JP2008120767A - Capsule, production process therefor and medicine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a capsule excellent in redispersibility in water, having higher hardness upon preparation into a drug, with a short oral cavity disintegration time, and capable of forming a poorly water-soluble medicine; and a medicine containing the capsule as a main ingredient. <P>SOLUTION: The capsule is characterized in that an electrostatically adsorptive first polyelectrolyte and a second polyelectrolyte having electric charge opposite to that of the first polyelectrolyte are laminated alternately covering a core containing a poorly water-soluble medicine. A production process is also provided which comprises steps of (a) preparing a suspension of a poorly water-soluble medicine having an average particle size of about ≤200 μm, (b) coating the poorly water-soluble medicine particles in the suspension by allowing the same to adsorb the electrostatically adsorptive first polyelectrolyte, (c) coating the resulting medicine particles by allowing the same to adsorb the second polyelectrolyte having electric charge opposite to that of the first polyelectrolyte, and (d) repeating the steps (b) to (c) to obtain a capsule. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a capsule containing a poorly water-soluble or water-insoluble drug and used for pharmaceutical purposes, a method for producing the capsule, and a drug based on the capsule. The capsules of the present invention can be used to produce new pharmaceutical formulations, in particular oral fast disintegrating formulations, taste masking formulations.

  Conventionally, various methods have been reported to produce aqueous micro and nano suspensions of pharmaceuticals that are sparingly soluble or insoluble in water. For example, in addition to mechanical grinding techniques such as dry grinding (ball mill, bead mill, air jet grinding) and wet grinding (initial grinding machine, ball or bead mill, air jet grinding), “via humida paratum” Various precipitation techniques such as precipitation by pouring the active substance solution into a non-solvent also belong to such a method (Hagers Handbuch dermazeutischen Praxis, Springer Publishing, Heidelberg, 1994).

  The micro- and nano-dispersed particles produced by the above-mentioned conventional production method, especially the suspension water thereof, do not exhibit sufficient stability unless the additive is added, and are therefore usually produced in the presence of this additive. (For example, it is disclosed in DE3013839, EP0499299, EP0275796, US6048550, WO01515196, DE3579385D, DE44040337, etc.). This is a significant drawback of the aforementioned technologies for producing and stabilizing dispersions. That is, the presence of significant amounts of such amphiphiles or surfactants, polymers and other additives can lead to significant “excipient-related toxicities”, in addition The relatively low stability of such surface coatings can result in easy aggregation, especially upon dilution and resuspension.

  On the other hand, in recent years, with the shift to an aging society and changes in the living environment, it has been desired to develop a pharmaceutical preparation that is easy to handle and easy to take for elderly people, children, and patients whose water intake is restricted. Conventionally, dosage forms of solid pharmaceutical preparations include tablets, granules, powders, capsules, and the like, but these tablets may reduce compliance of patients with low swallowing ability such as elderly people and children. Moreover, since a large amount of water is required when taking these solid preparations, it is a problem particularly when patients who have limited intake of water.

For this reason, preparations that are excellent in redispersibility in water when taking solid pharmaceutical preparations and rapidly disintegrate or dissolve in the oral cavity only with saliva without water or only with a small amount of water are drawing attention. . For example, R.A. P. Orally-dissolving preparation Zydis fast-dissolving preparation commercially available from Scherer, “orally disintegrating preparation and its production method” (see Patent Document 1), “rapidly dissolving solid preparation and its production method” (see Patent Document 2) , “Fast dissolving tablets” (see Patent Document 3), “wet tablet molding method and apparatus and wet tablet” (see Patent Document 4), “fast dissolving tablet manufacturing method and fast manufacturing speed by the manufacturing method” Examples thereof include “dissolvable tablets” (see Patent Document 5) and “manufacturing method of orally rapidly disintegrating tablets” (see Patent Document 6). Patent Document 7 discloses a production method that gives a good aqueous suspension of a poorly water-soluble medicine or the like and a fast release rate.
International Publication No. 93/12769 Pamphlet JP 11-116464 A International Publication No. 93/15724 Pamphlet JP-A-6-218028 JP-A-8-291051 Japanese Patent Laid-Open No. 11-12161 US Pat. No. 6,479,146

  However, in any of the production methods disclosed in Patent Documents 1 to 6, there is a drawback that a large amount of additive is used, resulting in an increase in volume of the final preparation.

