JPH029821A - Aqueous suspension composition of macrolide antibiotic - Google Patents
Aqueous suspension composition of macrolide antibioticInfo
- Publication number
- JPH029821A JPH029821A JP15925688A JP15925688A JPH029821A JP H029821 A JPH029821 A JP H029821A JP 15925688 A JP15925688 A JP 15925688A JP 15925688 A JP15925688 A JP 15925688A JP H029821 A JPH029821 A JP H029821A
- Authority
- JP
- Japan
- Prior art keywords
- aqueous suspension
- amorphous solid
- sucrose
- composition
- suspension composition
- 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.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 85
- 239000003120 macrolide antibiotic agent Substances 0.000 title claims abstract description 14
- 239000007900 aqueous suspension Substances 0.000 title claims description 67
- 239000007787 solid Substances 0.000 claims abstract description 46
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims abstract description 32
- 229930006000 Sucrose Natural products 0.000 claims abstract description 32
- 239000005720 sucrose Substances 0.000 claims abstract description 31
- 229920000642 polymer Polymers 0.000 claims abstract description 10
- 229920002678 cellulose Polymers 0.000 claims abstract description 9
- 239000001913 cellulose Substances 0.000 claims abstract description 9
- 239000000843 powder Substances 0.000 claims abstract description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 abstract description 21
- 239000006188 syrup Substances 0.000 abstract description 9
- 235000020357 syrup Nutrition 0.000 abstract description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 abstract description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 abstract description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 abstract description 6
- 238000001879 gelation Methods 0.000 abstract description 4
- 238000003860 storage Methods 0.000 abstract description 4
- 230000003115 biocidal effect Effects 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 229920003169 water-soluble polymer Polymers 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 25
- 239000007864 aqueous solution Substances 0.000 description 22
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 20
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 20
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 20
- 239000000499 gel Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000001856 Ethyl cellulose Substances 0.000 description 10
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 10
- 235000019325 ethyl cellulose Nutrition 0.000 description 10
- 229920001249 ethyl cellulose Polymers 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 230000008014 freezing Effects 0.000 description 7
- 238000007710 freezing Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000000859 sublimation Methods 0.000 description 7
- 230000008022 sublimation Effects 0.000 description 7
- 238000002156 mixing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229920002125 Sokalan® Polymers 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- DMUAPQTXSSNEDD-QALJCMCCSA-N Midecamycin Chemical compound C1[C@](O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C DMUAPQTXSSNEDD-QALJCMCCSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229960002757 midecamycin Drugs 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- OIQPTROHQCGFEF-UHFFFAOYSA-L chembl1371409 Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-UHFFFAOYSA-L 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は医薬品用組成物に１系り、殊にマクロライド系
抗生物質の水懸濁組成物に係る。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to pharmaceutical compositions, and particularly to aqueous suspension compositions of macrolide antibiotics.
（従来の技術及び課題〉
マクロライド系抗生物質は中範囲の抗菌スペクトルを有
しており、経口投与により吸収され、毒性が低いために
有用な抗生物質として汎用され、殊に小児用に多く使用
されている。(Prior art and problems) Macrolide antibiotics have a mid-range antibacterial spectrum, are absorbed by oral administration, and have low toxicity, so they are widely used as useful antibiotics, and are often used especially for children. has been done.
小児用として用いられる場合に、この種の抗生物質は通
例ドライシロップ剤又はシロップ剤として製剤化される
が、シロップ剤の方が嗜好性において潰れている。マク
ロライド系抗生物質の非晶質固体粉末を用いて慣用の方
法によりシロップ剤として製剤化する場合に、即ち甘味
料としての白糖を含有する水溶液に非晶質固体原末を添
加し、分散させることにより水懸濁物になした場合に、
この懸濁物は調製当初においては流動性を有しているが
経時的にゲル状態に変１ヒして流動性が失われる点に課
題３有していた。このゲル化は、保存温度が高い程早期
に生じる。When used for pediatric use, antibiotics of this type are typically formulated as dry syrups or syrups, but syrups are less palatable. When formulating a syrup by a conventional method using an amorphous solid powder of a macrolide antibiotic, the amorphous solid bulk powder is added to an aqueous solution containing white sugar as a sweetener and dispersed. When formed into an aqueous suspension,
This suspension has a problem 3 in that although it has fluidity at the beginning of preparation, it changes into a gel state over time and loses its fluidity. This gelation occurs earlier as the storage temperature is higher.
