JPS60228410A - Long-acting drug preparation - Google Patents

Abstract

PURPOSE:To provide a long-acting drug preparation effective by the application of only once a day, by coating carteolol useful as an antiarrhythmic agent and anti-stenocardia or its acid addition salt with a specific quick-releasing coating layer to obtain spherical particles, and mixing the particles with other spherical particles coated with two kinds of slow-releasing coatings. CONSTITUTION:Quick-releasing spherical particles containing carteolol [chemical name, 5-(2-hydroxy-3-t-butylaminopropoxy)-3,4-dihydrocarbostyryl] or its acid addition salt (10-60 titer %) are mixed with slow-releasing spherical particles containing carteolol (90-40 titer %). The quick-releasing particles is coated with 0.1-3wt% lower hydroxyalkyl lower alkyl cellulose, and the slow-releasing particle is coated with a slow-releasing coating film composed of 37.5-55wt% lower alkylcellulose and 62.5-45wt% lower hydroxyalkyl lower alkylcellulose phthalate. The activity of the drug lasts 3 times at long as that of the commercially available drug.

Description

DETAILED DESCRIPTION OF THE INVENTION 11 The present invention relates to a long-acting preparation, specifically, a long-acting preparation containing 5-(2-hydroxy-3-t-butylaminopropoxy)-3,4-dihydrocarbostyryl or a pharmaceutically acceptable drug thereof. The present invention relates to a preparation that contains an acid addition salt as an active ingredient and can sustainably exhibit the medicinal effects of the active ingredient over a long period of time.

1!盈1 5-(2-Hydroxy-3-t-butylaminopropoxy)-3,4-dihydrocarbostyryl and its pharmaceutically acceptable acid addition salts are known under the generic name luteol hydrochloride. It is used as a medicine for heart diseases such as arrhythmia and angina pectoris, and as a medicine for hypertension, in various instructional forms or dosage unit forms, but it must be administered several times daily to patients who require treatment for long-term prisoners. For example, it has the disadvantage that it is difficult to achieve sufficient effects in controlling angina pectoris attacks 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, then gradually decreases and finally reaches zero, and the plasma concentration is transient. It is 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, which can lead to seizures or Frequent use itself can put mental pressure on you.

OBJECTS OF THE INVENTION An object of the present invention is to provide a new long-acting preparation that can maintain the medicinal efficacy 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-
t-butylaminopropoxy)-3,4-dihydrocarbostyryl or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, and is made of hydroxy lower alkyl lower alkyl cellulose. Spherical particles coated with weight% (hereinafter referred to as "component a") 10 to 6
(b) Contains the same active ingredients as above, 37.5 to 55% by weight of lower alkyl cellulose and hydroxy lower alkyl lower alkyl cellulose phthalate 6
Spherical particles coated with 10 to 40% by weight of a sustained release film consisting of 2.5 to 45% by weight (hereinafter referred to as "component b") 9
A long-acting preparation containing 0 to 40% of the drug is provided.

According to the research of the present inventors, the above-mentioned active ingredient is granulated, for example, 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 a fixed amount is coated, coated particles with appropriate immediate release properties are obtained, and when the same raw material particles are coated with a predetermined amount of another specific coating agent, coated particles with appropriate sustained release properties are obtained. It has been found that when these two types of particles are used in combination at a predetermined ratio, a desired formulation that maintains excellent medicinal efficacy over a long period of time can be obtained. The long-acting preparation of the present invention can exhibit the desired drug effect very quickly by administering it once a day, for example, and can stably and sustainably exhibit the drug effect. That is, administration of the above formulation does not cause a transient increase in the plasma concentration of the active ingredient;
The concentration can be kept constant in a very stable manner, and thus the desired therapeutic effect can be effectively exerted. In particular, its lasting effect is
As will be detailed in the test examples below, this is about three times as effective as commercially available preparations of this type. 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 raw material particles, and the spherical particles mean particles having a spherical or spherical shape with a diameter of about 0.25 to 1. . In addition, as an active ingredient, 5-(2-hydroxy-3-t-butylaminopropoxy)-3,4-dihydrocarbostyryl may be used in free form, but it is usually a pharmaceutically acceptable acid addition salt thereof. It is preferred to use carteolol hydrochloride, particularly in the form of the hydrochloride known as carteolol hydrochloride. The above-mentioned spherical particles are produced according to a conventional method, for example, by molding a predetermined amount of the active ingredient into the above-mentioned form using a suitable molding means together with a commonly used pharmaceutical carrier. As the pharmaceutical carrier, a wide variety of carriers conventionally known in the art can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate,
Excipients such as kaolin, crystalline cellulose, and silicic acid, water,
Ethanol, propatool, simple syrup, glucose solution,
Starch liquid, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters , sodium lauryl sulfate,
Disintegrants such as stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; and humectants such as glycerin and starch. Examples include adsorbents such as , starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Further, as the forming means, any method capable of obtaining particles in the above-mentioned form can be adopted, but it is particularly preferable to use the commonly used centrifugal fluid coating granulation method, spray coating method using a coating pan, etc. be. The amount of the active ingredient to be used varies depending on which coating is subsequently applied to the obtained spherical particles, but as raw material particles for obtaining immediate release particles, about 3 to 5% by weight in the particles, and To obtain release particles, it is preferably present in an amount of about 3 to 5% by weight in the particles.

