JPH08133987A - Pharmaceutical preparation capable of controlling medicinal release - Google Patents

Abstract

PURPOSE: To obtain a pharmaceutical preparation capable of selectively and surely releasing a pharmacodynamically effective ingredient in the colon with good reproducibility by coating a composition containing the pharmacodynamically effective ingredient with a base containing a polymeric substance, having a specific intrinsic viscosity and decomposable in the colon. CONSTITUTION: This pharmaceutical preparation is obtained by coating a composition containing a pharmacodynamically effective ingredient with a base, having 0.2-2dl/g intrinsic viscosity and decomposable in the colon to preferably 10-200μm thickness. For example, a copolymer comprising structural units of formulas I and II [R is a bivalent organic group; R<1> is a saccharide residue decomposed or assimilated in the colon; X<1> and X<2> are each O, S, etc.; R<2> is a polyalkylene, a polyamide, etc.] is cited as the polymeric substance decomposable in the colon. A copolymer in which a dibasic acid constituting the units I and II is terephthalic or isophthalic acid, a saccharide constituting the unit I is cellobiose and a polyalkylene glycol constituting the unit II is polytetramethylene glycol or polypropylene glycol is preferred as the copolymer.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug release controlling preparation for releasing a pharmacologically active ingredient in the large intestine after oral administration. More specifically, a drug release for oral administration, which is obtained by coating a composition containing a medicinal component with a base material having a specific intrinsic viscosity and containing a polymer substance that is decomposed or assimilated by a degrading enzyme in the large intestine. Controlled formulation.

[0002]

2. Description of the Related Art The administration of protein / peptide drugs such as insulin and vasopressin is currently carried out by intravenous injection.
With the spread of these protein / peptide drugs,
A more convenient administration method has been sought, and methods such as oral, transdermal, nasal, and suppository are being studied. Among them, the oral administration method has been variously studied as the most general method. However, an orally administered protein / peptide drug is easily decomposed and deactivated by an enzyme present in the small intestine, so that it has a drawback of extremely low bioavailability.

Therefore, attempts have been made to improve the bioavailability by preparing a preparation for selectively releasing these protein / peptidic drugs in the large intestine in which digestive enzymes are scarcely present.

As one method for improving the bioavailability of protein / peptide drugs, enteric-coated preparations designed so that the film is dissolved by the increase of pH and the medicinal components in the preparation are released in the large intestine However, since the pH of the gastrointestinal tract on the living body side is greatly affected by food and the influence of food, it is a problem that the preparation is disintegrated in the upper part of the small intestine or, on the contrary, is excreted without being disintegrated.

Further, as another large intestine selective release preparation, a preparation utilizing a polymer which is specifically decomposed in the large intestine by an enzyme secreted by bacteria existing in the large intestine has been studied. There are many kinds of bacteria in the large intestine, and they secrete various enzymes that human digestive enzymes do not have. As one of such enzymes, there is an enzyme that reduces an azo group to an amino group, and a polymer containing an aromatic azo group cleaved by this azo reductase has been reported (US Patent Japanese Patent No. 4663308, JP-A-3-
7718). However, these methods have drawbacks in that the film forming property or solvent solubility of the polymer to be used is poor, or that an azo group having carcinogenicity is used.

It is known that polyesters obtained from sugars and dibasic acids that are specifically decomposed in the large intestine show large intestine-specific degradability, but these polymers are dimethyl sulfoxide (DMSO). , N, N-Dimethylformamide (DMF), N, N-Dimethylacetamide (DMAc) and other non-volatile aprotic polar solvents, which can be used for drug coating, such as acetone, ethanol, dichloromethane volatilization Since it was only suspended in a hydrophilic solvent, the operation was complicated when coating the drug, and it was difficult to form a uniform film.

Further, a preparation for oral administration, which is coated with a base material containing a macromolecular substance degrading in the large intestine, has a molecular weight of the macromolecular substance, an acid value, an intrinsic viscosity, a water absorption property, in various gastrointestinal mimetic solutions. Swelling degree, viscoelasticity, crystallinity, pH stability, crosslinking degree, film forming property, or the thickness, moisture permeability, tensile fracture strength, elongation, tear strength, etc. of the film formed by the polymer substance. It is greatly affected by its physical and / or chemical properties, which also changes the release profile of its active ingredient.

Therefore, even a preparation using a polymer substance which is confirmed to be specifically decomposed in the large intestine, depending on the physicochemical properties of the polymer substance to be used, may depend on the upper digestive tract, that is, the stomach or the stomach. It may be disintegrated in the small intestine to release the medicinal component, or the formulation may be discharged before the film is decomposed and the medicinal component is released. Considering the reproducibility of such disintegration, a drug release-controlled preparation that surely disintegrates in the large intestine and releases a medicinal component has not been put into practical use.

