JPH041139A - Sustained release drug composition - Google Patents
Sustained release drug compositionInfo
- Publication number
- JPH041139A JPH041139A JP9929090A JP9929090A JPH041139A JP H041139 A JPH041139 A JP H041139A JP 9929090 A JP9929090 A JP 9929090A JP 9929090 A JP9929090 A JP 9929090A JP H041139 A JPH041139 A JP H041139A
- Authority
- JP
- Japan
- Prior art keywords
- drug
- organic solvent
- chitosan
- water
- alkylene oxide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 24
- 229940079593 drug Drugs 0.000 title claims abstract description 23
- 239000000203 mixture Substances 0.000 title claims abstract description 11
- 238000013268 sustained release Methods 0.000 title claims description 7
- 239000012730 sustained-release form Substances 0.000 title claims description 7
- 229920001661 Chitosan Polymers 0.000 claims abstract description 20
- 229920002101 Chitin Polymers 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000000397 acetylating effect Effects 0.000 claims abstract description 5
- 239000011159 matrix material Substances 0.000 claims abstract description 5
- 238000004132 cross linking Methods 0.000 claims abstract description 4
- 125000003277 amino group Chemical group 0.000 claims abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 10
- 239000003431 cross linking reagent Substances 0.000 abstract description 6
- 239000002245 particle Substances 0.000 abstract description 6
- 235000019621 digestibility Nutrition 0.000 abstract description 5
- 238000006640 acetylation reaction Methods 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 abstract description 4
- 230000021736 acetylation Effects 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 230000007935 neutral effect Effects 0.000 abstract description 2
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 abstract 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 5
- 102000016943 Muramidase Human genes 0.000 description 3
- 108010014251 Muramidase Proteins 0.000 description 3
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000004325 lysozyme Substances 0.000 description 3
- 229960000274 lysozyme Drugs 0.000 description 3
- 235000010335 lysozyme Nutrition 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 239000012345 acetylating agent Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- WQJONRMBVKFKOB-UHFFFAOYSA-N cyanatosulfanyl cyanate Chemical compound N#COSOC#N WQJONRMBVKFKOB-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 229940054190 hydroxypropyl chitosan Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Compositions Of Macromolecular Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、キチン・キトサン誘導体を使用した薬剤組成
物に関し、該薬剤組成物は医薬等広い分野で使用可能で
ある。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a pharmaceutical composition using chitin/chitosan derivatives, and the pharmaceutical composition can be used in a wide range of fields such as medicine.
（従来の技術）
キチンはそれ自体非常にゆっくりであるが生体内消化性
を示すため、キチンを用いた薬剤組成物を製造すれば徐
放性薬剤となる可能性がある。しかしキチンは強固な結
晶構造のため溶解性が低く成形等の取扱いが難しい。(Prior Art) Chitin itself is very slowly digestible in the body, so if a pharmaceutical composition using chitin is produced, it may become a sustained-release drug. However, chitin has a strong crystalline structure, has low solubility, and is difficult to handle, such as by molding.
一方、キトサンを用いた薬剤組成物としてはキトサンの
酢酸塩を酸性条件下、架橋剤を用い架橋し薬剤を包接し
たものが知られているが、キトサンは酸性塩にしないと
溶解度が小さいため、耐酸性の薬剤に限定される等の問
題点を有している。On the other hand, as a pharmaceutical composition using chitosan, it is known that the acetate of chitosan is cross-linked using a cross-linking agent under acidic conditions to include the drug, but chitosan has low solubility unless it is made into an acid salt. However, it has problems such as being limited to acid-resistant drugs.
（課題を解決するための手段）
本発明者等はキチン・キトサン該誘導体を用いた徐放性
薬剤を鋭意研究した結果、水及び有機溶媒可溶性キトサ
ン誘導体を用いることにより、種々の薬剤を包接てきる
こと及び該包接したものをアセチル化することにより生
体内消化性か発現することを見出し本発明を完成した。(Means for Solving the Problems) As a result of intensive research into sustained-release drugs using chitin and chitosan derivatives, the present inventors have found that various drugs can be encapsulated by using water- and organic solvent-soluble chitosan derivatives. The present invention was completed based on the discovery that in vivo digestibility can be achieved by acetylating the clathrate.
即ち、本発明は水及び有機溶媒可溶性キトサン誘導体を
化学的に架橋して生成するマトリックス中に薬剤を包接
させた後、残存するアミノ基をアセチル化することを特
徴とする徐放性薬剤組成物である。That is, the present invention provides a sustained-release drug composition characterized by including a drug in a matrix produced by chemically crosslinking a water- and organic solvent-soluble chitosan derivative, and then acetylating the remaining amino groups. It is a thing.
水及び有機溶媒可溶性キトサン誘導体としてはキチン・
キトサンをアルキレンオキシドでエーテル化して得られ
るアルキレンオキシドの平均付加モル数１以上のヒドロ
キシアルキルキトサン誘導体が挙げられる。As a water and organic solvent soluble chitosan derivative, chitin
Examples include hydroxyalkyl chitosan derivatives having an average number of added moles of alkylene oxide of 1 or more, which are obtained by etherifying chitosan with alkylene oxide.