（課題を解決する手段及び作用）
本発明者等は、上記の課題を解決するために鋭意検討を
重ねた結果、意外にも、マクロライド系抗生物質の非晶
質固体原末に、水溶性セルロース系ポリマーと蔗糖とが
組み合わされて配合されている、マクロライド系抗生物
質の水懸濁組成物は長期間保存しても安定であり、ゲル
化しないことを見い出して本発明を完成するに至った。(Means and Effects for Solving the Problems) As a result of intensive studies to solve the above problems, the present inventors unexpectedly discovered that water-soluble The present invention was accomplished by discovering that an aqueous suspension composition of a macrolide antibiotic, which is formulated by combining a cellulose polymer and sucrose, is stable even when stored for a long period of time and does not gel. It's arrived.
本発明による水懸濁組成物を調製する場合に用いられる
水溶性セルロース系ポリマーとしては、ハイドロオキシ
プロピルメチルセルロース、ハイドロオキシプロピルセ
ルロース等を例示することができる。本発明による水懸
濁組成物におけるマクロライド系抗生物質と、水溶性セ
ルロース系ポリマーと、蔗糖との量割合は選択された抗
生物質やポリマーの種類等に依存して異なるが、一般的
にはマクロライド系抗生物質の非晶質固体原末２重量％
に対して、水溶性セルロース系ポリマーが０．７−１．
５重量％、蔗糖が２０−４０重量％程度であるのが好ま
しい。Examples of the water-soluble cellulosic polymer used in preparing the aqueous suspension composition of the present invention include hydroxypropylmethylcellulose and hydroxypropylcellulose. The proportions of the macrolide antibiotic, water-soluble cellulose polymer, and sucrose in the aqueous suspension composition of the present invention vary depending on the selected antibiotic and the type of polymer, but in general, Macrolide antibiotic amorphous solid bulk powder 2% by weight
In contrast, the water-soluble cellulose polymer has a molecular weight of 0.7-1.
It is preferable that the amount of sugar is 5% by weight, and the amount of sucrose is about 20-40% by weight.
尚、本発明による水懸濁組成物を製剤化してシロップ剤
になす場合には芳香剤、着色剤、保存剤、安定剤、懸濁
化剤、粘稠化剤等の通例の添加物を配合することができ
る。When formulating the aqueous suspension composition of the present invention into a syrup, conventional additives such as fragrances, colorants, preservatives, stabilizers, suspending agents, and thickening agents may be added. can do.
（製造例等）
次に、製造例及び比較例により本発明を更に具体的に説
明する。(Manufacturing Examples, etc.) Next, the present invention will be explained in more detail using manufacturing examples and comparative examples.
遣 ｌ び １
１Ｏ−アセチル−３″〜アセチルミデカマイシン （商
品名：ミオカマイシン） １０ｇを、エチルセルロース
１ｇ含有ジオキサン溶液１００１に溶解させた。この溶
液を一４０℃で凍結させた後に、１００ｍｍｔ１ｇ以下
の減圧下で溶媒を昇華除去して ｌＯ−アセチル−３″
−アセチルミデカマイシンの完全な非晶質固体を得た。10g of 10-acetyl-3''~acetylmidecamycin (trade name: myocamycin) was dissolved in dioxane solution 1001 containing 1g of ethylcellulose.After freezing this solution at -40°C, 100mmt of 1g or less was dissolved. The solvent was removed by sublimation under reduced pressure to obtain lO-acetyl-3″
- Completely amorphous solid of acetylmidecamycin was obtained.
この非晶質固体２ｇを採取し、ハイドロオキシ１０ビル
メチルセルロース０．５ｇ及び蔗糖３０ｇを含有する水
溶液１００ｍ１中に添加し混合して充分に分散させるこ
とにより水懸濁組成物を得た。2 g of this amorphous solid was collected, added to 100 ml of an aqueous solution containing 0.5 g of hydroxy-10-vinyl methylcellulose and 30 g of sucrose, and mixed and sufficiently dispersed to obtain an aqueous suspension composition.
この水懸濁組成物を２５°Ｃ及び４０℃の温度条件下で
それぞれ１年間保存した後に調べた処、依然として安定
な水懸濁状態を維持していた。When this aqueous suspension composition was stored for one year at 25°C and 40°C, it was found to still maintain a stable aqueous suspension state.
一方、ハイドロオキシプロピルメチルセルロース及び蔗
糖を含有しない単なる水に上記の非晶質固体を上記と同
様に分散させて水懸濁組成物（対照組成物）を調製した
。この対照組成物を２５℃の温度条件下に保存した処、
２４時間後にはゲル状態を呈していた。On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in plain water containing neither hydroxypropyl methyl cellulose nor sucrose in the same manner as above. When this control composition was stored under a temperature condition of 25°C,
After 24 hours, it was in a gel state.