[0009]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to find a formulation that is highly safe and that selectively releases a medicinal component in the large intestine, and as a result, it has a specific intrinsic viscosity. The large intestine-degradable polymeric substance was found to be excellent in safety, film-forming property and solvent solubility, and reproducible for disintegration in the large intestine, and the film of the base containing the polymeric substance was found. By controlling the thickness, a drug release controlling formulation suitable for the purpose was completed.

The present invention provides a composition containing a medicinal component,
A drug release-controlled preparation coated with a base containing a large intestine degradable polymer having an intrinsic viscosity of 0.2 dl / g or more and 2.0 dl / g or less, more specifically, a large intestine degradable polymer (I):

[0011]

Embedded image

(Wherein R represents a divalent organic group and R ¹ represents a sugar residue which is decomposed or assimilated in the large intestine) and a general formula (II) :

[0013]

[Chemical 4]

(In the formula, R represents a divalent organic group, X ¹ and X ² are independently an oxygen atom, an imino group or a sulfur atom, and R ² is a saturated or unsaturated hydrocarbon group or a polyalkylene group. , Which represents a polyalkylene glycol group, a polyarylene oxide group, a polyester group or a polyamide group), which is a copolymer composed of at least one structural unit.

The present invention uses the above-described polymer substance that is specifically decomposed or assimilated in the large intestine, and is physically and chemically decomposed in the stomach and small intestine and is chemically and / or enzymatically decomposed. It is intended to provide a drug release-controlled preparation for oral administration that can selectively and reliably deliver a medicinal component to the large intestine without any treatment.

[0016]

EXAMPLE The present invention is a drug release-controlled preparation in which a composition containing a medicinal component is coated with a base containing a large intestine-degrading polymer having a specific intrinsic viscosity. The intrinsic viscosity of the polymeric substance used is selected according to the form of the preparation (capsule preparation, coating preparation, sheet preparation, etc.), the shape and size of the composition containing the medicinal ingredient, or the delivery site of the medicinal ingredient. It

The intrinsic viscosity referred to in the present invention is an amount used for determining the molecular weight of a polymer substance from the viscosity measurement of a dilute solution of the polymer substance, and the viscosity of the solution and the solvent is η, η ₀ , and the concentration, respectively. When c is

[0018]

[Equation 1]

## EQU1 ## Generally, the intrinsic viscosity [η]
Is different depending on the molecular weight and / or structural unit of the polymer substance, and further depending on the copolymerization ratio of the structural unit. Therefore, even in a polymer substance having the same structural unit, various characteristics are different due to the difference in intrinsic viscosity.

For example, most of the preparations coated with the base containing the above-mentioned polymer having an intrinsic viscosity of less than 0.2 dl / g disintegrate in the upper digestive tract and release the medicinal component. Further, when the intrinsic viscosity is larger than 2.0 dl / g, most of the preparation is excreted as feces before releasing the medicinal component. Furthermore, a preparation coated with the polymer substance having an intrinsic viscosity of 0.3 dl / g or more and 1.5 dl / g or less is
All disintegrate specifically in the large intestine. Therefore, the range of intrinsic viscosity of the polymer substance used in the formulation of the present invention is preferably 0.2 dl / g or more and 2.0 dl / g or less, and more preferably 0.25 dl / g or more and 1.7.
dl / g or less, and most preferably 0.3 dl / g or more and 1.5 dl / g or less.

Further, the release characteristics of the drug release-controlled preparation for oral administration which selectively releases the medicinal component in the large intestine are also affected by the thickness of the film to be coated. Therefore, the thickness of the film for specifically and surely releasing the medicinal component in the large intestine is preferably 5 to 300 μm, more preferably 7 μm.
˜250 μm, most preferably 10 to 200 μm. If the thickness of the film is less than 5 μm, the preparation will be subjected to mechanical stress before it reaches the large intestine and will be disintegrated in the upper digestive tract to release the medicinal component. Coating thickness is 300 μm
If it exceeds, the drug product will be excreted as it is before the medicinal component is released due to the decomposition of the film.

Next, the large intestine degradable polymer substance used in the present invention will be described.

Examples of the macromolecular substance capable of decomposing in the colon used in the present invention include general formula (I):

[0024]

Embedded image

(Wherein R represents a divalent organic group and R ¹ represents a sugar residue which is decomposed or assimilated in the large intestine) and a general formula (II) :

[0026]

[Chemical 6]

(In the formula, R represents a divalent organic group, X ¹ and X ² independently represent an oxygen atom, an imino group or a sulfur atom, and R ² represents a saturated or unsaturated hydrocarbon group or polyalkylene group. , A polyalkylene glycol group, a polyarylene oxide group, a polyester group, or a polyamide group).

Among the above copolymers, the intrinsic viscosity is 0.2 dl
/ G or more and 2.0 dl / g or less are used.

