samples were taken at regular intervals, and the amount of 4-diethylamino-1,1-dimethyl-2-butenyl (±)-α-cyclohexyl-α-phenyl glycolate hydrochloride monohydrate released was measured by high-performance liquid chromatography.

The results are shown in Figures 7 and 8. It is clear that Pre-Granule-4 (Figure 7) exhibited release that was affected by the fluid properties of the 1st Circadian Fluid and the 2nd Circadian Fluid, whereas Inventive Product-4 (Figure 8) exhibited a numerical ratio that was less affected by the fluid properties.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1 and 3 show the dissolution test results of oxybutynin hydrochloride for pregranules-1 and 2 obtained in Example 1 and Example 2, respectively. △ represents the dissolution curve for JP 1st Fluid, and ☐ represents the dissolution curve for JP 2nd Fluid. The horizontal axis represents time (minutes), and ☐ represents the dissolution rate (%).

Figures 2 and 4 show the results of dissolution tests of oxybutynin hydrochloride for Invention Product-1 obtained in Example 1 and Invention Product-2 obtained in Example 2, respectively. Δ represents the dissolution curve for JP Fluid 1, and μ represents the dissolution curve for JP Fluid 2. The horizontal axis represents time (minutes), and the vertical axis represents the dissolution rate (%).

Figure 5 shows the results of the dissolution test of flavoxate hydrochloride from Pregranule-3 obtained in Example 3. Δ represents the dissolution curve in JP Fluid 1, and m represents the dissolution curve in JP Fluid 2.

The horizontal axis represents time (minutes) and the vertical axis represents dissolution rate (%).

Figure 6 shows the results of the dissolution test of flavoxate hydrochloride (Product-3) obtained in Example 3. Δ represents the dissolution curve in JP Fluid 1, and ℓ represents the dissolution curve in JP Fluid 2. The ℓ axis represents time (minutes), and the ℓ axis represents dissolution rate (%).

Figure 7 shows the results of a dissolution test for 4-diethylamino-1,1-dimethyl-2-butenyl (=)-α-cyclohexyl-α-phenyl glycolate hydrochloride monohydrate (pre-granule-4) obtained in Example 4. △ represents the dissolution curve in JP Fluid 1, and ✽ represents the dissolution curve in JP Fluid 2. The horizontal axis represents time (minutes), and the vertical axis represents the dissolution rate (%).

Figure 8 shows the results of a solubility test for 4-diniteramino-1,1-dimethyl-2-butynyl (±)-α-cyclohexyl-α-phenylglycolate hydrochloride monohydrate, Product 4 of the present invention obtained in Example 4. Δ represents the dissolution curve in JP Fluid 1, and μ represents the dissolution curve in JP Fluid 2. The horizontal axis represents time (minutes), and the vertical axis represents the dissolution rate (%).

INDUSTRIAL APPLICABILITY As described above, the sustained-release formulation of the present invention can be a useful device for drugs that exhibit high solubility in the acidic range and low solubility in the neutral to alkaline range.

Claims (2)

[Claims] 1. A sustained-release pharmaceutical formulation characterized by having, on the surface of a drug or a composition containing such a drug whose physicochemical properties make it highly soluble in acidic pH ranges and less soluble in neutral or alkaline pH ranges, a double coating made of two types of substances, in the order (a) and (b): (a) a water-insoluble substance whose solubility in water does not change depending on the pH, and (b) a substance that dissolves at a pH of 5 or higher. 2. A sustained-release pharmaceutical formulation characterized by having, on the surface of a drug or a composition containing such a drug whose physicochemical properties make it highly soluble in acidic regions and less soluble in neutral or alkaline regions, two coatings made of two types of substances: (a) a substance that is insoluble at pH 7 or below, and (b) a substance that dissolves at pH 5 or above, in the order (a) and (b).