WO1991006291A1

WO1991006291A1 - Sustained release preparation

Info

Publication number: WO1991006291A1
Application number: PCT/JP1990/001364
Authority: WO
Inventors: Makoto Sugiyama; Kouichi Ushimaru; Tomini Ando; Kouichi Nakamichi; Hiroyuki Yasuura
Original assignee: Nippon Shinyaku Co., Ltd.
Priority date: 1989-10-26
Filing date: 1990-10-24
Publication date: 1991-05-16
Also published as: JP3158435B2

Abstract

A double-coating sustained release preparation which can release a drug in vivo at a constant rate, comprising one part of a drug which has a high solubility in an acidic region while a low solubility in a neutral or alkaline region or a composition containing the same, 0.01 to 0.5 part, desirably 0.05 to 0.3 parts of a coating material, applied to the surface of the drug or composition, mainly comprising either a substance which is water-insoluble and does not change the water-solubility with the nature of liquid or a substance which is insoluble at a pH of 7 or below, and 0.05 to 5 parts, desirably 0.1 to 1.5 parts of a coating material, further applied thereto, comprising a substance which is soluble at a pH of 5 or above.

Description

Specification

Sustained-release pharmaceutical technology

The present invention is directed to a drug for maintaining a constant release rate in the body of a drug having the property of having a high solubility in an acidic region and a low solubility in a neutral or alkaline region as a physicochemical property of the drug. It relates to a release preparation.

Background Technology-Sustained-release preparations reduce the number of doses for the benefit of patients, maintain effective onset by maintaining the effective concentration of the drug for a long time, and enhance efficacy by maintaining the prescribed concentration It has many therapeutic benefits, such as suppressing toxicity and side effects without impairing it, so many types have been developed so far.

In general, for example, preparations in which a poorly soluble substance is coated on the surface of tablets or granules, preparations mixed in tablets or granules, preparations in which a polymer compound is mixed to control drug release, and the like are known.

However, if the drug has a physicochemical property that the solubility is high in the acidic region and the solubility decreases in the neutral or alkaline region, the drug is manufactured by the general manufacturing method as described above. Sustained-release preparations exhibit a release property dependent on the solubility of the drug in liquid form. As a result, the release rate of the drug is high in the acidic region, and neutral to low Slow phenomena occur in the alkaline region.

Normally, it is known that the return pH in the gastrointestinal tract shows an acidic region of about 1 to 3 in the stomach and about 5 to 8 neutral to alkaline region in the small intestine. When taking such preparations, the pH in the gastrointestinal tract is inevitably affected, and there is a concern that drug release with individual differences and sometimes irregular drug release may occur even in the same person, resulting in variations in blood concentration, Or, there is a risk of lowering the bay endurance.

Therefore, as a basic condition when such a drug is made into a sustained-release preparation, some measures must be taken to ensure a stable release rate that is not easily affected by liquidity.

For the method of improving the release of drugs with different solubilities in the acidic region and the neutral region to the neutral region, an organic acid and an ice-soluble polymer are mixed in the formulation, and the eluate penetrating into the formulation is reduced to the low PH region. And a method of making the release rate less affected by the pH of the test solution (Japanese Patent Application Laid-Open No. 62-283926).

However, the results obtained by this method are not guaranteed to keep the drug in the acidic region during the final release of the drug, and are not applicable 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 disadvantages of the prior art, the present inventors have conducted intensive studies. Therefore, the physicochemical properties of the drug The purpose of the present invention is to create a completely new sustained-release formulation that eliminates the above-mentioned disadvantages for drugs that have the property of decreasing solubility in the neutral to alkaline region, with high solubility in the acidic region. It was an issue 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 that is permanently insoluble and whose permanent solubility does not change due to wave properties, and a coating of a substance that dissolves at a pH of 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 coated with such a double coat and obtain the desired sustained-release property by such a method can be obtained for the first time by the present inventors.

^ Below, the structure of this pit light is described in detail.

The drug which is the object of the present invention possesses such a property that its solubility is high in the acidic region and the solubility decreases in the neutral to alkaline region as its physicochemical properties.

