MXPA96002863A - Pharmaceutical preparation in the form of a liberable coated capsule at the bottom of the digest tract - Google Patents

Abstract

A pharmaceutical preparation in the form of a coated capsule that can release contents of a capsule in a lower part of the digestive tract comprising (a) a hard capsule containing at least one acidic substance, (b) a soluble polymer film at pH low that is formed on the surface of said hard capsule, and (c) an enteric coating film that is formed on a surface of said soluble polymer film at low pH; in accordance with the pharmaceutical preparation of the present invention, any type of medicament can be delivery to any desired site between the upper part of the small intestine and the lower part of the large intestine in the digestive tract by controlling the amount of polymer used for the soluble polymer film at low pH and / or selecting the type of soluble polymer film at low pH and / or the substance without any complicated requirement for each medicine

Description

PHARMACEUTICAL PREPARATION IN THE FORM OF A LIBERABLE COATED CAPSULE IN THE BOTTOM OF THE DIGESTIVE TRACT BACKGROUND OF THE INVENTION The present invention relates to a pharmaceutical preparation which can release contents of a capsule &a lower part of the digestive tract and more particularly to a pharmaceutical pre-parac tion in the form of a coated capsule by means of which the contents of a The capsule can be selectively delivered to a desired site, for example the large intestine, and released quickly there. The selective delivery of a drug to the large intestine has been desired in drug therapies, eg, local therapy, for inflammatory disease in the digestive tract such as ulcerative colitis or Crohn's disease or oral administration therapy, can a drug of a peptide that is apt to be decomposed chemistry or enz. in the digestive tract, a medically for which the absorption site is limited, or with another medication. In order to efficiently perform the selective delivery of the drug site to the large intestine, it is necessary to design a pharmaceutical preparation taking into account the physical and physiological environment in the human digestive tract and the type of permanence of the pharmaceutical preparation in the digestive tract. With respect to the physical and physiological environment in the digestive tract, it is recognized that the pH value in the stomach is usually 1 to 4.5 in a healthy human being and that the pH value in the intestines is 6.5 to 7.5. In accordance with the results of the widespread research of Davis et al., The residence time of a pharmaceutical preparation in the stomach of the human sec is 0.5 to 10 hours. Furthermore, not only is the variation of the large pecmanence time, but also the residence time is considerably influenced, for example, by the feeding, the size of the pharmaceutical preparation administered and the like. On the other hand, the passage time of a pharmaceutical preparation through the small intestine is recognized to be generally 3 ± 1 hours and the intra- and intra-individual variation is relatively small (Journal of Controlled Relay, 2, 27-36). (1965)). With respect to a method by which a drug can be selectively released into the gutus intestine, several investigations have been carried out so far. A pharmaceutical preparation has been proposed which is obtained by coating a pharmaceutical preparation of sustained release with an enteric coating (Apnals of t.he New York Acade and of Science, 616. 4A2-44-0 (1991)), a pharmaceutical preparation which uses a technique to control the time of onset of release (Chemical &Pharmaceutica Bulletin, 40, 30-36-3041 (1992), Patent Publication Furopea Wo. 0425699 and Japanese Patent Publication Unexamined No 256166/1994), a pharmaceutical preparation in the form of a tablet which is obtained by coating insulin with a soluble azopalimer in the gutus intestine (Saffran et al, Science, 233. 1061-1064 (1966)) and the like. , as well as pharmaceutical preparations using known techniques such as an enteric pharmaceutical preparation and a sustained release pharmaceutical preparation. However, C or conventional method has a problem such as insufficient selectivity of the site, poor practical ability due to the peculiarity of the material to be used or complicated procedure for The manufature of a preparation. For example, as the pharmaceutical preparation begins to release a drug abruptly in the upper part of the small intestine, a selective supply of the drug can no longer be obtained. When the sustained release pharmaceutical preparation is used, a fatiguing amount of a drug is released while the pharmaceutical preparation remains in the stomach and passes through the small intestine because the drug is released unusually.Attempts have been made to suppress the release of a drug in the stomach by coating a sustained-release pharmaceutical preparation with an enteric coating. However, the problem of the drug being released during the passage of the pharmaceutical release through the small intestine, has not been solved by the above mentioned enteric coated sustained release pharmaceutical preparation. The conventional pharmaceutical coated preparation requires the use of, for example, a combination of a medicament and a coating agent, a coating amount, a type of a solvent for a coating liquid, a coating condition, a condition of drying and the like, so that each medicine is used. In the case of a drug that is easily broken down by heat or by a solvent that is going to be used, the use requires much more work. In addition, there are some cases where the optimal conditions obtained are not applicable to another medicine, in fact the cases where the conditions are not applicable are numerous compared to the cases where they are applicable. Therefore, it is difficult to say that the conventional pharmaceutical preparation is excellent in wide-ranging use. Additionally, prior to coating, the conventional pharmaceutical coated preparation essentially requires procedures such as the granulation process, the screening procedure and the tablet formation process. Therefore, it takes more time, work and cost. An object of the invention is to provide a pharmaceutical preparation that is excellent in a site selection supply. In particular, the object of the invention is to provide a pharmaceutical preparation wherein the medicaments, pharmaceutical preparations, functional substances or the like contained in a hard capsule can be delivered to any desired site of the lower part of the digestive tract. A further object of the invention is to provide a pharmaceutical preparation in the form of a coated capsule wherein any type of drugs etc. They can be used commonly or extensively without a special formulation. These and other objects of the present invention will become apparent from the following description.

BRIEF DESCRIPTION OF THE INVENTION It has been found that (i) a hard capsule containing an acidic substance, which is first coated with a substance soluble at low pH and coated with an enteric layer, can rapidly release contents from the hard capsule at any desired location. between the upper part of the small intestine and the lower part of the large intestine according to the type of acidic substance and the type and amount of soluble substance at low pH, and (ii) only if said capsule is used, a pharmaceutical preparation can be obtained wherein any type of a medicament, a pharmaceutical preparation or a functional substance or if ar can be sec-delivered and rapidly released to any site between the upper part of the small intestine and the lower part of the intestine in the digestive tract. In accordance with the present invention there is provided a pharmaceutical preparation in the form of a coated capsule that can release contents of a capsule in the lower part of the digestive tract comprising (a) a hard capsule containing at least one acidic substance, (b) a low pH soluble polymer film that is formed on a surface of said hard capsule and (c) an enteric coating film that is formed on a surface of said soluble polymer film at low pH. The pharmaceutical preparation of the present invention refers to a hard capsule for delivering the contents to the lower part of the digestive tract. In other words, the pharmaceutical preparation of the present invention has the following characteristics: when a pharmaceutical preparation remains in the stomach, an enteric coating film protects the pharmaceutical preparation. Successively when the preparation passes from the stomach to the upper part of the small intestine, the enteric coating film dissolves and begins to disappear. Subsequently, the digestive juice gradually penetrates through a film of soluble polymer at low pH and a hard capsule to enter the hard capsule and in this fashion dissolves an acidic substance, the solution that has low pH that is produced by the dissolution of the acidic substance, dissolves the hard capsule and the soluble polymer film at low pH, resulting in the disappearance thereof. Then, the contents of the hard capsule such as drugs, pharmaceutical preparations and functional substances are rapidly released. Accordingly, the rate of release of the contents of the hard capsule does not vary substantially with the type of a hard capsule, the type or amount of polymer or polymers used for a soluble polymer film at low pH or the type of a substance It takes about an hour after the start of the release to release 60% of the contents of the hard capsule. The hard capsule in the pharmaceutical preparation of the present invention dissolves rapidly by a solution having a low pH which is produced by the dissolution of the acidic substance. Subsequently, the pharmaceutical preparation of the present invention has the characteristic that the delay time, the period from the discharge of the pharmaceutical preparation in the stomach until the contents of the hard capsule begin to be released, can be controlled to a length by the selection of the type and / or amount of polymer or polymers used for a soluble polymer film at low pH and / or the type of & acid substance. Therefore, the pharmaceutical preparation of the present invention has an advantage that the contents of the hard capsule can be released quickly and at any desired site from the lower part of the digestive tract. Also, a μ > Conventional pharmaceutical repair soluble in the infectious part of the digestive tract can be obtained only after the complicated determination of the conditions taking into account various procedures such as granulation and tablet formation, protection of a drug in the stomach and the upper part of the small intestine, the property of disintegration in the large intestine, the loss of a drug during the preparation of a pharmaceutical preparation and the like. However, the pharmaceutical preparation of the present invention has the outstanding advantage that they do not need complicated determination of conditions. That is, in accordance with the present invention, it is not required to determine the conditions for the purpose of for example the protection of a medicament etc., in the process of preparing a pharmaceutical preparation after a hard capsule is filled with a medicament already that the medicine with which the hard capsule is filled will be delivered to the lower part of the digestive tract.

