JP3122478B2 - Lower gastrointestinal release oral formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a lower gastrointestinal release type oral preparation for releasing a pharmacologically active drug from the lower gastrointestinal tract after oral administration.

[0002]

2. Description of the Related Art Chitin is a natural basic polysaccharide that is widely contained in nature and is contained as a component of the exoskeleton of crustaceans and insects such as crab, shrimp and krill. Chitin in which N-acemol-D glucosamine is linked in a straight chain, and chitosan obtained by deacetylation of chitin have long been left as unused biological resources. In recent years, however, attention has been paid to its non-toxicity and its physicochemical properties, and studies on the effective use of chitin and chitosan have been actively pursued. Coagulants, ion exchangers, enzyme fixing agents, hair cosmetic raw materials, medical materials It is expected to be used in a wide range of fields, such as food additives, food additives, and soil conditioners. In particular, chitosan easily dissolves in dilute hydrochloric acid or an aqueous solution of organic acid, etc., and a glucosamine residue constituting a molecular chain has a free primary amine group (-N
It is promising because of its advantages such as being a polymer electrolyte having H ₂ ).

On the other hand, in the field of pharmaceuticals, formulation techniques for suppressing the release of a drug in the stomach and upper small intestine after oral administration and allowing the drug to reach the lower gastrointestinal tract such as the lower small intestine or the large intestine are being studied.

[0004] Since physiologically active polypeptide hormones such as insulin and calcitonin are water-soluble high molecular compounds which are easily decomposed by gastric juice and intestinal proteases such as pepsin and trypsin, they are not degraded by the above-mentioned proteases. There is significance in the development of lower gastrointestinal release oral preparations for absorption in the gastrointestinal tract. It is also significant from the viewpoint that a drug effective for lower gastrointestinal diseases such as ulcerative colitis and Crohn's disease is directly administered to the diseased part without causing side effects.

[0005] Although the above-mentioned various drugs have been developed in the form of enema administration, they have the drawback that they are not only practically inconvenient in that the operation is complicated but also burden the patient. For these reasons, it is desired that the dosage form be oral administration as much as possible.

[0006] Conventional lower gastrointestinal release type oral preparations have high p
Generally, the surface of the preparation is film-coated with a polymer compound that dissolves in the H region, and the absorption site is generally adjusted by the thickness. However, the pH value in the digestive tract varies from individual to individual, and the above-described pH-dependent preparation has a problem that the site at which the preparation disintegrates tends to vary from individual to individual. For example, when the drug is released by the disintegration of the preparation in the upper small intestine, the drug is degraded depending on the drug (such as the polypeptide described above), and the drug effect is not achieved. When the pH value in the large intestine is lowered due to metabolism by intestinal bacteria, etc., the coating film applied to the preparation does not dissolve, the drug is not released from the preparation, and no pharmacological action is exhibited. Sometimes it is excreted as it is. As a surface coating agent for a lower gastrointestinal release type oral preparation, a technique of using a polymer membrane that is decomposed by bacteria in the large intestine to disintegrate the preparation in the large intestine has been proposed. However, there are problems that the disintegration time varies due to individual differences in colonic bacteria and that it takes time to decompose the polymer membrane.

[0007]

DISCLOSURE OF THE INVENTION The present invention has been made under such circumstances, and an object of the present invention is to provide a lower gastrointestinal release type oral preparation in the most suitable form utilizing chitosan effectively. It is in.

[0008]

The present invention, which has achieved the above object, is a lower gastrointestinal release oral preparation for releasing a main drug in the lower gastrointestinal tract, comprising a base mainly composed of chitosan. The gist of the present invention is that a hard capsule is filled with a solid organic acid that dissolves chitosan in a solution state and a solid preparation containing the active ingredient, and an enteric coating is formed on the surface of the hard capsule. In the above configuration,
Depending on the thickness of the hard capsule and the physicochemical properties of chitosan, the permeability of water into the capsule can be controlled, and the release site of the drug (main drug) can be controlled without depending on the pH. It is also effective to include a lubricant, and the release site can be controlled by adjusting the ratio of chitosan to the lubricant in the base.

[0009]

The present inventors have studied from various angles the optimal form of the preparation, based on the viewpoint of effectively using non-toxic chitosan as a material for the oral preparation of the lower gastrointestinal tract. As a result, a hard capsule composed of a base mainly composed of chitosan is filled with a solid preparation containing a solid organic acid that dissolves chitosan in a solution and a main drug, and an enteric coating is formed on the surface of the hard capsule. It has been found that the above-mentioned object can be achieved brilliantly by adopting such a configuration.
The present invention has been completed.

