JPH0418015A - Stable aqueous solution of clemastine fumarate - Google Patents
Stable aqueous solution of clemastine fumarateInfo
- Publication number
- JPH0418015A JPH0418015A JP2121797A JP12179790A JPH0418015A JP H0418015 A JPH0418015 A JP H0418015A JP 2121797 A JP2121797 A JP 2121797A JP 12179790 A JP12179790 A JP 12179790A JP H0418015 A JPH0418015 A JP H0418015A
- Authority
- JP
- Japan
- Prior art keywords
- clemastine fumarate
- tween
- aqueous solution
- clear
- precipitate
- 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
- PMGQWSIVQFOFOQ-BDUVBVHRSA-N (e)-but-2-enedioic acid;(2r)-2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound OC(=O)\C=C\C(O)=O.CN1CCC[C@@H]1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PMGQWSIVQFOFOQ-BDUVBVHRSA-N 0.000 title claims abstract description 31
- 229960002689 clemastine fumarate Drugs 0.000 title claims abstract description 31
- 239000007864 aqueous solution Substances 0.000 title claims abstract description 21
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 16
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 16
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 16
- 239000004094 surface-active agent Substances 0.000 claims abstract description 11
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 9
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 8
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 8
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 8
- 229920001213 Polysorbate 20 Polymers 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims abstract description 7
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims abstract description 7
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 7
- 229920001214 Polysorbate 60 Polymers 0.000 claims abstract description 6
- 239000008363 phosphate buffer Substances 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 20
- 239000000243 solution Substances 0.000 abstract description 11
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 5
- 239000007853 buffer solution Substances 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000003889 eye drop Substances 0.000 abstract description 2
- 229940012356 eye drops Drugs 0.000 abstract description 2
- 239000006210 lotion Substances 0.000 abstract description 2
- 239000007923 nasal drop Substances 0.000 abstract description 2
- 229940100662 nasal drops Drugs 0.000 abstract description 2
- 239000007924 injection Substances 0.000 abstract 1
- 238000002347 injection Methods 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 239000002244 precipitate Substances 0.000 description 23
- 238000012360 testing method Methods 0.000 description 8
- 229920000136 polysorbate Polymers 0.000 description 7
- 239000013078 crystal Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- -1 alkali metal salt Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 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】
技術分野
本発明はフマル酸クレマスチンの安定な水溶液に関する
ものである。DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to stable aqueous solutions of clemastine fumarate.
従来技術
フマル酸クレマスチンは日本薬局方にも記載されている
有用な抗ヒスタミン作用を持つ薬剤で、アレルギー症状
やかゆみ等の治療に用いられている。しかしながら、フ
マル酸クレマスチンは一般によく知られているように、
水に極めて溶けにくく、治療の為に速効性１便利性を期
待される水溶液化は困難であると一般に考えられ、これ
までは主として経口剤、またはけん濁液として用いられ
てきた。過酷な条件、例えば、アルカリ性水溶液にすれ
ば水溶液化できるが、この場合はタール状の色素を生じ
、変性し、薬理作用は失活する。もし、本薬剤が水溶液
化されるとなれば非経口剤、例えば、外用剤として、点
鼻１点眼、ローションなどまた注射用溶液として幅広い
応用が期待されるわけである。しかしながら本薬剤の水
溶化を試みた報告はまだ報告されていない。Prior Art Clemastine fumarate is a drug with a useful antihistamine effect that is also listed in the Japanese Pharmacopoeia, and is used to treat allergic symptoms, itching, and the like. However, as is generally well known, clemastine fumarate
It is extremely difficult to dissolve in water, and it is generally thought that it is difficult to form an aqueous solution that is expected to be fast-acting and convenient for treatment, and so far it has been mainly used as an oral preparation or a suspension. It can be made into an aqueous solution under harsh conditions, for example, in an alkaline aqueous solution, but in this case a tar-like pigment is produced, denatured, and the pharmacological action is inactivated. If this drug were to be made into an aqueous solution, it would be expected to have a wide range of applications as parenteral preparations, such as external preparations, nasal and eye drops, lotions, and injectable solutions. However, there have been no reports yet on attempts to make this drug water-soluble.