  In addition, the production method disclosed in Patent Document 7 provides a good aqueous suspension of a poorly water-soluble pharmaceutical and the like and a fast release rate. However, in order to identify a specific drug and to develop a preparation that can be sufficiently put into practical use as compared with conventional intraoral rapidly disintegrating tablets and taste-removing preparations, an excellent stable aqueous suspension and a fast In addition to the release rate, the dry powder has an appropriate interparticle bonding force and fluidity, and the tablet hardness after molding and the speed of resuspension are important points. Generally, the higher the tablet size, the higher the hardness required. When the compression molding pressure is increased to increase the hardness in preparation for cases where the transport conditions of the tablets are poor, a delay in the oral disintegration time and tableting troubles may be observed. For these reasons, development of a preparation having higher hardness and a shorter oral disintegration time is desired.

  The present invention has been made in view of the above circumstances, a capsule capable of preparing a poorly water-soluble pharmaceutical having excellent redispersibility in water, high hardness upon formulation, and short disintegration time in the oral cavity, and the capsule It aims at providing the medicine which has as a main component.

  In order to achieve the above object, the present invention provides a first polymer electrolyte having an electrostatic adsorption force to a nucleus containing a poorly water-soluble drug, and a second polymer electrolyte having a charge opposite to that of the first polymer electrolyte. A capsule in which the polyelectrolyte is alternately laminated and coated.

In the capsule of the present invention, the average particle size of the capsule is preferably 200 μm or less.
In the capsule of the present invention, the poorly water-soluble drug is preferably clarithromycin.

  In the capsule of the present invention, the first polyelectrolyte or the second polyelectrolyte is protamine, gelatin A, collagen, albumin, casein, chitosan, poly- (L) -lysine, carboxymethylcellulose, alginate, heparin, hyaluro Nick Acid, Chondroitin Sulfate, Gelatin B, Carrageenan, Dextran Sulfate, Poly- (L) -Glutamic Acid Other Biocompatible Polymers, Biodegradable Polymers, DNA, RNA, Enzymes or Antibodies Other Biopolymers, One or more kinds selected from the group consisting of polymethacrylic acid-based polymers (for example, trade name Eudragit), polydiaryldimethylammonium and other synthetic polymers, or polymers in which they are cross-linked with a suitable linker Be a molecular electrolyte Is preferred.

  In the capsule of the present invention, the poorly water-soluble drug is clarithromycin, and the first polyelectrolyte or the second polyelectrolyte is protamine, gelatin A, collagen, albumin, casein, chitosan, carboxymethylcellulose, alginate, heparin 1 or 2 selected from the group consisting of hyaluronic acid, chondroitin sulfate, gelatin B, carrageenan, dextran sulfate, poly- (L) -glutamic acid, polymethacrylic acid-based polymer (for example, trade name Eudragit) The above polymer electrolyte is preferable.

  In the capsule of the present invention, it is preferable that the coating of the capsule is composed of a plurality of layers, preferably 3 to 20 layers.

  In the capsule of the present invention, the average thickness of the capsule coating is preferably about 80 nm or less.

  In the capsule of the present invention, it is preferable that at least 90% by weight of the medicine is disintegrated and released in water within 2 minutes.

  In the capsule of the present invention, the capsule preferably has an average particle size of 20 μm or less.

  The capsule of the present invention preferably has a positive or negative zeta potential of 10 mV or more.

  In the capsule of the present invention, the content of the poorly soluble drug is preferably 90% by mass or more of the total amount of the capsule.

The present invention also provides
(A) preparing a suspension of a poorly water-soluble pharmaceutical having an average particle size of about 200 μm or less;
(B) adsorbing the first polymer electrolyte having electrostatic adsorption force to the poorly water-soluble drug particles in the suspension prepared in the step (a) and coating the first polymer electrolyte;
(C) A step of adsorbing and coating a second polymer electrolyte having a charge opposite to that of the first polymer electrolyte on the drug particles coated with the first polymer electrolyte obtained by the step (b) When,
(D) The process of obtaining the capsule in any one of Claims 1-10 by repeating the said (b) process-(c) process,
And a method for producing a capsule.