リム
１０−アセチル−３゛−アセチルミデカマイシン ｌＯ
ｇをジオキサン溶液１００１に溶解させた。この溶液を
一４０℃で凍結させた後に、１００ ｍｍＨｇ以下の減
圧下で溶媒を昇華除去して ｌＯ−アセチル−３°゛−
アセチルミデカマイシンの完全な非晶質固体を得た。Rim 10-acetyl-3'-acetylmidecamycin lO
g was dissolved in dioxane solution 1001. After freezing this solution at -40°C, the solvent was removed by sublimation under reduced pressure of 100 mmHg or less to obtain lO-acetyl-3°-
A completely amorphous solid of acetylmidecamycin was obtained.
この非晶質固体２ｇを採取し、ハイドロオキシプロピル
メチルセルロース０．５ｇ、蔗糖１５ｇ及びアクリル酸
重合体０．０５ｇを含有する水溶液１００１中に添加し
混合して充分に分散させることにより水懸濁組成物を得
た。Collect 2 g of this amorphous solid, add it to an aqueous solution 1001 containing 0.5 g of hydroxypropyl methylcellulose, 15 g of sucrose, and 0.05 g of an acrylic acid polymer, mix it, and fully disperse it to form an aqueous suspension. I got something.
この水懸濁組成物を２５°Ｃ及び４０°Ｃの温度条件下
でそれぞれ１年間保存した後に調べた処、依然として安
定な水懸濁状態を維持していた。When this aqueous suspension composition was stored for one year under temperature conditions of 25°C and 40°C, it was examined and found to still maintain a stable aqueous suspension state.
一方、ハイドロオキシプロピルメチルセルロース、蔗糖
及びアクリル酸重合体を含有しない単なる水に上記の非
晶質固体を上記と同様に分散させて水懸濁組成物（対照
組成物）を調製した。この対照組成物を２５°Ｃの温度
条件下に保存した処、２４時間後にはゲル状態を呈して
いた。On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in plain water not containing hydroxypropyl methylcellulose, sucrose, and acrylic acid polymer in the same manner as above. When this control composition was stored under a temperature condition of 25°C, it exhibited a gel state after 24 hours.
１″１ ３ ３
１０−アセチル−３゛−アセチルミデカマイシン １０
ｇを、エチルセルロース１ｇ含有ジクロロメタン溶液１
００１に溶解させた。この溶液を常法により噴霧乾燥さ
せて ｌＯ−アセチル−３゛−アセチルミデカマイシン
の完全な非晶質固体を得た。1″1 3 3 10-acetyl-3′-acetylmidecamycin 10
g, dichloromethane solution containing 1 g of ethyl cellulose 1
001. This solution was spray-dried in a conventional manner to obtain a completely amorphous solid of lO-acetyl-3'-acetylmidecamycin.
この非晶質固体２ｇを採取し、ハイドロオキシプロピル
メチルセルロース１．０ｇ及び蔗糖４０ｇを含有する水
溶液１００ｍ１中に添加し混合して充分に分散させるこ
とにより水懸濁組成物を得た。2 g of this amorphous solid was collected, added to 100 ml of an aqueous solution containing 1.0 g of hydroxypropyl methylcellulose and 40 g of sucrose, and mixed and sufficiently dispersed to obtain an aqueous suspension composition.
この水懸濁組成物を２５°Ｃ及び４０’Ｃの温度条件下
でそれぞれ１年間保存した後に調べた処、依然として安
定な水懸濁状態を維持していた。When this aqueous suspension composition was stored for one year under temperature conditions of 25°C and 40'C, it was examined and found to still maintain a stable aqueous suspension state.
一方、ハイドロオキシプロピルメチルセルロース及び蔗
糖を含有しない単なる水に上記の非晶質固体を上記と同
様に分散させて水懸濁組成物（対照組成物）を調製した
。この対照組成物を２５℃の温度条件下に保存した処、
２４時間後にはゲル状態を呈していた。On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in plain water containing neither hydroxypropyl methyl cellulose nor sucrose in the same manner as above. When this control composition was stored under a temperature condition of 25°C,
After 24 hours, it was in a gel state.
り造 ４ び ４
１Ｏ−アセチル−３′−アセチルミデカマイシン ｌＯ
ｇを、エチルセルロース１ｇ含有ジクロロメタン溶液１
００１に溶解させた。この溶液を常法により噴霧乾燥さ
せて １０−アセチル−３パ−アセチルミデカマイシン
の完全な非晶質固体を得た。Reconstruction 4 and 4 1O-acetyl-3'-acetylmidecamycin 1O
g, dichloromethane solution containing 1 g of ethyl cellulose 1
001. This solution was spray-dried in a conventional manner to obtain a completely amorphous solid of 10-acetyl-3-per-acetylmidecamycin.
