JPH0466846B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD The present invention relates to depot formulations, specifically 5-(2-hydroxy-3-t-butylaminopropoxy)-
The present invention relates to a preparation that contains 3,4-dihydrocarbostyril or a pharmaceutically acceptable acid addition salt thereof as an active ingredient and can sustainably exhibit the medicinal effects of the active ingredient over a long period of time. BACKGROUND ART 5-(2-Hydroxy-3-t-butylaminopropoxy)-3,4-dihydrocarbostyryl and its pharmaceutically acceptable acid addition salts, commonly known as carteolol hydrochloride, are available in various forms. It is used as a medicine for heart diseases such as arrhythmia and angina pectoris and as a medicine for high blood pressure in the form of preparations or dosage units. The drawback was that it was difficult to achieve sufficient effects in controlling heart attack and high blood pressure. However, with such administration several times a day, the plasma concentration of the drug increases each time it is administered, reaches a peak, and then gradually decreases until it finally reaches zero.
The plasma concentration increases transiently, making it difficult to maintain a constant plasma concentration, and patients may forget when and how often to take the drug, especially when taking it for a long period of time. This can lead to seizures, and frequent use itself can lead to mental stress. OBJECT OF THE INVENTION The object of the present invention is to provide a new long-acting preparation that can maintain the medicinal effects of the above-mentioned drug over a long period of time and does not require frequent administration as seen in conventional preparations. Structure of the Invention According to the present invention, (a) 5-(2-hydroxy-3-
0.1 to 3% by weight of an immediate release coating made of hydroxy lower alkyl lower alkyl cellulose containing t-butylaminopropoxy)-3,4-dihydrocarbostyryl or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. spherical particles coated with (hereinafter referred to as "component a") 10 to 60% in potency and (b) containing the same active ingredients as above, 37.5 to 55% by weight of lower alkyl cellulose and hydroxy lower alkyl lower alkyl cellulose phthalate. 62.5-45% by weight
Spherical particles (hereinafter referred to as "component b") coated with 10 to 40% by weight of a sustained release coating consisting of 90 to 40% titer
A long-acting preparation is provided. According to the research of the present inventors, the above-mentioned active ingredient is granulated with a commonly used appropriate excipient to form suitable spherical to spherical particles, and the raw material particles are placed in the above-mentioned specific coating agent. When coated in a fixed amount, coated particles with moderate immediate release properties are obtained,
Furthermore, when the same raw material particles are coated with a predetermined amount of another specific coating agent, coated particles with appropriate sustained release properties can be obtained, and when these two particles are used together in a predetermined ratio, they can be used for a long period of time. It has been found that a desired formulation that exhibits excellent medicinal efficacy for a sustained period of time can be obtained. The long-acting preparation of the present invention can exhibit the desired drug effect very quickly, for example, when administered once a day, and can stably and sustainably exhibit the drug effect. That is, by administering the above-mentioned preparation, the plasma concentration of the active ingredient does not increase transiently, and the concentration can be maintained at a constant level in a very stable manner, thus effectively exerting the desired therapeutic effect. In particular, its sustained effect is about three times as long as that of commercially available preparations of this type, as detailed in the test examples below. Such a sustained effect is achieved for the first time by the formulation of the present invention, and such a formulation has not been previously known. Hereinafter, the preparation of the present invention will be explained in detail, starting with its manufacturing method. In the present invention, it is important to use spherical particles containing the active ingredient as the raw material particles, and the spherical particles mean particles having a spherical or spherical shape with a diameter of about 0.25 to 1 mm. In addition, as an active ingredient, free form 5-(2-hydroxy-3
Although t-butylaminopropoxy)-3,4-dihydrocarbostyryl may be used, it is usually preferable to use its pharmaceutically acceptable acid addition salts, particularly in the form of the hydrochloride known as carteolol hydrochloride. Preferably. The above spherical particles are
According to conventional methods, e.g. a predetermined amount of the active ingredient,
It is manufactured by molding the above-mentioned form together with a commonly used pharmaceutical carrier using an appropriate molding means. As the pharmaceutical carrier, a wide variety of carriers conventionally known in the art can be used, such as excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid, water,
Ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose,
Potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate,
Calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, stearic acid, cocoa butter,
Disintegration inhibitors such as hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, and purification. Examples include lubricants such as talc, stearate, boric acid powder, and polyethylene glycol. Further, any forming means that can obtain particles in the above-mentioned form can be used, but it is particularly preferable to use the commonly used centrifugal fluid coating granulation method, spray coating method using a coating pan, etc. . The amount of active ingredient used varies slightly depending on which coating is subsequently applied to the obtained spherical particles, but as raw material particles for obtaining immediate release particles, it is about 3 to 5% by weight in the particles, and sustained release It is preferable that the amount of the compound is about 6 to 10% by weight in order to obtain the desired particle size. The production of component a, that is, immediate release particles, from the raw material particles thus obtained is advantageously carried out by coating the raw material particles with a solvent solution of hydroxy lower alkyl lower alkyl cellulose.