The present invention also includes (a) preparing a suspension of a poorly water-soluble pharmaceutical having an average particle size of about 200 μm or less;
(B) The poorly water-soluble drug particles in the suspension prepared in the step (a) are coated with the first polymer electrolyte having electrostatic adsorption force adsorbed thereon, and the drug particles are washed and purified. And a process of
(C) The second polymer electrolyte having the opposite charge to the first polymer electrolyte is adsorbed onto the drug particles coated with the first polymer electrolyte obtained by the step (b), and coated. And further washing and purifying the medicinal particles;
(D) The process of obtaining the capsule in any one of Claims 1-10 by repeating the said (b) process-(c) process,
And a method for producing a capsule.
In the capsule manufacturing method of the present invention, it is preferable that the suspension prepared in the step (a) is prepared by precipitating a poorly water-soluble drug in advance.

  In the method for producing a capsule of the present invention, the sedimentation is performed by diluting or removing a solvent or a solvent mixture, and in that case, it is preferable that a poorly soluble medicine is previously dissolved in the solvent or the solvent mixture.

  In the capsule manufacturing method of the present invention, it is preferable that the suspension prepared in the step (a) is prepared by pulverizing a poorly water-soluble drug in advance.

  The present invention also provides a pharmaceutical comprising the above-mentioned capsule according to the present invention as a main component and formulated in such a manner that it can be applied orally, parenterally, pulmonary, nasal, ocular or transdermally.

  The present invention also provides a medicament comprising the above-described capsule according to the present invention as a main component and a solid preparation that can be rapidly disintegrated and released by oral application.

  The present invention also provides the use of the capsule according to the present invention as described above for formulating a medicament for application by oral, parenteral, lung, nose, eye, skin or transdermal.

  The present invention also provides the use of the capsule according to the present invention described above for the preparation of a solid preparation that rapidly disintegrates and releases a poorly soluble drug for the purpose of oral application.

According to the capsule of the present invention, a capsule that is excellent in redispersibility in water, has a higher hardness at the time of formulation, has a short oral disintegration time, and can prepare a slightly water-soluble pharmaceutical, Can be provided.
According to the production method of the present invention, the capsule can be efficiently produced by a continuous film-forming method that does not require a complicated separation and purification step.

  In order to achieve the above-described object, the present inventors have determined that the polyelectrolyte to be used, particularly the approved polyelectrolyte, depending on the specific physical properties of the pharmaceutical, especially the acidity and basicity. And the amount of addition, pH at the time of coating, etc. were examined in detail. As a result, the present inventors have found conditions for obtaining capsules that are optimal for different orally disintegrating preparations and taste-removing preparations, depending on each specific medicine. In addition, the present invention has been completed by improving the production method disclosed in Patent Document 7, which requires separation and purification for each coating layer, and finding a continuous coating method that does not require a complicated separation and purification step.

  The capsule of the present invention comprises a first polymer electrolyte having an electrostatic adsorptive power to a nucleus containing a poorly water-soluble drug, and a second polymer electrolyte having a charge opposite to that of the first polymer electrolyte. Are alternately laminated and coated, and have an average particle size of 200 μm or less.

  In the present invention, a poorly water-soluble drug refers to a drug whose solubility is in the range of “extremely insoluble in water” and “almost insoluble” as defined in the Japanese Pharmacopoeia Law. Typical examples of poorly water-soluble drugs include clarithromycin.

  In the present invention, a combination of polymer electrolytes having opposite charges can be used as the first polymer electrolyte and the second polymer electrolyte constituting the capsule coating. Preferred first polyelectrolytes or second polyelectrolytes in the present invention include protamine, gelatin A, collagen, albumin, casein, chitosan, poly- (L) -lysine, carboxymethylcellulose, alginate, heparin, hyaluronic. Acid, chondroitin sulfate, gelatin B, carrageenan, dextran sulfate, poly- (L) -glutamic acid, other biocompatible polymers, biodegradable polymers, DNA, RNA, enzymes or antibodies other biopolymers, poly One or more polymers selected from the group consisting of methacrylic acid-based polymers (for example, trade name Eudragit), polydiaryldimethylammonium and other synthetic polymers, or polymers in which they are cross-linked with an appropriate linker List electrolyte However, it is not limited to these.

