JP2005220124A - Sustained release composition and sustained release formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a sustained release composition excellent in stability without using gelatin and an organic solvent which are problematic in stability. <P>SOLUTION: The sustained release composition has a repeating unit U-1 expressed by formula (1) and a repeating unit U-2 expressed by formula (2) and contains a polyalkylene polyol derivative having U-1/U-2=0.5/0.5-0.99/0.01 (in molar ratio) and a water soluble cellulose ether. In formula (1), A expresses a divalent polyoxyalkylene residue derived from a water soluble polyalkylene polyol expressed by HO-A-OH having hydroxyl groups at least in both terminals and 400-100,000 number average molecular weight; B expresses a divalent organic residue derived from a polyisocyanate expressed by OCN-B-NCO having 3-18 total carbon numbers; D expresses a divalent organic group derived from a dihydroxy compound selected from formulae (3)-(5). <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a sustained release composition and a sustained release preparation.

Conventionally, as a method for controlling the release of a drug, a method of wrapping a drug solution with a film agent to form a microcapsule or impregnating an adsorbent with a drug solution is used, and these include drugs, health foods, perfume products, and agricultural chemicals. It is applied in various fields.
As the wall material for coating the chemical solution, natural polymers such as gelatin and cellulose derivatives and synthetic polymers such as polyamide are used. Gelatin is generally used as a base material that is currently in practical use. However, recently, the suspected mad cow disease infection from cattle to humans, which is its source, cannot be dispelled. The demand is growing.

For example, Patent Document 1 (Japanese Patent Laid-Open No. 63-287543) uses one or more polymer compounds selected from polyvinyl acetal diethylaminoacetate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate phthalate and the like as a wall material. There has been proposed a method for producing microcapsules in which an aqueous solution is added to a solution obtained by dissolving these in an organic solvent such as ethanol, and an acid / base is further added as necessary to coacervate (phase separation).
However, in this method, an organic solvent may be used in the process. In this case, there is a concern not only about the remaining organic solvent in the capsule, but also a problem in terms of work safety.

Therefore, it has been proposed to make a wall material from two types of polymer compounds using coacervation (Patent Document 2: JP 2000-33259 A). In this method, an aqueous solution of hydroxypropylmethylcellulose phthalate or hydroxypropylmethylcellulose acetate succinate is mixed with an aqueous solution of an identically charged methacrylic acid copolymer under alkaline conditions, and a coagulant is added by adding a separating agent such as sodium chloride. Is to be manufactured.
However, in this case, there is a problem in that a film formed by mixing two different polymer compounds has poor compatibility and does not necessarily provide stable sustained release.

JP-A 63-287543 JP 2000-33259 A

  The present invention has been made in view of the above circumstances, and does not use gelatin or an organic solvent, which is considered to be a safety issue, and has a sustained release composition excellent in sustained release stability and a sustained release using the same. The purpose is to provide a pharmaceutical preparation.

〔式中、Ａは少なくとも両末端に水酸基を有し、数平均分子量が４００〜１００，０００のＨＯ−Ａ−ＯＨで示される水溶性ポリアルキレンポリオールに由来する二価のポリオキシアルキレン残基を示す。ＢはＯＣＮ−Ｂ−ＮＣＯで示される全炭素数が３〜１８のポリイソシアナートに由来する二価の有機残基を示す。Ｄは下記一般式（３）〜（５）から選ばれるジヒドロキシ化合物に由来する二価の有機残基を示す。

（式中、Ｒ¹及びＲ⁴は炭素数１〜２０の非置換又はハロゲン置換一価炭化水素基、Ｒ²、Ｒ³、Ｒ⁵及びＲ⁶は互いに同一でも異なっていてもよい炭素数４〜２１の非置換又はハロゲン置換一価炭化水素基、Ｙ及びＹ’は互いに同一でも異なっていてもよい水素原子、メチル基又はＣＨＣｌ₂基、Ｚ及びＺ’は酸素原子、硫黄原子又はＣＨ₂基であり、ｎはＺが酸素原子の場合は０〜１５の整数、Ｚが硫黄原子又はＣＨ₂基の場合は０、ｎ’はＺ’が酸素原子の場合は０〜１５の整数、Ｚ’が硫黄原子又はＣＨ₂基の場合は０であり、ｎ及びｎ’は互いに同一でも異なっていてもよい。Ｘ、Ｘ’及びＸ”は互いに同一でも異なっていてもよい炭素数２〜１０のアルキレン基、Ｒ⁷は炭素数２〜１０のアルキレン基であり、ｋは０〜１５の整数である。Ｒ⁸及びＲ⁹は互いに同一でも異なっていてもよく、それらの炭素数の合計が２〜２０の一価炭化水素基、Ｒ¹⁰及びＲ¹¹は互いに同一でも異なっていてもよい炭素数４〜２１の一価炭化水素基、Ｒ¹²は炭素数２〜７のアルキレン基である。）〕
［２］前記一般式（３）又は（４）で示されるジヒドロキシ化合物が、一般式（６）又は（７）で示されるジヒドロキシ化合物であることを特徴とする［１］の徐放化組成物、