BRIEF EXPLANATION OF THE DRAWINGS Figure 1 shows a sectional view of one embodiment of the pharmaceutical preparation of the present invention. Figure 2 shows a sectional view of another embodiment of the pharmaceutical preparation of the present invention wherein sealing means are provided around the body joint and the cap of the hard capsule. Figure 3 shows a sectional view of another embodiment of a pharmaceutical preparation of the present invention wherein an intermediate layer is provided between the polymer film e-> 4. oluble at low pH and the enteric coating film. Figure 4 shows a perspective view of a hard capsule with a sealing means around the unic'm thereof. Fig. 5 is a graph showing a result of a dielectric test with the first fluid JP and the second fluid JP for a pharmaceutical preparation of the present invention in the experimental example i. The term "JP" means the 12th Japanese Pharmacapaeia. Figure 6 is a graph showing the change of concentation of a drug in the plasma in the case that the pharmaceutical preparation of the present invention is administered to dogs in the experimental example 1.

Figure 7 is a graph showing the results of the dissolution test with the second JP fluid for preparations in the form of a r-capsule with Fu ragit The OOO which are different in the coating amount of Eudragit E100, in experimental example 2. Figure 6 is a graph showing the relationship between the coating amount of Eudcagit E 100 and the type of delay. Figure 9 is a graph showing the results of the dissolution test with the second JP fluid for the preparations in the form of a capsule re-covered with Eudragit ElOO which are different in the type of acidic substance, in the experimental example 3. Figure 10 is a graph showing the results of the dissolution test with the second JP fluid for the pharmaceutical preparations of the present invention which are different in the amount of succinic acid, in the experimental example 4 Figure 11 is a graph showing the results of the dissolution test with the second fluid JP for the pharmaceutical preparations of the present invention wherein a sealing means is provided, in the experimental example 5. 1. 1 DETAILED DESCRIPTION OF THE INVENTION In the present invention, the term "lower part of the digestive tract" means a part from the duodenum as the upper part of the small intestine, through the jejunum, the ileum, the cecum, the ascending colon, the transverse colon, the descending colon and the sigmoid calum to the rectum. In accordance with the pharmaceutical preparation of the present invention, the contents of a capsule such as a medicament, a pharmaceutical preparation, or a functional substance can be selectively released at any desired site of the lower part of the digestive tract as mentioned. before. In order to exhibit efficiently the characteristics of the present invention, preferably the contents of a capsule are released at any desired site between the jejunum and the rectum, more preferably at any desired site between the ileum and the rectum, much more preferably in any desired location of the large intestine between the cecum (the ostium ileocecale) and the rectum. More preferably the contents of a capsule are released at any desired site of the ascending colon, the transverse colon, the descending colon or the sigmoid colon. With respect to the hard capsule used in the present invention, any type of hard capsule suitable for ocal administration without limitation and preferably a commercially available hard capsule can be used, it is seen in the simplification of the preparation procedure. . The hard capsule examples are, for example, a gelatin capsule such as the CGN'I-SNAP capsule (trade name, commercially available from CAPSUGEL AG, Japan), a corn starch capsule such as CAPILL (trade name, commercially available from Warner- L mbert Company, USA) a hydroxypropyl capsule and an ilcellulase such as an HPMC capsule (trade name, commercially available from J PAN E ANCO CO. LTD., Japan) and the like. Among these, a gelatin capsule and a hydroxyl capsule are preferable. propi l et i J cellulose, and a gelatin capsule is more preferable from a point of view of its good dissolution pattern. The hard capsule in the present invention can be of various types. A size of the hard capsule is not particularly limited. The preferable capsules have a size of NO size. 2 NQ: 3 and No. 4 described in 12th Japapese Pharmaco oeia (in the following referred to as JP XII) in view of the handling. The dried substance contained in the hard capsule used in the present invention is a solid substance of which the aqueous solution has a pH value of at most 5. The form of the acidic substance is not particularly limited and the acidic substance may be used in various forms such as glass, powder and ganoderm. Examples of the acidic substances are, for example, an organic acid such as succinic acid, maleic acid, tartaric acid, citric acid, fu aric acid or malic acid and an inorganic acid such as boric acid. These acidic substances can be used alone or in combination of one or more types thereof. A preferable acidic substance is an organic acid such as succinic acid, maleic acid, tartaric acid, citric acid, fumaric acid or malic acid, and particularly preferably succinic acid, due to its good physical and chemical stability, etc. An acid substance that will be contained in a hard capsule can be a medicine if the medicine is acidic. The amount of the acidic substance that sec contained in the hard capsule is not particularly limited and can be an amount sufficient to dissolve the soluble polymer film at low pH (hereinafter also referred to as a soluble polymer film at low pH) which It forms around the hard capsule. The optimum amount of the acidic substance can be easily determined by carrying out the dissolution test. The term "low pH" means a pH ranging from pH 1 to pH 5, preferably from pH 1 to pH 3. The soluble polymer at low pH used for the soluble polymer film at low pH in the pharmaceutical preparation of the present invention. The invention may be a polymeric substance formed in film which is suitable in a quantity from HCl to pH 5 although it is not soluble in the neutral and alkaline scales of a pH greater than 5. Accordingly, a polymer generally used as a polymer Gastric soluble in this pharmaceutical field can be used properly. Examples of the soluble polymer at low pH are, for example, polyvinyl acetal diethylamide, methylactyl methacrylate copolymer of butyl-methacrylate di-di-aminoethyl ester such as Fuclragit F100 (trade name, available co-cially from Rohm Phar a, Germany), polyvinylacetal and the like. These soluble polymers at low pH can be used alone or in combination therewith. Among these, dietary and polyvinylacetal inoacetate, and the butyl-methacrylate copolymer of dime and lamethyl butyl-methacrylate are preferable since such polymers are frequently used in current pharmaceutical production. The enteric polymer used for the enteric coating film in the pharmaceutical preparation of the present invention can be a film forming polymeric substance which is soluble in an aqueous medium of pH greater than 5 although it is not soluble in an aqueous medium of a pH of more than 5. The enteric polymer used in the present invention includes, for example, a cellulose derivative, an acrylic copolymer, a maleic copolymer, a polyvinyl derivative, lacquer and the like. The examples of cellulose derivatives are 1.5example, acetate-succ inate of h idrox ipro i Ime i lcellulos, phylate of hirirox propi lmet ilceluJosa, phthalate of hydrox ii et i let i lulaulasa, cellulose acetate succinate, cellulose acetate maleate, benzoate-f alato of cellulose, cellulose propionate-phthalate, methallyl-cellulose phthalate, carboxy et i let ilceJulose, phthalate of eti J.hio'rox etiul cejulose and the like. Among these, hydroxypropylmethylcellulose acetate-hydroxypropylmethylcellulose acetate and carboxymethylcellulose acetate-succinate are preferable. In addition, the hydroxyethyl acetate and succinate acetate succinate is more preferable. Examples of acrylic copolymers are, for example, styrene-acrylic acid copolymer, methyl acrylate copolymer-acrylic acid, methyl acrylate-methacrylic acid copolymer, butyl acrylate copolymer-it is non-acrylic acid, copoJ number of methacrylic acid-methyl methacrylate such as Eudragit S or Eudragit SIO (each being the trade name, available from Rohm Phar a, Germany), ethacrylic acid-ethyl acrylate copolymer such as Eudragit L100-55 (trade name, available for sale from Rohm Fhrma, Germany), copolymer of methyl acrylate-methacrylic acid-octyl acetate and the like. Among these, the copolymer of methacrylic acid-methyl ethacrylate is preferable. Examples of the maleic echo copal are, for example, copolymer of vinylacetate 1-anhydride of maleic acid, styrene-anhydride copolymer of maleic acid, styrene-like copolymer, monaestec de á gone maléica, copolymer of ether vi ni lmet í 1 ico-anhídrido of malic acid, copoJ mere of ethylena-anhydric acid acid, copolymer of vinyl ether butyl-anhydride of maleic acid, copolymer of acrylic or t.ri lore of metha-maleic acid anhydride, copolymer of butyl acrylate-maleic acid anhydride and the like. Examples of polyvinyl derivatives are, for example, polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate, polyvinyl acetaacetate phthalate and the like. In the pharmaceutical preparation of the present invention, the above-mentioned enteric polymer can be used alone or in combination of one or more types thereof. Among the above-mentioned enteric polymers, the cellulose decivalate and the eco-acrylic copolymer are preferred. Particularly, the cellulose derivative is preferable. The mechanism in the pharmaceutical preparation of the present invention is as follows: when a pharmaceutical preparation remains in the stomach, an enteric coating film protects the pharmaceutical preparation from the solution. Subsequently, when the preparation passes from the stomach to the upper part of the small intestine, the enteric retraction film dissolves and begins to disappear. Afterwards, the digestive juice gradually penetrates through a film of soluble polymer at low pH and a hard capsule to enter the hard capsule, and therefore the acidic substance dissolves. The solution having a low pH which is produced by the dissolution of the acid substance, dissolves the hard capsule and the soluble polymer film at low pH, results in the disappearance thereof. At that time, the contents of the hard capsule are released quickly. Accordingly, the pharmaceutical preparation of the present invention makes it possible for the contents of a hard capsule to be selectively released at any desired site in the lower part of the digestive tract by controlling the amount of polymers used for a soluble polymer film at pH. low and by selecting the type of a soluble polymer at low pH and an acidic substance. The period from the unloading of the pharmaceutical preparation into the stomach until the contents of the hard capsule begin to be released into the intestine (hereinafter referred to as "time delay") can be determined by controlling the amount of polymer used for a polymer film is low pH and by the selection of the type of a soluble polymer at low pH and a citric substance. For example, when the amount of polymer used for a soluble polymer film at low pH is increased or decreased, the delay time becomes larger or shorter.

