HK1039889A - Preparations with controlled release - Google Patents

Description

Controlled release formulations

Technical Field

The present invention relates to novel formulations for the controlled release of active substances, in particular pharmaceutical active ingredients. More particularly, the present invention relates to a preparation suitable for releasing a drug within a relatively short time after a certain delay time (time period during which the drug is not released) after administration, that is, a pulse-type release preparation.

Background

In the field of drug therapy, it is desired that a drug selectively reach the lower small intestine or the large intestine in (1) local treatment of inflammatory bowel diseases such as ulcerative colitis or (2) oral administration treatment of a peptide drug in which the content of the small intestine is easily decomposed by chemical decomposition or by enzymes. Therefore, in recent years, in order to allow a drug to selectively reach the lower small intestine or the large intestine, formulation design has been made in consideration of physical and physiological environments in the human digestive tract and the time for which the formulation moves in the digestive tract.

For example, the conventional enteric preparations and sustained-release preparations are not designed from such a viewpoint that the former preparation effectively suppresses drug elution in the stomach, and the drug rapidly dissolves in the upper small intestine, and most of the drug is absorbed or decomposed and does not reach the large intestine. In addition, the latter formulation has problems: since the drug is continuously dissolved, the preparation is dissolved out quite a lot when passing through the stomach and small intestine.

Further, a preparation having a controlled-release membrane comprising a combination of a water-insoluble polymer and an enteric polymer is also known (Japanese patent application laid-open No. 3-7238, European patent No. 40590), which is a preparation in which a drug is slowly eluted after oral administration or after migration to the small intestine, and which does not control the elution start time or the elution start pH and does not bring the drug to the lower part of the digestive tract in a concentrated manner.

In view of the above-mentioned drawbacks of the conventional enteric preparations and sustained-release preparations, a novel controlled-release preparation has been developed which can release a drug at a suitable site in the digestive tract (particularly, a lower part of the digestive tract such as the small intestine and the large intestine) as a target site and which is aimed at a higher-level and higher-performance drug delivery system.

As various oral administration systems that specifically release a drug at a lower part of the digestive tract, which are prepared by a pharmaceutical method, a method of controlling the release start time by using the time when the pharmaceutical moves in the digestive tract, a method of controlling the release site by using intestinal bacteria, and the like are known.

Japanese examined patent publication No. 2-58246 discloses a compressed tablet which disintegrates specifically in the colon to release the active ingredient regardless of the residence time of the drug in the stomach. However, this compressed tablet is a preparation using bacteria present in the colon, and thus has the following disadvantages: since the disintegration time varies among individuals of bacteria in the colon, it takes time for the disintegration when the disintegration activity of intestinal bacteria is low.

JP-A-4-235123 discloses a film-coated controlled-release preparation comprising a copolymer of ethyl acrylate, methyl methacrylate and trimethylethammonium methacrylate (Eudragit RS, registered trademark, Rohm Pharma corporation) and a hydrophobic salt (calcium stearate). This is a so-called S-type controlled release preparation which releases a drug compound after a certain time, and controls the time of starting elution by controlling the permeation rate of water in the coating film. In addition, when the coating film is thick, there is a disadvantage that it is difficult to obtain a rapid drug elution rate after the start of elution. Moreover, the preparation is a system for releasing the drug after oral administration for a certain period of time, and it is difficult to determine a specific release site.

Japanese patent application laid-open No. 4-264022 discloses a lower gastrointestinal release type oral preparation in which a hard capsule comprising a matrix mainly composed of chitosan is filled with a solid preparation containing a solid organic acid and a main ingredient, and an enteric coating is formed on the surface of the capsule. This is to adjust the dissolution start time by the thickness of the hard capsule, and in order to control the dissolution start time, the thickness of the capsule film must be accurately controlled.

Japanese patent application No. 4-505004 discloses a controlled release preparation, which is prepared by plugging a water-insoluble capsule with a water-swellable suppository, wherein the suppository begins to swell while absorbing water, and falls off after a certain period of time, thereby releasing the drug in the capsule. However, since this preparation is a system that releases the drug after oral administration for a certain period of time and the residence time of the preparation in the stomach varies among individuals, it is very difficult to determine the release site in the digestive tract.