この非晶質固体ハを採取し、ハイドロオキシプロピルメ
チルセルロース１．Ｏｇ及び蔗糖３５ｇを含有する水溶
液１００ｍ１中に添加し混合して充分に分散させること
により水懸濁組成物を得た。This amorphous solid was collected and hydroxypropyl methyl cellulose 1. An aqueous suspension composition was obtained by adding the mixture to 100 ml of an aqueous solution containing Og and 35 g of sucrose, mixing and thoroughly dispersing it.
この水懸濁組成物を２５°Ｃ及び４０℃の温度条件下で
それぞれ１年間保存した後に調べた処、依然として安定
な水懸濁状態を維持していた。When this aqueous suspension composition was stored for one year at 25°C and 40°C, it was found to still maintain a stable aqueous suspension state.
一方、ハイドロオキシプロピルメチルセルロース及び蔗
糖を含有しない単なる水に上記の非晶質固体を上記と同
様に分散させて水懸濁組成物（対照組成物）を調製した
。この対照組成物を２５℃の温度条件下に保存した処、
２４時間後にはゲル状態を呈していた。On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in plain water containing neither hydroxypropyl methyl cellulose nor sucrose in the same manner as above. When this control composition was stored under a temperature condition of 25°C,
After 24 hours, it was in a gel state.
製」Ｌ伊 ５ び ５
１０−アセチル−３″−アセチルミデカマイシン ｌＯ
ｇを、エチルセルロ−ス
液１ ０ ０ ｍ ｌに溶解させた。この溶液を常法に
より噴霧乾燥させて １０−アセチル−３°゛−アセチ
ルミデカマイシンの完全な非晶質固体を得た。10-acetyl-3″-acetylmidecamycin 1O
g was dissolved in 100 ml of ethyl cellulose liquid. This solution was spray-dried in a conventional manner to obtain a completely amorphous solid of 10-acetyl-3'-acetylmidecamycin.
この非晶質固体１ｇを採取し、ハイドロオキシプロピル
メチルセルロース０．７ｇ 、蔗ＮＩＯｇ及びアラビア
ゴム０．５ｇを含有する水溶液５０ｍｌ中に添加し混合
して充分に分散させることにより水懸濁組成物を得た。Collect 1 g of this amorphous solid, add it to 50 ml of an aqueous solution containing 0.7 g of hydroxypropyl methylcellulose, NIOg of sugarcane, and 0.5 g of gum arabic, mix well, and disperse thoroughly to form an aqueous suspension composition. Obtained.
この水懸濁組成物を２５℃及び４０°Ｃの温度条件下で
それぞれ１年間保存した後に調べた処、依然として安定
な水懸濁状態を維持していた。When this aqueous suspension composition was stored for one year under temperature conditions of 25° C. and 40° C., it was examined and found to still maintain a stable aqueous suspension state.
一方、アラビアゴムを含有し、ハイドロオキシプロピル
メチルセルロース及び蔗糖を含有しない水溶液に上記の
非晶質固体を上記と同様に分散させて水懸濁組成物（対
照組成物）を調製した。この対照組成物を２５℃の温度
条件下に保存した処、２４時間後にはゲル状態を呈して
いた。On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in an aqueous solution containing gum arabic but not containing hydroxypropylmethylcellulose or sucrose in the same manner as above. When this control composition was stored under a temperature condition of 25° C., it exhibited a gel state after 24 hours.
１゛告 ６６
１０−アセチル−３″′−アセチルミデカマイシン ｌ
Ｏｇを、エチルセルロース１ｇ含有ジクロロメタン溶液
１００ｍｌに溶解させた。この溶液を常法により噴霧乾
燥させて ｌＯ−アセチル−３′−アセチルミデカマイ
シンの完全な非晶質固体を得た。1 Notice 66 10-acetyl-3″'-acetylmidecamycin l
Og was dissolved in 100 ml of a dichloromethane solution containing 1 g of ethyl cellulose. This solution was spray-dried in a conventional manner to obtain a completely amorphous solid of lO-acetyl-3'-acetylmidecamycin.
この非晶質固体１ｇを採取し、ハイドロオキシプロピル
メチルセルロース１．５ｇ． ！糖３０ｇ及び安息香酸
０．５ｇを含有する水溶液５０１中に添加し混合して充
分に分散させることにより水懸濁組成物を得た。1 g of this amorphous solid was collected, and 1.5 g of hydroxypropyl methyl cellulose was collected. ! An aqueous suspension composition was obtained by adding it to an aqueous solution 501 containing 30 g of sugar and 0.5 g of benzoic acid, mixing it, and sufficiently dispersing it.
この水懸濁組成物と２５°Ｃ及び４０℃の温度条件下で
それぞれ１年間保存した後に調べた処、依然として安定
な水懸濁状態を維持していた。When this aqueous suspension composition was stored for 1 year at 25°C and 40°C, it was found that it still maintained a stable aqueous suspension state.
