JPS6259207A - Solid dispersion or microencapsulation of drug - Google Patents

Abstract

PURPOSE:To obtain a spherical granular solid dispersion or microcapsule without using an organic solvent, by adding a main drug and an acrylic copolymer to an alkaline aqueous solution and feeding the resultant solution or suspension to a spray dryer. CONSTITUTION:A main drug and a copolymer of (meth)acrylic acid and an alkyl (meth)acrylate are added to an alkaline aqueous solution to give a solution or suspension, which is then fed to a spray dryer. Alternatively, a suspension obtained by adding the main drug and a water-dispersible copolymer prepared by emulsion polymerizing the (meth)acrylic acid with alkyl (meth)acrylate or water-dispersible copolymer of the alkyl acrylate with alkyl methacrylate to water is fed to the spray dryer to give the aimed spherical granular solid dispersion or microcapsule. The resultant pharmaceutical has sustained release properties and enteric effect and is capable of holding the concentration of the drug in the blood for a long period.

Description

[Detailed Description of the Invention] [A] Object of the Invention The present invention uses an acrylic acid-based polymer substance as the main drug,
It relates to a novel method of solid dispersion or microencapsulation formed by spray drying.

[Industrial application field]

According to the solid dispersion or microencapsulation method according to the present invention, since no organic solvent is used in the process,
It enables efficient mass production without any danger, and can be used to make spherical micropowders of various drugs for pharmaceuticals and other uses.

In particular, the solid dispersion or microcapsule according to the present invention has a sustained release effect and an enteric coating effect, and can be used in formulations where necessary to improve the long-lasting blood concentration of a drug during oral administration. It can be used in

[Conventional technology]

No other examples have been found in which microcapsules or solid dispersions were manufactured by spray drying using acrylic acid-based polymer substances.

Acrylic acid-based polymer substances have conventionally been used as coating agents for tablets. The solid dispersion in the present invention means that the main drug in the finally formed spherical particulate powder is in an amorphous state. In other words, in the case of microcapsules, the main drug is encapsulated in the film of the coating agent (carrier) in a crystalline state, whereas in the case of solid dispersions, the main drug is dispersed in the carrier at the molecular level. It refers to the formed spherical particulate powder.

As a method for obtaining a solid dispersion using an acrylic acid polymer as a carrier, when the main drug is a powder substance, a method of obtaining it by evaporating the main drug and the carrier in a solution consisting of an organic solvent is described in 'Pharmacy H Magazine. 104, 485F, (1984). The solid dispersion obtained by this method is in the form of a lump and requires a pulverization step to make it into granules (powder). Furthermore, it is not easy to form spherical particles.

[Problem that the invention seeks to solve]

Simple mass production technology for microcapsules and solid dispersions has been desired in order to miniaturize the dosage form and make it easier to take when the main drug is orally administered. Unfortunately, however, as a means of mass production using conventional methods, organic solvents must be used for any of the carriers, and for this reason, final steps such as drying, etc.
It required a complete removal operation of the organic solvent used in the process, and the amount of organic solvent used was also large, resulting in a high degree of danger. Therefore, there have been disadvantages such as increased size of equipment for removing the organic solvent, equipment for storage, and the like.

13 = In other words, to obtain microcapsules and solid dispersions,
Even if spray drying is a method for mass production, conventionally known carriers require a large amount of organic solvent, so if they are suddenly fed to a spray dryer, residual organic solvent will be removed. There is a danger of explosion, and its complete removal operation is an essential condition, which leads to high costs [problem solved by the invention]. The objective is to discover a carrier that can be produced without using any organic solvents, naturally subject to the spray drying method. The inventor is
As a result of conducting research based on various polymeric materials, we have completed a new microencapsulation or solid dispersion method using acrylic acid-based polymeric substances, as shown in the following examples. It's arrived.

[Example] Structure of the Invention The present invention is based on the method of preparing a main drug, acrylic acid or methacrylic acid, and an acrylic acid alkyl ester having 1 to 4 carbon atoms, or an alkyl group having 4 to 4 carbon atoms, in an alkaline aqueous solution. A copolymer consisting of methacrylic acid alkyl ester having 1 to 4 carbon atoms is added and stirred with or without addition of a plasticizer to form a solution or suspension, and this solution is spray-dried. solid dispersion or microencapsulation method. Furthermore, in water, the main drug and acrylic acid or methacrylic acid and an alkyl acrylate in which the alkyl group has 1 to 4 carbon atoms are methacrylic acid alkyl esters in which the alkyl group has 1 to 4 carbon atoms. A water-dispersible copolymer obtained by emulsion polymerization, or an alkyl acrylate ester in which the alkyl group has 1 to 4 carbon atoms, and an alkyl methacrylate in which the alkyl group has 1 to 4 carbon atoms. Add a water-dispersible copolymer obtained by emulsion polymerization of ester in the form of a suspension, emulsion, or paste containing 10 to 70% solids, and further add a plasticizer, And, if necessary, an emulsifier is added and stirred to form a suspension, and this liquid is supplied to a spray dryer to form a microcapsule.