その中で、ヒドロキシプロピルキトサン（以下、ＨＰＣ
Ｈと言う。）、ヒドロキシエチルヒドロキシプロピルキ
トサン、ヒドロキシプロピルヒドロキシブチルキトサン
のアルキレンオキシドの平均付加モル数２以上のものが
特に好ましい。Among them, hydroxypropyl chitosan (hereinafter referred to as HPC)
Say H. ), hydroxyethylhydroxypropylchitosan, and hydroxypropylhydroxybutylchitosan in which the average number of moles of alkylene oxide added is 2 or more are particularly preferred.
マトリックス中に包接する薬剤としてはアントリン等の
ホルモン剤をはじめ種々の薬剤が使用できる。Various drugs including hormones such as antolin can be used as drugs to be included in the matrix.
架橋剤としてはグルタルアルデヒド等のジアルデヒド類
をはじめジハロカルボン酸類、ジ（チオ）シアネート順
算通常の架橋剤か使用できる。As the crosslinking agent, common crosslinking agents such as dialdehydes such as glutaraldehyde, dihalocarboxylic acids, and di(thio)cyanate can be used.
以下、キトサン誘導体としてＨＰＣＨを例にして本発明
を説明する。ＨＰＣＨを水等の溶剤に溶解し、この溶液
に薬剤を加え混合する。この溶液に架橋剤を加え、０〜
室温で数時間から数１０時間撹拌する。生成したゲルを
粉砕し、粒径を調節した後エタノール等の溶剤に懸濁さ
せ、無水酢酸等でアセチル化し、通常の後処理を行い目
的の組成物を得る。Hereinafter, the present invention will be explained using HPCH as an example of a chitosan derivative. HPCH is dissolved in a solvent such as water, and a drug is added to this solution and mixed. Add a crosslinking agent to this solution and
Stir at room temperature for several hours to several tens of hours. The resulting gel is pulverized and the particle size is adjusted, then suspended in a solvent such as ethanol, acetylated with acetic anhydride, etc., and subjected to usual post-treatment to obtain the desired composition.
ＨＰＣＨと薬剤、架橋剤との量比は任意に変更が可能で
あり、また、アセチル化剤の量を変化させることにより
、生体内消化性の速度も調節することができる。The amount ratio of HPCH, drug, and crosslinking agent can be changed arbitrarily, and the rate of in vivo digestibility can also be adjusted by changing the amount of the acetylating agent.
（実施例）
次に実施例を挙げ、本発明を更に詳細に説明するが本発
明は実施例に限定されるものでない。(Example) Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the Examples.
実施例１
ヒドロキシプロピル−キトサン−２（ＨＰＣＨ２）１．
５ｇを４０艷の脱イオン水に溶解し、これにアントリン
−１０液（１０■／２ｄ生理食塩水）２−を加え４℃で
１時間撹拌した。これにグルタルアルデヒド生理食塩水
溶液０．５ｒＲ１を加え更に撹拌後４°Ｃで一夜静置す
る。生成したゲルを８０−のエタノール中へ入れマイク
ロデイスペンサーで１分間ゲルを粉砕し、粒子径を調節
した。エタノールで充分洗滌後エタノール８０−に再懸
濁させ、氷水で冷却しながら無水酢酸０．５４を加え１
．５時間撹拌しＮ−アセチル化を行った。６０＋＋ｔｔ
’のア七トンを加え遠心分離で沈澱を集め、遠心分離で
アセトン洗滌をくり返しアントリンの吸収（２６６閣）
が無くなるまで続け、次いでエーテル洗滌、風乾粒子径
０．２〜０．７−の組成物を得た。Example 1 Hydroxypropyl-chitosan-2 (HPCH2)1.
5 g was dissolved in 40 liters of deionized water, and antolin-10 solution (10 ml/2 d physiological saline) was added thereto and stirred at 4°C for 1 hour. To this was added 0.5rR1 of a glutaraldehyde physiological saline solution, and after further stirring, the mixture was allowed to stand overnight at 4°C. The resulting gel was placed in 80-mL ethanol, and the gel was crushed for 1 minute using a microdispenser to adjust the particle size. After thoroughly washing with ethanol, resuspend in 80-mL ethanol, and add 0.54-mL of acetic anhydride while cooling with ice water.
．． N-acetylation was performed by stirring for 5 hours. 60++tt
' Add A7T, collect the precipitate by centrifugation, and repeat washing with acetone by centrifugation to absorb anthrin (266 Kaku)
The process was continued until the particles disappeared, and then washed with ether and air-dried to obtain a composition having a particle size of 0.2 to 0.7.
実施例２
３．０ｇのＨＰＣＨ−２を５０−の脱イオン水に溶解し
、アントリンｌＯ■／２−生理食塩水溶液２１ｎＩを加
え実施例１と同条件下で処理、１．０−の無水酢酸を用
いたアセチル化し、粒子径０．２〜０，７Ｍの組成物を
得た。Example 2 3.0 g of HPCH-2 was dissolved in 50-deionized water, 21 nI of anthrin 1O/2-physiological saline solution was added and treated under the same conditions as in Example 1, and 1.0-acetic anhydride was dissolved. Acetylation was performed using the following to obtain a composition having a particle size of 0.2 to 0.7M.