In general, the release rate is controlled by applying only a PH-independent film agent to such drugs, and the release test is performed using JP Pharmaceutical First Solution (H1.2) and JP Pharmaceutical Second Solution (PH6.8 ), The solubility of the drug in the liquid is different, so that the amount of drug that passes through the coated film thickness differs depending on the liquid. Being slow with two liquids Becomes This means fast release in the stomach and slow release 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 soluble on PH51, which is on the surface, has the properties of an intestinal coating agent, and therefore does not dissolve in the acidic region, and does not dissolve in water. It shows the same mechanism as a film of a substance that is insoluble and does not change its solubility in water due to liquidity, or a film of a substance that does not dissolve at pH of 7 or less.

Therefore, at this stage, a film of a substance that dissolves at a pH of 5 or more, 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, Since release is performed through the added film thickness, it exhibits an excellent release suppressing effect in an acidic region where drug solubility is high.

In the preparation of the present invention, a coating of a substance which is insoluble in ice and whose solubility in ice does not change due to liquidity, a coating of a substance which does not dissolve below PHT, or a coating of a substance which dissolves at pH 5 or more. In the case of neutral to alkaline, first, the film of the substance that dissolves on the PH 521 in the surface layer dissolves immediately, and the ice-insoluble and Film or pH of a substance whose solubility in water does not change due to sputum properties

Only a film of a substance that does not dissolve below 7 is formed. As a result, the film thickness for suppressing release decreases, and in this state, the release form of membrane permeation only via (a) is taken, and even in the neutral to alkaline region where drug solubility is low. Release can be significantly accelerated.

That is, the present invention relates to a substance which dissolves at a pH of 5 or more on a film of a substance which is insoluble in water and whose solubility in water does not change due to liquidity, or on a film of a substance which does not dissolve at a pH of 7 or less. The drug film permeates in the acidic region where the substance film that dissolves at pH 5 or higher does not dissolve, and in the neutral to alkaline region where the substance film that dissolves at pH 5 or higher dissolves. The film thickness to be used is different, and by using this difference in film thickness, it is possible to obtain a release rate that is not affected by the liquid property.

Regarding the release control of the preparation of the present invention, since the basic release mechanism is based on membrane permeation, the film thickness or the thickness of the coating of a substance that is permanently insoluble and does not change its solubility in liquid due to liquidity. The release rate is determined by the film thickness obtained by adding the film thickness of the material that does not dissolve at pH 7 or less and the film thickness of the material that dissolves at pH 5 or more.

Here, the usage ratio of the coating of a substance that dissolves at pH 5 £ 1 is the coating of a substance that is water-insoluble and does not change its solubility in ice due to liquidity, or a coating that does not dissolve under PH 7 i¾. 1 to 10 times, preferably 2 to 5 times, the effect of the preparation of the present invention even if a double membrane is applied at a ratio exceeding this range. You can't get it.

This usage ratio is defined as a film of a substance that dissolves in ΡΗ5 or more, a film of a substance that is ice-insoluble and does not change its solubility in water due to liquidity, or a film of a substance that does not dissolve in ΡΗ7 or less. The thickness ratio is specified, but the drug release rate can be adjusted by changing the thickness of the two films while keeping this ratio constant.

In the practice of the present invention, the object can be achieved by a simple method simply by adjusting the amount of a substance to be coated in the production of a pharmaceutical 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 according to the present invention which is insoluble and whose dissolution is not affected by the liquid property include, but are not limited to, the following.

Ethylcellulose, amino alkyl methacrylate copolymer (Eudragit RS, RN100 SPL, RN100, RSPM), higher fatty acids, higher fatty acid ester derivatives, high-grade alcohol, high-grade alcohol Fats and oils such as ester derivatives and waxes.

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

Hydroxypropyl propyl methylcellulose acetate (AQQAT H), Metaacrylic acid copolymer S (Eudragit 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 propyl methyl cellulose phthalate (HP-55, HP-55S, HP-50), cellulose acetate phthalate, lip mouth ), Carboxysilyl methylcellulose, methacrylic acid copolymer (Budragit L30D55, 100) _0. These materials are permanent and insoluble in the drug or 1 part of the composition containing them. The coating of a substance whose solubility in water does not change due to the liquid property or the coating of a substance that does not dissolve at a pH of 7 or less may be applied in an amount of 0.01 to 0.5 part, preferably 0.05 to 0.3 part.

In addition, the coating of substances that dissolve at pH 5 or higher

It may be applied in an amount of 0.01 to 5 parts, preferably 0.1 to 1.5 parts.