〔式中、Ｒ¹³は炭素数４〜１８の直鎖状又は分岐状アルキル基、Ｒ¹⁴及びＲ¹⁵は互いに同一又は異なっていてもよい炭素数４〜１８の直鎖状又は分岐状アルキル基、Ｒ¹⁶は炭素数１〜１８のアルキル基、Ｒ¹⁷及びＲ¹⁸は互いに同一の炭素数４〜２１の非置換又はハロゲン置換一価炭化水素基である。Ｒ¹⁹は１，２−エチレン基、１，３−プロピレン基又は１，４−ブチレン基である。〕
［３］さらに、水溶性セルロースエーテルを含むことを特徴とする［１］又は［２］の徐放化組成物、
［４］前記水溶性セルロースエーテルが、アルキルセルロース又はヒドロキシアルキルアルキルセルロースであることを特徴とする［３］の徐放化組成物、
［５］［１］〜［４］のいずれかの徐放化組成物を用いてなることを特徴とする徐放性製剤
を提供する。 As a result of intensive studies to achieve the above object, the present inventor has found that a sustained release composition containing a predetermined polyalkylene polyol derivative obtained using a comb-shaped diol is excellent in safety and stability. The present invention has been completed by finding that an adhesive film is formed, and that a sustained-release preparation using this composition exhibits stable and excellent sustained-release performance of a drug.
Therefore, the present invention
[1] It has a repeating unit U-1 represented by the general formula (1) and a repeating unit U-2 represented by the general formula (2), and U-1 / U-2 = 0.5 / 0.5 to A sustained release composition comprising a polyalkylene polyol derivative having a molar ratio of 0.99 / 0.01,

[In the formula, A represents a divalent polyoxyalkylene residue derived from a water-soluble polyalkylene polyol represented by HO-A-OH having hydroxyl groups at both ends and having a number average molecular weight of 400 to 100,000. Show. B represents a divalent organic residue derived from a polyisocyanate having a total carbon number of 3 to 18 represented by OCN-B-NCO. D represents a divalent organic residue derived from a dihydroxy compound selected from the following general formulas (3) to (5).

(In the formula, R ¹ and R ⁴ are unsubstituted or halogen-substituted monovalent hydrocarbon groups having 1 to 20 carbon atoms, and R ² , R ³ , R ⁵ and R ⁶ may be the same or different from each other. 21 to 21 unsubstituted or halogen-substituted monovalent hydrocarbon group, Y and Y ′ may be the same or different from each other, hydrogen atom, methyl group or CHCl ₂ group, Z and Z ′ are oxygen atom, sulfur atom or CH ₂ N is an integer of 0 to 15 when Z is an oxygen atom, 0 when Z is a sulfur atom or a CH ₂ group, n ′ is an integer of 0 to 15 when Z ′ is an oxygen atom, Z When 'is a sulfur atom or a CH ₂ group, it is 0, and n and n ′ may be the same or different. X, X ′ and X ″ may be the same or different from each other. alkylene group, R ⁷ is an alkylene group having 2 to 10 carbon atoms, k is an integer of 0 to 15 .R ⁸及R ⁹ may be the same or different from each other, their sum 2-20 monovalent hydrocarbon radical of carbon number one of R ¹⁰ and R ¹¹ are 4 to 21 carbon atoms, which may be the same or different Valent hydrocarbon group, R ¹² is an alkylene group having 2 to 7 carbon atoms.)]
[2] The sustained release composition of [1], wherein the dihydroxy compound represented by the general formula (3) or (4) is a dihydroxy compound represented by the general formula (6) or (7) ,

[Wherein R ¹³ is a linear or branched alkyl group having 4 to 18 carbon atoms, and R ¹⁴ and R ¹⁵ are linear or branched alkyl groups having 4 to 18 carbon atoms which may be the same or different from each other. R ¹⁶ is an alkyl group having 1 to 18 carbon atoms, and R ¹⁷ and R ¹⁸ are the same unsubstituted or halogen-substituted monovalent hydrocarbon group having 4 to 21 carbon atoms. R ¹⁹ is a 1,2-ethylene group, a 1,3-propylene group or a 1,4-butylene group. ]
[3] The sustained release composition according to [1] or [2], further comprising a water-soluble cellulose ether,
[4] The sustained-release composition according to [3], wherein the water-soluble cellulose ether is alkyl cellulose or hydroxyalkyl alkyl cellulose.
[5] Provided is a sustained-release preparation comprising the sustained-release composition according to any one of [1] to [4].

  According to the present invention, since it is a sustained release composition containing a predetermined polyalkylene polyol derivative produced using a comb-shaped diol, it is only possible to form a sustained release film excellent in safety and stability. First, a sustained-release preparation using this composition exhibits a stable and good sustained-release performance of a drug.

Hereinafter, the present invention will be described in more detail.
The polyalkylene polyol derivative in the sustained release composition of the present invention has repeating units represented by the general formulas (1) and (2), the unit of the formula (1) is U-1, and the unit of the formula (2) Is U-2, U-1 / U-2 satisfies the range of 0.5 / 0.5 to 0.99 / 0.01 (molar ratio).