一方、安息香酸を含有し、ハイドロオキシプロピルメチ
ルセルロース及び蔗糖を含有しない水溶液に上記の非晶
質固体を上記と同様に分散させて水懸濁組成物（対照組
成Ｔｈ）を調製した。この対照組成物を２５℃の温度条
件下に保存した処、２４時間後にはゲル状態を呈してい
た。On the other hand, an aqueous suspension composition (control composition Th) was prepared by dispersing the above amorphous solid in the same manner as above in an aqueous solution containing benzoic acid but not containing hydroxypropylmethylcellulose or sucrose. When this control composition was stored under a temperature condition of 25° C., it exhibited a gel state after 24 hours.
潰 ７ び ７
１０−アセチル−３″−アセチルミデカマイシン ＩＯ
ｇをジクロロメタン溶液１００１に溶解させた。この溶
液を常法により噴霧乾燥させて １０−アセチル３°′
−アセチルミデカマイシンの完全な非晶質固体を得た。7 and 7 10-acetyl-3″-acetylmidecamycin IO
g was dissolved in dichloromethane solution 1001. This solution was spray-dried using a conventional method to obtain 10-acetyl 3°'
- Completely amorphous solid of acetylmidecamycin was obtained.
この非晶質固体２ｇを採取し、ハイドロオキシプロピル
メチルセルロース１．Ｏｇ．蔗糖３０ｇ及びアクリル酸
重合体０．０５ｇを大有する水溶液１００ｍｌ中に添加
し混合して充分に分散させることにより水懸濁組成物を
得た。2 g of this amorphous solid was collected and hydroxypropyl methylcellulose 1. Og. An aqueous suspension composition was obtained by adding 30 g of sucrose and 0.05 g of acrylic acid polymer to 100 ml of an aqueous solution and mixing to sufficiently disperse the mixture.
この水懸濁組成物を２５℃及び４０°Ｃの温度条件下で
それぞれ１年間保存した後に調べた処、依然として安定
な水懸濁状態を維持していた。When this aqueous suspension composition was stored for one year under temperature conditions of 25° C. and 40° C., it was examined and found to still maintain a stable aqueous suspension state.
一方、ハイドロオキシプロピルメチルセルロース、蔗糖
及びアクリル酸重合体を含有しない単なる水に上記の非
晶質固体を上記と同様に分散させて水懸濁組成物（対照
組成物）を調製した。この対照組成物を２５°Ｃの温度
条件下に保存した処、２４時間後にはゲル状態を呈して
いた。On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in plain water not containing hydroxypropyl methylcellulose, sucrose, and acrylic acid polymer in the same manner as above. When this control composition was stored under a temperature condition of 25°C, it exhibited a gel state after 24 hours.
造 ８ び ８
１０−アセチル−３′−アセチルミデカマイシン １０
ｇを、エチルセルロース１ｇ含有ジオキサン溶液１００
ｍ１に溶解させた。この溶液を一４０°Ｃで凍結させた
後に、Ｉ００ｍｉＨｇ以下の減圧下で溶媒を昇華除去し
て ｌＯ−アセチル−３゛′−アセチルミデカマイシン
の完全な非晶質固体を得た。Structure 8 and 8 10-acetyl-3'-acetylmidecamycin 10
g, 100 g of dioxane solution containing 1 g of ethyl cellulose
It was dissolved in m1. After freezing this solution at -40°C, the solvent was removed by sublimation under reduced pressure of less than 100 miHg to obtain a completely amorphous solid of lO-acetyl-3'-acetylmidecamycin.
この非晶質固体２ｇを採収し、ハイドロオキシプロピル
メチルセルロース０．５ｇ及び蔗糖２５ｇを含有する水
溶液１００１中に添加し混合して充分に分散させること
により水懸濁組成物を得た。2 g of this amorphous solid was collected, added to an aqueous solution 1001 containing 0.5 g of hydroxypropyl methylcellulose and 25 g of sucrose, mixed and sufficiently dispersed to obtain an aqueous suspension composition.
一方、ハイドロオキシプロピルメチルセルロースを含有
し、蔗糖を含有しない水溶液に上記の非晶質固体を上記
と同様に分散させて水懸濁組成物（対照組成物）を調製
した。On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in the same manner as above in an aqueous solution containing hydroxypropyl methyl cellulose but not containing sucrose.
これらの水懸濁組成物を５０℃の温度条件下でそれぞれ
保存し経時的に調べた処、対照組成物は３日間でゲル状
態を呈したのに対して本発明による水懸濁組成物は２週
間経過後にも安定な水懸濁状態を維持していた。When each of these aqueous suspension compositions was stored under a temperature condition of 50°C and examined over time, the control composition exhibited a gel state within 3 days, whereas the aqueous suspension composition according to the present invention Even after two weeks had passed, a stable water suspension state was maintained.