Here, it is important to use the above-mentioned hydroxy lower alkyl lower alkyl cellulose as the coating agent, and specific examples thereof include hydroxypropyl methyl cellulose (HPMC), hydroxyethyl ethyl cellulose (HEEC), hydroxyethyl methyl cellulose (HEMC), etc. can. Among these, HPMC is preferred;
This is "HPMC TC-5R" from Shin-Etsu Chemical Co., Ltd.
It is marketed under the trade name. The HPMC TC-5R
The methoxy group content is 28-30%, the hydroxypropoxyl group content is 7-12%, and the viscosity (cs, 2%, 20℃) is
6cs±20%. The solvent for preparing the solvent solution of the above-mentioned coating agent is not particularly limited, but usually water, alcohols such as methanol, ethanol, isopropanol, a mixture thereof, a mixture of such and methylene chloride, etc. are used. . The coating agent is usually approx.
It is preferable to prepare a solution containing 0.4 to 5% by weight of the above hydroxy lower alkyl lower alkyl cellulose, and the solution may further contain additives such as a coloring agent, a masking agent, a plasticizer, a flavoring agent, etc. as necessary. It can also be added as appropriate. Coating of the raw material particles with the above-mentioned coating agent solution can be carried out according to a conventional method, such as a centrifugal fluid coating method or a spray coating method using a coating pan, and after coating, the particles are dried according to a conventional method.
The coating amount of the coating agent solution is such that the hydroxy lower alkyl lower alkyl cellulose coating is 0.1 to 3% by weight based on the resulting coated particles,
By forming this film, spherical particles having the desired immediate release properties are obtained. In addition, the other component (component b) which is an essential component of the preparation of the present invention, that is, sustained release particles, contains 37.5 to 55% by weight of lower alkyl cellulose in the same raw material particles as above.
and 62.5 to 45% by weight of hydroxy lower alkyl cellulose phthalate in a solvent solution. The lower alkyl cellulose used here as a coating agent is typically ethyl cellulose, and the hydroxy lower alkyl lower alkyl cellulose phthalate is preferably hydroxyethyl ethyl cellulose phthalate (HEECP), hydroxypropyl methyl cellulose phthalate (HPMCP), etc.
Examples of HPMCPs can be given. The HPMCP is, for example, commercially available from Shin-Etsu Chemical Co., Ltd. as "HPMCPHP-55S", which has 18 to 22 methoxyl groups.