The main drug release mechanism of the preparation according to the present invention is as follows. The orally administered preparation of the present invention reaches from the stomach to the upper small intestine while being prevented from being disintegrated in the stomach by the outermost enteric coating. After the enteric coating is dissolved in the upper small intestine, water gradually permeates into the hard capsule mainly composed of chitosan, and the permeated water dissolves the solid organic acid in the capsule to form an aqueous solution. The aqueous solution of the organic acid dissolves chitosan, which is a composition of the hard capsule, gradually disintegrates the hard capsule, and releases the main drug inside the capsule. In this way, by adopting a configuration utilizing the permeation of water into the hard capsule without depending on the pH, the inconvenience as described in the prior art does not occur.

In the preparation of the present invention, after the enteric coating on the surface of the hard capsule is dissolved and removed, the time for which water penetrates into the capsule is independent of the pH value in the digestive tract and the physicochemical properties of chitosan (desiccant) (Acetyl level, molecular weight, etc.) and capsule thickness. As described above, it is also effective to add a lubricant to the base of the capsule, and the permeability of moisture to the capsule can be controlled by the mixing ratio of chitosan and the lubricant. These facts indicate that the lower gastrointestinal tract site where the main drug is released can be appropriately controlled by the physicochemical properties of chitosan, the capsule thickness and the amount of the lubricant added.

The chitosan used in the present invention is obtained by deacetylating chitin, which is dissolved in a dilute acid solution. If the degree of deacetylation is 60% or more, the source organism, purification method and deacetylation method are used. It is not limited at all. As a solvent for dissolving chitosan when manufacturing hard capsules,
Solutions such as acetic acid, lactic acid, citric acid, malic acid, tartaric acid and the like can be mentioned.

If necessary, a lubricant is added to the hard capsule. Examples of such a lubricant include talc, magnesium stearate, aluminum stearate (mono,
Di and tri), calcium stearate and the like, and one or more of these can be used. When a lubricant is contained, if the ratio of the lubricant is too large, the hard capsule becomes brittle and cracks or the like occur, which is not preferable. Therefore, the upper limit of the mixing ratio of chitosan and the lubricant is 5%. : Up to about 95.

An enteric coating is formed on the surface of the hard capsule. That is, by forming the above-mentioned coating on the surface of the hard capsule, the hard capsule is allowed to pass through the stomach while preventing dissolution in the stomach. Examples of the enteric compound serving as a material of such a coating include methacrylic acid copolymer (Eudragit L, Eudragit S, both trade names), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose Enteric polymer compounds such as acetate phthalate (CAP), hydroxypropyl methylcellulose (HPMC), and shellac. If necessary, the coating may contain a plasticizer or a lubricant as described above. Examples of the plasticizer include castor oil, polyethylene glycol, sodium citrate, triacetin, and fatty acid glycerin ester. Incidentally, the formulation of the present invention, as described above, the thickness of the base portion of the hard capsule, the physicochemical properties of chitosan, the ratio of the amount of lubricant added, etc.,
Since the purpose is to control the release site,
The enteric coating, whose dissolution rate is easily influenced by the pH value, should be kept to the minimum necessary to pass through the stomach as much as possible.

The solid organic acid used in the present invention is a solid at room temperature and dissolves chitosan in a solution. Such organic acids include citric acid, tartaric acid, malic acid, succinic acid, and the like. Adipic acid, benzoic acid, etc .;
One or more of these may be used. The compounding amount of the solid organic acid is suitably about 5 to 90% based on the total amount of the solid preparation to be filled in the hard capsule, but is preferably 10% or more based on chitosan contained in the hard capsule. Is preferred.

The main drug used in the present invention is not particularly limited, and includes various compounds as described below. Examples of such main drugs include drugs effective for lower gastrointestinal diseases such as Crohn's disease, ulcerative colitis, and colon cancer, such as salazosulfapyridine, cortisone acetate, triamcinolone,
Tegafur, fluorouracil and the like. Also, like insulin, calmitonin, angiotensin, pasopressin, desmopressin, luteinizing hormone-releasing hormone (LHRH), somatostatin, glucagon, oxytocin, gastrin, cyclosporine, etc., it is easily decomposed in the upper gastrointestinal tract and absorbed in the lower gastrointestinal tract to physiologically. Various polypeptides exhibiting activity and derivatives thereof can also be effectively used as the main drug of the present invention.