１゛責ダ ９ び ９
１０−アセチル−３′−アセチルミデカマイシンｌＯｇ
を、エチルセルロース１ｇ含有ジオキサン溶液１００１
に溶解させた。この溶液を一４０℃で凍結させた後に、
１００ｍｍＨｇ以下の減圧下で溶媒を昇華除去して １
０−アセチル−３′°−アセチルミデカマイシンの完全
な非晶質固体を得た。1゛Response 9 and 9 10-acetyl-3'-acetylmidecamycin lOg
, dioxane solution containing 1 g of ethyl cellulose 1001
It was dissolved in After freezing this solution at -40°C,
The solvent is removed by sublimation under reduced pressure of 100 mmHg or less. 1
A completely amorphous solid of 0-acetyl-3'°-acetylmidecamycin was obtained.
この非晶質固体２ｇを採取し、ハイドロオキシプロピル
セルロース０．５ｇ及び蔗糖３５ｇを含有する水溶液１
００１中に添加し混合して充分に分散させることにより
水懸濁組成物を得た。2 g of this amorphous solid was collected and an aqueous solution 1 containing 0.5 g of hydroxypropyl cellulose and 35 g of sucrose was prepared.
001 and mixed to sufficiently disperse the composition, an aqueous suspension composition was obtained.
一方、ハイドロオキシプロピルセルロースを含有し、蔗
糖を含有しない水溶液に上記の非晶質固体を上記と同様
に分散させて水懸濁組成物（対照組成物）を調製した。On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in an aqueous solution containing hydroxypropyl cellulose but not containing sucrose in the same manner as above.
これらの水懸濁組成物を５０℃の温度条件下でそれぞれ
保存し経時的に調べた処、対照組成物は３日間でゲル状
態を呈したのに対して本発明による水懸濁組成物は２週
間経過後にら安定な水懸濁状態を維持していた。When each of these aqueous suspension compositions was stored under a temperature condition of 50°C and examined over time, the control composition exhibited a gel state within 3 days, whereas the aqueous suspension composition according to the present invention After 2 weeks, a stable water suspension state was maintained.
ｊ告 １０ １０１０−アセ
チル−３“°−アセチルミデカマイシン ｌ（Ｉｇを、
エチルセルロース１ｇ含有ジオキサン溶液１００１に溶
解させた。この溶液を一４０℃で凍結させた後に、１０
０ｍｍＨｇ以下の減圧下で溶媒を昇華除去して ｌＯ−
アセチル−３”−アセチルミデカマイシンの完全な非晶
質固体を得た。j Notification 10 1010-acetyl-3"°-acetylmidecamycin l (Ig,
It was dissolved in dioxane solution 1001 containing 1 g of ethyl cellulose. After freezing this solution at -40°C,
The solvent is removed by sublimation under reduced pressure of 0 mmHg or less.
A completely amorphous solid of acetyl-3''-acetylmidecamycin was obtained.
この非晶質固体２ｇを採取し、ハイドロオキシプロピル
セルロース １．５ｇ及び蔗糖４０ｇを含有する水溶液
１００１中に添加し混合して充分に分散させることによ
り水懸濁組成物を得た。2 g of this amorphous solid was collected, added to an aqueous solution 1001 containing 1.5 g of hydroxypropyl cellulose and 40 g of sucrose, mixed and sufficiently dispersed to obtain an aqueous suspension composition.
一方、蔗糖を含有し、ハイドロオキシプロピルセルロー
スを含有しない水溶液に上記の非晶質固体を上記と同様
に分散させて水懸濁組成物（対照組成物）を調製した。On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in an aqueous solution containing sucrose but not containing hydroxypropyl cellulose in the same manner as above.
これらの水懸濁組成物を５０℃の温度条件下でそれぞれ
保存し経時的に調べた処、対照組成物は２４時間でゲル
状態を呈したのに対して本発明による水懸濁組成物は２
週間経過後にも安定な水懸濁状態を維持していた。When each of these aqueous suspension compositions was stored under a temperature condition of 50°C and examined over time, the control composition exhibited a gel state in 24 hours, whereas the aqueous suspension composition according to the present invention 2
A stable water suspension state was maintained even after a week had passed.
Ｉ造１１び較１１
１Ｏ−アセチル−３″−アセチルミデカマイシン ＩＯ
ｇを、エチルセルロース１ｇ含有ジオキサン溶液１００
１に溶解させた。この溶液を一４０℃で凍結させた後に
、Ｉ００ｍｍＨｇ以下の減圧下で溶媒を昇華除去してＩ
Ｏ−アセチル−３′−アセチルミデカマイシンの完全な
非晶質固体を得た。I construction 11 comparison 11 1O-acetyl-3″-acetylmidecamycin IO
g, 100 g of dioxane solution containing 1 g of ethyl cellulose
It was dissolved in 1. After freezing this solution at -40°C, the solvent was removed by sublimation under reduced pressure of I00 mmHg or less.