  In a preferred embodiment of the present invention, the first polyelectrolyte or the second polyelectrolyte is one already approved as a pharmaceutical or food additive, ie protamine, gelatin A, collagen, albumin, casein, chitosan, carboxymethylcellulose, One selected from the group consisting of alginate, heparin, hyaluronic acid, chondroitin sulfate, gelatin B, carrageenan, dextran sulfate, poly- (L) -glutamic acid, polymethacrylic acid polymer (for example, trade name Eudragit) Or 2 or more types of polymer electrolytes are desirable.

  The capsule of the present invention has an average particle size of 200 μm or less, and preferably has an average particle size of 20 μm or less. If the average particle size of the capsules exceeds 200 μm, the size of the capsules becomes large and it becomes difficult to drink.

  The capsule of the present invention has a structure in which a core containing a poorly water-soluble medicine is coated with a first polymer electrolyte and a second polymer electrolyte alternately by adsorption or electrostatic interaction. With this structure, the number of layers in the capsule wall can be accurately controlled, and thereby the average thickness of the capsule wall can also be controlled. The coating is preferably a plurality of layers, and more preferably in the range of 3 to 20 layers in order to achieve a fast release rate of the poorly water-soluble drug. When the coating is less than 3 layers, the coating stability is deteriorated. On the other hand, when the coating exceeds 20 layers, it is difficult to quickly release the poorly water-soluble drug from the capsule.

  Further, the average thickness of the capsule coating is preferably about 80 nm or less, and more preferably about 30 nm or less. When the average thickness of the capsule coating exceeds 80 nm, the release rate is slow, which is not preferable.

  Also, the capsule coating has a positive or negative zeta potential of at least 10 mV, preferably at least 20 mV, due to adsorption of the polyelectrolyte. If the zeta potential is less than 10 mV, the stability of the coating is deteriorated, which is not preferable.

  The capsule of the present invention can disintegrate and release at least 90% by mass of the poorly water-soluble drug within 2 minutes. In addition, this method can prepare a stable aqueous suspension with a small amount of the coating substrate of several mass% or less as compared with the conventional method. As a result, it is suitable for downsizing of the preparation. If the amount of the poorly water-soluble medicine that disintegrates and releases within 2 minutes is less than 90% by mass, the release of the medicine deteriorates, which is not preferable.

Next, the manufacturing method of the capsule of this invention is demonstrated. The method for producing the capsule of the present invention comprises:
(A) preparing a suspension of a poorly water-soluble pharmaceutical having an average particle size of about 200 μm or less;
(B) adsorbing the first polymer electrolyte having electrostatic adsorption force to the poorly water-soluble drug particles in the suspension prepared in the step (a) and coating the first polymer electrolyte;
(C) A step of adsorbing and coating a second polymer electrolyte having a charge opposite to that of the first polymer electrolyte on the drug particles coated with the first polymer electrolyte obtained by the step (b) When,
(D) The process of obtaining the capsule in any one of Claims 1-10 by repeating the said (b) process-(c) process,
It has each process.

  In the production method of the present invention, the materials of the poorly water-soluble drug, the first polymer electrolyte, and the second polymer electrolyte are as described in the description of the capsule of the present invention.

  In the step (a), the core of the poorly water-soluble drug can be produced by a well-known method. In particular, a method of pulverizing a medicine by a dry method or a wet method may be mentioned, and also by a precipitation method or a crystallization method such as diluting or removing a solvent or solvent mixture in which a medicine hardly soluble or insoluble in water is dissolved beforehand. Can be manufactured. By this step (a), an aqueous suspension in which the core of the poorly water-soluble pharmaceutical having an average particle diameter of about 200 μm or less is uniformly dispersed is prepared.

  In order to minimize reaggregation of the poorly water-soluble drug, the suspension prepared in the step (a) is immediately brought into contact with the first polyelectrolyte having electrostatic adsorptive power to the core of the poorly water-soluble drug. Thus, it is desirable to execute the step (b) in which the first layer is formed. In this step (b), the first polymer electrolyte is preferably mixed with the suspension in the form of an aqueous solution in advance in order to bring it into contact with the poorly water-soluble drug quickly and uniformly. In addition, when the suspension and the aqueous solution of the first polymer electrolyte are mixed, the aqueous solution of the first polymer electrolyte is added continuously or intermittently while sufficiently stirring the suspension. It is desirable.