徐放性測定
前記実施例１と２で得た乾燥粉末２４■を５ｒｎｌのＡ
ｃｅｔａｔｅ ｂｕｆｆｅｒ（ｐＨ６，２）に懸濁し、
３７°Ｃて１ｎｃｕｂａｔｅした。（盲検＝ ｂｌａｎ
ｋ）
一方粉末２４■を４．８５１ｄ！のＡｃｅｔａｔｅ ｂ
ｕｆｆｅｒ（ｐＨ６，２）に懸濁し、３７℃で卵白リゾ
チーム水溶液（２，３２Ｘ１０’ ｕｎｉｔ／１ｄりを
加え担体の消化反応を開始させ液中に放出されるアント
リン量の時間変化を２６６闘の吸収で２５０時間に亙っ
て追跡した。（第１図）いずれも盲検（未消化）より高
いアントリン放出を示している。尚消化反応に用いたリ
ゾチーム量は手筋内申のりゾチーム量を反映させたもの
である。Sustained release measurement 24 cm of the dry powder obtained in Examples 1 and 2 above was added to 5 rnl of A.
Suspended in cetate buffer (pH 6,2),
It was incubated for 1 incubation at 37°C. (blind = blan
k) On the other hand, powder 24■ is 4.851d! Acetate b
buffer (pH 6,2), add an aqueous egg white lysozyme solution (2,32 x 10' units/1 d) at 37°C to start the digestion reaction of the carrier, and observe the time change in the amount of anthrin released into the solution for 266 hours. (Fig. 1) Both showed higher release of anthrin than the blinded (undigested) test.The amount of lysozyme used in the digestion reaction was adjusted to reflect the amount of lysozyme in the hands. It is something.
（発明の効果）
本発明は水及び有機溶媒可溶性キトサン誘導体を使用す
ることにより、中性あるいは有機溶媒中で薬剤をマトリ
ックス中に包接できるため、耐酸性が無く、従来包接す
ることが困難であった薬剤も使用が可能となつかばかり
てなく、架橋度アセチル化度を調節することにより、生
体内消化性もコントロールか可能な優れた徐放性薬剤組
成物である。(Effects of the Invention) The present invention uses water and organic solvent soluble chitosan derivatives to encapsulate drugs in a matrix in neutral or organic solvents. It is an excellent sustained-release drug composition that not only allows the use of conventional drugs, but also allows control of in vivo digestibility by adjusting the degree of crosslinking and acetylation.
第１図はアントリン量の放出速度を示したグラフである
。FIG. 1 is a graph showing the release rate of the amount of antolin.
Claims (3)
架橋して生成するマトリックス中に薬剤を包接させた後
、残存するアミノ基をアセチル化することを特徴とする
徐放性薬剤組成物。(1) A sustained-release drug composition characterized by including a drug in a matrix produced by chemically crosslinking a water- and organic solvent-soluble chitosan derivative, and then acetylating the remaining amino groups.
びキトサンをアルキレンオキシドでエーテル化して得ら
れるヒドロキシアルキルキトサン誘導体である特許請求
の範囲第１項記載の薬剤組成物。(2) The pharmaceutical composition according to claim 1, wherein the water and organic solvent soluble chitosan derivative is a hydroxyalkyl chitosan derivative obtained by etherifying chitin and chitosan with an alkylene oxide.
あるヒドロキシアルキルキトサン誘導体である特許請求
の範囲第１項又は第２項記載の薬剤組成物。(3) The pharmaceutical composition according to claim 1 or 2, which is a hydroxyalkyl chitosan derivative having an average number of added moles of alkylene oxide of 1 or more.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9929090A JPH041139A (en) | 1990-04-17 | 1990-04-17 | Sustained release drug composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9929090A JPH041139A (en) | 1990-04-17 | 1990-04-17 | Sustained release drug composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH041139A true JPH041139A (en) | 1992-01-06 |
Family
ID=14243513
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9929090A Pending JPH041139A (en) | 1990-04-17 | 1990-04-17 | Sustained release drug composition |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH041139A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000027889A1 (en) * | 1998-11-10 | 2000-05-18 | Netech Inc. | Functional chitosan derivative |
| WO2005100468A1 (en) * | 2004-03-31 | 2005-10-27 | Dainichiseika Color & Chemicals Mfg. Co., Ltd. | Temperature-responsiive composition and hydrogel thereof |
-
1990
- 1990-04-17 JP JP9929090A patent/JPH041139A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000027889A1 (en) * | 1998-11-10 | 2000-05-18 | Netech Inc. | Functional chitosan derivative |
| WO2005100468A1 (en) * | 2004-03-31 | 2005-10-27 | Dainichiseika Color & Chemicals Mfg. Co., Ltd. | Temperature-responsiive composition and hydrogel thereof |
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