JPS58172311A - Prolonged pharmaceutical preparation and its preparation - Google Patents

Abstract

PURPOSE:A prolonged type pharmaceutical preparation capable of regulating freely the release of a drug in an organism, cotaining cyclodextrin, ethyl cellulose, and a glycerol ester of a higher fatty acid as prolonged components, obtained by adding various kinds of drugs to the components. CONSTITUTION:The titled preparation containing ethyl cellulose, glycerol ester of a higher fatty acid, cyclodextrin, and a drug-containing component. In the pharmaceutical manufacturing, the prolonged components are blended with the drug by a proper method, dissolved or dispersed into a solvent, molded, or the prolonged components are blended with the drug, and, if necessary, various kinds of auxiliaries for pharmaceutical manufacturing, and processed into various kinds of dosage forms. In the amount blended of each component, the amount of cyclodextrin is 1/10-8 times, preferably 1/4-5 times as much as that of the drug, and the amount of the glycerol ester of a higher fatty acid is 1/10-10 times, preferably 1/2-5 times as much as that of the drug.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention (a) relates to a long-acting preparation and its manufacturing method. , dispersed inside polymeric materials such as waxes, lacquers, and glass sticks, methods for forming granules, pills, tablets, etc., or on the surface of stiff molded products containing active ingredients. , fats and oils.

Apply a coating with wax*, lacquer, plastic, etc.
．． Therefore, methods have been adopted to delay the release of active ingredients in vivo.

1. However, in the conventional method, there is a problem that the active ingredient a is easily released non-uniformly. For example, the absorption of the active ingredient into the living body often fluctuates due to the influence of the pulsating motion of element 5II, p)l, and Ik in the living body, and the absorption of the active ingredient into the living body often fluctuates. It cannot be expected that the active ingredients will be released continuously, and in some long-acting preparations, due to individual differences in living organisms, the active ingredients may not be digested and may be excreted from the body unabsorbed. Generally, in long-acting preparations, the release of the drug reaches the effective plasma sr as soon as possible after taking the drug, which may cause mental agitation to the user.11. After that, it is ideal to physically release the drug in an amount that maintains its effective concentration gradually and over as long a period of time as possible without being affected by raw salts. 9. Among drugs, especially those that are water-soluble, if the release is suppressed by the conventional method described above for sustained release, not only will the initial blood concentration of 11 kl not increase, but the effective blood concentration f-transfer will also decrease. If it takes too long to dissolve, or if the strength does not increase within 1-2 seconds, the dosage may need to be increased, and measures to increase the solubility may be required for practical use. It is often very difficult to control the amount released, and for water-soluble drugs. .

The initial release amount is slightly higher (if you try to increase the plasma concentration immediately after administration with 1-4), you will not be able to obtain a sustained release as much as +4, and the blood plasma concentration will continue to rise and fall rapidly. Due to the rounding that occurs, it is possible to maintain an effective concentrated concentration after the highest concentration in the blood vessel -1, vh, thus, by simple adjustment of the released amount, it is possible to control the mtie in the plasma. and 1. τ is also subject to physiological influences in living organisms.
1 is often the case.

In order to improve the above-mentioned problems, the present inventors have been diligently researching long-acting preparations, and have discovered a long-acting preparation (rx) that allows the release amount in the living body to be adjusted much more freely than before.
We succeeded in obtaining a long-acting formulation).

Namely, 1) the present invention uses rff cyclodextrino, ethyl cellulose, and higher fatty acid glycerin ester as a sustaining component; 4, which provides sex preparations and methods for producing the same. Sustaining ingredients and drugs a.

Mixing by appropriate method12. Melt! Dissolve in Lea dispersion 1-1 and form 11 to obtain a preparation. In addition, in addition to the sustaining ingredients and drug, if necessary, various formulation auxiliaries that are not acceptable to pharmaceutical agents may be added. Granulate 1−τ
Add auxiliary ingredients from 1. When processed into various dosage forms, it is easy to mix with auxiliary ingredients.

□ Cyclodextrin used in the present invention 1) Non-volatization of volatile substances, protection of easily oxidized substances and photodegradable substances, masking of bitterness, emulsification of water-insoluble fats, steroids, and hydrophilic substances, etc. , if possible by inclusion etc., 1-
It is obtained by treating one length of cyclodextrin with an enzyme, and there are three types of cyclodextrin: α, β, and r. Of each type, you can use the v-h suwa, but in reality, the σβ type is Tango himself 1. It's easy to use, so it's best to use stiff.