The molecular weight of the copolymer is not particularly limited, but is preferably 2,000 to 1,000,000, more preferably 5,000 to 500,000, and most preferably 10,000 to 300,000. .

Intrinsic viscosity of 0.2 dl / g or more and 2.0 dl
Although the molecular weight of the above-mentioned copolymer of not more than / g cannot be generally said, it is 2,000 to 1,000,000. As an example, in a copolymer comprising a structural unit (I) obtained by esterifying terephthalic acid and cellobiose and a structural unit (II) obtained by esterifying terephthalic acid and polytetramethylene glycol, a structural unit When the ratio of (I) and (II) is 0.6: 1.0 and the intrinsic viscosity is 0.51 dl / g (solvent N, N-dimethylacetamide), the molecular weight is 100,000. As described above, the intrinsic viscosity differs depending on the structural unit, the degree of polymerization, etc., and the relationship between the intrinsic viscosity and the molecular weight shown here is only an example.

The copolymerization ratio of the two structural units (I) and (II) is preferably 1:99 to 99: 1, more preferably 5:95 to 80:20, most preferably 10:90 to.
It is 70:30. The binding direction of structural units (I) and (II) is not determined.

The structural unit represented by the general formula (I) is, for example, a dibasic acid represented by HOOC-R-COOH and HO.
It is obtained by forming an ester bond with a sugar that is decomposed or assimilated in the large intestine represented by —R ¹ —OH.

There are many kinds of bacteria in the large intestine,
Recent research has shown that these bacteria utilize indigestible saccharides that cannot be digested and absorbed by the human body or are difficult to produce by fermentation, and therefore, saccharides that were previously not used in the human body also pass through this process. I've learned to be absorbed. Further, in the study of carcinogen production in the human body, the presence of specific sugar hydrolase in the large intestine has been highlighted. These hydrolases include β-glucosidase, β-galactosidase,
In addition to β-glucuronidase, xylanase, β-
Examples thereof include glycolytic enzymes such as glucanase, galactomannase, polygalacturonase, mucinase, chondroitin lyase, carboxymethylcellulase, cellulase, and polygalacturonate lyase.

The sugar represented by HO-R ¹ -OH is a sugar that is decomposed or assimilated in the large intestine and has two or more sugar residues,
And preferably 100 or less, more preferably 50 or less,
More preferably, it is an indigestible sugar composed of 10 or less. R ¹ represents the sugar residue of such a sugar. The indigestible sugar refers to sugar that is difficult or incapable of being digested and absorbed in the human small intestine.

As such a sugar, for example, a galacto-oligosaccharide in which several molecules of galactose are bound to galactose residues of lactose such as 6'-galactosyl lactose and 4'-galactosyl lactose at β-1,4 or β-1,6; 1 -Fructose at the fructose residue of sucrose such as kestose and nystose contains α-1, β
-2 several molecules bound fructooligosaccharide; sucrose glucose residues such as raffinose and stachyose galactose β-1,6 soybean oligosaccharides several molecules bound; xylobiose and xylotriose xylose β-1, Xylooligosaccharides having several molecules bound at 4; Isomalto-oligosaccharides having glucose bound to non-reducing glucose of isomaltose such as isomaltose, isomaltotriose and panose at several molecules at α-1,4 or α-1,6; Oligocellulose in which several molecules of glucose such as cellobiose and cellotriose are bound by β-1,4; lactose, lactosucrose, lactulose, palatinose, melezitose, turanose,
Examples include, but are not limited to, melibiose; disaccharide alcohols such as maltitol, lactitol, isomaltitol, and glucopyranosyl-α-1,6-mannitol; and carboxymethyl cellulose, guar gum, tragacanth gum, xylan, and the like.
Among these, from the viewpoint of film forming property and solubility in solvent,
Those composed of 5 or less sugar residues such as cellobiose, lactose, raffinose and stachyose are preferable, and disaccharides, particularly cellobiose, are most preferable.

Further, these sugars may be modified with an acyl group such as acetyl group and benzoyl group, an alkyl group such as methyl group and ethyl group, or a hydroxyalkyl group such as hydroxylethyl group and hydroxypropyl group. . These modifying groups may be bound to any number of molecules as long as two or more unmodified hydroxyl groups remain in one molecule of sugar, and may be modified with one kind or two or more kinds of modifying groups.

The copolymer of the present invention includes the above sugar HO-R.
Two or more kinds of ^1- OH may be contained, but one kind is preferable.