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), hydroxyethylethyl cellulose (HEEC), hydroxyethyl methyl cellulose (HEMC), etc. can. Among these, HPM
C is preferred, which is rHPMCT from Shin-Etsu Chemical ■
It is commercially available under the trade name C-5RJ. Said 1-(PMC
TC-5R4 [specific gravity approximately 0.5-0.7 g/C13, methoxyl group content 28-30%, hydroxypropyloxy group content 7-12%, viscosity (cps, 2%,
20°C) is 20% above Q cps.

The solvent for preparing the solvent solution of the coating agent mentioned above is not particularly limited, but usually includes water, alcohols such as methanol, ethanol, and isopropanol, a mixture of these and methylene chloride, etc. used. The coating agent is preferably prepared as a solution containing usually 0.4 to 5% by weight of the above-mentioned hydroxy lower alkyl lower alkyl cellulose, and the solution further contains a coloring agent, a masking agent, a plasticizer, and a flavoring agent as required. Additives such as flavoring agents may 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, and the formation of this coating results in spherical particles having the desired immediate release properties. is obtained.

In addition, the other component (component b) which is an essential component of the formulation of the present invention
That is, the sustained-release particles contain 37.5 to 55% by weight of lower alkyl cellulose and 62.5% by weight of hydroxy lower alkyl lower alkyl cellulose phthalate in the same raw material particles as above.
45% by weight in a solvent solution in a similar manner. The lower alkyl cellulose used as the coating agent is typically ethyl cellulose, and the hydroxy lower alkyl lower alkyl cellulose phthalate is, for example, hydroxyethyl ethyl cellulose phthalate (HEECP).
), hydroxypropyl methylcellulose phthalate (HPMCP), and preferably HPMCP. The HPMCP is, for example, rHP from Shin-Etsu Chemical Co., Ltd.
It is commercially available as MCPHP-55SJ, which contains 18-22% methoxyl groups and 4% hydroxypropoxyl groups.
-9%, carboxybenzoyl group 27-35%, and the viscosity (20°C) in 15% acetone solution is about 290
20% on cps. It is important that the above two types of coating agent components are used together in the above specified 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 deviates from 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 37.51i1%, it is not possible to obtain a sufficient sustained effect of the medicinal effect of the active ingredient compound. Further, when a coating agent containing more than 55% by weight of lower alkyl cellulose is used, there is a drawback that the absorption rate of the active ingredient compound in the gastrointestinal tract is lower than that of conventional commercially available tablets. 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 coating amount of the solution 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 either case, it becomes difficult to form the desired sustained-release coating.

The sustained-release preparation of the present invention comprises spherical particles formed with an immediate-release coating (component a) obtained as described above and spherical particles formed with a sustained-release coating (component b), with a ratio of 10 to 10 to 6
It is manufactured by blending at a blending ratio of 0% by weight to 90 to 40% by weight. When this blending ratio deviates from the above ratio, it is difficult to obtain a long-acting preparation that has both immediate release and long-lasting properties, which is the objective of the present invention.

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. Further, the capsules described above 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 a conventional method.

The preparation of the present invention usually contains 10 to 201 g of active ingredient per dose.
It is orally administered in a unit form containing 1,000 ml, and achieves the desired therapeutic effect immediately after administration, and the desired therapeutic effect lasts for about 24 to 72 hours thereafter, so that a sufficiently stable effect can be achieved with once-daily administration. It can be played.

K-East-1 Examples of the present invention will be shown below.

Example 1 (1) Refined sucrose 400Q was put into a centrifugal fluid coating granulator, and carteolol hydrochloride 40a was added.

Granulation is carried out with 120Q of purified water while sprinkling a mixture consisting of 280Q of refined white sugar and 280g of cornstarch. Subsequently, 1% hydroxypropyl methylcellulose solution (rHPMcTC-5RJ (Shin-Etsu Chemical Co., Ltd.)
(dissolved in a 1:1 mixture of ethanol and purified water to a concentration of 1%) 250Q was used to coat by spraying, and after drying at 60°C, it was sieved to obtain a 0.
25-1 ms carteolol hydrochloride immediate release spherical particles are obtained.

(2) Put 400Q of refined white sugar into a centrifugal fluid coating granulator, and add 80Q of carteolol hydrochloride.