%, 5 to 9% of hydroxypropoxyl groups, and 27 to 35% of carboxybenzoyl groups, and the viscosity (at 20°C) in a 10% methanol-dichloromethane mixture (1:1) is about 170cs±20%. It is important that the above two types of coating agent components are used together in the above specific ratio, and the desired sustained release particles can only be obtained by coating the raw material particles with a predetermined amount of this mixture. However, when using a coating agent that does not meet the above ratio, it is difficult to form a desired sustained release coating. That is, when lower alkyl cellulose is used in an amount less than 37.5% by weight, sufficient sustained effect of the medicinal effect of the active ingredient compound cannot be obtained. In addition, when using a coating agent containing more than 55% by weight of lower alkyl cellulose,
Compared to conventional commercially available tablets, they have the disadvantage that the absorption rate of the active ingredient compound in the gastrointestinal tract is reduced. The solvent solution of the above-mentioned mixed coating agent is prepared using the same solvent as used for forming the above-mentioned immediate release coating, and as described above, suitable additives can be added to the solution as necessary. can be,
The coating agent solution thus obtained is applied to the raw material particles by the same method. However, the amount of the solution applied must be such that the mixed coating agent film accounts for 10 to 40% by weight of the resulting coated particles, and if this is less than 10% by weight or exceeds 40% by weight. In both cases, it becomes difficult to form the desired sustained-release coating. The long-acting formulation of the present invention is. The spherical particles formed with an immediate release coating (component a) obtained as above and the spherical particles formed with a sustained release coating (component b) were mixed so that the potency of component a to component b was 10 to 60% to 90 to 90%. It is produced by blending at a blending ratio of 40% potency, or about 18-75% by weight to about 82-25% by weight. If this blending ratio deviates from the above ratio, it is difficult to obtain a long-acting preparation desired by the present invention that has both immediate release and long-lasting properties. The thus obtained preparation of the present invention can be put to practical use in the form of mixed particles simply by mixing a predetermined amount of the above components a and b, but it is usually preferable to fill the mixed particles into suitable capsules and form capsules. It is put into practical use in the form of A representative example of the capsule is a hard capsule commonly used in the art, and the capsules are filled with the mixed particles according to a conventional method. In addition, the above capsules can be filled with the mixed particles alone, but they can also be filled with a suitable pharmaceutically acceptable carrier, other colorants, lubricants, excipients, etc. according to the usual method. can. The preparation of the present invention usually contains 10 to 20 active ingredients per dose.
It is administered orally in a unit form containing mg, and the desired therapeutic effect is exerted immediately after administration, and the desired therapeutic effect continues for about 24 to 72 hours thereafter, and the result is sufficiently stable with once-daily administration. can be played. Examples Examples of the present invention are shown below. Example 1 (1) 400 g of refined white sugar is placed in a centrifugal fluid coating granulator, and granulated with 120 g of purified water while sprinkling a mixture consisting of 40 g of carteolol hydrochloride, 280 g of refined white sugar, and 280 g of cornstarch.
Subsequently, 250 g of a 1% hydroxypropyl methylcellulose solution ("HPMC TC-5R" (Shin-Etsu Chemical Co., Ltd.) dissolved in a 1:1 mixture of ethanol and purified water to a concentration of 1%) was added to the granules.
Coating is carried out by a spray method, and after drying at 60°C, it is sieved to obtain immediate-release spherical particles of carteolol hydrochloride with a size of 0.25 to 1 mm. (2) Put 400 g of refined white sugar into a centrifugal fluid coating granulator and granulate it with 120 g of purified water while sprinkling a mixture of 80 g of carteolol hydrochloride, 260 g of refined white sugar, and 260 g of cornstarch.
Subsequently, hydroxypropyl methyl cellulose phthalate and ethyl cellulose solution (2500 g of ethanol and 2500 g of dichloromethane) were added to the granules.
Inside, 150g of hydroxypropyl methylcellulose phthalate "HPMCP HP-55S" (Shin-Etsu Chemical Co., Ltd.), ethylcellulose "Ethocel"
STD 10cps” (Dow Chemical Company) 120g and glycerin fatty acid ester “Mybaset 9-
40T (Koyo Shokai, plasticizer)) was coated by spraying, dried at 60°C, and sieved to obtain sustained-release spherical particles of carteolol hydrochloride with a size of 0.25 to 1 mm. (3) Mix 50 parts by weight of the immediate-release spherical particles obtained in (1) above with 50 parts by weight of sustained-release spherical particles obtained in (2) above in an amount equivalent to 15 mg of total carteolol hydrochloride. is filled into 250 mg capsules to obtain the preparation of the present invention. Examples 2 to 6 In Example 1(3), the mixing ratio of immediate release spherical particles and sustained release spherical particles was changed as shown in Table 1 below, and the preparations (capsules) of the present invention were obtained in the same manner. Ta. Table 1 also shows the formulation of the present invention obtained in Example 1.