  By the step (b), the first polymer electrolyte is adsorbed on the surface of the core of the poorly water-soluble drug, and a first layer film composed of the first polymer electrolyte is formed. Since this first layer coating has either a positive or negative charge, the first layer coated drug particles have good dispersibility in aqueous media and are stable. An aqueous suspension can be formed.

  The coated drug particles in the first layer can be separated from the polyelectrolyte solution using centrifugation, filtration or dialysis, and the separated coated drug particles in the first layer If necessary, it may be washed with an appropriate washing solution such as water and dried.

  Next, the obtained first layer-coated pharmaceutical particles are placed in an aqueous solution of a second polyelectrolyte having a charge opposite to that of the first polyelectrolyte, and resuspended. The step (c) of forming a second layer coating composed of the second polymer electrolyte on the surface of the first layer coating of the particles is performed.

  In the step (c), an aqueous solution of the second polymer electrolyte charged opposite to the surface charge of the first layer-coated pharmaceutical particles obtained in the step (b), that is, the first layer When the eyes have a positive surface charge, the first layer coated drug particles are resuspended in the polyacid solution, and in the case of a negative surface charge, the first layer coated drug particles are resuspended. The second polymer electrolyte in the aqueous solution is adsorbed on the first coating based on the electrostatic interaction, and a second coating film made of the second polymer electrolyte is formed on the first coating film.

  The coated drug particles in the second layer prepared in the step (c) can be separated from the polyelectrolyte solution using centrifugation, filtration or dialysis, and further, the separated second layer The coated drug particles are washed with an appropriate washing solution such as water as necessary and dried.

  The coated drug particles in the second layer are put in an aqueous solution of the first polyelectrolyte and resuspended, and the step (b) is performed again to obtain the coated drug particles in the third layer. Further, the step (c) is carried out to form the fourth coated drug particles, and the step (b) and the step (c) are further repeated, so that the first high particle is formed on the surface of the slightly water-soluble drug core. A capsule of the present invention is obtained in which a coating in which a molecular electrolyte and a second polymer electrolyte are alternately laminated in any number of layers is formed (step (d)). In addition, as above-mentioned, it is preferable that the coating in this capsule shall be the range of 3-20 layers.

  The capsule of the present invention obtained through the step (d) can be prepared as a dry powder by lyophilization in the form of an aqueous suspension. The dry powder can also be resuspended in water.

  This capsule or a stabilized suspension of the capsule is used directly or indirectly to produce a pharmaceutical preparation of a medicament. The medicament can be in a form to be applied orally, parenterally (subcutaneous injection, intramuscular injection, intravenous injection), transpulmonary, nasal, ocular or transdermal. More preferably, it is suitable for production of a solid preparation that rapidly releases an orally rapidly disintegrating preparation or other poorly water-soluble pharmaceutical for oral application. Also important is the use to produce rapid release lyophilized, rapid release films and rapid release tablets suitable for the treatment of acute diseases or conditions.

[Example 1]
Micronized clarithromycin (100 mg; mean particle size 7 μm) was suspended in a carrageenan hydrochloric acid solution (1 mL; 1 mg / mL carrageenan; 0.5 M sodium chloride; clarithromycin saturated) using ultrasound (30 minutes). It became cloudy. Subsequently, the supernatant was removed by centrifugation (2 minutes; 4000 U / min), suction filtration (filter pore size 1 μm) or centrifugal filtration (filter pore size 0.2 μm; 1 minute; 10,000 rpm). The separated clarithromycin particles were washed twice with pure water (1 mL; saturated with clarithromycin), and each time the supernatant was centrifuged again (2 minutes; 4000 U / min), suction filtered (filter pore size 1 μm) or centrifuged It was removed by filtration (filter pore size 0.2 μm; 1 minute; 10,000 rpm). The resulting particles were resuspended in saline (0.5 mL; 0.5 M sodium chloride; clarithromycin saturated) and chitosan hydrochloric acid solution (0.5 mL; 2 mg / mL chitosan; 0.5 M sodium chloride) ; Saturated with clarithromycin) and shaken for 15 minutes. Subsequently, the supernatant was removed by centrifugation (2 minutes; 4000 U / min), suction filtration (filter pore size 1 μm) or centrifugal filtration (filter pore size 0.2 μm; 1 minute; 10,000 rpm). The particles were washed twice with pure water (1 mL; saturated clarithromycin), and the supernatant was centrifuged again (2 minutes; 4000 U / min), suction filtration (filter pore size 1 μm) or centrifugal filtration (filter pore size 0.2 μm; 1 minute; 10,000 rpm). The resulting particles were resuspended in pure water (1 mL; saturated clarithromycin) to obtain a stable bilayer-coated clarithromycin suspension with an average particle size of 7 μm. By repeating the above laminating operation as needed, a desired multilayer coated clarithromycin suspension was obtained. This suspension was filtered and air-dried to obtain a multilayer coated clarithromycin powder.