The present invention can be specifically illustrated as follows, for example.

As a solid dispersion or microcapsule carrier of the main drug, a copolymer of methacrylic acid and methyl methacrylate, a copolymer of methacrylic acid and ethyl acrylate, or a copolymer of methacrylic acid and ethyl acrylate. Alternatively, it can be produced by spray drying a water-dispersible copolymer obtained by emulsion polymerization of ethyl acrylate and methyl methacrylate.

In addition, in the examples, the copolymers specified in each process are shown, and thereby the method that does not use any organic solvent is limitedly shown. As a prerequisite, not only all the copolymers used in Examples 1 and 2, but also all the copolymers, such as those from the combinations (a) to (d) in the following table (Table 1), are required. It has also been found that solid dispersions or microcapsules can be produced by using either of these copolymers as carriers for solid dispersion or microencapsulation.

"Table 1, Carrier when using an organic solvent (Example 1) Copolymer consisting of 1 part methacrylic acid and 1 part methacrylic acid methyl ester, or a copolymer of methacrylic acid and acrylic acid ethyl ester The ratio is 30 parts of an unspecified copolymer (published by Higuchi Shokai: Eudragit L-100 or Eudragit L-100-55), 3 parts of polyethylene glycol 6000 (PEG6000),
It was dissolved in 1000 parts of 2% ammonia water, and further, 10 parts of theophylline and 1.3 parts of colloidal silica were added thereto as drugs, and the mixture was stirred with a homomixer and then fed into a spray dryer to form uniform spherical fine particles (for convenience, Sample A) was obtained.

Although the main drug does not need to be particularly limited, it is preferably a powdery substance that is soluble in alkali.

(Example 2) 15 parts of a copolymer consisting of 1 part methacrylic acid and 2 parts methacrylic acid methyl ester (Eudragit S-100, sold by Higuchi Shokai), 1 part PEG6000.
5 parts of the drug was dissolved in 1000 parts of 2% ammonia water, and then 15 parts of theophylline was dissolved in the same manner as in Example 1, although any powdered substance may be used as the main drug without any particular restrictions. , add 2 parts of colloidal silica. Thereafter, the same operations as in the example were performed to obtain uniform spherical fine particles (referred to as sample B for convenience).

(Example 3) A water-dispersible copolymer obtained by emulsion polymerization of methacrylic acid and acrylic acid ethyl ester, or acrylic acid ethyl ester and methacrylic acid methyl ester, and containing 30% solid content ( As an emulsifier, polysorbate 80 is contained in an amount of 3% based on the solid matter.
D) 100mj! 3.0g of PEG6000 and 900m of distilled water! Prepare a solution in advance, then take 40.0 g of theophylline and 5.0 g of colloidal silica,
After preparing a solution with a total volume of 1000 ml by adding water, both prepared solutions were simultaneously fed into a spray dryer in equal amounts to obtain uniform spherical fine particles (referred to as sample C for convenience).

[Comments to Examples]

(A) The conditions of the spray dryer shown in each of the above Examples are as follows.

(a) Atomizer rotation speed 2000 Or p m (
b) Liquid supply rate 1000ml/h
(c) Hot air inlet temperature: 170°C (d) Hot air outlet temperature: 105-110°C CB) The use of colloidal silica during the process improves fluidity, promotes uniform spherical powdering, and improves the finished product. It was used because it can improve the powder properties of the product. (Colloidal Silicani Nippon Aerosil Co., Ltd.: Aerosil 200) [C
] Polyethylene glycol 6000 (PEG6000
) was used as a plasticizer, but it can be made without it. Also, other plasticizers may be used. The use of a plasticizer has the same effect as CB) and is effective in improving the dispersibility or uniformity of the solution and increasing productivity.

[D] In Example 3, since an acrylic acid-based water-dispersible copolymer containing an emulsifier was used during the process, only a plasticizer was added without adding an emulsifier. The addition of an emulsifier is effective in making the suspension uniform, and it is desirable to use it as necessary.

In addition, the use of appropriate amounts often improves productivity in the same way as the addition of the above-mentioned chemicals [B] and [C].

Next, the physical properties (actions or effects) of samples A to C obtained in Examples 1 to 3 are as follows.

[Confirmation of physical properties]

(1) In each case of samples A-C, the composition is
The composition was the same as that in the stock solution in each example.

(2) Both samples A-C have a spherical shape,
It was homogeneous.

(3) Among samples A to C, X-ray analysis of both samples A and B revealed that part or all of theophylline, the main drug, was completely amorphous. Ta. FIG. 1 shows the X-ray analysis patterns of sample A, and FIG. 2 shows the X-ray analysis patterns of a simple powder mixture of theophylline, the main drug, and Eudragit L, the membranous agent, using the same composition as used in sample A.