These conventional enteric preparations for topical treatment also have disadvantages of complicated structure, varying dissolution time depending on individual differences such as pH and gastric retention time, difficulty in controlling delay time, and insufficient in view of obtaining effective blood concentration by rapid total dissolution after the start of dissolution.

Therefore, as a system utilizing the transit time of the preparation in the digestive tract, since the time for the preparation to pass through the small intestine is almost constant between individuals, several systems are considered which can eliminate the difference in the retention time of the preparation in the stomach and utilize the transit time in the small intestine. These systems do not release the drug when it is retained in the stomach, and it is discharged from the stomach and travels to the small intestine for a certain period of time, i.e., it can specifically release the drug at a site distant from the stomach, for example, the large intestine, which is the lower part of the digestive tract.

Specifically, for example, Japanese patent laid-open No. 4-501411 discloses a preparation for releasing a drug after a certain delay time by applying 3 coatings, the 3 coatings being: an inner layer formed by coating an anionic copolymer dissolved at pH7.0 or more, an intermediate layer containing a gelling polymer which swells and gels to form a gel layer independent of pH, and an outer layer portion containing an appropriate amount of a gastric resistant polymer which rapidly dissolves in the intestine. However, this preparation is disadvantageous in that the dissolution rate of the gelled polymer is easily affected by the movement in the digestive tract, and the delay time may vary, and as described above, it is a very complicated system in structure and preparation method.

Further, a system in which the preparation of Japanese patent publication Hei 4-505004 is coated with an enteric coating to reach the large intestine is disclosed, a preparation coated with an acrylic polymer mixture is disclosed in Japanese patent laid-open No. 8-143476, and a capsule system containing an acidic substance is coated with a low-pH substance-soluble coating is disclosed in Japanese patent laid-open No. 9-87169.

However, these systems having both the enteric coating function and the drug release time controlling function are currently very complicated in structure and require time and labor for preparation.

The object of the present invention is to provide a formulation which can rapidly release a drug at a predetermined time and pH.

DISCLOSURE OF THE INVENTION

The present inventors have made intensive studies to develop an oral preparation which does not release a drug until it reaches a specific site in the lower part of the digestive tract such as the small intestine or the large intestine and rapidly releases the entire amount of the drug by a pulse after reaching the site, and as a result, have found that the oral preparation is formed only by at least 2 mutually engaging members, wherein the preparation in which the negative member containing an active substance is enclosed by a positive member (plug) formed of an intestinal fluid gelling material, the drug is not released at all in the low pH region in the stomach, the side of the positive member contacting the intestinal fluid is slowly gelled only in the region where the pH is relatively close to neutral such as the small intestine or the large intestine, and the part of the positive member having the thinnest thickness after a certain time is gelled to be permeable to water, and the drug is released in a short time by a pulse.

The controlled release preparation of the present invention is a controlled release preparation containing at least 1 pharmaceutically active ingredient, and is characterized by comprising a positive member and a negative member, which are integrally fitted to each other and in which an active substance is enclosed, wherein the positive member is formed of an enteric gelation material.

Preferably, the male member contains a copolymer of ethyl acrylate, methyl methacrylate, trimethylethylmethyl methacrylate, and a copolymer of methacrylic acid and ethyl acrylate as the intestinal fluid gelling material.

More preferably, the copolymerization ratio of the ethyl acrylate/methyl methacrylate/trimethylethylammonium methacrylate copolymer (ethyl acrylate: methyl methacrylate: trimethylethylammonium methacrylate (molar ratio)) is about 1: 2: 0.1 to 0.2, and still more preferably, the copolymerization ratio of the ethyl methacrylate/ethyl acrylate copolymer (methacrylic acid: ethyl acrylate (molar ratio)) is about 1: 1.