In addition, a plasticizer that is usually used in pharmaceuticals can be added to these for the purpose of forming a uniform and good film. For example, propylene glycol, polyethylene glycol, glycerin, triethyl citrate and the like can be used.

In addition, water-soluble mosquitoes or powders can be added to these materials for the purpose of promoting release. One or two kinds of commonly used pharmaceutically substances can be used. For example, hydroxypropyl cellulose, hydroxy pi-xypropylmethyl cellulose, methyl reserulose, polyvinylpyrrolidone, polyvinyl alcohol, talc, cone starch, mannit, Lactose or the like can be used.

The drug used in the present invention generally has different solubility in the acidic region and the neutral to alkaline region, and the release rate in the neutral to alkaline region compared to the acidic region. Any kind of drug can be applied as long as the drug decreases. The following various drugs can be given as typical examples of these.

1. Facial urine remedy

Flavoxate hydrochloride, oxybutynin hydrochloride, terodine hydrochloride, 4-Jetyl-mino-1,1,1-dimethyl-1-2-butynyl

(Sat) 1 ct—square α-Fe / G / G / N / D

2. Arrhythmia treatment agent

Hydrochloric acid hydrochloride, mexiletine hydrochloride, procaine hydrochloride, α-tinol hydrochloride

3. jS—booker

Carteolol hydrochloride, pi-Planol hydrochloride, Labetalol hydrochloride, Metobu tartrate π-roll

4. Coronary vasodilators Dilazep hydrochloride, trimetadine hydrochloride, etafunon hydrochloride

5. Allergic disease therapeutic agent

Ketotifen fumarate, Zelastine hydrochloride

6. Airway lubricating expectorant

Hydrochloric acid

7. Therapeutic agent for Parkinson's syndrome

Amantadyl hydrochloride

8. Circulation enhancer

Echirefrine hydrochloride

9. Heart function / tissue circulation promoter

Soprote hydrochloride

0. Brain circulation, metabolic improver

Chiapride hydrochloride

1. Anesthetic

Hydrochloric acid dokain

2. Antidepressants

Maprotirin hydrochloride

13. Antiemetic

Difunidole hydrochloride

14. Central antitussive

Hydrochloric acid π-Pdanol

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, 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

Non-barrel (Front) 24 to 32 Mesh 900 g is put into a centrifugal transfer type granulator (Front CF-360), and a 5% solution of hydroxypropyl cellulose is added. (50% ethanol in water) while spraying the mixture, gradually adding a mixture of 100 g of oxybutynin hydrochloride, 680 g of corn starch, and 70 g of low-substituted hydroxypropylcellulose, granulating, and drying to obtain a ball of about 1800 g. Next, 500 g of the spherical granules were introduced into a centrifugal flow type coating granulator, and 25 g of ethyl cellulose and propylene glycol were added.

750 ml of a mixed solution of ethanol / methylene chloride (11) containing 2.5 g and 7.5 g of talc was sprayed to obtain about 530 g of coated granules [Pre-granule-1].

Further, 500 g of the pregranules (11) is charged into a centrifugal flow type coating granulator, and hydroxypropyl methylcellulose acetate succinate (50 g of AQ0AT, 10 g of triethyl citrate, talc) 1250 ml of an ethanol / permanent (6Z4) mixed solution containing 15 g was sprayed to obtain about 570 g of double-film coated granules [Product 1 of the present invention].

Example 2

500 g of the spheroidal granules obtained in Example 1 were charged into a centrifugal flow type coating granulator, and ethanol / methylene chloride containing 50 g of ethyl cellulose, 5 g of propylene glycol, and 15 g of talc was used. (1 /.1) Spray the mixed solution About 560 g of coated granules were obtained [Pre-granule 1].

Further, 500 g of the pregranules 12 is put into a centrifugal flow type coating granulator, which contains 100 g of hydroxypropyl methylcellulose acetate succinate (AQOAT L), 20 g of triethyl citrate, and 30 g of talc. Ethanol Z water (6Z4) mixed solution

2500 πι £ was sprayed to obtain about 650 g of double-coated granules [Product 1 of the present invention].