The general passage time of a pharmaceutical preparation through the small intestine is recognized to be 3 + 1 hours. Therefore, when the delay time is set to be 2 hours, approximately 4 hours and approximately 7 days, pharmaceutical preparations of the present invention can be obtained from which the contents of the hard capsule would be released in the most appropriate part of the invention. low of the ileum, the ascending colon and the transversal colon respectively. When the delay time is determined to last longer, a pharmaceutical preparation can be obtained from which the contents of the hard capsule would be released approximately in the lower part of the intestine. The pharmaceutical preparation of the present invention is suitably designed so that the contents of a hard capsule can not be released substantially during the time corresponding to the desired delay time when the dissolution test is carried out with the second fluid JP (JP XII) in accordance with the dissolution test (paddle method) I declined in the 12th Japonse Pharmacopaeia (P XII). Each amount of the polymer film suitable for low pH and the enteric coating film is not particularly limited. A suitable amount of the soluble polymer film at low pH varies with the predetermined delay time length and the combination of the components. The appropriate amount of the enteric coating film may be an amount in the extent of the contents of a hard capsule that are not released into the stomach. These quantities can easily be determined by carrying out the dissolution test. In general, it is preferable that the amount of polymer film at low pH ee determines to be from 5 to 500 amp; by weight and the amount of enteric coating film is determined to make from 10 to 400 by weight, based on the weight of the hard capsule itself (empty capsule). Since the combination of each polymer of the low pH soluble polymer film and the enteric coating film in the present invention, the low pH soluble polymers and the enteric polymers as mentioned above are selected and used taking into account the predetermined delay time, the properties of the hard capsule, the type of acid substance and the like. Examples of preferable combinations of each polymer of the low pH soluble polymer film and the enteric coating film of the present invention are shown in Table 1, and examples of preferable combinations of each particular polymer thereof in the table. 2.

