Preparations with controlled release

A controlled release preparation containing at least one kind of a pharmaceutically active ingredient, a male piece and a female piece, the pieces fitting together to enclose the active substance therein, wherein the male piece is made from a material that gels in the intestinal juice, is disclosed. In a preferable mode, the male piece contains an ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer and a methacrylic acid-ethyl acrylate copolymer. In a preferable mode, the female piece is made from a water insoluble polymer. In a preferable mode, the dosage form is a tablet or a capsule. The controlled release preparation of the present invention does not at all release a drug in the region having a low pH, such as in the stomach, but only in the region having a pH relatively near the neutral range, such as in the small bowel and the large bowel, the plug gradually gels from the upper surface and, after a given time when a part of the male piece (plug) having the least thickness gels and has become permeable, concurrently releases the drug in a short time in a pulse manner. Consequently, the drug can act effectively at a local site in the lower part of the small bowel, the large bowel and the like, and a drug can be delivered to the lower part of the small bowel or the large bowel without undergoing decomposition of peptides and proteins.

This application is a 371 application of PCT/JP99/00570 filed Feb. 10,
 1999.
 1. Technical Field
 The present invention relates to a novel preparation used for controlling
 the release of an active substance, particularly a pharmaceutically active
 ingredient. More particularly, the present invention relates to a
 preparation suitable for releasing a drug in a comparatively short time
 following a given period of lag time (time during which a drug is not
 released) after administration, namely, a pulse release preparation.
 2. Background Art
 In the treatment using drugs, a selective delivery of a drug to the lower
 part of the small bowel and the large bowel is desired in the fields of
 (1) a local treatment of inflammatory bowel diseases such as ulcerative
 colitis, (2) a treatment by oral administration of a peptide drug which is
 susceptible to chemical decomposition and enzymatic degradation in the
 small bowel, and the like. For a selective drug delivery to the lower part
 of the small bowel and the large bowel, therefore, the preparation design
 in recent years involves consideration of the physical and physiological
 environment in the gastrointestinal tract of humans and the time necessary
 for the transfer of the preparation within the gastrointestinal tract.
 For instance, conventional enteric preparations and sustained release
 preparations are not designed from these viewpoints. As a result, although
 the former preparation effectively inhibits the dissolution of a drug in
 the stomach, it fails to deliver the drug to the large bowel, because the
 drug is rapidly dissolved in the upper part of the small bowel and mostly
 absorbed or decomposed there. The latter preparation is associated with a
 problem in that a considerable part of the drug is dissolved during the
 passage of the preparation through the stomach and the small bowel,
 because the drug is dissolved in a sustained manner.
 In addition, preparations having a release control film made from a water
 insoluble polymer and an enteric polymer in combination are known
 (JP-A-3-7238, EP-B-40590). In these preparations, a drug is gradually
 dissolved after oral administration or after transfer into the small
 bowel, which means that the time of start of dissolution and pH at which
 the dissolution is started are not controlled, thus failing to direct the
 drug concentratively to the lower part of the gastrointestinal tract.
 In view of the above-mentioned defects of the conventional enteric
 preparations and sustained release preparations and with the aim of
 providing a higher level and higher performance drug delivery system
 targeting a specific region of an appropriate part in the gastrointestinal
 tract (particularly, lower part of the gastrointestinal tract, such as the
 small bowel, the large bowel and the like), a new controlled release
 preparation that enables accurate drug release at this region is being
 developed.
 As an oral administration system to release a drug site-specifically at
 various lower parts of the gastrointestinal tract based on a preparation
 formulation method, for example, there have been known a method for
 controlling the release start time by utilizing the time necessary for
 transfer of the preparation in the gastrointestinal tract, a method for
 determining the release site by utilizing enterobacteria, and other
 methods.
 JP-B-2-58246 discloses a compressed tablet that is specifically
 disintegrated in the colon to release an active ingredient, irrespective
 of the length of drug residence time in the stomach. Because this
 compressed tablet utilizes bacteria present in the colon, however, the
 time of disintegration varies depending on the inter-individual difference
 in the bacteria present in the colon, and the decomposition takes
 defectively long when the enterobacteria have a lower decomposition
 activity.