In the dibasic acid represented by HOOC-R-COOH, R represents a divalent organic group. Examples of such an organic group include aromatic hydrocarbons and their derivatives, aliphatic hydrocarbons and Examples thereof include derivatives thereof, alicyclic hydrocarbons and derivatives thereof. Examples of aromatic hydrocarbons include benzene ring, naphthalene ring and 1,2-bis (phenoxy) ethane, and examples of aliphatic hydrocarbons include methylene group, ethylene group, propylene group and butylene group. Examples of the alicyclic hydrocarbon include cyclohexane and the like. Specific examples of the dibasic acid are preferably terephthalic acid, isophthalic acid, 4,4'-dicarboxybiphenyl and 2,6.
-Dicarboxynaphthalene, 1,2-bis (phenoxy) ethane-4,4'-dicarboxylic acid, 1,2-bis (2-chlorophenoxy) ethane-4,4'-dicarboxylic acid and other aromatic dibases Acid; adipic acid, 1,10-
Examples include, but are not limited to, aliphatic dibasic acids such as decanedicarboxylic acid, diethylmalonic acid, fumaric acid, maleic acid, and oxalic acid; and dibasic acids of alicyclic compounds such as cyclohexanedioic acid. However, from the viewpoints of film forming property and solvent solubility, more preferably aromatic dibasic acids such as terephthalic acid and isophthalic acid; aliphatic dibasic acids such as adipic acid, fumaric acid, maleic acid and oxalic acid. And most preferably terephthalic acid, isophthalic acid, adipic acid and oxalic acid.

Two or more kinds of these dibasic acids may be contained in the copolymer of the present invention, but one kind is preferable.

Above, HOOC-R-COOH and HO
Examples of —R ¹ —OH are shown, but preferred structural units (I)
As, those obtained by ester-bonding terephthalic acid and cellobiose, those obtained by ester-bonding isophthalic acid and cellobiose, those obtained by ester-bonding adipic acid and cellobiose, and oxalic acid and cellobiose. What is obtained by ester-bonding with is preferable from the viewpoints of disintegration in the large intestine, mechanical properties and safety.

On the other hand, the structural unit represented by the general formula (II) includes the dibasic acid represented by HOOC-R-COOH and the compound represented by H-X ¹ -R ² -X ² -H. Can be obtained by combining.

As the dibasic acid represented by HOOC-R-COOH, the same dibasic acids as those exemplified in the description of the structural unit (I) can be mentioned.

In H-X ¹ -R ² -X ² -H, X ¹ and X ² independently represent an oxygen atom, an imino group or a sulfur atom, and R ² is a saturated or unsaturated hydrocarbon group or polyalkylene. Represents a group, a polyalkylene glycol group, a polyarylene oxide group, a polyester group or a polyamide group. Specific examples of H—X ¹ —R ² —X ² —H are roughly classified into four types (general formulas (III) to (VIII)), and the examples are described below.

(1) General formula (III): H--X ¹ --R ³ --X ² --H (III) (wherein, X ¹ and X ² independently represent an oxygen atom, an imino group or a sulfur atom, R ³ represents a saturated or unsaturated hydrocarbon group). That is, it is a saturated or unsaturated hydrocarbon compound having independently a hydroxyl group, an amino group or a thiol group at both ends. Specifically, for example, alkylene glycols such as ethylene glycol, propylene glycol, 1,2-butanediol, 1,3-butanediol, and 1,4-butanediol; alkylenediamines such as hexamethylenediamine, ethylenediamine, and tetramethylenediamine. Alkanedithiols such as 1,4-butanedithiol and ethanedithiol;
4-hydroquinone, 1,3-hydroquinone, 2,7
-Aromatic diols such as dihydroxynaphthalene, catechol, 1,3-di (hydroxymethyl) benzene;
Aromatic diamines such as 1,4-diaminobenzene and 3,5-diaminotoluene can be given.

(2) General formula (IV): H--X ^1- (R ⁴ O) _n --R ⁵ --X ² --H (IV) (In the formula, X ¹ and X ² are the same as the above. R ⁴ , R ⁵ each independently represents an alkylene group or an aryl group having 1 to 10 carbon atoms, and n represents an integer of 1 to 100). That is, it is a polyalkylene glycol or polyarylene oxide having independently a hydroxyl group, an amino group or a thiol group at both ends. Specifically, for example, polyethylene glycol, polypropylene glycol, polytetramethylene glycol, polyphenylene oxide, etc., each independently having a hydroxyl group, an amino group or a thiol group at both ends, can be mentioned.