In the present invention, rX, ? The use of cyclodextrins improves the solubility and dispersibility of lI compounds and increases the initial release rate of the drug when the drug is soluble in water to 0% and is used as a sustained formulation. The effect is remarkable. That is, higher fatty acid glycerin ester A, which is used to suppress the drug release rate, excessively suppresses the initial release to 1% of the drug release, which compromises the absorption of the drug into the body, but this problem In order to solve the problem, in the present invention, a? The surfactant action of cyclodextrin improves the drug's zero-phase release and absorption into the body. Also, in general rxllll
1. Create a soluble drug a clathrate and make it easily soluble. (a) Although it is difficult to achieve easy dispersibility, the method of the present invention
It is not necessary to include it in t￥f, just to mix it with the above-mentioned specific components? The advantage of cyclodextrin is that the solubility is 41<a and the dispersity is improved due to the surfactant effect. In the case of busy, government officials, water-soluble drugs?
If cyclodextrin is added, the above-mentioned effects cannot be obtained, and the solubility of the product may be increased unnecessarily.
Na ^.

Furthermore, adding nyclodextrin 1. The crack 1!1IIa of the present invention was formed by molding, and the other side was compression by pressure molding.

The formulation solidifies due to pressure.1. In such cases, there is no change in the permeability of the liquid into the inside of this preparation.In other words, since cyclodextrin A has a high affinity for water, when the liquid penetrates into the preparation, it swells the molded scoop and absorbs the drug. It has the effect of keeping it constant.

Ethylcellulose n, body Qt4iFI-τ! lf4'!
It has the effect of suppressing the elution of drugs to a certain extent. When ethylcellulose a is added to a drug component at a low concentration, it only suppresses the initial release amount of the drug, so the maximum plasma concentration a does not decrease much, but when added at a high concentration, the drug's In order to strongly suppress the release, it will be possible to maintain a constant amount of release over a long period of time.1.
By adjusting the amount of ethylcellulose added depending on the absorption and metabolic rate of the drug.

It is possible to impart release characteristics to the formulation depending on the purpose. In addition, the range of a1 ethoxy group in ethyl cellulose is 45L.
The medium type of θ ~ 465- and the range of cy group in etho is 48
．． There are 4 standard types ranging from 0 to 49.5-. Type 4 of Azuwa can be used in the present invention, but the viscosity is 7 to 250.
cps/) 4 is good (among them, 4 is practical [RFF viscosity 10-100 cpsf) 4 is suitable.

Higher fatty acid glycerin varnish"1□, as chill, monoglycerin stearate, monoglycerin oleate,
Monoglycerides such as monoglyceryl laurate are preferred, although diglycerides and triglycerides may be used. Higher fatty acid glycerin esters do not have the effect of suppressing drug release over a long period of time when added to formulations, but when administered to a living body, they suppress the initial rapid release of drugs and reach the maximum plasma concentration. You can delay your time. .

In this way 1. τ, in the present invention, by combining ethyl cellulose and higher fatty acid glycerin ester, it is possible to obtain both the effect of suppressing the rapid initial release of the drug due to the glycerin ester and the effect of sustaining constant release over a long period of time due to the ethyl cellulose. In addition to this, the addition of cyclodextrin can improve the solubility of drugs that are poorly soluble in water, while also providing an appropriate amount of release.

The amount of cyclodextrin H is preferably 1/10 to 8 times the weight ratio of the above-mentioned ingredients to la% drug.

In addition, the stability of some drugs is affected by the PHK at the absorption site, so even if the drug has a constant release as described above, it may have a long-lasting effect due to inactivation or decomposition of the drug itself. The effect may not be fully demonstrated. In such cases, known coating agents such as enteric coated siglovir methylcellulosephthalate in Hyde I2 (HPMCP), cellulose acetate phthalate (CAP), methyl Methacrylic acid methacrylate 1) kll copolymer (Ewdragit” (L,
8. It is preferable to perform a protective coating with R2Op(), etc. Other commonly used coating agents, such as HA%AEA, can also be used as appropriate depending on the properties of the drug.

To obtain a formulation by the method of the present invention, the sustaining ingredient and the drug are granulated by a spray granulation method and a fluidized bed granulation method,
It is convenient to use this as a granule as it is or to process it into various dosage forms by combining it with other ingredients. Pharmaceutically acceptable anhydrous silica or its salts can be used as a glidant during granulation. By adding talc, aluminum metasilicate-intoxicated magnesium, kaolin, and bentonite e,
Since it can prevent particles from adhering to each other and inside the machine shelf, which one is suitable? It is best to interpret and use it.

As the solvent for molding according to the present invention, pharmaceutically acceptable organic solvents such as acetone, ethanol, methyl ethyl ketone, ethyl cellosolve, ethyl cellosolve,
A mixed solvent with isopropyl alcohol, methylene chloride, ethylene chloride, trichloroethane, etc. is used. In addition, water may be used next to the water-soluble drug.To process the microparticles obtained in this way into formulations, various known additives may be added to form tablets, capsules, etc.
It can be formed into pills, active ingredients, etc.

The present invention will be further described below based on Examples and Examples.
5L light.

Implementation full 1 25 parts of Indometacif, higher fatty acid glycerin ester and Nikkol-MOS (manufactured by Nikko Chemicals) 25NS, ethyl cellulose [F].

) Cell (Ethocal, p-chemical (Dow)
B) 5m, β-cyclodextrin ■.