More preferably, the copolymer of ethyl methacrylate and ethyl acrylate is contained in an amount of 0.3 to 20 parts by weight based on 1 part by weight of the copolymer of ethyl acrylate, methyl methacrylate and trimethylethylmethacrylate.

In a preferred embodiment of the controlled-release preparation of the present invention, the negative member is made of a water-insoluble polymer.

In addition, the controlled-release preparation of the present invention is preferably in the form of a tablet or capsule.

Brief description of the drawings

FIG. 1 is a schematic diagram of a preparation (capsule) of the present invention.

FIG. 2 is a schematic diagram of the preparation (tablet) of the present invention.

FIG. 3 is a graph showing the results of the drug dissolution test in the Japanese pharmacopoeia No. 2 liquid of test example 1.

Detailed description of the invention

The present invention provides a controlled release preparation containing an active ingredient, which is formed of at least 2 parts containing an active substance inside, which are fitted to each other, and the positive part of which is made of an intestinal fluid gelling material, which does not change in form in gastric fluid having a low pH and which slowly gels to become permeable only when wetted in intestinal fluid having a high pH (pH5.5 or more).

The preparation of the present invention is preferably such that the negative member has 1 to 2 openings, the openings are closed by plugs made of a gelation material of intestinal fluid, and the plugs are gelled from the surface to be permeable to water when immersed in the intestinal fluid, and the thinnest part is completely gelled and the active material is released into the surrounding environment in a pulsed manner.

The male member used in the preparation of the present invention is made of an intestinal fluid gelling material. The intestinal fluid gelling material is preferably a mixture of ethyl acrylate/methyl methacrylate/trimethylethyl methacrylate ammonium chloride copolymer and methacrylic acid/ethyl acrylate copolymer. In particular, it is more preferable to use a mixture of the above polymers in which the copolymerization ratio of the copolymer of ethyl acrylate/methyl methacrylate/trimethylethylammonium methacrylate (molar ratio) is about 1: 2: 0.1 to 0.2 and the copolymerization ratio of the copolymer of methacrylic acid/ethyl acrylate (molar ratio) is about 1: 1.

Specific examples of the copolymer of ethyl acrylate, methyl methacrylate and trimethylethammonium methacrylate having a copolymerization ratio (ethyl acrylate, methyl methacrylate, trimethylethammonium methacrylate) of about 1: 2: 0.1 to 0.2 include Eudragit RS (registered trademark, manufactured by Rohm Pharma corporation) series, and the copolymer having a copolymerization ratio of about 1: 2: 0.1 include Eudragit RS100 (particles), RSPO (fine powder) and RS30D (aqueous dispersion liquid with 30% solid content), and Eudragit RS100 or RSPO is particularly preferably used. Further, examples of the material having a copolymerization ratio of about 1: 2: 0.2 include Eudragit RL100 (particulate), RLPO (fine powder) and RL30D (aqueous dispersion containing 30% of solid content), and Eudragit RL100 and RLPO are particularly suitable for use.

Specific examples of the methacrylic acid/ethyl acrylate copolymer having a copolymerization ratio (methacrylic acid/ethyl acrylate (molar ratio)) of about 1: 1 include Eudragit LD (registered trademark, manufactured by Rohm Pharma corporation) series, Eudragit L100-55 (fine powder) or L30D-55 (aqueous dispersion liquid containing 30% solid content) are preferable, and Eudragit L100-55 is particularly preferable.

In the present invention, the compounding ratio of the two copolymers in the male member is not particularly limited as long as the two copolymers are contained, and it is generally preferable to contain 0.3 to 20 parts by weight, preferably 0.4 to 15 parts by weight, and particularly preferably 0.5 to 10 parts by weight of the ethyl methacrylate/ethyl acrylate copolymer based on 1 part by weight of the ethyl acrylate/methyl methacrylate/trimethyl ethyl ammonium methacrylate copolymer. The male member may further contain various additives commonly used in the art, such as an excipient, a binder, a lubricant, an anti-agglomerating agent, and a dissolution aid for pharmaceutical compounds, which will be described later.