Example 3

After mixing 150g of flavoxate hydrochloride, 152.5g of lactose, 152.5g of cornstarch and 25g of crystallite cell, add 20g of polyvinyl alcohol and 180m £ of shaving ice solution and knead with kneader did. This was extruded by an extrusion granulator (0.5), dried and sized to obtain about 500 g of cylindrical silicon granules.

Next, 300 g of the columnar elementary granules are put into a fluidized bed granulator (STREA), and 225 ml of an ethanol solution containing 9 g of Budrag it RS30D, 0.9 g of triethyl citrate, and 2.7 g of talc is added. By spraying, about 310 g of coated granules were obtained [pre-granules-1].

Further, 300 g of the pre-granules 13 is put into a fluidized bed granulator, and ethanol Z containing 18 g of hydroxypropyl methylcellulose phthalate (HP-55), 1.8 g of propylene glycol, and talc 5. Methylene chloride (1Z1) mixed solution

450 m2 was sprayed to obtain about 320 g of a double-coated granule [Product 1 of the present invention 3]. Example 4

900 g of the non-barrel 24 to 32 mesh is put into a centrifugal flow type coating granulator, and sprayed with a 5% solution of hydroxypropylcellulose (50% ethanol, Seinaga) while 4—Jetylami No. 1, 1-dimethyl-2 — Butynyl (Sat) 1 or — Cyclohexyl-Pull-Ni-D-Collate Noid T-c σ Ride Mono-Hydrate 100g, Corn Starch 680g, Low Substitution A mixture of 70 g of hydroxypropyl cellulose cellulose was gradually added and granulated, followed by drying to obtain about 1800 g of spherical granules.

Next, 500 g of the spheroidal granules are put into a centrifugal flow type coating granulator, and 25 g of ethyl cellulose, 2.5 g of propylene glycol, and talc? 750? ^ Of a mixed solution of ethanol / methylene chloride (1Z1) containing 0.5 g was sprayed to obtain about 530 coated granules [Pregranule 14].

Further, 500 g of the pre-granules 14 was put into a centrifugal flow type coating granulator, and 50 g of hydroxypropyl methylcell π-succinate succinate (AQQATL), triethyl tenoate 10 g were added. g of ethanol and 15 g of talc were sprayed with 1250 ml of a mixed solution of ethanol Z water (6Z4) to obtain about 570 g of double-coated granules [product of the present invention 1-4].

Example 5

500 g of 24-32 mesh non-barrel is charged to a centrifugal flow type coating granulator, and a hydroxypile and a pill cell are added. And a mixture of 250 g of dihydrochloride dihydrochloride, 315 g of corn starch, and 60 g of low-substituted hydroxypropylcellulose was slowly added while spraying a 5% solution (containing 50% ethanol in water). After granulation, drying was performed to obtain about 1150 g of spherical granules.

Next, 500 g of the spherical Qin granules are charged into a centrifugal flow type coating granulator, and ethanol methyl π-ride containing 15 g of ethyl cellulose, 1.5 g of propylene glycol, and 4.5 g of talc is used. 1) 1) 500 mixed solutions were sprayed to obtain about 520 coated granules [Pre-granule-1 5].

Further, 500 g of the pre-granules-5 was put into a centrifugal flow type coating granulator, and 40 g of hydroxypropyl methylcellulose phosphate (HP-55), 4 g of propylene glycol and 12 g of talc 12 were added. g of ethanol / methylene chloride (1Z1) mixed solution was sprayed to obtain about 550 g of double-coated granules [Product 1-5 of the present invention].

Test example 1

The pre-granules 1-1, 2 of the coated granules and the product of the present invention, 1-2, were weighed in amounts equivalent to loxyng of oxiptinin hydrochloride, respectively, and a dissolution test was carried out by the paddle method. The test solution was JP 1 (PH 1.2) and JP 2 (PH 6.8).

Each sample was sampled every 900 hours, and the amount of oxybutynin hydrochloride released was measured by high performance liquid chromatography. The results are shown in FIGS. Preliminary particles 1 and 2 (Fig. 1 and Fig. 3) were released by the liquid In contrast to the above, it is clear that the products 1 and 2 of the present invention (FIGS. 2 and 4) show a release that is not affected by the liquid property.

Furthermore, comparing FIGS. 2 and 4 of the product of the present invention, different release rates are obtained. This is the result of changing the thickness of each of the double coatings, indicating that the release rate is adjusted by the film thickness.