  In the formula (1), A is a HO-A- having hydroxyl groups at both ends and having a number average molecular weight of 400 to 100,000, preferably 500 to 80,000, more preferably 1,000 to 50,000. 2 shows a divalent polyoxyalkylene residue derived from a water-soluble polyalkylene polyol represented by OH. This water-soluble polyalkylene polyol is an alkylene oxide polymer having hydroxyl groups at both ends. Examples of the alkylene oxide include ethylene oxide, propylene oxide, butylene oxide, epichlorohydrin, pentylene oxide, and hexylene oxide. Etc. These alkylene oxides can be used singly or in combination of two or more. In addition, the said number average molecular weight is a measured value by GPC-MALLS method.

In the formulas (1) and (2), B is a divalent derivative derived from a polyisocyanate having a total carbon number of 3 to 18, preferably 3 to 16, more preferably 4 to 15 represented by OCN-B-NCO. Organic residues are shown. As this polyisocyanate, a chain or cyclic aliphatic polyisocyanate and an aromatic polyisocyanate can be appropriately selected and used.
Examples of chain aliphatic diisocyanates include methylene diisocyanate, ethylene diisocyanate, trimethylene diisocyanate, 1-methylethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, 2-methylbutane. -1,4-diisocyanate, hexamethylene diisocyanate (HDI), heptamethylene diisocyanate, 2,2'-dimethylpentane-1,5-diisocyanate, lysine diisocyanate methyl ester (LDI), Octamethylene diisocyanate, 2,5-dimethylhexane-1,6-diisocyanate, 2,2,4-trimethylpentane-1,5-diisocyanate, nonamethyl diisocyanate, 2,4,4- Trimethylhexane-1,6-diisocyanate Decamethylene diisocyanate, undecamethylene diisocyanate, dodecamethylene diisocyanate, tridecamethylene diisocyanate, tetradecamethylene diisocyanate, pentadecamethylene diisocyanate, hexadecamethylene diisocyanate, trimethylhexamethylene diisocyanate Narto etc. are mentioned.

  Cycloaliphatic polyisocyanates include cyclohexane-1,2-diisocyanate, cyclohexane-1,3-diisocyanate, cyclohexane-1,4-diisocyanate, 1-methylcyclohexane-2,4-di Isocyanate, 1-methylcyclohexane-2,6-diisocyanate, 1-ethylcyclohexane-2,4-diisocyanate, 4,5-dimethylcyclohexane-1,3-diisocyanate, 1,2-dimethylcyclohexane -Ω, ω'-diisocyanate, 1,4-dimethylcyclohexane-ω, ω'-diisocyanate, isophorone diisocyanate (IPDI), dicyclohexylmethane-4,4'-diisocyanate, dicyclohexylmethylmethane 4,4'-diisocyanate, dicyclohexyldi Tylmethane-4,4'-diisocyanate, 2,2'-dimethyldicyclohexylmethane-4,4'-diisocyanate, 3,3'-dimethyldicyclohexylmethane-4,4'-diisocyanate, 4,4 '-Methylene-bis (isocyanatocyclohexane), isopropylidenebis (4-cyclohexylisocyanate) (IPCI), 1,3-bis (isocyanatomethyl) cyclohexane, hydrogenated tolylene diisocyanate (HTDI), hydrogenated 4 4,4'-diphenylmethane diisocyanate (HMDI), hydrogenated xylylene diisocyanate (HXDI), norbornane diisocyanate methyl (NBDI), and the like.

  Aromatic polyisocyanates include 1,3- and 1,4-phenylene diisocyanate, 1-methyl-2,4-phenylene diisocyanate (2,4-TDI), 1-methyl-2,6. -Phenylene diisocyanate (2,6-TDI), 1-methyl-2,5-phenylene diisocyanate, 1-methyl-3,5-phenylene diisocyanate, 1-ethyl-2,4-phenylene diisocyanate Narate, 1-isopropyl-2,4-phenylene diisocyanate, 1,3-dimethyl-2,4-phenylene diisocyanate, 1,3-dimethyl-4,6-phenylene diisocyanate, 1,4-dimethyl -2,5-phenylene diisocyanate, m-xylene diisocyanate, diethylbenzene diisocyanate, diisopropylbenzene di Sodiumate, 1-methyl-3,5-diethylbenzene-2,4-diisocyanate, 3-methyl-1,5-diethylbenzene-2,4-diisocyanate, 1,3,5-triethylbenzene-2,4 -Diisocyanate, naphthalene-1,4-diisocyanate, naphthalene-1,5-diisocyanate, 1-methylnaphthalene-1,5-diisocyanate, naphthalene-2,6-diisocyanate, naphthalene- 2,7-diisocyanate, 1,1-dinaphthyl-2,2'-diisocyanate, biphenyl-2,4'-diisocyanate, biphenyl-4,4'-diisocyanate, 1,3-bis (1-isocyanato-1-methylethyl) benzene, 3,3′-dimethylbiphenyl-4,4′-diisocyanate, diphenylmethane-4 4'-diisocyanate (MDI), diphenylmethane-2,2'-diisocyanate, diphenylmethane-2,4'-diisocyanate, and the like xylylene diisocyanate (XDI).