TABLE 1 Low pH polymer - Polymer film film polymer Water-soluble coating layer Die i inacetata Derivative of cellulose Polyvinyl acetal enteric D e ila naceta or Lacquer poly v Mil acetal Die and acrylic copolymer laminate. ico polyvinyl aceta! Enteric acid ilaminoacetate of maleic copolymer polyvinyl acetic acid Diethylamine Polyvinyl derivative polyanil acetyl ether entéri or Ethacrylate copolymer of cellulose derivative methylolactyl butylacetyl ether dimethylaminoe etaccylate eta l Ethacrylate copolymer here the methacrylate of butyl methacrylate of dimethylaminoe and Jo Copolymer of methacrylate of acrylic copolymer methylo-meta-butyl-enteric methacrylate dimethyl methacrylate and the oleyl Capol methacrylate copolymer of maleic copolymer methylo- methacrylate of butyl-enteric ico methacrylate of dime i laminoe i lo Copolymer of methacrylate of polyvinyl derivative methylo- methacrylate of dimethyl ether dimethyl urate methacrylate TABLE 2 or. Polymer of low pH-film Polymer of film of soluble polymer coating of enteric layer 11 Diethylaminoacetate Acetate-succinate polyvinyl acetal hydroxylpropylmethylcellulose 12 Diethylaminoacetate of isopropanol Phthalate 1-polyvinyl acetal met i J.cellulose 13 Diet and Carbax meth i leccelulase polysaccharide acetal 14 Diet and methacrylic copolymer Copolymer methacrylate acetal of ethyl methacrylate Methacrylate Copolymer of Methacryl Succinate Methyl-Metacrylate Butyl Hydraxipropy J.met ilcelluloea Metamethoxymethacrylate Dimethyl Methacrylate Copolymer of Phthalate Methacrylate of Hydro-ipropy 1- et i lo-et.ac Butyl Rilate - met i J. cellulose methacrylate of dimethyl laminoetiol. Carboxymethyl methacrylate copolymer ethyl ethyl-methacrylate dimethyl butylacrylate dimethylaminolate 16 Copol. Meco methacrylate methacrylamide methylamide methyl butyl methacrylate, ethyl methacrylate, methacrylate methylamide, dimethylamine A medicament, a pharmaceutical preparation, a functional substance or the like may be contained in the hard capsule in the pharmaceutical preparation of the present invention. The medicine that is going to be contained in the hard capsule is not limited particularly as long as it is administered orally. Examples of such medicaments are, for example, chemotherapeutic agents, to tibiotics, they are imitative respirators, anti-users, expectorants, agents against malignant tumors, autonomic agents, topical cytotoxic agents, JocaJes anesthetics, effective relaxants, agents that affect digestive organs. , anti-istamines, ophthalmic agents, hypnotics, sedatives, anti-epileptics, antipyretics, analgesics, anti-inflammatory agents, cardiotonic agents, anti-arrhythmic agents, diuretics, vasodilators, anti-lipemic agents, nutrients, tonics, alterants, anticoagulants, agents for liver disease, hypoglycemic, anti-hypertensive and similar. Par- ticularly, it is beneficial to use a drug that acts locally on the large intestine, a drug that is desired to be absorbed in the large intestine for the reason that the drug is rapidly degraded in the small intestine and the like. The pharmaceutical preparation that is to be contained in the hard capsule is not limited to part in the way that it can be administered orally. Examples of such pharmaceutical preparations are, for example, powders, fine granules, granules, tablets, oily suspensions and the like. These physical preparations can have a controlled release property such as the sustained release property. The functional substance qu * -? It has to be contained in the hard capsule, it is a substance that has physiological action but exerts a beneficial influence. Examples of functional substances are, for example, useful L-tabacilli, bacteria-containing enterobacteria, which are expanded in the large intestine to facilitate defecation, and the like. The functional substance can not be an indi idual substance. For example, the above-mentioned calcium polyfloride can be added, for example, cellulose, a carbohydrate starch of sodium such as Exprotab (trade name available commercially in tea from Kimura Sangya Co., Ltd. Japan), a pretreated starch such as Starch 1500 (trade name, commercially available from Japan Colorcon Ltd, Japan) and the like. In the event that a drug and an acid substance are contained in a hard capsule, the drug is filled into the capsule in the state that the chemical stability of the drug and the drug substance can be ensured during storage over a long period. The form of both components and the method of filling them are not particularly limited. For example, after mixing a drug and a substance in the form of glass or powder as it is, the resulting mixture can be filled into a hard capsule, or the resulting mixture can be granulated and the granule is formed into powder , fine granule, granule or tablet and filled inside a hard capsule. Alternatively, for the purpose of avoiding the interaction between a medicine and an acidic substance, each material in the form of a crystal or powder can be layered separately using a separation layer to avoid direct contact of the materials andAfter preparing tablets of a medicament and an acidic substance separately, the tablets can be filled with a hard capsule. For partitioning, any substance that does not cause an unfavorable effect on the pharmaceutical preparation of the present invention can be used for the dividing material, and, for example, an excipient, etc. which are usually used in this field can be used. In the event that a functional substance is contained in a hard capsule, the filling of the functional substance can be carried out in the same manner as in the case of a medicament. In the pharmaceutical preparation of the present invention, an intermediate layer comprises at least one member selected from the group consisting of a medicament and a water-soluble substance which can be provided between the soluble polymer film at low pH and the enteric coating, if desired. It may be possible to provide an intermediate layer comprising a water-soluble substance to avoid the possible alteration of the characteristic of the soluble polymer film at pH under which it occurs in the formation of the enteric coating film. The drug contained in the intermediate layer may be the same or different from a drug that may be contained in a hard capsule. Examples of the medicament usable for the intermediate layer are not particularly limited insofar as it is a medicine that can be administered orally as cited above. Examples of the water-soluble substances which are used for the intermediate layer are, for example, a water-soluble polymeric substance, for example a water-soluble polysaccharide ether such as methylocellulose, hydro-ip-hydrocellulose or hydro-ipropylmet-I-cellulase ( for example TC-5 (trade name, commercially available from Shin-Etsu Chemical Co., Ltd)), a water-soluble polyvinyl derivative such as polyvinylpyrrolidone or polyvinyl alcohol, a polysaccharide such as pullulan , a pal iet ilenglicol etc; a saccharide, for example a monosaccharide such as glucose, a disaccharide such as sucrose etc; a lower molecular electrolyte, for example a Norwegian salt such as sodium chloride; and similar. It is preferred that the amount of the intermediate layer is determined to be from 6 to 320% by weight, in particular from 16 to &0% by weight based on the weight of the hard capsule itself (empty capsule). The method for preparing the pharmaceutical preparation of the present invention is not particularly limited and the general method known to a person skilled in the art can be used. The form of the acid substance and the contents of the hard capsule can be crystal, powder, fine particle, granule, tablet and the like. For example, when a hard capsule containing medicament can be prepared by mixing a drug substance and a medicament together with an excipient, a binder, a lubricant and the like and by preparing a granule from the resulting mixture of conformed with the general method such as wet granulation or dry granulation and then filling the granules into a hard capsule. The coating of the soluble polymer film at low pH, the enteric coating film and an intermediate layer between the low pH soluble polymer film and the enteric coating film can be carried out in accordance with the method usually used in this field by means of HICOATER (trade name, made by Freund Industrial Co., Ltd., Tokyo, Japan), a tray coating apparatus, a coating and granulation apparatus of the centrifugal fluidization type or the like, both coating methods Aqueous and non-aqueous coating methods generally used in this case may be employed for the aforementioned coating. For a coating solution, examples of the solvent used for the coating solution are, for example, an alcohol such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, 2-methanol, ethanol. (trade name Methyl cellasolve, commercially available from ATAYAMA CHEMICAL INDUSTRJFS CO., LTD., Japan) or 2-et.oxethanol (trade name: Ce c-solve, available from ee KATAYAMA CHEMICAL INDUSTRIES COL., LTD ., Japan); a hydrocarbon such as hexane, hexane, petroleum ether, petroleum benzine, ligroin, benzene, toluene or carbon; a ketone such as acetone or met ile il tone; a halocarbon of a hydrocarbon such as dichloromethane, chloroform, carbon tetraclacide, ethylene dichloride, trichloroethane or 1, 1-trichloroethane; an ester such as methyl acetate, ethyl acetate or butyl acetate; an ether such as isopropyl ether or dioxane; Water; and if you are. Among the solvents mentioned above, a solvent to be used can be selected in accordance with a property of each of the coating layers and can be suitably used in combination therewith. Among those examples, particularly an alcohol, a hydrocarbon halogen, a ketone, water and the like are preferable, and with advantage ethyl alcohol, ketone, water and the like are preferable. In the pharmaceutical preparation of the present invention, sealing means may be provided around a joint of a body and a cap of the hard capsule. By providing sealing means, an excellent pharmaceutical preparation having a scale variation of the delay time between each pharmaceutical preparation can be obtained. The sealing agent used for the sealing means may be a substance which may be the surface of the hard capsule at the junction of a body and a lid surface. Examples of the sealing agent are, for example, a water-soluble polymer, a water-insoluble polymer, a low-pH soluble polymer, an enteric polymer, a saccharide, a lower molecular electrolyte and the like. When the water-soluble polymer is used as the Jado sel agent, water-soluble polymers that can be used for the intermediate layer can be used. Examples of the water-soluble polymer are, for example, a water-soluble polysaccharide ether such as ethylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulase.; a water-soluble polyvinyl derivative such as polyvinyl pyrrol idone or polyvinyl alcohol; a polysaccharide such as pullulan; a paliet i lenglicol; and yes ilares. Examples of the water-insoluble, water-insoluble polymer used as the sealing agent are, for example, a water-insoluble acrylic polymer copolymer, for example, methylmercury of ethylene methacrylate methyl-methacrylate chloride of tri-ethyl acetate and such as Eudragit RS or Eu cagit RL, (each being the commercial name, commercially available from Rohm Pharma, Germany), copolymers of ethyl acetate-methyl methacrylate such as Fuclragit ME (trade name, commercially available from Rohm Pharma, Germany) and the like; a derivative of water-insoluble cellulose such as ethyl acetate or cellulose acetate; an insoluble polyvinyl derivative in water such as polyanil acetate or polyvinyl chloride; and a mixture of them. As the polymer downstream H used as sealing agents, soluble polymers at low pH can be used which can be used in the soluble polymer film at low pH in J to present invention, for example diet i the polyvinylacetal inoacetate and the like. As the enteric polymer used as the selladsc agent, enteric polymers can be used which can be used in the enteric coating film in the present invention, for example, hydroxypropyl acetate succinate, methylcellulose, methylmethacrylatemethacrylate copolymer, copolymer. from ethyl acetate to ethyl rilate and the like. As the saccharide and the lower molecular electcolyte used as the sealing agent, lower molecular saccharides and electrolytes that can be used for the intermediate layer can be used. Examples of the saccharide are, for example, a monasaccharide such as glucose, a disaccharides such as sucrose and the like, and examples of the lower molecular electrolytes are, for example, an inorganic salt such as sodium chloride, and the like. The above-mentioned sealing agent can be used alone or in a mixture thereof. The sealing means can be provided by applying a solution obtained by dissolving the sealing agent in a solvent over the joint, using a capsule sealing machine such as The Ma. SL / M (trade name, developed by MG 2 SpA Italy) or HICAPSEAL 15 (trade name, developed by Japan Elanca Ca., Ltd., Japan) or using for example a pipette such bed a Pasteur pipette and by drying, to seal the Union. The amount of coating of the sealing means is 0.15 to 16% by weight, preferably 0.6 to 3.2% by weight based on the weight of the hard capsule itself (empty capsule). Examples of the solvent are the same as those of the coating solutions used for the coating of the soluble polymer film at low pH etc. For each of the contents of the hard capsule, the sealing means, the low-soluble polymer film, the coating film, and the intermediate layer between the polymer film at low pH and the coating film and, if necessary, various additives generally used in the art of pharmaceutical preparations can be added, for example, an excipient, a binder, a disintegrant, a lubricant, an aggregation prevention agent, a coating aid, an entraining agent, a masking agent, a plasticizer for improving the coating property and the film-forming capacity, etc., a surfactant, an antistatic agent, an additive for controlling the transmission of light and chemicals.