Granulation is carried out with 120Q of purified water while sprinkling a mixture consisting of 260Q of refined white sugar and 260Q of corn starch. Subsequently, hydroxypropyl methyl cellulose phthalate and ethyl cellulose solution (ethanol 250
Hydroxypropyl methylcellulose phthalate (rHPMCPHP
-55SJ (Shin-Etsu Chemical Co., Ltd.) 150Q.

Ethyl cellulose (r Ethocel STD I
Coating was performed using a spray method using Qcps J, Dow Chemical Company) 120q and glycerin fatty acid ester ([Mybaset Q-40TJ, Koyo Shokai, plasticizer) 15Q], dried at 60°C, and sieved. Carteolol hydrochloride sustained release spherical particles having a particle diameter of 0.25 to 1111 are obtained.

(3) 50 parts by weight of the immediate-release spherical particles obtained in (1) above and 501 parts by weight of sustained-release spherical particles obtained in (2) above were mixed to give a total amount of carteolol hydrochloride equivalent to 15 g. The amount is filled into 2508 (l 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 1 The titers in Table 1 above are based on high performance liquid chromatography (Shimadzu LC-5A), mobile phase: 1% vinegar I!
=Ethanol=7=3, Column: Micro-Bonda pak C1s (manufactured by Waters, inner diameter 3.911 IIX, length 3 Qci), measurement wavelength UV 254 rv, internal standard: Measured using anhydrous caffeine.

Example 7 (1) Hydroxypropyl methyl cellulose phthalate and ethyl cellulose solution (ethanol 220
In 0CJ and 2200 g of dichloromethane, hydroxypropyl methyl cellulose phthalate (rHPMcPH
P-55SJ150tllll, ethyl cellulose (r
EthocelSTD 10cps J 90Q and glycerin fatty acid ester ([Myvaset Q-40TJ
15Q) was applied by spraying, dried at 60°C, and sieved to obtain a 0.
Carteolol hydrochloride-releasing spherical particles of 25 to 1.0 mm are obtained.

(2) Immediate-release spherical particles obtained in Example 1 (1) and the above (
The sustained-release spherical particles obtained in 1) were mixed in the same manner as in Example 1 (3) so that the titer ratio was 1:2 and 1:1, and an amount equivalent to 15 mg of total carteolol hydrochloride was prepared. is filled into capsules to obtain the preparation (capsule) of the present invention.

Example 8 (1) Hydroxypropyl methyl cellulose phthalate and ethyl cellulose solution (ethanol 2
Hydroxypropyl methylcellulose phthalate (rHPM) in 900 CJ and 290 Oo dichloromethane
CPHP-55SJ 1 50a1x Circe) 1. t
O-7. (rohocetSTD 10cps
Using J 1 5 (l and glycerin fatty acid ester (containing 5 g of Mybaset Q-40TJ 1),
Coating is done using a spray method, and this is applied at 60%
It is dried at 0.degree. C. and sieved to obtain sustained-release spherical particles of carteolol hydrochloride having a particle size of 0.25 to 1.01.

(2) Immediate-release spherical particles obtained in Example 1 (1) and the above (
The sustained-release spherical particles obtained in 1) were mixed in the same manner as in Example 1 (3) so that the titer ratio was 1:2 and 1:1, and an amount equivalent to 15 m + 7 as total carteolol hydrochloride was obtained. is filled into capsules to obtain the preparation (capsule) of the present invention.

Example 9 (1) 400a of refined white sugar was put into a centrifugal fluid coating granulator, and 400Q1 of Carteolol hydrochloride 28
Granulate with 120Q of purified water while sprinkling a mixture of 0Q and 280g of cornstarch. Subsequently, 0.4% hydroxypropyl methylcellulose solution (
Coating was performed by spraying using IN-IPMCTC-5RJ (Shin-Etsu Chemical Co., Ltd.) 250Q (a solution prepared by dissolving 0.4% concentration in a 1:1 mixture of ethanol and purified water), and this was dried at 60°C. After that, sieve, 0
．． 25 to 1 inch carteolol hydrochloride immediate release spherical particles are obtained.

(2) Hydroxypropyl methyl cellulose phthalate and ethyl cellulose solution (ethanol 40
Hydroxypropyl methyl cellulose phthalate (r) IPMCP in 00 g and 4000 g of dichloromethane
HP-55SJ 222Q, ethyl cellulose ("Et
hocelsTD 10cps J 178g and glycerin fatty acid ester (Mybaset Q-40TJ
15Q) was applied by spraying, dried at 60°C, and sieved to give a 0.2
Carteolol hydrochloride sustained release spherical particles having a particle size of 5 to 1.0 mm are obtained.