[Table] The titers in Table 1 above are for high performance liquid chromatography (Shimadzu LC-5A), mobile phase:
1% acetic acid: methanol = 7:3, column: Micro Bondapak C ₁₈ (μ-Bondapak C ₁₈ , manufactured by Waters, inner diameter 3.9 mm x length 30 cm), measurement wavelength
Measured using UV254nm, internal standard: anhydrous caffeine. Example 7 (1) Carteolol hydrochloride granules obtained in Example 1 (2)
1000g of hydroxypropyl methylcellulose phthalate and ethylcellulose solution (in 2200g of ethanol and 2200g of dichloromethane, 150g of hydroxypropylmethylcellulose phthalate "HPMCP HP-55S", 90g of ethylcellulose "Ethocel STD 10cps" and 15g of glycerin fatty acid ester "Mybaset 9-40T")
Coating is carried out by a spray method using (including g), dried at 60° C., and sieved to obtain sustained-release spherical particles of carteolol hydrochloride with a size of 0.25 to 1.0 mm. (2) The immediate release spherical particles obtained in Example 1 (1) and the sustained release spherical particles obtained in (1) above were mixed in the same manner as in Example 1 (3) so that the titer ratio was 1:2 and The mixture is mixed at a ratio of 1:1, and an amount equivalent to 15 mg of total carteolol hydrochloride is filled into capsules to obtain a preparation (capsule) of the present invention. Example 8 (1) Carteolol hydrochloride granules obtained in Example 1 (2)
1000g of hydroxypropyl methylcellulose phthalate and ethylcellulose solution (in 2900g of ethanol and 2900g of dichloromethane, 150g of hydroxypropylmethylcellulose phthalate "HPMCP HP-55S", 150g of ethylcellulose "Ethocel STD 10cps" and 15g of glycerin fatty acid ester "Mybaset 9-40T")
Coating is carried out by a spray method using (including g), dried at 60° C., and sieved to obtain sustained-release spherical particles of carteolol hydrochloride with a size of 0.25 to 1.0 mm. (2) The immediate release spherical particles obtained in Example 1 (1) and the sustained release spherical particles obtained in (1) above were mixed in the same manner as in Example 1 (3) so that the titer ratio was 1:2 and The mixture is mixed at a ratio of 1:1, and an amount equivalent to 15 mg of total carteolol hydrochloride is filled into capsules to obtain a preparation (capsule) of the present invention. Example 9 (1) 400 g of refined white sugar is placed in a centrifugal fluid coating granulator, and granulated with 120 g of purified water while sprinkling a mixture consisting of 40 g of carteolol hydrochloride, 280 g of refined white sugar, and 280 g of cornstarch.
Subsequently, 0.4% hydroxypropyl methylcellulose solution ("HPMC TC-5R" (Shin-Etsu Chemical Co., Ltd.) was added to the granules at a ratio of ethanol:purified water = 1:1).
Coating was carried out by spraying using 250 g of the solution (dissolved in the mixed solution at a concentration of 0.4%), and after drying at 60°C, it was sieved to form a 0.25 to 1 mm
Immediate-release spherical particles of carteolol hydrochloride are obtained. (2) Carteolol hydrochloride granules obtained in Example 1 (2)
1000g of hydroxypropyl methylcellulose phthalate and ethylcellulose solution (in 4000g of ethanol and 4000g of dichloromethane, 222g of hydroxypropylmethylcellulose phthalate "HPMCP HP-55S", 178g of ethylcellulose "Ethocel STD 10cps" and 15g of glycerin fatty acid ester "Mybaset 9-40T")
Coating is carried out by a spray method using (including g), dried at 60° C., and sieved to obtain sustained-release spherical particles of carteolol hydrochloride with a size of 0.25 to 1.0 mm. (3) The immediate release spherical particles obtained in the above (1) and the sustained release spherical particles obtained in the above (2) were prepared in the same manner as in Example 1 (3) so that the titer ratio was 1:2 and 1: Mix it so that it becomes 1,
An amount equivalent to 15 mg of total carteolol hydrochloride is filled into capsules to obtain a preparation (capsule) of the present invention. Example 10 (1) 400 g of refined white sugar is placed in a centrifugal fluid coating granulator, and granulated with 120 g of purified water while sprinkling a mixture consisting of 40 g of carteolol hydrochloride, 280 g of refined white sugar, and 280 g of cornstarch.