Examples of the excipient & amp; eg, a saccharide such as sucrose, mannitol lactose or glucose, starch, partially pregelatinized starch, crystalline cellulose, calcium phosphate, calcium sulfate, precipitated calcium carbonate, hydrated silicon dioxide and the like . Examples of the agglutinator are, for example, an oligosaccharide or sugar alcohol such as sucrose, glucose, lactose, maltose, sorbitol or anitol; a polysaccharide such as dextrin, starch, sodium alginate, carrageenan, guar gum, gum arabic or agar; a natural higher molecular substance such as tragacanth, gelatin or gluten; a cellulose derivative such as meth i -cellulose, etlcelulp-a, carboxymethylcellulase of eodium or hydroxypropylmethylcellulose; a synthetic polymer such as polyvinyl pyrrolidone, vinyl alcohol, polyvinyl acetate, polyethylene glycol, polyalkyl acid or polyacrylic acid; and similar. Examples of disintegrants are, for example, calcium carboxylate, calcium acetate, sodium starch, corn starch, hydroxypropyl starch, partially pregelatinized starch, low substitution hydroxypropylcellulose, polyvinylhydrolidone, crosslinked carboethanol and cellulose. of calcium and the like. Examples of the lubricant and the aggregation prevention agent are, for example, calcium carbonate, magnesium stearate, calcium stearate, silicon dioxide, stearic acid, hydrated silicon dioxide, synthetic magnesium silicate, fine-grained silicon oxide. , starch, sodium lauryl sulfate, basic acid, magnesium oxide, a wax, a hydrogenated oil, a polyethylene glycol, sodium benzoate and the like. Examples of the coating aid are, for example, a hydrogenated oil such as K-3 WAX (trade name, available from Kawaken Fine Chemicals Co., Ltd., Japan), stearic acid such as NAA-174 (trade name, available commercially from NOF Corporation, Japan), calcium stearate, a polyaxyl stearate, such as NONICN S-154 (trade name, commercially available from MATSUM0T0 TRADING CO., LTD., Japan), magnesium stearate, cetanol, such as NAA-44 (trade name, commercially available from NOF (Corporation) and the like). Examples of the coloring agent are, for example, a food coloring, a lacquer, caramel, a carotene, a bijal, cochineal, iron sesquioxide, an opaque coloring agent OPAL UX made mainly of a lacquer and syrup, and if appropriate. Concrete examples thereof are, for example, a food coloring such as red for food No. 2, red for food Na. 3, yellow for food Na. 4, yellow for food No. 5, green for food No.3, blue for food Na. 1, blue for food No. 2, or lodging for food Na. 3, an aluminum lacquer for food such as aluminum lacquer red for food No. 2, lacquer for aJu inio red for decoration No. 3, yellow aluminum lacquer for food Na. 4, yellow aluminum lacquer for food No. 5, green aluminum lacquer for lime No. 3, blue aluminum lacquer for Na food. 1, blue aluminum lacquer for food No. 2 or purple aluminum lacquer for food No. 1, a b jol (a natural colorant derived from Bi a orellana L.). crimson (aluminum carme), a pearl essence (the main ingredient of it is guanine) and if i lares. Examples of the masking agent are, for example, titanium dioxide, precipitated calcium carbonate, secondary calcium phosphate, calcium sulfate and the like. Examples of the plasticizer are, for example, a phthalic acid derivative such as diethyl phthalate, dibutyl phthalate, diethyl phthalate, dibutyl phthalate or butyl-butyl-butyl glycolate, a silica oil, triacetin, propyl lenglical, poliet i lenglical and similars. Examples of the surfactant are, for example, a nonionic surfactant such as sorbitan sesquioleate, polyoxyalkylene sorbitan monaleate, glycol montearate, polyethylene glycolate montearate, propylene glycol monalaurate, polyoxyethylene ether and lauryl ether. ico, ether pol io iet i lence il lico or castor oil pol io iet ilene hidrogenated; an ionic surfactant such as sodium dodecyl sulfate or benzalkonium chloride; and similar. Suitable axes of the antistatic agent are, for example, silicon dioxide hydrate, silicic acid and the like. Examples of the additive for controlling the transmission of light, for example titanium oxide, talc and the like. These additives may be added in an amount and at a time within the scope of the conaizimiento generally used in the field of pharmaceutical preparation. As the pharmaceutical preparation of the present invention, the typical ones are shown in FIGS. 1 to 3. In the pharmaceutical preparation of the present invention, it shows in FIG. 1, an acidic substance and, if a drug is desired, a pharmaceutical preparation or a pharmaceutical preparation. a functional substance, 1 are contained in a hard capsule and the hard capsule is first coated with a low-pH soluble poly eco film 4 and then coated with an enteric coating film 5. In the pharmaceutical preparation of the present invention shown in FIG. Fig. 2 a sealing means 6 is provided around the joint 6 of the body 3 and the cap 2 in the hard capsule in the pharmaceutical preparation in Fig. 1. The joint 6 represents a limit of a connecting portion of the body 3 and cover 2 of the hard capsule. In the pharmaceutical preparation of the present invention shown in FIG. 3, is a sealing means provided? around the junction 6 in the hard capsule and an inner layer 7 comprising a medicament and / or a water-soluble substance is provided between the soluble polymer film at low pH 4 and the enteric coating film 5 in the preparation. Figure 1 shows a perspective view of a hard capsule with a sealing means around the joint of the body 3 and the lid 2 thereof. The preferred embodiments of the pharmaceutical preparation of the present invention are given below. (1) The type and amount of the polymer used for the low pH soluble polymer film and the type of acid substance are selected so that the contents of the hard capsule can be released at any desired site in the lower part of the digestive tract; (2) The type and amount of polymer used for the soluble polymer film at low pH and the type of acidic substance is selected so that the contents of a hard capsule can be released at any desired site between the jejunum and the rectum; (3) The type and amount of polymer used for the polymer film at low pH and the type of acidic substance are selected so that the contents of the hard capsule can be released at any desired site between the ileum and the ileum. straight; (4) The type and amount of the polyolefin used for the polymer film at low pH and the type of substance-acid is selected so that the contents of a hard capsule can be released at any desired site of the large intestine; (5) The types and amount of the polymer used for the polymer film at low pH and the type of acidic substance are determined so that the contents of a hard capsule can be released after the desired time when a dissolution test with the second JP fluid in accordance with the disintegration test described in JPXII; (6) The substance cida is organic acid; (7) The acidic substance is at least one member selected from the group consisting of succinic acid, maleic acid, tartaric acid, citric acid and malic acid; (6) The hard capsule is commercially available; (9) The hard capsule is a gelatin capsule, a corn starch capsule or a hydroxypropylmethylcellulose capsule; (10) The hard capsule is a gelatin capsule or a capsule of hydroxypropyl cellulose; (11) The hard capsule is a gelatin capsule; (J2) The polymer film at low pH comprises a polymeric substance which foamed to film which is soluble on a scale from pH 1 to pH 5 although it is not soluble on a neutral and alkaline scale of a pH of more than 5.; (13) The polymer film soluble at low pH comprises at least one member selected from the group consisting of diethyl methacrylate of polyvinyl chloride and methaccylate copolymer of methyl methacrylate. ethyl acetate butylacrylate; (14) The enteric coating film comprises a polymeric substance that forms film that is soluble in an aqueous medium having a pH of more than 5 although it is not soluble in an aqueous medium of a pH of when much 5; (15) The enteric coating film comprising at least one member selected from the group consisting of a cellulose derivative, shellac, an acrylic copolymer, a maleic copolymer and a polyvinyl derivative; and (.1.6) The enteric coating film comprises at least one member selected from the group consisting of hydroxypropylmethacrylate lcellulase acetate, hydropropylmethasone phthalate 1, carboxymethyltimethylcellulose and copolymer acid methyl ethacrylate-ethacrylate; The present invention is described more specifically and is explained by means of the following examples and experimental examples.