[Example 2]
Micronized clarithromycin (100 mg; average particle size 7 μm) was used in chondroitin sulfate solution (1 mL; 1 mg / mL chondroitin sulfate; 0.5 M sodium chloride; clarithromycin saturated) using ultrasound (30 minutes) And suspended. Subsequently, the supernatant was removed by centrifugation (2 minutes; 4000 U / min), suction filtration (filter pore size 1 μm) or centrifugal filtration (filter pore size 0.2 μm; 1 minute; 10,000 rpm). The separated clarithromycin particles were washed twice with pure water (1 mL; saturated with clarithromycin), and each time the supernatant was centrifuged again (2 minutes; 4000 U / min), suction filtered (filter pore size 1 μm) or centrifuged It was removed by filtration (filter pore size 0.2 μm; 1 minute; 10,000 rpm). The resulting particles are resuspended in saline (0.5 mL; 0.5 M sodium chloride; clarithromycin saturated) and protamine sulfate solution (0.5 mL; 2 mg / mL protamine sulfate; 0.5 M sodium chloride). ; Saturated with clarithromycin) and shaken for 15 minutes. Subsequently, the supernatant was removed by centrifugation (2 minutes; 4000 U / min), suction filtration (filter pore size 1 μm) or centrifugal filtration (filter pore size 0.2 μm; 1 minute; 10,000 rpm). The particles were washed twice with pure water (1 mL; saturated with clarithromycin), and the supernatant was centrifuged again (2 minutes; 4000 U / min), suction filtration (filter pore size 1 μm) or centrifugal filtration (filter pore size 0.2 μm). 1 minute; 10,000 rpm). The resulting particles were resuspended in pure water (1 mL; saturated with clarithromycin) to obtain a stable bilayer-coated clarithromycin suspension with an average particle size of 7 μm. By repeating the above laminating operation as needed, a desired multilayer coated clarithromycin suspension was obtained. This suspension was filtered and air-dried to obtain a multilayer coated clarithromycin powder.

[Example 3]
In Example 1, the zeta potential of the particles was measured at each lamination step, and the minimum amount of the polymer electrolyte necessary for the value to reach the maximum value was obtained in advance. This minimum amount was continuously added to the particles to form a laminated film. The laminating reaction conditions for each coating were the same as in Example 1. By the above method, a 5-layer clarithromycin suspension was obtained without separation and purification. This suspension was filtered and air-dried to obtain a 5-layer coated clarithromycin powder.

[Example 4]
In Example 2, the zeta potential of the particles is measured at each lamination step, and the minimum amount of polymer electrolyte necessary for the value to reach the maximum value is obtained in advance. This minimum amount is continuously added to the particles to form a laminated film. The lamination reaction conditions for each film formation are the same as in Example 2. A 5-layer coated clarithromycin suspension was obtained without separation and purification by the above method. This suspension was filtered and air-dried to obtain a 5-layer coated clarithromycin powder.