Test example 2

Pre-granules 13 of the coated granules thus obtained and Product 13 of the present invention were each weighed in an amount equivalent to 300 tng of flavoxate hydrochloride, and a dissolution test was carried out according to Test Example 1. The absorbance was measured at 316 nm using a spectrophotometer (manufactured by Hitachi).

The results are shown in Figs. Pregranule-1 (Fig. 5) shows release affected by liquidity in JP-1 and JP-2, whereas Product 1-3 of the present invention (Fig. 6) affected liquidity. It is evident that this represents a difficult release.

Test example 3

Pre-granules 14 of the resulting coated granules and the product 14 of the present invention were used in combination with 4—Jetyl-mino-1,1-dimethyl-2—butynyl (sat) 1-cyclohexylyl-phenylidarylate Nono Lee de port Kurorai de Monohai Dre preparative 10 _m g equivalent amount weighed and a dissolution test was performed according to test example 1. Measurements were taken at each time interval and sampled at high speed by liquid chromatography. 4-Jetyl-mino-1,1-dimethyl-2-butynyl (A) -α-cyclohexyl-α-phenylglycolate Measure the release amount of Hydride D-ride monohydrate and l ^-o

The results are shown in FIGS. Pregranules 1-4 (Figure?) Show release affected by liquidity in JP1 and JP2 liquids, whereas Product 1-4 of the present invention (Fig. 8) affects liquidity. It is evident that this represents a difficult release.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1, _D厶showing a 3予顆particle one 1 obtained in each of Example 1, elution tests予顆grains one 2 hydrochloride Okishipuchinin obtained in Example 2 results in the first solution Japanese Pharmacopoeia The elution curve represents the elution curve, and the triangle represents the elution curve for JP 2nd solution. The horizontal axis represents time (minutes) and the vertical axis represents dissolution rate (%).

2 and 4 show the dissolution test results of oxyptinin hydrochloride of the product of the present invention 1 obtained in Example 1 and the product of the present invention 1 obtained in Example 2, respectively. .DELTA. Represents the elution curve of .B 1st liquid, and .DELTA. Represents the elution curve of JP 2nd liquid. The horizontal axis represents time (min) and the vertical axis represents the dissolution rate (%). FIG. 5 shows the results of the dissolution test of the pregranules 13 obtained in Example 3 using flavoxacin hydrochloride. Represents the elution curve of the first solution of JP, and Δ represents the elution curve of the second solution of JP. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

FIG. 6 shows the results of a dissolution test of flavoxate hydrochloride of Product 13 of the present invention obtained in Example 3. △ indicates the JP The elution curve is shown, and ▲ shows the elution curve of JP2 solution. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate ().

Figure 4 shows the pre-granules obtained in Example 4-14- 4-ethyl-mino 1,1-dimethyl-2-butynyl (sat) hexyl mono-phenylglycolate-noid Έ3 The results of the dissolution test of D-monohydrate are shown. Represents the elution curve of the first JP liquid, and ▲ represents the elution curve of the second JP liquid. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

Fig. 8 shows the product of the present invention obtained in Example 4, 4- (4-ethyl) amino-1,1-dimethyl-2-butynyl (Ethyl), one cyclohexyl, and one monounylglycolate monodrotita D-ray. The results of the dissolution test of demonohydrate are shown. The symbol represents the elution curve of the first solution of JP, and the symbol ▲ represents the elution curve of the second solution of JP. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%). '

Industrial applicability

As described above, the sustained-release preparation according to the present invention becomes a useful device when sealed in a drug having a property of high solubility in an acidic region and low solubility in a neutral to alkaline region. obtain.

Claims

The scope of the claims

1. As a physicochemical property of a drug, a drug having a property of having a high solubility in an acidic region and having a low solubility in a neutral region or an alkaline region, or on a surface of a composition containing these,

(a) a substance which is insoluble in water and whose solubility in water does not change due to liquidity;

(b) substances that dissolve at pH 5 or higher,

A sustained-release pharmaceutical preparation characterized in that it comprises, in the order of (a) and (b), two layers of each of the two types of substances.

2. As a physicochemical property of the drug, the solubility is low in the acidic region and the solubility is low in the neutral region or the alkaline region.

(a) Substance that does not dissolve under pH 7 J¾

(b) substances that dissolve at pH 5 or higher,