 JP-A-4-235123 discloses a controlled release preparation having a film
 coating made from an ethyl acrylate-methyl
 methacrylate-trimethylammonioethyl methacrylate chloride copolymer
 (Eudragit RS; trademark, Rohm Pharma) and a water-repellent salt (calcium
 stearate). This is a so-called sigmoid type controlled release preparation
 that releases a pharmaceutical compound after a given time. This
 preparation controls the time before the start of dissolution by
 controlling the water-permeation rate of the film coating, and requires an
 accurate control of the amount of the film coating, so as to appropriately
 control the time before the start of dissolution. The preparation also has
 a defect in that a thicker film makes quick dissolution of the drug after
 the start of the dissolution difficult to achieve. Moreover, the system of
 this preparation involves a drug release after a given time from the oral
 administration of the preparation, which makes it difficult to specify the
 site where the release occurs.
 JP-A-4-264022 discloses an oral preparation for release in the lower part
 of the gastrointestinal tract, which is obtained by filling a hard capsule
 made from a base mainly composed of chitosan with a solid preparation
 containing a solid organic acid and the principal agent ingredient, and
 forming an enteric film e coating on the surface of the capsule. This
 preparation controls the time before the start of dissolution by changing
 the thickness of the hard capsule, and requires an accurate control of the
 thickness of the capsule wall for controlling the dissolution start time.
 Japanese Patent Application under PCT laid-open under kohyo No. 4-505004
 discloses a controlled release preparation based on the system wherein a
 water insoluble capsule is capped with a water swellable plug, and the
 plug begins to swell upon water absorption, and, after a given time, comes
 out to release the drug in the capsule. This preparation employs a system
 of releasing a drug after a given time from oral administration. This
 makes specification of the release site in the gastrointestinal tract very
 difficult, because the residence time of the preparation in the stomach
 varies due to the inter-individual difference.
 These conventional enteric preparations for topical treatment are defective
 because they have complicated structures and the time before the start of
 dissolution varies depending on pH and inter-individual difference in the
 residence time in the stomach and the like, which in turn makes the
 control of the lag time difficult and makes these preparations
 insufficient to achieve an effective blood concentration by quick
 dissolution of the entire amount of the drug after the start of
 dissolution.
 As a system that utilizes the transfer time of a preparation in the
 gastrointestinal tract, several systems based on the transfer time in the
 small bowel, that disregards the variation in the residence time of the
 preparation in the stomach, have been developed noting the fact that the
 passage of the preparation through the small bowel takes almost the same
 length of time for any individual. These systems are free of drug release
 during the intragastric residence time and enable a specified release of
 the drug after a certain time after transfer into the small bowel
 following discharge from the stomach, namely, at a site a certain distance
 away from the stomach, such as in the large bowel which is in the lower
 part of the gastrointestinal tract.
 To be specific, for example, JP-A-4-501411 discloses a preparation that
 releases a drug after a given lag time, which is achieved by applying a
 three-layer coating comprising an inner layer coated with an anionic
 copolymer that dissolves at a pH of not less than 7.0, an intermediate
 layer comprising a gelling polymer that swells and gels in a pH
 non-dependent manner to form a gel layer, and an outer layer comprising an
 appropriate amount of a stomach resistant polymer that quickly dissolves
 in the bowels. However, this preparation is defective in that the
 dissolution rate of the gelling polymer often changes due to the kinetics
 within the gastrointestinal tract, resulting in inconsistent lag time, and
 the system is extremely complicated both in the structure and production
 method, as mentioned in the above.
 Besides the above-mentioned, there has been disclosed a large bowel
 delivery system comprising the aforementioned preparation of Japanese
 Patent Application under PCT laid-open under kohyo No. 4-505004 applied
 with an enteric film coating; JP-A-8-143476 discloses a preparation
 applied with an acrylate polymer mixture film coating; and JP-A-9-87169
 discloses a system wherein a capsule containing an acidic substance is
 coated with a low pH soluble film and an enteric film.
 As the situation stands, a system having both the function of an enteric
 film coating and the function of controlling the drug release time is
 structurally very complicated and requires time and labor for the
 production.
 The present invention aims at providing a preparation capable of releasing
 a drug rapidly at a predetermined time and pH.