(3) General formula (V) or (VI):

[0047]

[Chemical 7]

(In the formula, X ¹ and X ² are the same as the above. X ³ and
X ⁶ are each independently an oxygen atom or an imino group,
X ⁴ and X ⁵ each independently represent an oxygen atom, a sulfur atom or an imino group, R ⁶ represents an alkylene group having 1 to 20 carbon atoms, a divalent group of an aromatic compound or an alkylene glycol group, and m and L are Each independently represent an integer of 0 to 100, and p represents an integer of 1 to 12) or the general formula (VII):

[0049]

Embedded image

(Wherein X ¹ , X ² , X ³ , X ⁴ , X ⁵ ,
X ⁶ is the same as above. R ⁷ , R ⁹ and R ¹⁰ are each independently 2 of an alkylene group having 1 to 20 carbon atoms or an aromatic compound.
Represents a valent group, R ⁸ represents a divalent organic group, and q represents 1 to 10
Represents an integer of 0). That is, X ³ , X
^{When 6} is an oxygen atom, it is a polyester having a hydroxyl group, an amino group or a thiol group independently at both ends, and specifically, poly ε-caprolactone, polyglycolic acid, polylactic acid, polyethylene terephthalate, polyethylene adipate, etc. A compound having independently a hydroxyl group, an amino group or a thiol group at both terminals of X ³ , X
^{When 6} is an imino group, it is a polyamide having a hydroxyl group, an amino group or a thiol group independently at both ends, and specifically poly (epsilon) -caprolactam, hexamethylenediamine-adipic acid copolymer and the like at both ends. Independently hydroxyl group,
The compound which has an amino group or a thiol group is mentioned.

(4) General formula (VIII): H—X ¹ — (CH ₂ CR ¹¹ R ¹² ) _r —X ² —H (VIII) (In the formula, X ¹ and X ² are the same as the above. R ¹¹ , R ¹² are each independently a hydrogen atom, an alkyl group, an acetyl group, a phenyl group, a phenyl group substituted with 1 to 4 alkyl groups or a nitro group, a carboxyl group, a carboxymethyl group, a carboxyethyl group, a carboxyisopropyl group. , A carboxy-2-hydroxyethyl group, a carboxy-2-hydroxypropyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a 1-hydroxyethoxycarbonyl group or a 2-hydroxypropoxycarbonyl group, and r is 1 to 1000. Represents the integer of
A compound represented by the formula: That is, hydroxyl groups independently at both ends,
It is a polyalkylene having an amino group or a thiol group. Specific examples include compounds having independently a hydroxyl group, an amino group or a thiol group at both ends, such as polystyrene, polyvinyl acetate, polymethyl methacrylate, and polyhydroxyethyl methacrylate.

The above specific compounds are examples, and H
The compound represented by -X ¹ -R ² -X ² -H is not limited to these, but as a compound having improved solubility in a solvent and high safety, polypropylene having both hydroxyl groups at both ends is used. Most preferred are polyalkylene glycols such as glycol or polytetramethylene glycol, and polyesters such as poly ε-caprolactone having hydroxyl groups at both ends or polyglycolic acid.

Above, HOOC-R-COOH and H-
Examples of X ¹ -R ² -X ² -H are shown, but preferable structural units (II) are those obtained by ester-bonding dibasic acid and polyester, and dibasic acid and polyalkylene glycol ester. Those obtained by combining them are preferable, especially those obtained by forming an ester bond between terephthalic acid and polytetramethylene glycol, those obtained by forming an ester bond between terephthalic acid and polypropylene glycol, and isophthalic acid and polytetramethylene glycol. And those obtained by ester-bonding isophthalic acid and polypropylene glycol are preferable.

Further, in the preparation of the present invention, the large intestine degrading polymer is a dibasic acid in which the structural unit (I) of the copolymer is represented by HOOC-R-COOH and HO-R.
^1- OH is a structural unit obtained by esterifying a sugar that is decomposed or assimilated in the large intestine, and the structural unit (II) is a dibasic acid represented by HOOC-R-COOH and HO. A copolymer which is a structural unit obtained by ester-bonding with a polyalkylene glycol represented by —R ² —OH, and further represented by HOOC-R—COOH which constitutes the structural unit (I) of the copolymer. The dibasic acid used is terephthalic acid or isophthalic acid, and the sugar that is decomposed or assimilated in the large intestine represented by HO-R ¹ -OH is cellobiose, and HOOC- constituting structural unit (II) is used. R-
The preparation is preferably a copolymer in which the dibasic acid represented by COOH is terephthalic acid or isophthalic acid and the polyalkylene glycol represented by HO-R ² -OH is a copolymer of polytetramethylene glycol or polypropylene glycol, It is not limited to these.

The copolymer having the above structural units and used in the present invention is synthesized by a known method (Kurita, K. et al., Journal of Polymer Chemistry Edition (J. Pol).
ymer Chem. Ed. ), 18, 365, (19
80)). That is, polyalkylene glycol that is copolymerized with sugar that is decomposed or assimilated in the large intestine and chloride of dibasic acid are dimethylsulfoxide (DMSO), N, N-
It is carried out by using tertiary amines such as pyridine or triethylamine as a deprotonating agent in a non-volatile aprotic polar solvent such as dimethylformamide (DMF) or N, N-dimethylacetamide (DMAc), and reacting.

If desired, the base material containing a large intestine-degrading polymer substance used in the present invention may contain various compounding agents commonly used in this field in addition to the above-mentioned large intestine-decomposing polymer substance. Good.