A completely amorphous solid of O-acetyl-3'-acetylmidecamycin was obtained.
この非晶質固体２ｇを採取し、ハイドロオキシプロピル
メチルセルロース１．Ｏｇ及び蔗糖２０ｇを含有する水
溶ｉ１１００ｍ１中に添加し混合して充分に分散させる
ことにより水懸濁組成物を得た。2 g of this amorphous solid was collected and hydroxypropyl methylcellulose 1. An aqueous suspension composition was obtained by adding the mixture to 1,100 ml of an aqueous solution containing Og and 20 g of sucrose, mixing and thoroughly dispersing it.
一方、蔗糖を含有し、ハイドロオキシプロピルメチルセ
ルロースを含有しない水溶液に上記の非晶質固体を上記
と同様に分散させて水懸濁組成物（対照組成物）を調製
した。On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in an aqueous solution containing sucrose but not hydroxypropylmethylcellulose in the same manner as above.
これらの水懸濁組成物を５０℃の温度条件下でそれぞれ
保存し経時的に調べた処、対照組成物は２４時間でゲル
状態を呈したのに対して本発明による水懸濁組成物は２
３ＦＩ間経過後にも安定な水懸濁状態を維持していた。When each of these aqueous suspension compositions was stored under a temperature condition of 50°C and examined over time, the control composition exhibited a gel state in 24 hours, whereas the aqueous suspension composition according to the present invention 2
A stable water suspension state was maintained even after 3 FIs had elapsed.
Ｊ造 １２ び １２
１０−アセチル−３”′−アセチルミデカマイシン １
０ｇを、エチルセルロース１ｇ含有ジオキサン溶液１０
０ｍ１に溶解させた。この溶液を一４０°Ｃで凍結させ
た後に、１００ｍ＋ａＨｇ以下の減圧下で溶媒を昇華除
去して１０−アゼチル−３“°−アセチルミデカマイシ
ンの完全な非晶質固体を得た。J-made 12 and 12 10-acetyl-3'''-acetylmidecamycin 1
0g of dioxane solution containing 1g of ethyl cellulose
It was dissolved in 0ml. After freezing this solution at -40°C, the solvent was removed by sublimation under reduced pressure of less than 100 m+aHg to obtain a completely amorphous solid of 10-azetyl-3"°-acetylmidecamycin.
この非晶質固体２ｇを採取し、ハイドロオキシブ［Ｖピ
ルセルロース０．５ｇ 、蔗糖２０ｇ、カルボキシメチ
ルセルロースナトリウム０．５ｇ、安息香酸ナトリウム
０．５ｇ、クエン酸緩衝１３０ｇ及び食用黄色５号０．
ＯＩｇを含有する水溶液１００１中に添加し混合して充
分に分散させることにより水懸濁組成物を得た。2 g of this amorphous solid was collected, 0.5 g of hydroxybu [V-pill cellulose, 20 g of sucrose, 0.5 g of sodium carboxymethylcellulose, 0.5 g of sodium benzoate, 130 g of citric acid buffer, and 0.5 g of food yellow No. 5.
An aqueous suspension composition was obtained by adding it to an aqueous solution 1001 containing OIg, mixing it, and sufficiently dispersing it.
一方、ハイドロオキシ１０ビルセルロースを含有せず、
他の上記諸成分を含有する水溶液に上記の非晶質固体を
上記と同様に分散させて水懸濁組成物（対照組成！ｔ！
１ｌＪ）を調製した。On the other hand, it does not contain hydroxy-10-vinyl cellulose,
The above amorphous solid is dispersed in an aqueous solution containing the other above components in the same manner as above to form an aqueous suspension composition (control composition!t!
1 lJ) was prepared.
これらの水懸濁組成物を５０’Ｃの温度条件下でそれぞ
れ保存し経時的に調べた処、対照組成物は２４時間でゲ
ル状態を呈したのに対して本発明による水懸濁組成物は
２週間経過後にも安定な水懸濁状態を維持していた。When each of these aqueous suspension compositions was stored under a temperature condition of 50'C and examined over time, the control composition exhibited a gel state in 24 hours, whereas the aqueous suspension composition according to the present invention remained in a stable water suspension state even after two weeks.