 DISCLOSURE OF THE INVENTION
 The present inventor has conducted intensive studies to develop a
 preparation for oral administration, which does not release a drug until
 it reaches a specific site in the lower part of the gastrointestinal
 tract, such as the small bowel, the large bowel and the like, and, upon
 delivery to the intended site, quickly releases the entire amount of the
 drug in a pulse manner, and found that a preparation comprising at least
 two mutually fitting pieces, wherein a female piece enclosing an active
 substance is plugged with a male piece (plug) made from a material that
 gels in the intestinal juice, does not release the drug at all in a low pH
 range, such as in the stomach, but only in the region having a pH
 relatively near the neutral range, such as in the small bowel and the
 large bowel, the male piece gradually gels from the side in contact with
 the intestinal juice, and, after a given time when a part of the male
 piece having the smallest thickness gels and has become permeable,
 releases the drug in a pulse manner in a short time, which resulted in the
 completion of the present invention.
 The controlled release preparation of the present invention comprises at
 least one kind of a pharmaceutically active ingredient, a male piece and a
 female piece, the male and female pieces being fitted together to enclose
 the active substance and the male piece being made from a material that
 gels in the intestinal juice.
 In a preferable mode, the male piece contains, as the material that gels in
 the intestinal juice, an ethyl acrylate-methyl
 methacrylate-trimethylammonioethyl methacrylate chloride copolymer and a
 methacrylic acid-ethyl acrylate copolymer.
 The above-mentioned ethyl acrylate-methyl
 methacrylate-trimethylammonioethyl methacrylate chloride copolymer more
 preferably has a copolymerization ratio (ethyl acrylate:methyl
 methacrylate:trimethylammonioethyl methacrylate chloride (molar ratio)) of
 about 1:2:0.1-0.2, and the methacrylic acid-ethyl acrylate copolymer more
 preferably has a copolymerization ratio (methacrylic acid:ethyl acrylate
 (molar ratio)) of about 1:1.
 The methacrylic acid-ethyl acrylate copolymer is more preferably contained
 in a proportion of 0.3-20 parts by weight per part by weight of the
 above-mentioned ethyl acrylate-methyl methacrylate-trimethylammonioethyl
 methacrylate chloride copolymer.
 In a preferable mode of the controlled release preparation of the present
 invention, the female piece is made from a water insoluble polymer.
 Moreover, in a preferable mode of the controlled release preparation of the
 present invention, the dosage form is a tablet or capsule.

DETAILED DESCRIPTION OF THE INVENTION
 The present invention provides a controlled release preparation containing
 an active ingredient, which is made of at least two mutually fitting
 pieces containing the active substance therein, wherein the male piece is
 formed from a material that gels in the intestinal juice. The preparation
 shows no changes in the shape in the gastric juice having a low pH and
 gradually gels and becomes permeable only when it gets wet with the
 intestinal juice having a high pH (pH of not less than 5.5).
 The preparation of the present invention has, for example, 1 or 2 openings
 in the female piece and the aforementioned openings are preferably closed
 with a plug made from a material that gels in the intestinal juice. In
 this case, the aforementioned plug gels and becomes permeable from the
 surface upon immersion in the intestinal juice, and when the thinnest part
 has become a gel, the active substance is concurrently released into the
 surrounding environment in a pulse manner.
 The male piece to be used for the preparation of the present invention is
 made from a material that gels in the intestinal juice. The material that
 gels in the intestinal juice is preferably a mixture of an ethyl
 acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride
 copolymer and a methacrylic acid-ethyl acrylate copolymer. Particularly, a
 mixture of an ethyl acrylate-methyl methacrylate-trimethylammonioethyl
 methacrylate chloride copolymer having a copolymerization ratio (ethyl
 acrylate:methyl methacrylate:trimethylammonioethyl methacrylate chloride
 (molar ratio)) of about 1:2:0.1-0.2 and a methacrylic acid-ethyl acrylate
 copolymer having a copolymerization ratio (methacrylic acid:ethyl acrylate
 (molar ratio)) of about 1:1 is more preferably used.
 Specific examples of the ethyl acrylate-methyl
 methacrylate-trimethylammonioethyl methacrylate chloride copolymer having
 a copolymerization ratio (ethyl acrylate:methyl
 methacrylate:trimethylammonioethyl methacrylate chloride (molar ratio)) of
 about 1:2:0.1-0.2 include Eudragit RS (Eudragit RS:trademark, manufactured
 by Rohm Pharma) series, and examples of the copolymer having a
 copolymerization ratio of about 1:2:0.1 include Eudragit RS100 (granules),
 RSPO (fine powder), RS30D (solid content 30%, aqueous dispersion) and the
 like, with particular preference given to Eudragit RS100 and RSPO.