The negative part of the formulation when used as an oral administration formulation may be formed of a material that is biologically and medically compatible, non-allergenic, non-irritating to body fluids and biological tissues. The female part can be made of a water-impermeable material or a water-permeable material, more preferably of a water-impermeable material. When a water-permeable material is used, it is preferable to select a material which is impermeable to a gelled liquid solution or intestinal fluid. In addition, the female member is preferably made of a non-water swellable material.

The water-impermeable material or water-permeable material in the female member may be a water-insoluble polymer selected from polyethylene, polypropylene, polymethyl methacrylate, polyvinyl chloride, polyvinyl acetate, polystyrene, polyurethane, polyester, cellulose acetate, nitrocellulose, ethyl cellulose, a copolymer of ethyl acrylate-methyl methacrylate-trimethylethyl ammonium methacrylate, and the same material as that used for the plug. The water-insoluble polymer may be used in 1 or 2 or more species. The female features may be structurally uniform or may be a laminate structure (a structure formed from a plurality of different material layers).

The female member may be formed of a biodegradable material (azo-based polymer, polysaccharide, or the like decomposed by intestinal bacteria) or a water-soluble material (gelatin, starch, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, or the like) if the structural strength thereof can be maintained at least for the delay time. When the wall of the female member has a non-uniform structure, the wall portion forming the opening is preferably made of a non-water-swellable material.

Alternatively, the female member main body may be formed of a biodegradable material or a water-soluble material, and the exterior and/or interior may be coated with a water-insoluble coating. In this case, the outer part may be covered almost entirely, and the inner part may be covered entirely; at least a portion contacting the male member may be covered. It is also preferable that the end face of the wall of the opening of the female member main body is covered with a water-insoluble film, not only on the outside but also on the inside. The main body of the female member formed of a biodegradable material or a water-soluble material is not decomposed or swollen (dissolved) before the male member is gelled to cause the release of the drug, and the male member is detached from the female member. Such a coating layer can be formed by immersing a member body made of a biodegradable material or a water-soluble material in a solution of any of the above-mentioned water-insoluble polymers to form a water-insoluble layer, or by spraying a solution of any of the above-mentioned water-insoluble polymers on a member made of a biodegradable material or a water-soluble material. Specific examples of preferable female members include a member body made of a normal hard gelatin or starch capsule, which is covered with an ethyl cellulose solution, a polyvinyl acetate solution, or the same polymer as that used for the male member, or a member body made of a capsule made of a water-soluble material, which is covered with the biodegradable material.

The female part may be shaped to be suitable as a preparation, for example, elliptical, ellipsoidal, cylindrical, etc. Cylindrical capsules are generally preferred, but are not limited thereto. The preparation of the present invention preferably has a male part, i.e., a plug made of an enterohydrogelling material, in one open end or both open ends of a cylindrical female part which is open at one end or both ends. Such formulations can be readily formed from extruded plastic tubing which is cut to length and either end sealed by welding and then closed at the open end, or both ends by inserting a plug. The female member may be produced by forming a cylindrical shape on the outer periphery of a rod-shaped die, applying a polymer solution to the forming die, compression molding or injection molding an appropriate thermoplastic polymer, compression molding a powder, direct reaction molding, or the like.

The male member (pin) can be inserted into the female member so that the top thereof is at the same height as the end face of the opening of the female member, or the top thereof can protrude from the end face of the opening within a range where the pin does not come off, or the cylindrical wall of the female member exceeds the depth of the insertion pin. The plug is conveniently cylindrical, and the material having such a shape can be easily obtained by forming the above-mentioned intestinal fluid gelling material into a rod shape and then cutting the formed rod-like material. In addition, it can be easily manufactured by using a general tablet machine used for manufacturing a medicine. Even if the peg has a cavity of a certain depth above it, it does not matter if the peg is concave. In addition, V-shaped grooves can be dug to form a tablet shape with a cutting line. Other shapes such as a conical section are also possible. The ratio of the length to the diameter (length: diameter) of the cylindrical plug is preferably in the range of 0.1: 10 to 20: 1, more preferably in the range of 0.2: 10 to 3: 1, but is not limited thereto.