  In the formula (2), D represents a divalent organic residue derived from a dihydroxy compound selected from the following general formulas (3) to (5).

In the above formula, R ¹ and R ⁴ are unsubstituted or halogen-substituted monovalent hydrocarbon groups having 1 to 20 carbon atoms, preferably 2 to 18 carbon atoms, and R ² , R ³ , R ⁵ and R ⁶ are the same or different from each other. An unsubstituted or halogen-substituted monovalent hydrocarbon group having 4 to 21 carbon atoms, preferably 5 to 18 carbon atoms, Y and Y ′ may be the same or different from each other, a hydrogen atom, a methyl group or a CHCl ₂ group, Z And Z ′ is an oxygen atom, a sulfur atom or a CH ₂ group, n is an integer of 0 to 15, preferably 2 to 12 when Z is an oxygen atom, and 0 when Z is a sulfur atom or a CH ₂ group, n ′ is an integer of 0 to 15, preferably 4 to 8 when Z ′ is an oxygen atom, and 0 when Z ′ is a sulfur atom or a CH ₂ group, and n and n ′ are the same or different from each other. Also good. X, X ′ and X ″ may be the same or different from each other, and may be an alkylene group having 2 to 10 carbon atoms, preferably 4 to 8 carbon atoms, and R ⁷ is an alkylene group having 2 to 10 carbon atoms, preferably 4 to 8 carbon atoms. , K is an integer of 0 to 15, preferably 2 to 12. R ⁸ and R ⁹ may be the same as or different from each other, and the total number of carbon atoms thereof is 2 to 20, preferably 2 to 16. A valent hydrocarbon group, R ¹⁰ and R ^{11, which} may be the same or different, each having 4 to 21 carbon atoms, preferably 4 to 18 monovalent hydrocarbon groups, and R ¹² has 2 to 7 carbon atoms, preferably 3 to 3 carbon atoms. 9 is an alkylene group.

In the above formula, examples of the unsubstituted or halogen-substituted monovalent hydrocarbon group having 1 to 20 carbon atoms include alkyl groups such as methyl, ethyl, propyl, butyl, and pentyl groups, butyl bromide, and propyl bromide groups. Examples include halogenated alkyl groups.
Examples of the unsubstituted or halogen-substituted monovalent hydrocarbon group having 4 to 21 carbon atoms include, for example, the groups having 4 to 20 carbon atoms mentioned above for the unsubstituted or halogen-substituted monovalent hydrocarbon group having 1 to 20 carbon atoms. Hexyl, cyclohexyl groups and the like.

Examples of the alkylene group having 2 to 10 carbon atoms include ethylene, propylene, butylene, amylene, and hexylene groups.
Examples of the combination of two monovalent hydrocarbon groups having 2 to 20 carbon atoms in total include a methyl group and a methyl group, a methyl group and an ethyl group, a methyl group and a propyl group, and a methyl group and a butyl group.
Examples of the alkylene group having 2 to 7 carbon atoms include the same groups as the groups having 2 to 7 carbon atoms among the above-described alkylene groups having 2 to 10 carbon atoms.

  In this case, in particular, the dihydroxy compound represented by the following general formula (6) or (7) is used as the dihydroxy compound represented by the formula (3) or (4) from the viewpoint of reactivity at the time of polyisocyanate formation. It is preferable.

In the above formula, R ¹³ has 4 to 18 carbon atoms, preferably 4 to 12 linear or branched alkyl groups, and R ¹⁴ and R ¹⁵ may have the same or different carbon numbers 4 to 18, preferably Is a linear or branched alkyl group having 4 to 12 carbon atoms, R ¹⁶ is an alkyl group having 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms, and R ¹⁷ and R ¹⁸ are the same carbon atoms having 4 to 21 carbon atoms, preferably Is a 4-16 unsubstituted or halogen substituted monovalent hydrocarbon group. R ¹⁹ is a 1,2-ethylene group, a 1,3-propylene group or a 1,4-butylene group.

Here, examples of the linear or branched alkyl group having 4 to 18 carbon atoms include 2-methyl-butyl and 2,3-dimethyl-butyl groups.
Examples of the alkyl group having 1 to 18 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, and nonyl groups.
Examples of the monovalent hydrocarbon group having 4 to 21 carbon atoms include the same groups as those described above for the unsubstituted or halogen-substituted monovalent hydrocarbon group having 4 to 21 carbon atoms.

In the present invention, the molar ratio U-1 / U-2 of the unit U-1 of the formula (1) and the unit U-2 of the formula (2) constituting the polyalkylene polyol derivative is 0.5 / 0.5 to It is 0.99 / 0.01, preferably 0.6 / 0.4 to 0.8 / 0.2.
If this ratio is less than the lower limit of the above range, the viscosity may be low and the gel-like characteristics may be lost, and if it exceeds the upper limit, it may be difficult to dissolve in water.