Weighed 100 parts of C@rdex-N (manufactured by Nihon Shokuhin Koko Co., Ltd.) and 50 parts of talc,
On a 70°C water bath, warm the solution* (methylene chloride 50%
(mixture of 50 parts of alcohol and 50 parts of methyl alcohol)]
Stir and mix to make a uniform suspension. This WI! The suspension is sprayed from a rotating disk or nozzle using a spray dryer and dried to obtain pale yellowish white particles of approximately 70μ to 500 particles, or the suspension is heated to a fluidized bed. Te! Using a method of spraying from a nozzle and drying, and using 25 parts of lactose as a core material, fluidize it in a fluidized bed granulator! ! l! Spraying the suspension from a nozzle: Approximately 150μ to 800μ depending on the coating method.
Obtain pale yellowish-white sustained fine particles. This sustained microparticle is then processed using the insertion and equipment commonly used in pharmaceuticals.
Additives shown in K were added and molded into tablets, capsules, bioactive materials, etc.

Example 2 Mefenam gSO part, higher fatty acid puricelli/ester 7
Weighed 5 ftB, ethyl cellulose S part, β-cyclodextrin y 300 parts and talc 100 parts,
Heat to 0'CK and add to ff1l [>400 parts of a good solvent (50 parts of isopropyl alcohol, !: 50 parts of ethyl alcohol) and stir and mix to make a uniform suspension. This suspension is dried in a spray dryer. Similar to Example 1, approximately 70μ to 25μ
Obtain the persistent particles of Tanroku Byakuya with 0 voice.

Example 3 Weighed 30 parts of acetaminophen, 30s of higher fatty acid glycerin ester, 60 parts of cyclodextrin, 11 ethyl cellulose and 0 part of tartar,
Add to 124011 a mixture of 50 parts of methylene chloride SOS and ethyl 74 solv heated to ℃ and mix with stirring to make a homogeneous suspension. Similarly, white sustained fine particles of about 60 μm to 300 μm were obtained.Also, the suspension was processed using a fluidized bed granulator for $111.
and the threshold Is (however, the nuclear material lactose was assumed to be 45 parts) about 1O
White sustained fine particles with a size of Oμ to 500μ are obtained.

Example 4 50 parts of theophylline, 5 parts of higher fatty acid glycerin ester
0 parts, 100 parts of β-cyclodextrin, and 400 parts of a mixed solution with 50 s of alcohol, and stirred and mixed to form a uniform suspension. This suspension was applied using a spray dryer f! Similar to Il, pale yellowish white sustained fine particles of about 6o11 to 406μ are obtained.

Experimental Example 1 The long-acting preparations manufactured in Examples 1 to 4 and the commercially available non-long-acting preparations as comparison controls were tested according to the dissolution test method (rotating basket method) K described in the 10th edition of the Japanese Pharmacopoeia. The elution rate was calculated using the absorbance method.

The results are shown in Figures 1 to 8, indicated by points * in these figures.
The dissolution curves of Fi Collection Examples 1 to 40 tablets and capsules are shown, and the solid line represents the dissolution:1:1 exit line of the comparative formulation. Compared to pharmaceutical preparations, it has a sustained effect due to sustained release, and this effect is particularly evident in % tablets.

Experimental Example 2 Using 10 healthy domestic rabbits weighing 25 to 10 mm, the concentration of indomethacin a in plasma when administered with the large animal produced in Example 1 was determined. The Vl rabbits were fasted for 42 hours in advance and given water ad libitum by a friend.The rabbits were fixed in the dorsal position and a feeding caniere was inserted into the femoral vein. A bioactive material was inserted into the anus of this domestic rabbit, and the anus was sandwiched with a clip to prevent the bioactive component from leaking. Blood is administered live, 0%%, 1.5.2.3
．． Blood was collected through each 3-cannula at 4.6 and 8 hours, and indomethacin in the plasma was quantified according to the method of Hucker et al.

The results are shown in Figure 9. In FIG. 9, 5JIIj is Example 1
The dotted line represents the plasma concentration curve of a commercially available non-persistent active substance #I-Ki as a comparison control.
In addition, the width ii of 6 in FIG. 9 represents the standard error. As is clear from this figure, the biotransfers of the present invention all have better initiation of drug transfer into the blood than commercially available biotransfers, and moreover, have a sustained effect due to sustained release.

[Brief explanation of the drawing]

Figures 1 to 8 are graphs showing the dissolution curves of the formulations of Examples 1 to 4 of the present invention and commercially available comparative formulations. It is a graph showing the time course of the plasma drug degree after administering a commercially available comparative drug. (1 other person) O8 figure +00 door-1 / / /! Te l off
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Claims (1)

[Claims] Oral) Active pharmaceutical ingredients and ethyldolulose. High-grade fatty acid glycol ester & chickpeas. A long-acting preparation made from dextrin. (2) Pharmaceutical active ingredients and ethylcellulose. A method for producing a long-lasting preparation, which comprises adding a suitable solvent to a mixture of higher fatty acid glycerin ester and Y-cyclodextrin and molding the mixture.