EXPERIMENTAL EXAMPLE 1 (1) Dissolution Test With respect to the pharmaceutical preparation containing prednisolone obtained in the following embodiment, a dissolution test was carried out with the first JP fluid of the disintegration test in JP XII (pH 1.2, in successively referred to as the first fluid JP) and the second JP fluid of the ion disintegration test in JP) (pH 6.6, hereinafter referred to as the second JP fluid), using 900 ml_ of the dissolution fluid at 37 ° C and at a rotation speed of 100 rpm in accordance with the pallet method based on the dissolution test specification described in -1P XII. The results of the dissolution test are shown in Figure 1. With respect to the pharmaceutical preparation of the present invention, the medicament did not dissolve completely for a long time in the first fluid JP, which means that the acid resistance of the Pharmaceutical preparation remained suf fi cient emen e. In the second JP fluid the drug dissolved rapidly after the approximately 4-hour delay time and it was observed that a drug was almost immediately after the start of the dissolution to dissolve 60% of the drug medically. (2) In vivo absorption test In the course of preparation of the aforementioned pharmaceutical preparation, an intermediate layer was provided between the Eudragit ElOO layer and the hydroxypropylmethyl cellulose acetase-succinate layer by coating the Eudcagit layer. Elo with tenf lina co to a gastric emptying indicator in an amount of coating Í9 of 20 mg p go capsule. In this way a pharmaceutical preparation having an intermediate layer in the pharmaceutical ion prena in Experimental Example 1 (1) was obtained. In each of three beagle dogs weighing 9 to 12 kgm that had fasted one day and one night, they injected intramuscularly tetragast r ina (10 μg / kg body weight). Ninety minutes after the injection, one of the pharmaceutical preparations containing 10 mg of prednisolone and 20 mg of theophylline as the gastric emptying indicator obtained above was orally administered to each beagle dog together with 50 ml of purified water. After the administration, was the blood collected at predetermined times? ee determined the concentration (μg / ml) of prednisolone and thiofilin in the plasma. The change of the prednisolone concentration in the plasma ee shows in figure 6 using the average of the three determined concentrations. The concentration of the drug in the plasma increased rapidly from approximately 3 hoas after gastric emptying and peaked approximately 5 hours after the gastric emptying. These results suggest that in the pharmaceutical preparation of the present invention, a medicament is released and then absorbed satisfactorily.

EXPERIMENTAL EXAMPLE 2 (1) Method of Freparation A white hard gelatin capsule of Size Number 2 (commercially available from CAPSUGF.L AG, Japan) was filled with a mixture of 20 ml of theophylline and 100 mg of succinic acid to obtain a core capsule . The core capsule was spray-coated with 5% by weight of Eudragit E OO coating solution (trade name, methylacitrate methacrylate methacrylate rilate copolymer of dimethyl ether, available from R? h Pharma, Germany) dissolved in ethanol, in a coating amount of 20, 30, 40, 50, 60, 70, 60, 90 or 100 mg per capsule or Eudragit ElOO by means of HICQATER (name commercial, manufactured by Freund Industrial Co., Ltd., Japan) to obtain nine tipcs of capsules coated with a film of soluble polymer at low pH that differ from each other in the amount of the soluble polymer film at low pH. (2) Dissolution Test With respect to each of the nine types of preparations obtained in the previous example (1), the dissolution test was carried out with the second JP fluid under the same conditions as in the experimental example 1 (1). The results of J to dissolution test ee are shown in Figure 7. Figure 6 shows the relationship between the delay time and the amount of Eudragit coating., which is based on the results of the dissolution test. It is understood that in accordance with the pharmaceutical preparation of the present invention, the time delay can be easily and widely controlled by a quantity of the polymer film salutable at low pH. Furthermore, it is understood that in each preparation, it takes approximately one hour after the start of the dissolution to dissolve 60% of the medicament and therefore the increase in the amount of the polymer film suitable for low pH does not influence the speed of the product. dissolution of the medication.

EXPERIMENTAL EXAMPLE 3 (1) Method of preparation Each white hard gelatin capsule of Size Number 2 (commercially available from CAPSURFL AG, Japan) was filled with a mixture of 20 ml of theophylline and 100 mg of maleic acid, tartaric acid, fumaric acid or acid citrus to obtain four types of core capsules. To each of the core capsules, a sealing means (1.5% by weight, based on the weight of the empty hard capsule used) was provided around the union of the body and the cap of the core capsule by the application of a 10% solution in weight of ethylcellulose in ethanol on the union using a Pasteur pipette and by drying using a dryer to seal the ion. The core capsule obtained with a sealing means was subjected to the same procedure as in the previous example 1 (2). Therefore, 4 types of capsules coated with a polymer film suitable for pH at which they differ from each other in the type of acid substance were obtained. (2) Dissolution test With respect to each of the four types of preparations obtained above, (1) the dissolution test was carried out with the second JP fluid under the same conditions as in the experimental example 1 (1) . The results of the dissolution test are shown in Figure 9. It is understood that in accordance with the pharmaceutical preparation of the present invention, a time delay can be controlled by changing the type of acidic substance. In addition, it is understood that in each preparation, it takes approximately one hour after the start of the release to release 60% of the drug, and subsequently the type of the substance does not influence the rate of dissolution of the drug.

EXPERIMENTAL EXAMPLE 4 (1) Preparation Method A white hard gelatin capsule of Size Number 2 was filled (commercially available from CAPSUGEL AG, Japan) with a mixture of 20 mg thiofilin and 0, 10, 20, 50 or 100 mg of succinic acid to obtain 5 types of cellulose capsules. The core capsules were subjected to the same procedures as in the following examples 1 (2) and 1 (3) to obtain 5 types of pharmaceutical preparations of the present invention, which differ from one to the other in the amount of acidic substance. (2) Dissolution test With respect to each of the five types of the pharmaceutical preparations obtained below (1), the dissolution test was carried out with the second JP fluid under the same conditions as in the experimental example. 1 (1) The results of the dissolution test are shown in Figure 10. It is understood that the delay time and dissolution rate of a drug are strongly influenced by the amount of succinic acid when the amount of succinic acid per capsule becomes less than about 20 mg.