 Examples of the copolymer having a copolymerization ratio of about 1:2:0.2
 include Eudragit RL100 (granules), RLPO (fine powder), RL30D (solid
 content 30%, aqueous dispersion) and the like, with particular preference
 given to Eudragit RL100 and RLPO.
 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 (Eudragit LD:trademark, manufactured by Rohm
 Pharma) series, with preference given to Eudragit L100-55 (fine powder)
 and L30D-55 (solid content 30%, aqueous dispersion), and particular
 preference given to Eudragit L100-55.
 In the present invention, the mixing ratio of the both of the
 above-mentioned copolymers in the male piece is not particularly limited
 as long as the both copolymers are contained. In general, the suitable
 proportion is 0.3-20 parts by weight, preferably 0.4-15 parts by weight,
 particularly preferably 0.5-10 parts by weight, of the methacrylic
 acid-ethyl acrylate copolymer per part by weight of the ethyl
 acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride
 copolymer. The male piece may contain various agents typically used in
 this field such as excipient, binder, lubricant, coagulation preventive,
 solubilizer of the pharmaceutical compound and the like to be mentioned
 below.
 When the preparation is used as a preparation for oral administration, the
 female piece may be formed from a material biologically and medically
 compatible, non-allergic, and nonirritative to the body fluids and
 biological tissues. The female piece can be produced from a water
 impermeable or water permeable material as a starting material, with
 preference given to a water impermeable material. When a water permeable
 material is used, a material that prevents permeation of a liquid solution
 or intestinal juice, with which the male piece is gelled, is preferable.
 The female piece is preferably formed from a water non-swellable material.
 As the water impermeable material and water permeable material to be used
 for forming the female piece, a water insoluble polymer is used, which is
 selected from polyethylene, polypropylene, polymethyl methacrylate,
 polyvinyl chloride, polyvinyl acetate, polystyrene, polyurethane,
 polyester, cellulose acetate, nitrocellulose, ethyl cellulose, and similar
 materials used for the ethyl acrylate-methyl
 methacrylate-trimethylammonioethyl methacrylate chloride copolymer and the
 plug. One or more kinds of the water insoluble polymers can be used. The
 female piece may have a uniform structure or laminate structure comprising
 a plurality of different material layers.
 In addition, the female piece can be made from a biodegradable material
 (e.g., azo polymer, polysaccharide and the like that are decomposed by
 enterobacteria) or a water soluble material (e.g., gelatin, starch,
 hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose,
 polyvinyl alcohol and the like), as long as the structural strength can be
 maintained at least for the lag time. When the wall of the female piece
 does not have a uniform structure, the wall part forming the opening is
 preferably made from a water non-swellable material.
 It is also possible to form the main part of the female piece from a
 biodegradable or water soluble material, and the outside and/or inside
 thereof may be coated with a water insoluble film. In this case, almost
 all surfaces of the outside is coated and at least the part of the inside
 that comes into contact-with the male piece is preferably coated, though
 the entirety of the inside may be coated. It is more preferable to coat
 not only the outside and the inside, but also an end of the wall of the
 opening in the body of the female piece, with a water insoluble film. In
 short, it should be prevented that the body of the female piece made from
 a biodegradable material or water soluble material be decomposed or swell
 (dissolve) to cause dissociation of the male piece from the female piece
 before release of the drug by the gelation of the male piece. The coating
 layer can be formed by immersing the body of the piece made from a
 biodegradable or water soluble material in a solution of the water
 insoluble polymer exemplified above to form a water insoluble layer, or by
 spraying a solution of the water insoluble polymer exemplified above onto
 the body of the piece made from a biodegradable material or water soluble
 material. Examples of preferable female piece include one obtained by
 coating a typical hard gelatin or starch capsule, as the body of a piece,
 with an ethylcellulose solution, polyvinyl acetate solution or a polymer
 similar to the material used for the above-mentioned male piece, one
 obtained by coating a capsule made from a water soluble material, as the
 body of a piece, with the aforementioned biodegradable material, and the
 like.