Further, the weight average molecular weight of the polyalkylene polyol derivative is not particularly limited, but from the viewpoint of imparting appropriate viscoelasticity to the sustained release composition containing the polyalkylene polyol derivative, it is several tens of thousands to several million, preferably 10,000 to 300,000 is desirable. The weight average molecular weight can be measured by gel permeation chromatography (GPC), and polyethylene oxide, pullulan and the like can be obtained as standard molecular weight substances.
The viscosity at 20 ° C. of the 2% by weight aqueous solution of the polyalkylene polyol derivative is 50 to 100, when measured at 10 rpm with a BH viscometer from the viewpoint of imparting good sustained release properties to the sustained release preparation. Those in the range of 000 mPa · s, particularly 100 to 100,000 mPa · s are preferred.
Specific examples of this polyalkylene polyol derivative include compounds used in mortar thickeners described in JP-A No. 2001-348256.

Since these polyalkylene polyol derivatives become a gel in water and exhibit sustained release properties, they can of course be used alone. However, when used in a formulation, the gel is weakly sticky in gastric juice and water, the gel dissolves in the gastric juice and water, and the sustained release of the gel may not last for the desired time .
Therefore, in order to stabilize the sustained release property of the film composed of the sustained release composition, it is preferable to further add a water-soluble cellulose ether to the sustained release composition of the present invention.

Here, the water-soluble cellulose ether is not particularly limited, but alkyl cellulose and hydroxyalkylalkyl cellulose are preferable from the viewpoint of imparting good sustained release property to the sustained release preparation. Specifically, methyl cellulose, human loxypropyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl ethyl cellulose and the like can be used, and these can be used alone or in combination of two or more.
The viscosity at 20 ° C. of a 2% by weight aqueous solution of this water-soluble cellulose ether is 50-100 when measured at 10 rpm with a BH viscometer from the viewpoint of imparting appropriate drug elution characteristics to the sustained-release preparation. It is preferably 10,000 mPa · s, more preferably 100 to 100,000 mPa · s.

  In the sustained release composition of the present invention, the blending ratio of the water-soluble cellulose ether and the polyalkylene polyol derivative is usually 1/99 to 40/60, preferably 10/90 to 30/70. If the blending amount of the water-soluble cellulose ether exceeds the above range, the initial dissolution of the sustained-release preparation may be extremely slow. On the other hand, when the compounding amount of the polyalkylene polyol derivative is increased from the above range, the sustained release stability may be lowered as described above.

When the water-soluble cellulose ether and the polyalkylene polyol derivative are used in combination, the total addition amount of both components in the sustained release composition improves the stability of the sustained release from the total amount of the sustained release composition. 3 to 50% by mass, particularly 5 to 30% by mass is preferable.
In the sustained release composition of the present invention, a polyhydric alcohol, a surfactant and the like can be blended for the purpose of controlling sustained release. In this case, the blending amount is based on the entire composition. Usually, it is 1 to 20% by mass. Moreover, in order to improve the hardness and solubility of the sustained release composition, the sustained release composition can be treated with an acid such as hydrochloric acid, acetic acid, phosphoric acid or the like.

The sustained-release preparation according to the present invention is obtained by using the above-mentioned sustained-release composition. For example, a sustained-release composition containing a polyalkylene polyol derivative and, if necessary, a water-soluble cellulose ether is gradually added. A drug to be released is contained and pressed into a preparation, or an adsorbent is mixed with an aqueous solution containing a polyalkylene polyol derivative and a water-soluble cellulose ether, granulated, dried, and then It can be obtained, for example, by impregnating the drug to be sustained-released into the granules.
The form of the sustained-release preparation is not particularly limited. Examples of the sustained-release preparation include a spherical or cylindrical shape having a diameter of about 5 to 15 mm in the case of a tablet and an average diameter of 1 to 5 mm in the case of a granule.

Examples of the adsorbent used for preparation of the preparation include inorganic adsorbent powders such as bentonite, talc and kaolin clay, and organic polymer material powders such as styrene, ethylene and acrylic. These adsorbents may be appropriately selected from those that permeate and adsorb the drug to be sustained-released.
The drug subject to sustained release may be appropriately selected from pharmaceuticals, foods, feeds, agricultural chemicals, and the like as needed. Specific examples include fat-soluble vitamins such as vitamins A, D, E, and K. And water-soluble vitamins such as vitamin C, polyethylene glycol dispersion, saccharides, amino acids, bifidobacteria and pheromones.

  In addition, a poorly water-soluble drug is also preferably used. In this case, a poorly water-soluble drug is a drug that is normally poorly absorbed by oral administration and is defined as “almost insoluble” or “extremely insoluble” as defined by the Japanese Pharmacopoeia. The drug solubility in the Japanese Pharmacopoeia refers to the degree to which a drug dissolves within 30 minutes when it is powdered and then placed in a solvent and shaken at 20 ± 5 ° C every 5 minutes for 30 seconds. "Almost insoluble" means the amount of solvent required to dissolve 1 g or 1 ml of drug (in this case, water) is 10,000 ml or more, and "very difficult to dissolve" means the amount of solvent required to dissolve 1 g or 1 ml of drug. Means a property of 1,000 ml or more and less than 10,000 ml. Specific examples include nifedipine, phenacetin, phenytoin, dichitoxin, nilpadipine, diazepam, griseofulvin, chloramphenicol and the like.