The solvent used in the preparation of the preparation of the present invention is
Desired concentration (0.1 to 50% (weight%, the same below)),
An appropriate one can be selected from the viewpoints of volatility and film-forming property, and it is not particularly limited. For example, water, alcohol having 1 to 5 carbon atoms, aromatic hydrocarbon, ester, ketone, ether, halide, olefin. , Amide,
One or more mixed solvents selected from oxides and glycols, preferably methanol, ethanol,
1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butyl alcohol, 1
-Pentanol, toluene, xylene, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, pentyl acetate, isopentyl acetate, acetone, diisobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, dichloroethane, chloroform 1 Or a mixed solvent of two or more kinds, more preferably a solvent selected from tetrahydrofuran or methyl ethyl ketone, a mixed solvent of methanol, ethanol or 2-propanol and toluene, a mixed solvent of methanol, ethanol or 2-propanol and ethyl acetate. , A mixed solvent of methanol, ethanol or 2-propanol and methyl ethyl ketone, a mixed solvent of methanol, ethanol or 2-propanol and acetone Solvent, methanol, a mixed solvent of ethanol or 2-propanol and dichloromethane,
It is a mixed solvent of methanol, ethanol or 2-propanol and chloroform.

The concentration of the base material containing the polymer substance varies depending on the composition of the polymer substance and / or the composition of the solvent, but the solubility or dispersibility in the solvent and the processability as a film-forming agent are changed. Considering this, preferably 0.1
It is 50%, more preferably 1 to 30%, but not limited to these.

The medicinal component formulated in the present invention is not particularly limited as long as it is intended for targeting of the large intestine, and any medicinal component can be used. For example, prednisolone, 5-aminosalicylic acid and other therapeutic agents for colorectal ulcers or their derivatives, bleomycin and other anticancer agents that are highly effective against colon cancer, insulin, vasopressin, calcitonin, human granulocyte growth factor (G-CS
F), protein / peptide drugs such as erythropoietin, various interleukins, guanidinobenzoic acid derivatives such as gabexate mesylate, camostat mesylate and nafamostat mesylate, and anti-inflammatory agents such as aspirin.

Further, in the composition containing the medicinal component used in the present invention, in addition to the medicinal component, an excipient, a binder, a lubricant, an anticoagulant, a disintegrating agent, a foaming agent, an absorption promoter, Various compounding agents usually used in this field, such as a stabilizer, a solubilizing agent for a medicinal component, a plasticizer, and a polymeric substance other than the above-mentioned copolymer may be blended, if desired.

Examples of the excipient include sucrose, lactose, mannitol, glucose, starch, sugars such as crystalline cellulose, calcium phosphate, calcium sulfate, calcium lactate and the like. Examples of the binder include polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, glucose, sucrose, lactose, maltose, sorbitol, mannitol, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogol,
Examples include gum arabic, gelatin, agar and starch. Examples of lubricants include stearic acid and talc. As the anticoagulant, for example, the above-mentioned lubricants such as stearic acid and talc are preferably used, as well as light anhydrous silicic acid and hydrous silicon dioxide. Examples of the disintegrant include crystalline cellulose, carboxymethyl cellulose, carboxymethyl cellulose salt, starch, hydroxypropyl starch, sodium carboxymethyl starch, tragacanth gum and the like. Examples of the foaming agent include sodium hydrogen carbonate, tartaric acid and the like. As an absorption promoter,
Examples thereof include higher alcohols, higher fatty acids, and surfactants such as glycerin fatty acid esters. Examples of the stabilizer include benzoic acid, sodium benzoate, ethyl paraoxybenzoate and the like. Examples of the solubilizing agent for the medicinal component include organic acids such as fumaric acid, succinic acid and malic acid. Examples of the plasticizer include polyethylene glycol, polypropylene glycol, polytetramethylene ether glycol and the like.

The composition containing the medicinal component can be prepared by, for example, a method commonly used in this field, such as a powder manufacturing method, a granule manufacturing method, a tablet manufacturing method, a pill manufacturing method, a capsule manufacturing method and a sheet-shaped preparation manufacturing method. Is manufactured using.

The shape or form of the controlled drug release preparation of the present invention may be, for example, tablets, pills, granules; a composition containing a medicinal component in a capsule containing a base containing a large intestine-degradable polymer substance. Filled capsule formulation; Capsule formulation obtained by coating a gelatin capsule filled with a composition containing a medicinal component with a base containing a large intestine degrading polymer; Form of tablets, pills and granules containing a medicinal component An outer film-forming preparation or coating preparation obtained by coating or coating the composition of 1) with a base containing a large intestine degradable polymer; a composition containing a medicinal component is added to a base containing a large intestine degradable polymer. It includes, but is not limited to, a sheet-shaped preparation which is embedded. Here, the base containing a large intestine degradable polymer substance means, if desired, not only the large intestine degradable polymer substance but also one or more other polymeric substances (for example, ethyl cellulose, methacrylic acid copolymer, etc.) and / Alternatively, one or more plasticizers (such as polyethylene glycol) may be mixed.