 The female piece is formed to have a shape convenient as a preparation,
 such as ellipsoidal shape, spheroidal shape, cylindrical shape and the
 like. A cylindrical capsule is generally preferred but a different shape
 may be employed. The preparation of the present invention preferably
 comprises a cylindrical female piece having one open end or both open
 ends, and a plug (a male piece) made from a material that gels in the
 intestinal juice set in the one open end or both open ends. Such
 preparation can be easily formed from an extrusion-formed plastic tube cut
 in a certain length, with one end optionally sealed and the open end or
 both ends closed by insertion of plug(s). In addition, the female piece
 can be prepared by forming a cylinder around a rod mold, applying a
 polymer solution and the like onto a forming mold, compression forming or
 injection forming of a suitable thermoplastic polymer, compression forming
 of a powder, direct reaction forming and the like.
 The male piece (plug) can be inserted so as to make the summit thereof on
 the same plane with the end of the opening of the female piece; inserted
 so as to make the summit thereof protruding from the end of the opening to
 the extent that the protrusion prevents dissociation of the plug; or
 inserted to a depth that makes the cylindrical wall of the female piece
 extend beyond the summit of the plug. The plug is conveniently of a
 cylindrical shape, which can be obtained easily by cutting a rod material
 obtained by forming the aforementioned material, that gels in the
 intestinal juice, in the shape of a rod. It can be also formed easily
 using a tablet compressor and the like, which is typically used for the
 preparation of pharmaceutical products. The plug may have a concave shape
 with a cavity of a certain depth made therein. It may have a shape like a
 tablet having a cleavage line of a V shape groove. It may have a different
 shape such as a conical section. The ratio of length and diameter
 (length:diameter) of the cylindrical plug is preferably, but not limited
 to, in the range of from 0.1:10 to 20:1, more preferably from 0.2:10 to
 3:1.
 When a cylindrical preparation is produced, the preparation is beneficially
 of a size that allows swallowing. Such preparation advantageously serves
 for a preparation for oral administration particularly to human, and also
 to animals. The length of the hollow cylinder is typically 5-50 mm,
 preferably 10-30 mm, and the outer diameter is in the range of from 1 mm
 to 20 mm. The preparation generally has an outer diameter equivalent to
 that of known preparations for oral administration. For example, the
 capsule has a size within the range of from triple zeros to zero and from
 1 to 8. The length of the male piece (plug) then is preferably, but not
 limited to, from 1 mm to 10 mm. FIG. 1 shows one embodiment of the
 preparation of the present invention when it is made into a capsule,
 wherein a water insoluble capsule (a female piece) 1A has one closed end
 and the other open end, a plug (a male piece) 2A, that gels in the
 intestinal juice, is fitted into the opening, and a drug 3A is sealed in
 the capsule. FIG. 2 shows one embodiment of the preparation of the present
 invention when it is made into a tablet, wherein a drug layer 3B and a
 plug (a male piece) layer 2B, that gels in the intestinal juice, are
 sequentially fitted into the water insoluble tablet outer layer (a female
 piece) 1B. The tablet shown in FIG. 2 can be produced by, for example,
 compression molding the male piece layer and the drug layer into a
 two-layer tablet and forming an outer layer by a conventional
 compression-coating tablet machine.
 The material constituting the male piece, that gels in the intestinal
 juice, enables adjustment of the time of delay in the release (lag time)
 of the contents after immersion into the intestinal juice. The gelling
 rate and permeability of the material are the important parameters in
 determining the lag time of the preparation. For example, the mixing ratio
 of the methacrylic acid-ethyl acrylate copolymer to the ethyl acrylate -
 methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer
 exemplified as a preferable material, that gels in the intestinal juice,
 as mentioned above, is increased to raise the gelling rate and the
 permeability, thereby shortening the lag time. In other words, the lag
 time of the preparation is in reciprocal proportion to the gelling rate
 and the permeability of the male piece. By changing the thickness of the
 male piece, the lag time can be also changed. The lag time is in
 proportion to the thickness of the thinnest part of the male piece. To be
 more specific, it is in proportion to the thickness of the thinnest part
 of a plug which is the male piece.
 As mentioned above, in the preparation of the present invention, the lag
 time from the immersion in the intestinal juice to the drug release due to
 gelation of the plug, and acquired permeability can be varied by adjusting
 at least one of the above-mentioned parameters; namely, the gelling rate
 and the permeability of the material constituting the male piece, that
 gels in the intestinal juice, and the thickness of the male piece. The lag
 time can vary over a broad range of time of from 30 min to 24 hr depending
 on the utility. In general terms, when the lower part of the
 gastrointestinal tract or the large bowel is the delivery site, the target
 lag time is desirably set to 3-4 hours which is the time of transfer of
 the preparation in the small bowel.