Claims (20)

  The first polyelectrolyte having electrostatic adsorptive power to the nucleus containing the poorly water-soluble drug and the second polyelectrolyte having the opposite charge to the first polyelectrolyte are alternately laminated and coated. Capsule characterized by comprising.   The capsule according to claim 1, wherein the average particle size is 200 μm or less.   The capsule according to claim 1 or 2, wherein the poorly water-soluble drug is clarithromycin.   The first polyelectrolyte or the second polyelectrolyte is protamine, gelatin A, collagen, albumin, casein, chitosan, poly- (L) -lysine, carboxymethylcellulose, alginate, heparin, hyaluronic acid, chondroitin sulfate, Gelatin B, carrageenan, dextran sulfate, poly- (L) -glutamic acid and other biocompatible polymers, biodegradable polymers, DNA, RNA, enzymes or antibodies and other biopolymers, polymethacrylic acid polymers 2. Polydiaryldimethylammonium or other synthetic polymer, or one or more polyelectrolytes selected from the group consisting of polymers cross-linked by a suitable linker. The capsule in any one of -3.   The poorly water-soluble drug is clarithromycin, and the first polyelectrolyte or the second polyelectrolyte is protamine, gelatin A, collagen, albumin, casein, chitosan, carboxymethylcellulose, alginate, heparin, hyaluronic acid, chondroitin One or more polymer electrolytes selected from the group consisting of sulfate, gelatin B, carrageenan, dextran sulfate, poly- (L) -glutamic acid, and polymethacrylic acid-based polymer The capsule according to any one of claims 1 to 4.   The capsule according to any one of claims 1 to 5, wherein the capsule coating is composed of a plurality of layers.   The capsule according to claim 1, wherein the capsule has an average thickness of about 80 nm or less.   Capsules according to any one of the preceding claims, characterized in that at least 90% by weight of the medicament is disintegrated and released in water within 2 minutes.   The capsule according to any one of claims 1 to 8, wherein the capsule has an average particle diameter of 20 µm or less.   The capsule according to any one of claims 1 to 9, wherein the capsule has a positive or negative zeta potential of 10 mV or more.   The capsule according to any one of claims 1 to 10, wherein the content of the poorly water-soluble drug is 90% by mass or more of the total amount of the capsule. (A) preparing a suspension of a poorly water-soluble pharmaceutical having an average particle size of about 200 μm or less;
(B) adsorbing the first polymer electrolyte having electrostatic adsorption force to the poorly water-soluble drug particles in the suspension prepared in the step (a) and coating the first polymer electrolyte;
(C) A step of adsorbing and coating a second polymer electrolyte having a charge opposite to that of the first polymer electrolyte on the drug particles coated with the first polymer electrolyte obtained by the step (b) When,
(D) The process of obtaining the capsule in any one of Claims 1-10 by repeating the said (b) process-(c) process,
And a method for producing a capsule. (A) preparing a suspension of a poorly water-soluble pharmaceutical having an average particle size of about 200 μm or less;
(B) The poorly water-soluble drug particles in the suspension prepared in the step (a) are coated with the first polymer electrolyte having electrostatic adsorption force adsorbed thereon, and the drug particles are washed and purified. And a process of
(C) The second polymer electrolyte having the opposite charge to the first polymer electrolyte is adsorbed onto the drug particles coated with the first polymer electrolyte obtained by the step (b), and coated. And further washing and purifying the medicinal particles;
(D) The process of obtaining the capsule in any one of Claims 1-10 by repeating the said (b) process-(c) process,
And a method for producing a capsule.   14. The method for producing a capsule according to claim 12 or 13, wherein the suspension prepared in step (a) is prepared by precipitating a poorly water-soluble drug in advance.   15. The method for producing a capsule according to claim 14, wherein the precipitation is performed by diluting or removing the solvent or the solvent mixture, and in this case, the poorly soluble medicine is preliminarily dissolved in the solvent or the solvent mixture.   14. The method for producing a capsule according to claim 12 or 13, wherein the suspension prepared in step (a) is prepared by pulverizing a poorly water-soluble drug in advance.   A pharmaceutical comprising the capsule according to any one of claims 1 to 11 as a main component and formulated to be applicable orally, parenterally, pulmonarily, nasally, ocularly or transdermally.   A medicament comprising the capsule according to any one of claims 1 to 11 as a main component, and a solid preparation that can be rapidly disintegrated and released by a oral application.   Use of a capsule according to any of claims 1 to 11 for formulating a medicament for application by oral, parenteral, lung, nose, eye, skin or transdermal.   Use of the capsule according to any one of claims 1 to 11 for preparing a solid preparation that rapidly disintegrates and releases a poorly soluble drug for the purpose of oral application.