ｔｈ １３ び １３
ミデカマイシン（商品名：メデマイシン） ５ｇをジク
ロロメタン溶液１００ｍ１に溶解させた。この溶液を常
法により噴霧乾燥させてミデカマイシンの完全な非晶質
固体を得た。th 13 and 13 5 g of midecamycin (trade name: medemycin) was dissolved in 100 ml of dichloromethane solution. This solution was spray dried in a conventional manner to obtain a completely amorphous solid of midecamycin.
この非晶質固体ｔｇを採取し、ハイドロオキシプロピル
メチルセルロース１．Ｏｇ及び蔗糖３０ｇを含有する水
溶液１００１中に添加し混合して充分に分散させること
により水懸濁組成物を得た。This amorphous solid tg was collected and hydroxypropyl methylcellulose 1. An aqueous suspension composition was obtained by adding it to an aqueous solution 1001 containing Og and 30 g of sucrose, mixing it, and sufficiently dispersing it.
一方、ハイドロオキシプロピルメチルセルロース及び蔗
糖を含有しない単なる水に上記の非晶質固体を上記と同
様に分散させて水懸濁組成物（対照組成物）を調製した
。On the other hand, an aqueous suspension composition (control composition) was prepared by dispersing the above amorphous solid in plain water containing neither hydroxypropyl methyl cellulose nor sucrose in the same manner as above.
これらの水懸濁組成物を４０℃の温度条件下でそれぞれ
保存し経時的に調べた処、対照組成物は１週間でゲル状
態を呈したのに対して本発明による水懸濁組成物は１年
間保存後にも安定な水懸濁状態を維持していた。When each of these aqueous suspension compositions was stored under a temperature condition of 40°C and examined over time, the control composition exhibited a gel state within one week, whereas the aqueous suspension composition according to the present invention It maintained a stable aqueous suspension state even after storage for one year.
（発明の効果）
マクロライド系抗生物質をシロップ剤として製剤化する
場合に、常法に従い、その非晶質固体原末を蔗糖含有水
溶液に分散させて得られる水懸濁組成物は経時的にゲル
化して流動性を失うが、本発明方法により水溶性セルロ
ース系ポリマーを共存させることによりゲル化を阻止乃
至著しく遅延させることができる。(Effect of the invention) When formulating a macrolide antibiotic as a syrup, an aqueous suspension composition obtained by dispersing the amorphous solid bulk powder in a sucrose-containing aqueous solution according to a conventional method will Although it gels and loses fluidity, gelation can be prevented or significantly delayed by coexisting with a water-soluble cellulose polymer according to the method of the present invention.
従って、本発明は安定なマクロライド系抗生物質含有シ
ロップ剤の製造を可能にするものであり、その保存管理
を容易ならしめる。Therefore, the present invention enables the production of stable syrups containing macrolide antibiotics and facilitates their storage management.
Claims (1)
溶性セルロース系ポリマーと蔗糖とが組み合わされて配
合されていることを特徴とする、マクロライド系抗生物
質の水懸濁組成物。(1) An aqueous suspension composition of a macrolide antibiotic, comprising a combination of a water-soluble cellulose polymer and sucrose in an amorphous solid bulk powder of the macrolide antibiotic. .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63159256A JPH078800B2 (en) | 1988-06-29 | 1988-06-29 | Aqueous suspension composition of macrolide antibiotics |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63159256A JPH078800B2 (en) | 1988-06-29 | 1988-06-29 | Aqueous suspension composition of macrolide antibiotics |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH029821A true JPH029821A (en) | 1990-01-12 |
| JPH078800B2 JPH078800B2 (en) | 1995-02-01 |
Family
ID=15689782
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63159256A Expired - Lifetime JPH078800B2 (en) | 1988-06-29 | 1988-06-29 | Aqueous suspension composition of macrolide antibiotics |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH078800B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06114079A (en) * | 1992-04-02 | 1994-04-26 | Kaltenbach & Voigt Gmbh & Co | Tooth articulator |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53145906A (en) * | 1977-05-25 | 1978-12-19 | Yamanouchi Pharmaceut Co Ltd | Stable aqueous dispersion of 10-propionyl gosamycin |
| JPS565412A (en) * | 1979-05-19 | 1981-01-20 | Meiji Seika Kaisha Ltd | Pharmaceutical composition |
-
1988
- 1988-06-29 JP JP63159256A patent/JPH078800B2/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53145906A (en) * | 1977-05-25 | 1978-12-19 | Yamanouchi Pharmaceut Co Ltd | Stable aqueous dispersion of 10-propionyl gosamycin |
| JPS565412A (en) * | 1979-05-19 | 1981-01-20 | Meiji Seika Kaisha Ltd | Pharmaceutical composition |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06114079A (en) * | 1992-04-02 | 1994-04-26 | Kaltenbach & Voigt Gmbh & Co | Tooth articulator |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH078800B2 (en) | 1995-02-01 |
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