 The preparation is preferably constituted to make the conjunction between a
 male piece and a female piece completely watertight throughout the release
 delay period. The wall of the female piece is constituted to ensure
 structural association with the male piece until at least the thinnest
 part of the male piece gels and becomes permeable. This means that the
 male piece and the female plug should stay undetached and adhered until
 the drug release begins. The present invention differs in this aspect from
 Pulsincap (controlled release preparation described in Japanese Patent
 Application under PCT laid-open under kohyo No. 4-505004) that allows
 separation of a plug (male piece) from a female piece on the way.
 The contents of the preparation are, for example, an active substance in
 the form of solid particles, or an active substance in a different and
 convenient administration form. For example, the active substance, in
 combination with typical additives for pharmaceuticals, can be enclosed in
 the preparation as a powder, fluid solution or suspension. Note that the
 fluid medium should not interact with the material used for the formation
 of a female piece or a male piece. It can take the form of a compression
 formed tablet containing an excipient and the like, which may enclose a
 single tablet or a plurality of such tablets. Examples of the additives
 for pharmaceuticals include excipient, binder, lubricant, coagulation
 preventive, solubilizer of a pharmaceutical compound and the like, that
 are typically used in this field. Examples of the excipient include sugars
 such as sucrose, lactose, mannitol, glucose and the like, starches,
 crystalline cellulose, calcium phosphate, calcium sulfate and the like,
 and examples of the binder include polyvinyl alcohol, polyacrylic acid,
 polymethacrylic acid, polyvinylpyrrolidone, glucose, sucrose, lactose,
 maltose, dextrin, sorbitol, mannitol, hydroxyethylcellulose,
 hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogols, gum
 arabic, gelatin, agar, starches and the like. Examples of the lubricant
 and coagulation preventive include talc, magnesium stearate, calcium
 stearate, colloidal silica, stearic acid, waxes, castor oil, polyethylene
 glycols, sodium benzoate and the like. Examples of the solubilizer of a
 pharmaceutical compound include organic acids, such as fumaric acid,
 succinic acid, malic acid, adipic acid and the like, various surfactants,
 such as sodium laurylsulfate and the like, aromatic, coloring matter and
 the like.
 As mentioned above, the preparation comprising at least two mutually
 fitting pieces does not release a drug until it reaches a specific site in
 the lower part of the gastrointestinal tract, such as the small bowel, the
 large bowel and the like, and once it reaches the site, can release the
 entire amount of the drug quickly in a pulse manner, by only plugging the
 water insoluble female piece, which contains the active substance, with
 the male piece (plug) made from a polymer that gels in the intestinal
 juice. In other words, the preparation of the present invention does not
 at all release a drug in the region having a low pH, such as in the
 stomach, but only in the region having a pH relatively near the neutral
 range, such as in the small bowel and the large bowel, the plug gradually
 gels from the upper surface and, after a given time when a part of the
 male piece (plug) having the least thickness gels and has become
 permeable, concurrently releases the drug in a short time in a pulse
 manner.
 The kind of the drug to be used as the active substance of the pulse
 release preparation of the present invention is subject to no particular
 limitation as long as it can be administered orally. Examples of such
 pharmaceutical compound include chemotherapeutics, antibiotics,
 respiratory stimulants, antitussive expectorantia, antineoplastic agent,
 agent for autonomic nerve, agent for neurosis, topical anesthetic, muscle
 relaxant, agent for digestive organ, antihistamines, therapeutics for
 toxicosis, sedative hypnotic, antiepileptic agent, antipyretic analgesic
 antiphlogistics, cardiotonic, antiarrhythmic agent, diuretic, vasodilator,
 antilipemic agent, analeptic alterant, anticoagulant, agent for liver,
 hypoglycemic agent, hypotensive agent, therapeutics for colitis, peptide,
 protein and the like. Among others, the present invention is suitable for
 a therapeutic for colitis, a therapeutic agent for Crohn's disease, which
 require efficient action on the lesion in the lower part of the small
 bowel and the large bowel, and peptide and pharmaceutical protein products
 susceptible to decomposition in the stomach.
 EXAMPLES AND EXPERIMENTAL EXAMPLES
 The present invention is explained in detail by referring to Example and
 Experimental Example that do not limit the present invention in any way.