EXAMPLES Hereinafter, although a synthesis example, an Example, and a comparative example are given and this invention is demonstrated more concretely, this invention is not limited to the following Example.
[1] Synthesis of dihydroxy compound [Synthesis Example 1] Synthesis of dihydroxy compound 1 To a 500 ml round bottom flask equipped with a magnetic stirrer, thermometer and dropping funnel, 64.6 g of 2-ethylhexylamine (manufactured by Kanto Chemical Co., Inc.) And the inside of the flask was replaced with nitrogen. After heating the flask to 60 ° C. in an oil bath, 220.0 g of 2-ethylhexyl glycidyl ether (Asahi Denka Co., Ltd., Adeka Glycilol ED518, Epoxy value 220) was added dropwise over 40 minutes while stirring. did. After completion of dropping, the temperature of the oil bath was raised to 80 ° C., and the flask was heated at this temperature for 10 hours. Thereafter, the temperature of the oil bath was raised to 120 ° C., and a small amount of unreacted material was distilled off under reduced pressure at a vacuum degree of 400 Pa using a vacuum pump. Dihydroxy compound 1 (average molecular weight 532 based on OH value) in which 2-ethylhexyl glycidyl ether was added at a ratio of 2 mol to 1 mol of 2-ethylhexylamine was obtained in a yield of 90%.

Synthesis Example 2 Synthesis of Dihydroxy Compound 2 3- (dodecyloxy) -1-propylamine (manufactured by Koei Chemical Co., Ltd.) was added to a 500 ml round bottom flask equipped with a magnetic stirrer, thermometer and dropping funnel. 7 g was charged and the inside of the flask was replaced with nitrogen. While heating the flask to 60 ° C. in an oil bath and stirring, 188.0 g of 2-ethylhexyl glycidyl ether (manufactured by Nagase Kasei Kogyo Co., Ltd., Denacol EX-121, epoxy value 188) is added dropwise over 40 minutes while stirring. did. After completion of dropping, the temperature of the oil bath was raised to 80 ° C., and the flask was heated for 10 hours. Thereafter, the temperature of the oil bath was raised to 120 ° C., and a small amount of unreacted substances were distilled off under reduced pressure at a vacuum degree of 400 Pa using a vacuum pump. Dihydroxy compound 2 (average molecular weight 620 from OH value) in which 2-ethylhexyl glycidyl ether was added at a ratio of 2 mol to 1 mol of 3- (dodecyloxy) -1-propylamine was obtained in a yield of 85%.

[2] Synthesis of polyalkylene polyol derivative [Synthesis Example 3] Synthesis of polyalkylene polyol derivative 1 A 1000 ml SUS separable flask was placed in a commercially available polyethylene glycol (PEG # 6000, manufactured by Sanyo Chemical Industries, Ltd., number average molecular weight 8). , 630) was charged in an amount of 200 g and melted at 150 ° C. under a nitrogen seal. This was stirred for 3 hours under reduced pressure (400 Pa) with stirring. At this time, the residual moisture was 200 ppm.
The temperature was lowered to 70 ° C., and the flask was filled with 101 kPa of nitrogen. 300 ppm of BHT (di-tert-butylhydroxytoluene) was added as an antioxidant. While stirring the flask, 1.70 g of the dihydroxy compound 1 obtained in Synthesis Example 1 and 4.35 g of hexamethylene diisocyanate (manufactured by Tokyo Chemical Industry Co., Ltd.) were charged (NCO / OH = 0.98 mol). / Mol). When 0.05 g of DBTDL was added as a catalyst, the viscosity increased rapidly in about 10 minutes. Stirring was stopped and the reaction was carried out at 70 ° C. for 2 hours, and then the temperature was raised to 120 ° C. and kept at a constant temperature for 30 minutes to obtain a polyalkylene polyol derivative 1 having a melting point of about 60 ° C.

[Synthesis Example 4] Synthesis of polyalkylene polyol derivative 2 A 1000 ml SUS separable flask was charged with 200 g of commercially available PEG # 6000 (manufactured by Sanyo Chemical Industries, Ltd., number average molecular weight 8,630), and 150 ml under a nitrogen seal. Melted at ℃. This was stirred for 3 hours under reduced pressure (400 Pa) with stirring. Residual moisture was 200 ppm.
The temperature was lowered to 70 ° C., and the flask was filled with 103 kPa of nitrogen. 300 ppm of BHT (di-tert-butylhydroxytoluene) was added as an antioxidant. While stirring the flask, 1.90 g of the dihydroxy compound 1 obtained in Synthesis Example 1 and 4.41 g of hexamethylene diisocyanate (manufactured by Tokyo Chemical Industry Co., Ltd.) were charged (NCO / OH = 0.98 mol). / Mol). When 0.05 g of DBTDL was added as a catalyst, the viscosity increased rapidly in about 10 minutes. Stirring was stopped and the reaction was carried out at 70 ° C. for 2 hours, and then the temperature was raised to 120 ° C. and kept at a constant temperature for 30 minutes to obtain a polyalkylene polyol derivative 2 having a melting point of about 60 ° C.