When the preparation is made into a cylindrical preparation, the preparation is convenient in swallowable size, and the preparation is particularly favorable for being made into oral preparations for human use and also can be made into oral preparations for animals. The hollow cylinder typically has a length of 5 to 50mm, preferably 10 to 30mm, and an outer diameter in the range of 1mm to 20 mm. The formulation may have an outer diameter consistent with the outer diameter of commonly known oral formulations. For example, the capsule has a size of from three times zero to one times zero, and in the range of from 1 to 8. In this case, the length of the male member (pin) is preferably 1mm to 10mm, but is not limited thereto. FIG. 1 shows a specific example of the form of the preparation of the present invention when it is made into a capsule. A liquid-enterogelling suppository (male member) 2A is inserted into an opening of a water-insoluble capsule (female member) 1A having one closed end and the other open end, and a drug 3A is sealed in the capsule. Fig. 2 shows a specific example of the preparation form of the present invention when it is formed into a tablet, and a drug layer 3B and a layer 2B of a plug for intestinal fluid gelation (male member) are sequentially filled in a water-insoluble tablet outer layer portion (female member) 1B. The tablet of fig. 2 can be produced by compressing the male member layer and the drug layer into a two-layer tablet and then imparting the outer layer portion thereof with a conventional core tablet machine.

The content release delay time (delay time) after intestinal fluid immersion can be adjusted by the intestinal fluid gelling material constituting the male member. The gelation rate and water permeability of the material are important parameters in determining the delay time of the formulation. For example, by increasing the ratio of the methacrylic acid/ethyl acrylate copolymer to the ethyl acrylate/methyl methacrylate/trimethylethylmethylammonium methacrylate copolymer, which is a preferred example of the intestinal fluid gelling material, the gelling rate and the water permeability can be increased, and the delay time can be shortened. That is, the delay time of the formulation is inversely proportional to the gelation rate and water permeability of the male member. In addition, varying the thickness of the male part can also vary the delay time. This delay time is proportional to the thickness of the thinnest portion of the male part. More specifically, when the male member is used as the plug, it is proportional to the thickness of the thinnest portion of the plug.

As described above, the preparation of the present invention can change the delay time until the plug gel permeates water to cause drug release after immersion in the intestinal fluid by adjusting at least one of the above parameters, i.e., the gelation rate of the hydrogelated material constituting the male member, the water permeability, and the thickness of the male member. The delay time may vary over a wide time range, i.e. between 30 minutes and 24 hours, depending on the application. In general, in order to reach the lower part of the digestive tract or the large intestine, it is preferable to set the delay time to a time period of 3 to 4 hours for the preparation to move in the small intestine.

The formulation is preferably completely water-tight in the bond between the male part and the female part during the delay in release. The wall of the female member can ensure structural adhesion to the male member at least until the gel in the portion where the thickness of the male member is the thinnest is hydrated. That is, the male and female parts must be tightly coupled and inseparable before drug release can begin. This is different from Pulsincap (controlled release preparation described in Japanese patent publication Hei 4-505004) in which the plug as the male member was partway released from the female member.

The contents of the formulation are, for example, the active substance in the form of a particulate solid, or other suitable form of administration. For example, the active substance may be combined with a conventional pharmaceutical additive, and sealed after being prepared into a powder, a fluid solution, or a suspension. However, the fluid medium should be a substance that does not interact with the material forming the female or male part. Further, the tablet may be compressed with an excipient or the like into a tablet shape, and one tablet or a plurality of such tablets may be enclosed. Various additives generally used in the art, such as excipients, binders, lubricants, anti-agglomeration agents, and dissolution aids for pharmaceutical compounds, may be added as pharmaceutical additives. Excipients such as sugars including white sugar, lactose, mannitol, and glucose, starch, crystalline cellulose, calcium phosphate, and calcium sulfate; examples of the binder include polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, glucose, white sugar, lactose, maltose, dextrin, sorbitol, mannitol, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycols, gum arabic, gelatin, agar, starch, and the like. Further, the lubricant and the anti-agglomerating agent may be talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hardened oils, polyethylene glycols, sodium benzoate, or the like. Examples of the dissolution aid for pharmaceutical compounds include organic acids such as fumaric acid, succinic acid, malic acid, and adipic acid, various surfactants such as sodium lauryl sulfate, perfumes, and colorants.