As a specific method for producing the drug release-controlling preparation of the present invention, for example, in the case of coating preparations, a base containing the polymer is dissolved and dispersed in an appropriate solvent as described above for coating. By using the composition, uniform coating is possible with a simple operation,
The thickness of the coating can also be easily controlled. Therefore, by using such a coating composition, a separately produced composition (tablets, pills, granules, etc.) containing a medicinal component can be coated by a pan coating method or a fluid coating method. The same applies to the case of the outer film forming preparation. In the case of a capsule preparation, for example, a base material containing the above copolymer is added to dichloromethane and ethanol in a ratio of 1:
After being dissolved or dispersed in a 1 (volume ratio) mixed solution, a Teflon rod or a stainless steel rod having an appropriate shape is dipped in this solution and dried. After drying, the obtained capsule is removed from the mold, and the composition containing the medicinal component is filled therein to produce the capsule. Alternatively, the capsule may be injection-molded without using a solvent. In the case of a capsule preparation coated with a base containing a large intestine-degradable polymer substance, a separately prepared composition containing a medicinal component is filled in an appropriate gelatin capsule, and the coating composition as described above is used. It can be manufactured by coating. In the case of a sheet-form preparation, a film is prepared by a conventional method using a film forming machine using the above-mentioned coating composition. For example, a base containing the above-mentioned copolymer, a medicinal component, a plasticizer, a stabilizer, an absorption promoter, etc. are decomposed or dispersed in a 1: 1 (volume ratio) mixed solution of dichloromethane and ethanol, and then the mixture is placed in a film forming machine. A film sheet is obtained by pouring, forming a coating film and drying. It can be produced by pulverizing this film sheet and filling it into a capsule or the like. The above-mentioned manufacturing method is a specific example and is not limited thereto.

Next, the controlled drug release preparation of the present invention will be explained based on Examples, but the present invention is not limited to such Examples as a matter of course.

Production Example Cellobiose, polytetramethylene glycol (PTM
G, average molecular weight 650) and pyridine in DMAc20
It stirred at 5 degreeC in ml, and terephthalic-acid dichloride was added there and it was made to react. Table 1 shows the charged amounts of raw materials and the reaction time.

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[Table 1]

The gelled substance and unreacted cellobiose were removed by filtration, and the solution was poured into water to cause precipitation.
The precipitate was washed with water, dried under reduced pressure, dissolved again in DMAc, reprecipitated with water, washed with water and dried to obtain a product. In order to obtain a product having a desired intrinsic viscosity, the product was again dissolved in DMAc and reprecipitated with methanol or a fractional precipitation method to obtain a product. Intrinsic viscosity is D
It was calculated from the value measured by an Ubbelohde viscometer using a MAc solvent.

Product 1: Intrinsic viscosity [η] = 0.15 dl / g Product 2: Intrinsic viscosity [η] = 0.21 dl / g Product 3: Intrinsic viscosity [η] = 0.28 dl / g Product 4: Intrinsic viscosity [η] = 0.35 dl / g product 5: Intrinsic viscosity [η] = 0.42 dl / g Product 6: Intrinsic viscosity [η] = 0.54 dl / g Product 7: Intrinsic viscosity [ η] = 0.69 dl / g Product 8: Intrinsic viscosity [η] = 0.85 dl / g Product 9: Intrinsic viscosity [η] = 1.18 dl / g Product 10: Intrinsic viscosity [η] = 1. 45 dl / g Product 11: Intrinsic viscosity [η] = 1.66 dl / g Product 12: Intrinsic viscosity [η] = 1.78 dl / g Product 13: Intrinsic viscosity [η] = 1.94 dl / g Product 14: Intrinsic viscosity [η] = 2.09 dl / g Examples 1 to 1 Amino Black (Nacalai Tesque Co., Ltd.) 3 mg, (manufactured by US FMC Corporation) croscarmellose sodium 3
mg, Avicel PH-102 (manufactured by Asahi Chemical Industry Co., Ltd.)
A mixture consisting of 9 mg was well mixed by a conventional method to give a powder, and gelatin capsules (manufactured by Nippon Elanco Co., Ltd .: φ
2 mm). This capsule was sprayed with a dichloromethane and ethanol 1/1 (v / v) solution (concentration 4 to 10%) of each of the products 2 to 13 obtained in the above Production Example, and dried to have a thickness of about 40 μm. Oral administration preparations 2 to 13 each having a film of

Comparative Examples 1 to 2 Powders were prepared in the same manner as in Examples 1 to 12 and filled in capsules, and then the products 1 and 1 obtained in the above-mentioned Production Example were prepared.
4 of dichloromethane and ethanol 1/1 (v / v) solution (concentration 4 and 10%) were sprayed and dried to obtain orally administered formulations 1 and 14 having a film thickness of about 40 μm.