[Synthesis Example 5] Synthesis of polyalkylene polyol derivative 3 A 1000 ml SUS separable flask was charged with 200 g of commercially available PEG # 6000 (manufactured by Sanyo Chemical Industries, Ltd., number average molecular weight 8,630), and 150 under a nitrogen seal. Melted at ℃. This was stirred for 3 hours under reduced pressure (400 Pa) with stirring. Residual moisture was 200 ppm.
The temperature was lowered to 70 ° C., and the flask was filled with 103 kPa of nitrogen. 300 ppm of BHT (di-tert-butylhydroxytoluene) was added as an antioxidant. While stirring the flask, 1.208 g of dihydroxy compound 2 obtained in Synthesis Example 2 and 3.995 g of hexamethylene diisocyanate (manufactured by Tokyo Chemical Industry Co., Ltd.) were charged (NCO / OH = 0.955 mol). / Mol). When 0.05 g of DBTDL was added as a catalyst, the viscosity increased rapidly in about 10 minutes. Stirring was stopped and the reaction was carried out at 70 ° C. for 2 hours, and then the temperature was raised to 120 ° C. and kept at a constant temperature for 30 minutes to obtain a polyalkylene polyol derivative 3 having a melting point of about 60 ° C.

[Synthesis Example 6] Synthesis of polyalkylene polyol derivative 4 Dihydroxy compound 2 and hexamethylene didioxide 2 / polyethylene glycol = 0.80 (mass%) and NCO / OH = 0.955 (molar ratio). A polyalkylene polyol derivative 4 was obtained in the same manner as in Synthesis Example 5 except that the amount of isocyanate was changed.

Synthesis Example 7 Synthesis of Polyalkylene Polyol Derivative 5 Dihydroxy Compound 2 and Hexamethylene Di Dioxide Compound 2 / Polyethylene Glycol = 0.50 (mass%) and NCO / OH = 0.955 (Molar Ratio) A polyalkylene polyol derivative 5 was obtained in the same manner as in Synthesis Example 5 except that the amount of isocyanate was changed.

  About the polyalkylene polyol derivatives obtained in Synthesis Examples 3 to 7, dihydroxy compound / polyethylene glycol (mass%), NCO / OH (molar ratio), U-1 / U-2 (molar ratio), weight average molecular weight and 2 The mass% aqueous solution viscosity is summarized in Table 1 below.

In Table 1, the weight average molecular weight and the 2 mass% aqueous solution viscosity were determined by the following methods.
(1) Weight average molecular weight It is the pullulan conversion value of the value measured on condition of the following using gel permeation chromatography (GPC-MALLS, Showa Denko Co., Ltd. product).
Detector: DAWN-DSP, Shodex RI-71, all manufactured by Showa Denko KK Column used: Shodex SB-806MHQ, Showa Denko KK Solvent used: 0.1M NaNO ₃
Measurement temperature: 40 ° C
(2) 2 mass% aqueous solution viscosity 2 mass% aqueous solution was prepared about each polyoxyalkylene polyol derivative, and the viscosity of the said aqueous solution in 20 degreeC was measured at 10 rpm using BH type | mold viscosity meter.

[Examples 1 to 8] Preparation of sustained-release composition Water-soluble cellulose ethers having different weight average molecular weights shown in Table 2 shown in Table 2 and the polyalkylene polyol derivatives shown in Table 1 (all Shin-Etsu Chemical Co., Ltd.) Are used in the combinations shown in Table 3, and 50 g of a 2% by weight aqueous solution of water-soluble cellulose ether is added to and mixed with 50 g of the polyalkylene polyol derivative, if necessary, and then bentonite (Kunibond, manufactured by Kunimine Kogyo Co., Ltd.). 50 g was added, and the mixture was placed in a 2 L container of a homogenizer (manufactured by Nippon Seiki Co., Ltd.) and stirred at 1,000 rpm. After granulating to a particle size of about 1 to 5 mm, it is dried using a fluidized bed dryer (midget dryer) at an exhaust temperature of 100 ° C., and the resulting granule is sieved with a wire mesh having a 5 mm opening to be coarse. The sized granule which consists of a sustained release composition except a grain was prepared.

[Comparative Example 1]
Granules were dried and sized in the same manner as in Example 1 with water alone without using a polyalkylene polyol derivative and a water-soluble cellulose ether to prepare sized granules.

  In Table 2, the weight average molecular weight was measured under the same conditions as described above. Moreover, the 2 mass% aqueous solution viscosity was measured on the same conditions as the above with a BH type viscometer.

[Examples 9 to 16 and Comparative Example 2] Preparation of sustained-release preparation The granules obtained in Examples 1 to 8 and Comparative Example 1 were immersed in vitamin C solution for 1 hour, and then the granules were dried in a 40 ° C dryer. Then, dry granules containing vitamin C were prepared to obtain a sustained-release preparation.
Place in the artificial gastric juice (35 ° C) described in the 14th revised Japanese Pharmacopoeia, and monitor the yellow color change of vitamin C eluting to the artificial gastric juice while stirring with a color meter (manufactured by Suga Test Instruments Co., Ltd.). As a result of the measurement, in the sustained release preparations of Examples 9 to 16, it was confirmed that the yellow color development gradually increased in 6 hours. Slow release was not observed. Table 4 shows the time when the yellow color change disappeared for the preparations of Examples 9 to 16 and Comparative Example 2.