As described above, a preparation comprising only at least 2 mutually engaging members, wherein the water-insoluble negative member containing an active substance is plugged with a positive member (plug) formed of a hydrogelated polymer, does not release the drug until it reaches a specific site in the lower part of the digestive tract such as the small intestine or the large intestine, and releases the entire amount of the drug in a pulse manner after it reaches the site. That is, the preparation of the present invention does not release the drug at all in the region of low pH in the stomach, but the gel slowly gels from above only in the region of relatively neutral pH such as small intestine and large intestine, and after a certain time, the gel becomes permeable in the portion where the thickness of the male member (plug) is the thinnest, and the drug is released in a short-time pulse manner.

The kind of the drug to be used as the active substance in the pulsatile release preparation of the present invention is not particularly limited as long as it is a drug that can be orally administered. Examples of the pharmaceutical compounds include chemotherapeutic agents, antibiotics, respiratory promoters, antitussive and expectorant agents, anti-malignant tumor agents, autonomic nerve agents, psychotropic agents, local anesthetics, muscle relaxants, digestive organ agents, antihistamines, toxic therapeutic agents, hypnotic and sedative agents, antiepileptic agents, antipyretic, analgesic and anti-inflammatory agents, cardiotonic agents, arrhythmia therapeutic agents, diuretic agents, vasodilating agents, antilipemic agents, tonic and tonic agents, anticoagulants, hepatic agents, blood sugar-lowering agents, blood pressure-lowering agents, colitis therapeutic agents, peptides, proteins, and the like. It is particularly suitable for therapeutic agents for colitis and Crohn's disease, which are required to effectively act on the lower small intestine and large intestine of a diseased region, or peptides and proteins which are easily decomposed in the stomach.

Examples experimental examples

The present invention will be described in detail with reference to examples and experimental examples, but the present invention is not limited to these examples and experimental examples.

Example 1

A series of preparations consisting of a cylindrical capsule (female part) closed at the open end by a plug (male part) of suitable diameter was made.

(preparation of suppositories)

50g of talc was charged into a rotary fluidized bed granulator (MP-01 type), and was subjected to rotary fluidization to spray granulation with a solution composed of 15g of Eudragit RSPO (Rohm Pharma corporation), 35g of Eudragit L100-55(Rohm Pharma corporation), 5g of triethyl citrate, 50g of talc, 900g of ethanol, and 100g of water, thereby obtaining a granulated powder. To 155g of this granulated powder, 0.7g of magnesium stearate was added and mixed to prepare a tableting powder. Then, a 100mg tablet was punched out from a plane having a diameter of 6mm by using a tablet machine (CLEANPRESS Correct 12HUK, manufactured by Chrysanthemum water). A cavity having a diameter of 4mm and a certain depth was drilled in the tablet to obtain a concave tablet (plug) having a bottom with a minimum thickness of about 400 μm, 500 μm, 600 μm.

(preparation of the preparation)

The female part was obtained by coating the inside and outside of a gelatin capsule (manufactured by Warner Lambert Co.) No. 2 capsule with ethyl cellulose. 50mg of acetaminophen and 50mg of croscarmellose sodium as a disintegrating agent were sealed in the capsule. Then, the opening of the capsule was closed with the plug prepared above to obtain the preparation of the present invention. That is, 3 formulations were prepared: the formulation obtained using a plug with a bottom minimum thickness of about 400 μm, the formulation obtained using a plug with a bottom minimum thickness of about 500 μm, and the formulation obtained using a plug with a bottom minimum thickness of about 600 μm.