Various forms such as granules, fine granules, powders and tablets can be used as the preparation form of the main drug to be filled in the capsule. In any case, the solid form containing the above-mentioned solid organic acid can be used. belongs to. In preparing the main drug into various preparations, a binder, an excipient, a disintegrant, or the above-mentioned lubricant can be used as necessary. Gelatin, hydroxypropylcellulose,
Polyvinylpyrrolidone and the like. Excipients include those commonly used for oral preparations, such as lactose, corn starch, potato starch, crystalline cellulose and the like. Disintegrators include carboxymethylcellulose calcium, low-substituted hydroxypropylmethylcellulose and the like.

The lower gastrointestinal release oral preparation of the present invention can be obtained, for example, as follows. The capsule mold is immersed in a chitosan solution or a chitosan solution containing a lubricant, and the capsule mold is pulled up and dried, or, if necessary, is immersed in an appropriate alkaline solution to remove the acid and then dried. To form hard capsules. This hard capsule is filled with a solid preparation containing a solid organic acid and a base drug, and the capsule joint is adhered with a chitosan solution or an adhesive, and then dried. An inventive formulation is obtained. When the thus obtained preparation is orally administered, it passes through the stomach by the action of the enteric coating, and then water penetrates into the capsule by the water permeability derived from the porosity of chitosan,
The solid organic acid in the capsule is dissolved to form a solution, dissolving the chitosan of the capsule base, disintegrating the formulation at the desired lower gastrointestinal tract site, releasing the active drug, and exerting a pharmacological action according to the type of active drug . Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are not intended to limit the present invention, and any design changes in the spirit of the preceding and following descriptions are not limited to the technical scope of the present invention. It is included in.

[0019]

EXAMPLES Example 1 A chitosan solution was prepared so as to have the composition shown in Table 1, and a hard capsule having a thickness of 150 μm was obtained from a capsule having a diameter of 6 mm (capsule body) and 6.2 mm (cap).

[0020]

[Table 1] Next, fine granules were prepared using lactose, corn starch, hydroxypropylcellulose and triamcinolone as the main drug among the solid preparation compositions shown in Table 2, and 10 g of citric acid powder was added to 10.6 g of the fine granules. To obtain a fine granule as a solid preparation.

[0021]

[Table 2] After 200 to 300 mg of the fine granules (solid preparation) were filled in the hard capsule, a chitosan solution was applied to the joint of the capsules and dried to obtain a capsule preparation.

Example 2 A capsule preparation was obtained in the same manner as in Example 1 using the hard capsule shown in Example 1 and a solid preparation having the composition shown in Table 3.

[0023]

[Table 3]

Example 3 After a chitosan solution was prepared using chitosan, acetic acid and purified water, talc was added to the solution to uniformly disperse the solution, and a chitosan-talc kneaded product was obtained. Hard capsules having the composition shown in Table 4 were produced in the same manner as in Example 1.

[0025]

[Table 4] The above hard capsules were filled with fine granules prepared in the same manner as in Table 2 except that cortisone acetate as the main drug was contained in an amount of 10 mg per capsule, and a chitosan-talc kneaded material was applied to the joint of the capsules. After drying, a capsule preparation was obtained.

Example 4 In the same manner as in Example 3, a hard capsule having the composition shown in Table 5 was obtained.
A capsule preparation was obtained in the same manner as in Example 3, except that the amount of fluorouracil as the main drug was 20 mg per capsule.

[0027]

[Table 5]

Example 5 In the same manner as in Example 3, hard capsules having the composition shown in Table 6 were obtained.
A capsule preparation was obtained in the same manner as in Example 3, except that insulin as a main drug was added to this hard capsule in an amount of 10 units per capsule.

[0029]

[Table 6]

Example 6 A chitosan-magnesium stearate kneaded product having the composition shown in Table 7 was obtained, and hard capsules were obtained from this kneaded material in the same manner as in Example 1.

[0031]

[Table 7] The above hard capsules were filled with the fine granules prepared in the same manner as in Table 2 except that the calcitonin as the main drug was 20 IU per capsule, and the kneaded chitosan-magnesium stearate was applied to the joints of the capsules. And dried to obtain the lower digestive tract release oral preparation of the present invention.

Example 7 Using a chitosan solution having the composition shown in Table 1, the thickness was 300
A hard capsule was prepared in the same manner as in Example 1 except that the particle size was changed to μm, and the solid capsules shown in Table 2 were filled in the same manner as in Example 1 and filled into the hard gastrointestinal release type of the present invention. An oral formulation was obtained.

Example 8 Using a chitosan-talc kneaded product having the composition shown in Table 6,
A hard capsule was prepared in the same manner as in Example 1 except that the thickness was changed to 300 μm, and a capsule preparation was obtained in the same manner as in Example 3.