EXPERIMENTAL EXAMPLE 5 Dissolution test. With respect to pharmaceutical preparations (n = 6) wherein a sealing means is provided, obtained in example 2 below, the dieting test was carried out with the second fluid JP under the same conditions in the experimental example 1 ( 1). The results of the dissolution test ee showed in Figure 11. It is understood that the pharmaceutical preparation of the present invention wherein sealing means are provided around the body junction and capsule lid is excellent because it has very little deviation of the dissolution pattern.

EXAMPLE 1 (1) A white hard gelatin capsule of size 2 (63 mg) (commercially available from CAPSL1RFL AG, Japan) was filled with a mixture of 10 mg of prednisolone and 100 mg of succinic acid to obtain a core capsule. (2) The core capsule was spray-coated with a 5% by weight solution of Fudragit F100 (trade name, methyl methacrylate-etacrylate layer of butyl acetate and dimeumine)., commercially available from Rohm Fharma, Germany) was dissolved in ethanol, in an amount of 30 ml per capsule (46% by weight, based on the weight of the empty hard capsule used) as Fu ragit F100 by means of HICDATER (trade name, made by Freund Industrial Co., Ltd., To io, Japan, hereinafter the same) to obtain a capsule coated with a soluble polymer film at low pH. (3) The coated capsule thus obtained was coated by additional spraying with a coating solution, which was prepared by dissolving HPMC-AS (trade name, hydroxypropyl acetate and commercially available Icelulose succinate from Shin-Etsu Chemical Co. ., Ltd., Japan) in a mixture of ethanol and water (5: 3 (w / w)) to obtain a 5 wt% solution of HPMC-AS and by adding to the same talc in an amount of 2.5% by weight. weight, based on the total weight of the 5% HPMC-AS solution, in a coating amount of 100 mg per capsule (159% by weight, based on the weight of the empty hard capsule used) with or HPCM- AB through HTCOATER. Therefore, a pharmaceutical preparation of the present invention was obtained in the form of a coated capsule releasable in the infectious part of the digestive tract.

EXAMPLE 2 (1) A white hard gelatin capsule of size 2 (commercially available from CAPSUGF.L AG, Japan) was filled with a 20 mg of theophylline and 100 mg of succinic acid to obtain a core capsule. At the union of the body and the cap of the core capsule, a sealing means (1.5% by weight, based on the weight of the empty hard capsule used) is provided by the application of a 10% solution in weight. of ethylcellulose in ethanol using a Pasteur pipette and drying with the use of a dryer to seal the union. (2) The core capsule obtained with a sealing means was subjected to the same procedures as in example 1 (2) and 1 (3) to obtain a pharmaceutical preparation of the present invention wherein sealing means are provided around the joined the hard capsule.

EXAMPLE 3 (1) A size 2 white hard gelatin capsule (commercially available from CAPSLIBL AG, Japan) was filled with a mixture of 10 mg of prednisalone and 100 mg of succinic acid to obtain a core capsule. At the union of the body and the lid, a sealing means (1.5% by weight, based on the weight of the empty hard capsule used) was provided by the application of a 10% solution in weight of the cellulose in Ethanol using a Pasteur pipette and by drying using a dryer to seal the joint. (2) The core capsule obtained with a sealing medium was subjected to the same procedure as in Example 1 (2) to obtain a capsule coated with a film of soluble polymer at low pH. (3) The coated capsule thus obtained was coated by additional spraying with a 5% by weight aqueous solution of TC-5 (trade name, hydropropylmethylcellulase, available ommercially from Shin-Etsu Chemical Co., Ltd., Japan) in a coating amount of 15 mg poc capsule (24% by weight, based on the weight of the empty hard capsule used) as a medium of HICOATER to obtain a double-coated capsule wherein the polymer film soluble at low pH is also coated with an intermediate layer. (4) The double-coated capsule thus obtained was subjected to the same procedure as in Example 1 (3) to obtain a pharmaceutical preparation of the present invention wherein the sealing means and an intermediate layer are provided.

EXAMPLE 4 (1) A size 2 white hard gelatin capsule (available from CAPSLIFFL AG, Japan) was filled with a mixture of 20 mg of teafilin and 100 mg of tartaric acid to obtain a core capsule. (2) The obtained core capsule was subjected to the same procedures as in example 1 (2) and 1 (3) to abtain a pharmaceutical preparation of the present invention.

EXAMPLE 5 (1) A white hard HPMC capsule of size 2 (commercially available from Japan Flanco CO., LTD., Japan) was filled with a mixture of 20 mg of theophylline and 100 mg of succinic acid to obtain a capsule of core. (2) The obtained core capsule was subjected to the same procedures as in example 1 (2) and 1 (3) to obtain a pharmaceutical preparation of the present invention.

EXAMPLE 6 (1) A white hard gelatin capsule of size 2 (commercially available from CAPSUGFL AG, Japan) was filled with a mixture of 20 mg of theophylline and 100 mg of maleic acid to obtain a core capsule. (2) The obtained core capsule was subjected to the same procedures as in example 1 (2) and 1 (3) to obtain a pharmaceutical preparation of the present invention.

EXAMPLE 7 (1) A white hard gelatin capsule of size 2 (commercially available from CAPSUGFL AG, Japan) was filled with a mixture of 20 mg of teafilin and 100 mg of citric acid to obtain a core capsule. (2) The obtained nugget capsule was subjected to the same procedures as in example 1 (2) and 1 (3) to obtain a pharmaceutical preparation of the present invention.

EXAMPLE ß (1) A size 2 white hard gelatin capsule (commercially available from CAPSliRFL AG, Japan) was filled with a mixture of 20 mg teoylin and 100 mg fumaric acid to obtain a core capsule. (2) The obtained core capsule was subjected to the same procedures as in example 1 (2) and 1 (3) to obtain a pharmaceutical preparation of the present invention.

EXAMPLE 9 (1) A size 2 white hard gelatin capsule (commercially available from CAPSUGFL AG, Japan) was filled with a mixture of 20 mg of theophylline and 100 mg of malic acid to obtain a core capsule. (2) The obtained core capsule was subjected to the same procedures as in example 1 (2) and 1 (3) to obtain a pharmaceutical preparation of the present invention.

EXAMPLE 10 (1) A size 2 white hard gelatin capsule (commercially available from CAPSUGF.L AG, Japan) was filled with a mixture of 20 mg of theophylline and 100 mg of succinic acid to obtain a core capsule. (2) The core capsule was replaced by spraying with a 5% by weight solution of diet i inoacetat or of polyvinylacetal in ethane.l in a coating amount of 30 mg per capsule (46% by weight). on the basis of the weight of the empty hard capsule used) as dietary polyacrylate polyacrylamide medium of HICOATER to obtain a capsule coated with a soluble polymer film at low pH. (3) The coated capsule thus obtained was subjected to the same procedure as in Example 1 (3) to obtain a pharmaceutical preparation of the present invention.

EXAMPLE 11 (1) A size 2 white hard gelatin capsule (commercially available from CAPSL1RFL AG, Japan) was filled with a mixture of 10 mg (6: 2 (w / w)) and 100 mg. mg of succinic acid to obtain a core capsule. (2) The core capsule was subjected to the same procedure as in Example 1 (2) to obtain a capsule coated with a soluble polymer film at low pH. (3) The coated capsule thus obtained was coated by additional spraying with a coating solution, which was prepared by dissolving hydroxypropylmethylcellulose phthalate in a mixture of ethanol and water (6: 2 (w / w)) to obtain an aqueous solution. 5% by weight of hydropropyl ethacrylate phthalate and added talcum powder in an amount of 2.5% by weight, in ba? to the total weight of the 5% solution, in a coating amount of 60 mg per capsule (127% by weight, based on the weight of the empty hard capsule used) with hydroxypropyl phthalate and ilcelulase medium of HICOATER. Therefore, a pharmaceutical preparation of the present invention was obtained in the form of a coated capsule releasable in the lower part of the digestive tract.