Experimental example 1

For the 3 kinds of preparations obtained in the above experimental example 1, dissolution tests were carried out according to the Paddle method (37 ℃ C., 50rpm) of the Japanese pharmacopoeia using the Japanese pharmacopoeia solution 1 (pH1.2) and the Japanese pharmacopoeia solution 2 (pH 6.8). From the test results, it was found that the drug was not dissolved out at all in solution 1 of each of the preparations obtained in example 1. In addition, in solution 2, as shown in FIG. 3, the delay time before the start of elution can be varied by the thickness of the bottom of the plug, and the drug is released rapidly at 100% even though the delay time varies, and a pulse-like elution pattern is exhibited. The value (μm) marked on the characteristic curve in fig. 3 is the bottom minimum thickness of the plug for each formulation.

Industrial applicability

The controlled release preparation of the present invention has the following characteristics: after oral administration, the shape of the composition in gastric juice can not change, namely the medicament can not be dissolved out, no matter how long the composition is retained in the stomach, the active ingredients of the medicament can not be dissolved out before a certain time passes through the stomach, and the active ingredients of the medicament can be rapidly released at the lower part of the digestive tract after a certain time, so that sufficient and effective blood concentration can be obtained. In particular, the following features are provided: the time until dissolution after passage through the stomach can be arbitrarily adjusted by changing the gelation rate and water permeability of the intestinal fluid gelling material contained in the male member and the thickness of the male member (for example, the ratio of these two copolymers in a plug containing an ethyl acrylate/methyl methacrylate/trimethyl ethyl ammonium chloride copolymer and a methacrylic acid/ethyl acrylate copolymer and/or the thickness of the plug). Therefore, after the drug is discharged from the stomach, the drug is rapidly eluted in a pulse form after a certain period of time, and the drug can be reliably eluted at a predetermined intestinal site, so that the drug can be allowed to act locally and effectively in the lower small intestine, the large intestine, or the like, and the drug can reach the lower small intestine or the large intestine while avoiding the decomposition of peptides and proteins. In addition, the present formulations can encapsulate a maximum amount of active substance in a capsule of a certain size, and are therefore particularly useful as oral formulations for humans and animals.

The present invention is based on Japanese application No. 28365 filed in Hecheng 10 years, the contents of which are also included in the present specification in their entirety.

Claims (8)

1. A controlled-release preparation containing at least 1 pharmaceutically active ingredient, characterized by comprising a male member and a female member, which are integrally fitted to each other and in which an active substance is enclosed, wherein the male member is formed of an enteric gelation material.

2. The controlled-release preparation according to claim 1, wherein the positive member comprises a copolymer of ethyl acrylate-methyl methacrylate-trimethylethylmethacrylate ammonium chloride and a copolymer of methacrylic acid-ethyl acrylate as the intestinal fluid gelling material.

3. The controlled-release preparation according to claim 2, wherein the copolymerization ratio of the copolymer of ethyl acrylate-methyl methacrylate-trimethylethammonium methacrylate (molar ratio) is 1: 2: 0.1-0.2.

4. The controlled-release preparation according to claim 2, wherein the copolymerization ratio of the methacrylic acid-ethyl acrylate copolymer (methacrylic acid: ethyl acrylate (molar ratio)) is 1: 1.

5. The controlled-release preparation according to claim 2, wherein the copolymerization ratio of the copolymer of ethyl acrylate-methyl methacrylate-trimethylethylammonium methacrylate (molar ratio) is 1: 2: 0.1 to 0.2, and the copolymerization ratio of the copolymer of methacrylic acid-ethyl acrylate (molar ratio) is 1: 1.

6. The controlled-release preparation according to claim 2, wherein the amount of the copolymer of ethyl methacrylate and ethyl acrylate is 0.3 to 20 parts by weight based on 1 part by weight of the copolymer of ethyl acrylate and methyl methacrylate and trimethylethylammonium methacrylate.

7. The controlled-release preparation according to claim 1, wherein the negative member is composed of a water-insoluble polymer.

8. The controlled release formulation of claim 1 in the form of a tablet or capsule.