 Example 1
 A series of preparations were produced, which comprised a cylindrical
 capsule (a female piece) whose open end was closed by a plug (a male
 piece) having a suitable diameter.
 Preparation of plug
 Talc (50 g) was placed in a fluidized bed granulator (MP-01 type) and
 fluidized. Thereonto was spray-granulated a solution of Eudragit RSPO (15
 g, manufactured by Rohm Pharma), Eudragit L100-55 (35 g, manufactured by
 Rohm Pharma), triethyl citrate (5 g), talc (50 g), ethanol (900 g) and
 water (100 g) to give granules. To the granules (155 g) was added and
 mixed magnesium stearate (0.7 g) to give a powder for compression. Using a
 tableting machine (CLEANPRESS Correct 12HUK;Kikusui Seisakusho Ltd.) and a
 plane pestle, 100 mg tablets having a diameter of 6 mm were tableted. A 4
 mm diameter cavity having a given depth was made in the tablets to give
 concave tablets (plugs) having a minimum bottom thickness of about 400
 .mu.m, 500 .mu.m or 600 .mu.m.
 Production of preparation
 Female pieces were obtained by coating the inside and outside of gelatin
 capsules (No. 2, manufactured by Warner-Lambert) with ethylcellulose.
 Acetoaminophene (50 mg) and croscarmellose sodium (50 mg) as a
 disintegrant were enclosed inside the capsules. The opening of the
 capsules was closed with the plug prepared in the above to give the
 preparations of the present invention. That is, three kinds of
 preparations including a preparation containing a plug having a minimum
 bottom thickness of about 400 .mu.m, a preparation containing a plug
 having a minimum bottom thickness of about 500 .mu.m and a preparation
 containing a plug having a minimum bottom thickness of about 600 .mu.m
 were obtained.
 Experimental Example 1
 The three kinds of preparations obtained in the above-mentioned Example 1
 were subjected to the dissolution test using Japanese Pharmacopoeia 1st
 Fluid (pH 1.2) and 2 nd Fluid (pH 6.8) according to the paddle method
 (37.degree. C., 50 rpm) described in the Japanese Pharmacopoeia. According
 to the test results, the preparations obtained in Example 1 showed no
 dissolution of the drug in 1 st Fluid. As shown in FIG. 3, the lag time
 until the start of the dissolution varied in 2nd Fluid according to the
 thickness of the bottom of the plug. Despite the variation in the lag
 time, the entirety of the drug was quickly released to 100%, demonstrating
 the pulse type dissolution pattern. The figures (.mu.m) attached to the
 characteristic line in FIG. 3 show the minimum bottom thickness of the
 plug used for each preparation.
 Industrial Applicability
 The controlled release preparation of the present invention is
 characterized in that it shows, after oral administration, no change of
 shape in the gastric juice, which means that a drug is not dissolved and a
 pharmaceutically active ingredient is not dissolved until after a
 predetermined time following passage through the stomach, irrespective of
 the length of the residence time in the stomach, but upon lapse of the
 predetermined time, quickly releases the pharmaceutically active
 ingredient in the lower part of the gastrointestinal tract to achieve
 sufficiently effective blood concentration. Particularly, it is
 characterized in that the time after passage through the stomach till the
 start of the dissolution can be adjusted as desired by changing the
 gelling rate and permeability of the material contained in the male piece,
 which gels in the intestinal juice, and the thickness of the male piece
 (e.g., mixing ratio of an ethyl acrylate-methyl
 methacrylate-trimethylammonioethyl methacrylate chloride copolymer and a
 methacrylic acid-ethyl acrylate copolymer contained in the plug and/or
 thickness of the plug). Therefore, radical dissolution occurs in a pulse
 manner after a predetermined time following discharge from the stomach,
 thereby enabling ensured dissolution of the drug at a predetermined site
 in the bowels. Consequently, a drug can act effectively at a local site in
 the lower part of the small bowel, the large bowel and the like, and the
 drug can be delivered to the lower part of the small bowel or the large
 bowel without undergoing decomposition of peptides and proteins. In
 addition, since the present preparation can enclose a maximum amount of an
 active substance in a capsule having a given size, it is particularly
 useful as an oral administration dosage form for human and animal.
 This application is based on application No. 28365/1998 filed in Japan, the
 contents of which are incorporated hereinto by reference.