EXAMPLE 12 (1) A size 2 white hard gelatin capsule (commercially available from CAPSUGFL AG, Japan) was filled with a mixture of 10 mg of prednisisalane and 100 mg of succinic acid to obtain a core capsule. (2) The core capsule was subjected to the same procedure as in example 1 (2) to obtain a capsule coated with a film of soluble polymer at low pH. (3) The coated capsule thus obtained was coated by additional spraying with a coating solution, which was prepared by dissolving cellulose acetate-phthalate in a mixture of ethanol and water (6: 2 (w / w)) to obtain a 5% by weight solution of cellulose acetatable cellulose and added to the same talc in an amount of 5% by weight, based on the total weight of the 5% solution, in a coating amount of 100 mg per capsule (159% by weight, based on the weight of the empty hard capsule used) as an acetatazole of cement by means of HICOATER. Therefore, a pharmaceutical preparation of the present invention was obtained in the form of a coated capsule releasable in the lower part of the digestive tract.

EXAMPLE 13 (1) A white hard gelatin capsule of size 2 number (commercially available from CAPSUPFL AG, Japan) was filled with a mixture of 10 mg of prednisolone and 100 mg of succinic acid to obtain a core capsule. (2) The core capsule was subjected to the same procedure as in Example 1 (2) to obtain a capsule coated with a polymer film suitable for low pH. (3) The coated capsule thus obtained was coated by additional spraying with a coating solution, which was prepared by dissolving Eudragit L100 (trade name, methyl methacrylic acid-ethacrylate copolymer, commercially available from Rohm Pharma, Germany) in a mixture of ethanol and water (6: 2 (w / w)) to obtain a 5% by weight solution of F? dragit L 100 and added to the same talc in an amount of 5% by weight, based on to the total weight of the 5% Eudcagit L100 solution in a coating amount of 60% per capsule (J27% by weight, based on the weight of the empty hard capsule used) as Fudragit L 100 by means of HICOATER. Therefore, a preparation of the present invention was obtained in the form of a releasable coated capsule in the lower part of the digestive tract.

EXAMPLE 14 (1) A white hard gelatin capsule of size 2 (available from CAPSUGEL AG, Japan) J dyed with a mixture of 10 mg of prednisolone and 100 mg of succinic acid to obtain a core capsule. (2) The core capsule was subjected to the same procedure as in Example 1 (2> to obtain a capsule coated with a film of soluble polymer at low pH. (3) The coated capsule thus obtained was coated by additional spraying with a coating solution, which was prepared by dissolving Futragit S100 (trade name, methyl ethacrylate-methyl methacrylate copolymer, commercially available from Rohm Pharma, Germany) in a mixture of ethanol and water (6: 2 ( p / p)) to obtain a 5% solution in weight of Eudragit S00 and adding to the same talc in an amount of 5% by weight, based on the total weight of the solution of Eudragit S100 at 5%, in an amount of coating of 90 mg per capsule (143% by weight, based on the weight of the empty hard capsule used) with Fudragit S100 by means of HTCÜATER.Therefore a pharmaceutical preparation of the present invention was obtained in the form of a coated capsule releasable in the Infectious part of the digestive tract.

EXAMPLE 15 (1) A size 2 white hard gelatin capsule (commercially available from CAPSLÍRFL AG, Japan) was filled with a mixture of 10 mg of prednisolone and 100 mg of succinic acid to obtain a core capsule. (2) The core capsule was subjected to the same procedure as in example 1 (2) to obtain a capsule coated with a film of soluble polymer at low pH. (3) The coated capsule thus obtained was coated by additional spraying with a coating solution, which was prepared by dissolving E '. cagit L10O-55 (trade name, rnetacic acid-ethyl methacrylate copolymer, commercially available from Rohm Pharma, Germany) in a mixture of ethanal and water (6: 2 (w / w)) to obtain a solution to 5% by weight of Fudragit L 100-55 and adding talc in the same amount in 5% by weight, based on the total weight of the 5% solution of Fu ragit L 100-55 in an amount of 100% per capsule (159% in weight, based on the weight of the empty hard capsule used) as Eudragit L100-55 by means of HIC0ATER. Therefore, a preparation of the present invention was obtained in J as a coated capsule releasable in the lower part of the digestive tract. In addition to the ingredients used in the examples, other ingredients may be used in the examples as set forth in the specification to obtain substantially the same results.

Claims (7)

J NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical preparation in the form of a recumbent capsule that can release contents of a capsule in a lower part of the digestive tract comprising (a) a hard capsule containing at least one acidic substance, (b) a film of soluble polymer at low pH that is formed on a surface of said hard capsule, and (c) an enteric re-greasing film which forms on a surface of said soluble polymer film at low pH »2.- The pharmaceutical preparation in accordance with claim 1, characterized in that a member selected from geups consisting of a medicament, a pharmaceutical preparation, and a functional substance is contained in said hard capsule. 3. The pharmaceutical preparation of deformity with claim 1, further characterized by sealing means sealing around a union of a body and a cover of said hard capsule. 4. The pharmaceutical preparation according to claim 1, further characterized in that the acid substance is a solid substance of which the aqueous solution has a value of pH of at most 5. 5.- The pharmaceutical preparation in accordance with Claim 1, further characterized in that said acidic substance is at least one member selected from the group consisting of an organic acid and an inorganic acid. 6. The pharmaceutical preparation according to claim 1, further side because said soluble polymer film at low pH comprises at least one member selected from the group consisting of polytalcium diethylaminoacetate, cobalt number of metacilata of e ila-metacc i lato de but i la-di et i laminaet i la and pol ivini lamino acetal. 7. The pharmaceutical preparation according to claim 1, further characterized in that said enteric coating film comprises at least one member selected from the group consisting of hydroxypropyl methacrylate, phthalate hidro ipropi l et i J e u J oea, phthalate of hidro i eti let i lulaulasa, acetate-phthalate of ceulose, cellulose acetate-suc, cellulose acetate-cellulose, cellulose-benzalfate-phthalate, cellulose propionate-phthalate , Methacelulase Phthalate, Carboxylic Acid, Phthalate of Ethylhydroxyethylcellulose, Shellac, Styrene-Acrylic Acrylic Copolymer, Methyl Acrylate-Methacrylic Acrylate Copolymer, Butyl Acrylate Copolymer -acrylic acid, ethacrylate acid copolymer- methyl ester, ethyl acetate-ethyl acetate capolymer, methyl acrylate-acid copolymer, acid-ethyl acetate. of octyl, copolymer laughs acet ato de vini the maleic acid anhydride, styrene-anhydride copolymer of maleic acid, styrene-monaester copolymer of maleic acid, maleic acid ether copolymer, maleic acid anhydride , copolymer of maleic anhydride of maleic acid, flake! etherium-buty 1-anhydride number? acid malicic, acrylic lamellar coating, methyl-maleic acid anhydride, butyl acrylate-isethic acid-maleic anhydride copolymer, polyvinyl alcohol phthalate, poly laceral phthalate, phthalate of pol ivi nibut ilato and phthalate of polyvinylacetoacetal. 6. The pharmaceutical preparation according to claim 1, further characterized in that an inner layer comprises at least one member selected from the group consisting of a medicament and a water-soluble substance is provided between said soluble polymer film. at low pH and the enteric coating film.