Examples 13 to 19 Powders were prepared in the same manner as in Examples 1 to 12 and filled in capsules. The product 7 obtained in the above Preparation Example 7 was diluted with dichloromethane and ethanol (1/1 (v / v )) Spraying solutions (concentration 3-8%) respectively and drying them to obtain thicknesses of 5, 10, 40, 80, 150, 200 and 300.
Oral formulations 16-22 having a μm coating were obtained.

Comparative Examples 3 to 4 Powders were prepared in the same manner as in Examples 1 to 12 and filled in capsules, and the product 7 obtained in the above Production Example was diluted with dichloromethane and ethanol (1/1 (v / v )) Solutions (concentrations 3 and 8%) were sprayed on and dried to give orally administered formulations 15 and 23 with film thicknesses of 3 and 350 μm, respectively.

Experimental Example For the preparations 1 to 23, the disintegration property and the elution property in the digestive tract in vivo were examined. The experiment was conducted using Wistar strain, 11-week-old male rats, and 10 animals were tested for each formulation.

Rats were fasted from the night before administration, and 1 capsule of each formulation was orally administered to the rats by using the preparations 1 to 23 using a rat sonde. This rat was kept in a clean environment, and laparotomy was performed 15 hours after administration,
The digestive tract was observed. Next, the digestive tract was taken out from the rat and cut open, and the shape of the administered formulation, the elution of amino black, and the staining of the digestive tract with amino black were observed.

The results are shown in Tables 2 and 3.

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[Table 2]

[0077]

[Table 3]

From Tables 2 and 3, it can be seen that the controlled release preparation of the present invention does not disintegrate in the stomach and small intestine and retains the contents. On the other hand, it can be seen that the preparation disintegrated in the large intestine and the contents were surely released.

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INDUSTRIAL APPLICABILITY When the drug release-controlled preparation of the present invention, which is coated with a base containing a large intestine-degradable polymer substance having a specific intrinsic viscosity, is orally administered, the preparation disintegrates only in the large intestine. Therefore, the medicinal component is selectively and surely released in the large intestine and can be reached at a high concentration. Therefore, the dose of the drug can be small and the side effects can be reduced. In addition, since the medicinal component is not released or decomposed in the small intestine or the like, a drug product design with improved bioavailability can be achieved. It will be possible.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C08G 73/00 NTB (72) Inventor Akitaka Tani 4-17-29 Fubunosato, Abeno-ku, Osaka City

Claims (6)

[Claims] 1. A drug release-controlled preparation, which is obtained by coating a composition containing a medicinal component with a base containing a large intestine-degrading polymer substance having an intrinsic viscosity of 0.2 dl / g or more and 2.0 dl / g or less. 2. The large intestine degradable polymer is represented by the general formula (I): (Wherein R represents a divalent organic group and R ¹ represents a sugar residue that is decomposed or assimilated in the large intestine) and a general formula (II): 2] (In the formula, R represents a divalent organic group, X ¹ and X ² are independently an oxygen atom, an imino group or a sulfur atom, and R ² is a saturated or unsaturated hydrocarbon group, a polyalkylene group or a polyalkylene group. Glycol group, polyarylene oxide group,
The drug release-controlled preparation according to claim 1, which is a copolymer comprising at least one type of structural unit represented by a polyester group or a polyamide group). 3. The structural unit (I) of the copolymer is HOO
Dibasic acid represented by C-R-COOH and HO-R ¹ -O
H is a structural unit obtained by forming an ester bond with a sugar that is decomposed or assimilated in the large intestine, and is a structural unit (I
I) is a dibasic acid represented by HOOC-R-COOH and H
^{3. A} structural unit obtained by forming an ester bond with a polyalkylene glycol represented by O—R ² —OH.
The described controlled-release formulation. 4. The dibasic acid represented by HOOC-R-COOH constituting the structural unit (I) of the copolymer is terephthalic acid or isophthalic acid, and the large intestine represented by HO-R ¹ -OH. The sugar decomposed or assimilated in the cell is cellobiose, and HOOC-R- constituting the structural unit (II)
The drug release-controlled preparation according to claim 3, wherein the dibasic acid represented by COOH is terephthalic acid or isophthalic acid, and the polyalkylene glycol represented by HO-R ² -OH is polytetramethylene glycol or polypropylene glycol. 5. The controlled drug release preparation according to claim 1, 2, 3 or 4, wherein the film has a thickness of 5 μm to 300 μm. 6. The drug release-controlled preparation according to claim 1, 2, 3, 4, or 5, wherein the large intestine-degradable polymer substance has an intrinsic viscosity of 0.3 dl / g or more and 1.5 dl / g or less.