(4) Both samples A to C can be made into tablets by direct compression. That is, if Samples A to C are used, they can be made into tablets by directly applying them to a high-pressure tableting machine without using binders or other excipients.

(5) For enteric-coated and sustained release effects, e.g.
The table is based on samples A-B, and the first liquid (pH 1 , 2) are the results of measuring the elution state when using the second solution (pH 6, 8).

Also, Fig. 3 is for sample A, and Fig. 4 is for sample B.
The elution concentration of theophylline, the main drug, was measured over the elution time using a spectrophotometer, and the elution rate was calculated.The graph shows the results of these measurements. As shown, theophylline elution in the first liquid is extremely small, and it has excellent enteric properties.
It can be seen that the tablet made from Kirani Sample B exhibits a sustained release function in both the first liquid and the second liquid. On the other hand, the tablets directly compressed using Sample C are
Both have good enteric action, similar to the dissolution pattern exhibited by direct compression.

In addition, the paddle rotation speed in the test was 1100 rpm, and the temperature was 37.0°C.

(6) The copolymer shown in Example 1 consisting of 1 part methacrylic acid and 2 parts methacrylic acid methyl ester as a carrier is used as the main drug in a ratio of 3 parts to 1 part theophylline. However, it was found that the degree of amorphization between the main drug and the carrier increases as the ratio of the carrier increases compared to the main drug (7 ) When using a copolymer consisting of 1 part methacrylic acid and 2 parts methacrylic acid methyl ester as the carrier shown in Example 2, the solid dispersion or microcapsules obtained thereby are It has the characteristic that a sustained release effect can be obtained in both the first liquid and the second liquid. This can be said to be because this carrier has the property of dissolving from pH 7.0 = 15 This was the first successful production of a spherical solid dispersion or microcapsule using an acrylic acid-based polymer material by spray drying. It is believed that this method will make a significant contribution to the medical and therapeutic fields.In other words, in contrast to conventional general solid dispersion and microencapsulation methods, this method adopts a spray drying method and uses an acrylic acid-based polymer material as a carrier. There are no other examples of this, and it is a great advantage that it can be done without using any organic solvents in the final process.

The effects of the present invention are summarized as follows.

(1) It is safe because no organic solvent is used in the process. Furthermore, since it does not take up much space in terms of equipment, is easy to operate, and has a simple process, it is easy to industrialize and the production cost is low.

(2) According to the powder method, both the obtained solid dispersion and microcapsules can be directly pressed into a high-pressure tablet machine to form tablets without using binders or excipients. Of course, it is also possible to automatically fill gelatin capsules according to the diurnal schedule.

(3) By changing the composition ratio of the main drug and carrier in the stock solution (system) before injection into the spray dryer during the process, fine granules and microcapsules in the form of a solid dispersion can be easily manufactured. What you can do. At the same time, enteric coating performance and sustained release performance can be freely controlled by changing the composition ratio.

etc.

[Brief explanation of drawings]

Figure 1 shows the X-ray analysis pattern of Sample A. Figure 2 shows theophylline and Eudra Liquid L-100.
An X-ray analysis figure based on a simple mixture of FIG. 3 is a graph showing the elution amount of Sample A in the elution test. In Figures 3 and 4, (a) is in the first liquid, (b) is in the second liquid.
Indicates the elution amount in the liquid. Figure 1 Figure 2 Diffraction angle (2θ) Figure 3
Figure 4 Procedural amendment (method) % formula % 2. Title of the invention

Claims (2)

[Claims] (1) In an alkaline aqueous solution, the main drug, acrylic acid or methacrylic acid, and an acrylic acid alkyl ester in which the alkyl group has 1 to 4 carbon atoms, or methacrylic acid in which the alkyl group has 1 to 4 carbon atoms. A solid dispersion formed by adding a copolymer consisting of an acid alkyl ester, stirring with or without adding a plasticizer to form a solution or suspension, and feeding this liquid to a spray dryer. encapsulation or microencapsulation method. (2) In water, the main drug, acrylic acid or methacrylic acid, and an acrylic acid alkyl ester in which the alkyl group has 1 to 4 carbon atoms, or a methacrylic acid alkyl ester in which the alkyl group has 1 to 4 carbon atoms. A water-dispersible copolymer obtained by emulsion polymerization, or an alkyl group having 1 to 4 carbon atoms
A water-dispersible copolymer obtained by emulsion polymerization of acrylic acid alkyl esters and methacrylic acid alkyl esters in which the alkyl group has 1 to 4 carbon atoms, and contains 10 to 70% as solid matter. A suspension, emulsion, or paste is added, and a plasticizer and, if necessary, an emulsifier are added and stirred to form a suspension, and this liquid is fed to a spray dryer to form a suspension. microencapsulation method.