Example 9 Using the capsule preparations obtained in Examples 1, 5, 7 and 8,
Using a corning solution having the composition shown in Table 8, film coating was carried out with a high coater to form an enteric coating having a thickness of 50 μm, thereby obtaining an oral preparation of the present invention having a lower digestive tract release type.

[0035]

[Table 8]

Comparative Example 1 Hard capsules having the compositions shown in Tables 1 and 6 were prepared, and each capsule was filled with fine granules having the composition shown in Table 9 to obtain a capsule preparation.

[0037]

[Table 9]

Comparative Example 2 An enteric coating (film thickness 50 μm) was formed on the capsule preparation obtained in Comparative Example 1 in the same manner as in Example 9 to obtain a lower gastrointestinal release oral preparation.

Example 10 In the capsule preparations obtained in Example 9 and Comparative Example 2,
Disintegration tests were carried out in accordance with the 11th revised Japanese Pharmacopoeia using food dye red No. 106 instead of the main drug. The test was first performed with the first liquid for the disintegration test for 2 hours, followed by a maximum of 4 hours using the second liquid. Table 10 shows the results for the first liquid. Second
The results for the liquid are shown in Table 11.

[0040]

[Table 10]

[0041]

[Table 11]

Example 11 In the capsules obtained in Examples 1, 3, 4 and 5, Comparative Example 1, Edible Dye Red No. 106 was used in place of the pharmaceutically active ingredient, and the eleventh revised Japanese Pharmacopoeia Dissolution Test Method 1 The dissolution test was performed according to the (rotating basket method). As the test liquid, the disintegration test second liquid was used, and the amount of the dye eluted from the capsule was measured by the absorbance at a wavelength of 565 nm, and the elution ratio with respect to the amount of the dye filled in the capsule was determined. The results are shown in FIG.

Example 12 The capsules obtained in Examples 7 and 8 were subjected to a dissolution test in the same manner as in Example 2 except that Edible Dye Red No. 106 was used instead of the medicinal ingredient. The results are shown in FIG.

[0044]

EFFECTS OF THE INVENTION The lower gastrointestinal release preparation of the present invention can control the thickness of a chitosan-based capsule or the water permeability derived from the porosity of chitosan, that is, adjust the penetration time of water into the capsule. However, it is a preparation aimed at rapidly destroying the capsule when water enters the capsule and releasing the contents in a short period of time, especially for the administration of drugs to the lower digestive tract, that is, the lower small intestine or the colon. It is valid. The method of reaching the drug administration site is not the pH-dependent method conventionally used, but is the time from when chitosan in the hard capsule starts to come in contact with moisture, and the present invention relates to a time-controlled release oral preparation. Is positioned. The use of the preparation of the present invention makes it possible to administer a drug requiring a locally high concentration in lower gastrointestinal tract absorption and to effectively administer a drug having a local action in lower gastrointestinal tract disease to a diseased site. It has effects such as

[Brief description of the drawings]

FIG. 1 is a graph showing the results of a dissolution test in Example 11.

FIG. 2 is a graph showing the results of a dissolution test in Example 12.

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Chiko Inamoto 2-15-34, Kaminomachi, Takamatsu City, Kagawa Prefecture (56) References JP-A-4-41422 (JP, A) JP-A-4-225922 ( JP, A) JP-A-2-237918 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 9/48 A61K 47/12 A61K 47/36

Claims (5)

(57) [Claims] 1. A lower gastrointestinal tract release oral preparation for releasing a main drug in the lower gastrointestinal tract, comprising: a solid organic acid which dissolves chitosan in a solution state in a hard capsule comprising a chitosan-based base; And a solid gastrointestinal release-type oral preparation characterized by being filled with a solid preparation containing the main drug and having an enteric coating formed on the surface of the hard capsule. 2. The lower digestive tract release oral preparation according to claim 1, wherein the base mainly composed of chitosan contains a lubricant. 3. The lower gastrointestinal release oral preparation according to claim 2, wherein the lubricant is at least one selected from the group consisting of talc, magnesium stearate, aluminum stearate and calcium stearate. 4. The lower part according to claim 1, wherein the solid organic acid is at least one selected from the group consisting of citric acid, tartaric acid, malic acid, succinic acid, adipic acid and benzoic acid. Gastrointestinal release oral preparation. 5. An enteric coating comprising one or more polymer compounds selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, methacrylic acid copolymer and shellac. The lower oral digestive tract release oral preparation according to any one of claims 1 to 4.