Subsequently, 600 g of 5% hydroxypropyl methylcellulose ("HPMC TC-5R" solution (ethanol: purified water = 1:1 mixture)) was added to the granules.
Coating is carried out by a spray method, and after drying at 60°C, it is sieved to obtain immediate-release spherical particles of carteolol hydrochloride with a size of 0.25 to 1 mm. (2) Carteolol hydrochloride granules obtained in Example 1 (2)
1000g of hydroxypropyl methylcellulose phthalate and ethylcellulose solution (in 1000g of ethanol and 1000g of dichloromethane, 55.5g of hydroxypropylmethylcellulose phthalate "HPMCP HP-55S", 44.5g of ethylcellulose "Ethocel STD 10cps" and 15g of glycerin fatty acid ester "Mybaset 9-40T")
Coating is carried out by a spray method using (including g), dried at 60° C., and sieved to obtain sustained-release spherical particles of carteolol hydrochloride with a size of 0.25 to 1.0 mm. (3) Example 1 using each of the particles of (1) and (2) above
In the same manner as in (3), the mixture is mixed so that the titers are 1:2 and 1:1, and then filled into capsules to obtain capsules containing 15 mg of total carteolol hydrochloride (preparation of the present invention). Examples 11 to 16 In Example 1 (3), the potency ratio of immediate release spherical particles and sustained release spherical particles was changed as shown in Table 2 below, and the preparations of the present invention (capsules) were prepared in the same manner as above. )
I got it.

[Table] The method for measuring titer in Table 2 is the same as that in Table 1. <Test Example> The present invention preparation obtained in Example 1 (per capsule,
Capsules containing 15 mg of total carteolol hydrochloride) were orally administered once a day to five healthy adult male subjects, and the changes in plasma concentration of the subjects after administration were measured and observed. The above plasma concentration is 1-methyl-
Quantification was performed by high performance liquid chromatography (Waters, compact model 204) using carteolol as an internal standard. As a quantitative condition, the column was a reversed-phase Micro Bonder Pack C ₁₈ (μ-
BondapakC ₁₈ , manufactured by Waters, diameter 3.9mm x
The mobile phase was 30% (v/v) acetonitrile, 0.02M NH ₄ H ₂ PO ₄ and 0.02M
(NH ₄ ) ₂ HPO ₄ was used. Detection was performed at UV=254 nm. The results are shown in Figure 1 as line (1). In the figure, the horizontal axis shows time after administration (hr), and the vertical axis shows plasma concentration (ng/ml). Figure 1 also shows, for comparison, that a commercially available carteolol hydrochloride preparation (5 mg tablet) was orally administered to five healthy adult male subjects three times a day (every 8 hours). The result of measuring the intermediate concentration transition in the same manner is shown as line (2). From FIG. 1, it is clear that the long-acting preparation of the present invention can exhibit the same effect when administered once a day as the commercially available preparation administered three times a day.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the changes in plasma active ingredient concentration of subjects who were administered the inventive preparation and the commercially available preparation.

Claims (1)

[Scope of Claims] 1 (a) Contains 5-(2-hydroxy-3-t-butylaminopropoxy)-3,4-dihydrocarbostyryl or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. , 10 to 10 spherical particles coated with 0.1 to 3% by weight of an immediate release coating consisting of hydroxy lower alkyl lower alkyl cellulose
60% potency and (b) containing the same active ingredients as above, 37.5-55% by weight of lower alkyl cellulose and hydroxy lower alkyl lower alkyl cellulose phthalate.
A long-acting preparation comprising 90-40% potency of spherical particles coated with 10-40% by weight of a sustained-release coating consisting of 62.5-45% by weight.