(3) Immediate-release spherical particles obtained in (1) above and (2) above
were mixed with the sustained-release spherical particles obtained in Example 1 (3) so that the titer ratio was 1:2 and 1:1, and an amount equivalent to 15 mg of total carteolol hydrochloride was poured into capsules. to obtain a preparation (capsule) of the present invention.

Example 10 (1) Put 40 liters of refined white sugar into a centrifugal fluid coating granulator, add 40q1 of refined white sugar, 2B of refined white sugar
Granulate with 120 q of purified water while sprinkling a mixture consisting of 280 g of OQ and cornstarch. Subsequently, 5% hydroxypropyl methylcellulose (rHPM) was added to the granules.
cTc-5R" solution (ethanol:purified water - 1:1 mixture) 600% by using I to coat by spraying method. After drying this at 60°C, it was sieved to give a 0.25%
~1+w+ carteolol hydrochloride immediate release spherical particles are obtained.

(2) Hydroxypropyl methyl cellulose phthalate and ethyl cellulose solution (ethanol 1 o
Hydroxypropyl methyl cellulose phthalate (“HPMcP”) in ooo and dichloromethane l ooo
HP-55SJ 55.5g, ethyl cellulose (rEthocel ST mouth 1Qcps J 44.5
g and glycerin fatty acid ester ([Mybaset Q-
40TJ15Q) by a spray method, dried at 60° C., and sieved to obtain sustained-release spherical particles of carteolol hydrochloride of 0.25 to 1.0 mm.

(3) The particles of (1) and (2) above were mixed in the same manner as in Example 1 (3) so that the titer ratio was 1:2 and 1:1, and then filled into capsules. Capsules (preparation of the present invention) containing 151 g of carteolol hydrochloride are obtained.

Test Example> The preparation of the present invention obtained in Example 1 (capsules containing 15 mg of total carteolol hydrochloride per capsule) was orally administered once a day to five healthy adult male subjects. We measured and observed the changes in plasma concentrations in the subjects. The above plasma concentration was determined by high performance liquid chromatography (manufactured by Waters Inc.,
204 compact type). As a quantitative condition, the column was a reversed-phase Micro Bonder Pack Cl8 (μm8
onda pak C18, made by Waters, diameter 3
．． 911X 30 C1 length) with a mobile phase of 30%
(V/V17 Setonitrile, 0.02MNH4H2PO
4 and 0.02M (NH4)2HPO4 were used. (Detected at JV=254ni. The results are shown in Table 1 as line (1).

In the figure, the horizontal axis shows the time after administration (hr), and the vertical axis shows the plasma concentration (μQ/111>).

Figure 1 also shows that for comparison, a commercially available carteolol hydrochloride preparation (5u tablets) was administered to five healthy adult male subjects three times a day.
The drug was orally administered twice (every 8 hours), and the change in plasma concentration of the subjects after administration was similarly measured, and the results are 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]

Figure 1 is a graph showing the change in plasma active ingredient concentration of subjects who were administered the formulation of the present invention and the commercially available formulation. Relationship with the case of the person making the amendment Patent applicant 4, agent 10 Sawa no Tsuru Building, 2 Hirano-cho, Higashi-ku, Osaka, Tel: 06-203
-0941 (generation) 7° Subject to 0 amendments ``Claims'' section in the specification and contents of the amendment (1) Correct the statement in the ``Claims'' section in the specification in an attached document. . (2) On page 3, line 16 of the specification, the statement ``rlO ~ 60% by weight'' is corrected to ``10-60 titer outside.'' (3) In the second line of page 4 of the specification, the statement "90-40% by weight" is corrected to "90-40% titer." (4) On page 11 of the specification, lines 13-14, “10-60・
9. Correct the following statement: ``Blending ratio of 10-60% to 90-40% titer, that is, about 18~
75% by weight to about 82 to 25% by weight” (above) Scope of Claim ■Ca) 5- (2-Storage C3-T-Butyl Amitub 0B-S)-3,4- An immediate release coating containing dihydrocarbostyril or a pharmaceutically acceptable wrinkle addition salt thereof as an active ingredient and consisting of didrocarbostyril lower alkyl lower alkyl. 10-60% titer of spherical particles coated with 3% by weight and (b) containing the same active ingredient as above, containing lower alkaline t
37.5-55% by weight of 0-sulphthalate and 2.5-45% by weight of
Weight: 90-40 titer of spherical particles coated with 10-40% by weight of a good sustained-release coating.

Claims (1)

[Claims] ■ (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 60% by weight of spherical particles coated with 0.1 to 3% by weight of an immediate release coating consisting of hydroxy lower alkyl lower alkyl cellulose, and (b) lower alkyl cellulose 37 containing the same active ingredients as above. .5-55% by weight and hydroxy lower alkyl lower alkyl cellulose phthalate 62.5-45
A sustained-release preparation comprising 90-40% by weight of spherical particles coated with 10-401i% by weight of a sustained-release coating.