[Example 17]
50 parts by mass of the powder of polyalkylene polyol derivative 1 in Table 1 (average particle size 60 μm) is added to 50 parts by mass of acetaminophen, and tablets with a diameter of 10 mm and a thickness of 5 mm are continuously tableted tester (manufactured by Kikusui Seisakusho). Prepared. According to the 14th revised Japanese Pharmacopoeia measurement of elution rate with artificial gastric juice, the time until elution was completed was 4 hours. The average particle size is a value measured by a fully automatic low-tap particle size distribution measuring device (manufactured by Seishin Enterprise Co., Ltd.).

[Example 18]
A tablet was prepared in the same manner as in Example 17 with respect to the sustained release composition prepared by mixing the powder of polyalkylene polyol derivative 1 in Table 1 (average particle size 60 μm) and hydroxypropylmethylcellulose at 1: 1 (mass ratio). When it was molded and subjected to a dissolution test, the time until the dissolution was completed was 6 hours.

[Comparative Example 3]
Except for using pregelatinized starch (manufactured by Matsutani Chemical Co., Ltd.) instead of the polyalkylene polyol derivative, a tablet was molded and the dissolution test was conducted in the same manner as in Example 17, but the dissolution was completed in about 15 minutes. The intended continuous preparation could not be obtained.

[Example 19]
The same procedure as in Example 5 was performed except that 7 g of the water-soluble polyalkylene polyol derivative was mixed with 100 g of a 3.0% aqueous solution of water-soluble cellulose ether and 50 g of bentonite (Kunibond Kunimine Kogyo Co., Ltd.) was added and mixed. To prepare granulated granules. The obtained granules were immersed in a vitamin C solution for 1 hour in the same manner as in Examples 9 to 16 and then put in a 40 ° C. dryer to prepare dry granules containing vitamin C. The time when the yellowing disappeared was measured. 8 hours, and it was confirmed that the release was sustained.

Claims (5)

It has a repeating unit U-1 represented by the general formula (1) and a repeating unit U-2 represented by the general formula (2), and U-1 / U-2 = 0.5 / 0.5 to 0.99. A sustained-release composition comprising a polyalkylene polyol derivative having a ratio of /0.01 (molar ratio).

[In the formula, A is a divalent polyoxyalkylene residue derived from a water-soluble polyalkylene polyol represented by HO-A-OH having hydroxyl groups at both ends and having a number average molecular weight of 400 to 100,000. Indicates. B represents a divalent organic residue derived from a polyisocyanate having a total carbon number of 3 to 18 represented by OCN-B-NCO. D represents a divalent organic residue derived from a dihydroxy compound selected from the following general formulas (3) to (5).

(In the formula, R ¹ and R ⁴ are unsubstituted or halogen-substituted monovalent hydrocarbon groups having 1 to 20 carbon atoms, and R ² , R ³ , R ⁵ and R ⁶ may be the same or different from each other. 21 to 21 unsubstituted or halogen-substituted monovalent hydrocarbon group, Y and Y ′ may be the same or different from each other, hydrogen atom, methyl group or CHCl ₂ group, Z and Z ′ are oxygen atom, sulfur atom or CH ₂ N is an integer of 0 to 15 when Z is an oxygen atom, 0 when Z is a sulfur atom or a CH ₂ group, and n ′ is an integer of 0 to 15 when Z ′ is an oxygen atom. , Z ′ is 0 when it is a sulfur atom or a CH ₂ group, n and n ′ may be the same or different. X, X ′ and X ″ may be the same or different from each other 10 alkylene group, R ⁷ is an alkylene group having 2 to 10 carbon atoms, k is an integer of 0 to 15. R ⁸ and R ⁹ may be the same or different from each other, and the total carbon number thereof is a monovalent hydrocarbon group having 2 to 20 carbon atoms, and R ¹⁰ and R ¹¹ may be the same or different from each other. 21 monovalent hydrocarbon groups, R ¹² is an alkylene group having 2 to 7 carbon atoms.)] The sustained-release composition according to claim 1, wherein the dihydroxy compound represented by the general formula (3) or (4) is a dihydroxy compound represented by the general formula (6) or (7).

[Wherein R ¹³ is a linear or branched alkyl group having 4 to 18 carbon atoms, and R ¹⁴ and R ¹⁵ are linear or branched alkyl groups having 4 to 18 carbon atoms which may be the same or different from each other. R ¹⁶ is an alkyl group having 1 to 18 carbon atoms, and R ¹⁷ and R ¹⁸ are the same unsubstituted or halogen-substituted monovalent hydrocarbon group having 4 to 21 carbon atoms. R ¹⁹ is a 1,2-ethylene group, a 1,3-propylene group or a 1,4-butylene group. ]   Furthermore, water-soluble cellulose ether is included, The sustained release composition of Claim 1 or 2 characterized by the above-mentioned.   The sustained-release composition according to claim 3, wherein the water-soluble cellulose ether is alkyl cellulose or hydroxyalkyl alkyl cellulose.   A sustained-release preparation comprising the sustained-release composition according to any one of claims 1 to 4.