発明が解決しようとする問題点
そこで、医薬組成物として有用なフマル酸クレマスチン
の安定且つ澄明な水溶液が要望されており、かかる水溶
液を提供することが本発明目的である。Problems to be Solved by the Invention Therefore, there is a need for a stable and clear aqueous solution of clemastine fumarate useful as a pharmaceutical composition, and it is an object of the present invention to provide such an aqueous solution.
問題点を解決するための手段
本発明に従えば上記発明目的が、フマル酸クレマスチン
を、３〜６％のポリビニルピロリドン。Means for Solving the Problems According to the present invention, the object of the invention is to mix clemastine fumarate with 3 to 6% polyvinylpyrrolidone.
ポリエチレングリコールおよびポリビニルアルコールか
らなる群より選ばれる水溶性高分子化合物および帆０１
〜０．５％のツイーン２０．ツイーン６０およびツイー
ン８０からなる群より選ばれる界面活性剤を含むリン酸
緩衝液に加え、ｐＨを５．５〜８．５に調節して得られ
る安定なフマル酸クレマスチン水溶液により達成せられ
る。Water-soluble polymer compound selected from the group consisting of polyethylene glycol and polyvinyl alcohol and sail 01
~0.5% Tween20. This can be achieved by adding a stable aqueous solution of clemastine fumarate to a phosphate buffer containing a surfactant selected from the group consisting of Tween 60 and Tween 80 and adjusting the pH to 5.5 to 8.5.
フマル酸クレマスチンを塩、例えばアルカリ金属塩にす
れば水溶化が可能であるが、その水溶性は保存中にター
ル状の色素を生じ、変性し、薬理作用を失うため、塩基
性物質を用い水溶性塩を形成せしめることはできない。Clemastine fumarate can be made water-soluble by making it into a salt, such as an alkali metal salt, but its water-solubility produces a tar-like pigment during storage, denatures, and loses its pharmacological action. cannot be caused to form salts.
本発明者らは鋭意研究の結果、今まで困難とされてきた
フマル酸クレマスチンの水溶液化を、３％以上、約６％
以下望ましくは約５％のポリビニルピロリドン、ポリエ
チレングリコール、またはポリビニルアルコールの水溶
性高分子化合物および０．０１〜０．５％、好ましくは
０．０１〜０．１％のツイーン２０．ツイーン６０ある
いはツイーン８０の界面活性剤を含むリン酸塩緩衝液に
加え、ｐＨを５．５〜８．５に調節することにより、ｐ
Ｈを ５．５〜８．５の生理的条件でフマル酸クレマス
チンの有効量を含み、長期にわたり安定な水溶液を得る
ことに成功したのである。As a result of intensive research, the present inventors have succeeded in making clemastine fumarate into an aqueous solution of 3% or more, approximately 6%, which has been considered difficult until now.
Desirably about 5% of a water-soluble polymer compound such as polyvinylpyrrolidone, polyethylene glycol, or polyvinyl alcohol and 0.01 to 0.5%, preferably 0.01 to 0.1% of Tween 20. By adding to a phosphate buffer containing Tween 60 or Tween 80 surfactant and adjusting the pH to 5.5 to 8.5,
They succeeded in obtaining a long-term stable aqueous solution containing an effective amount of clemastine fumarate under physiological conditions with H of 5.5 to 8.5.
本発明者らは、フマル酸クレマスチン安定水溶液の調製
を目標に各種溶解補助剤を検討し、先づ、ポリビニルピ
ロリドン、ポリエチレングリコール、ポリビニルアルコ
ールのみが有効であり、他の水溶性高分子化合物、グリ
セリン等では澄明な水溶液が得られないこと、また界面
活性剤としてはツイーン２０．ツイーン６０およびツイ
ーン８０が有効であることを知った。The present inventors investigated various solubilizing agents with the aim of preparing a stable aqueous solution of clemastine fumarate, and found that only polyvinylpyrrolidone, polyethylene glycol, and polyvinyl alcohol were effective, while other water-soluble polymer compounds, glycerin etc., it is not possible to obtain a clear aqueous solution, and as a surfactant, Tween 20. I learned that Tween 60 and Tween 80 are effective.
次にこれら水溶性高分子化合物の溶解補助剤と界面活性
剤を用い、フマル酸クレマスチン０．１％水溶液の調整
を目標に種々実験を繰返した結果、フマル酸クレマスチ
ンの溶解性に関し下記の如き知見を得た。Next, we repeated various experiments with the goal of preparing a 0.1% aqueous solution of clemastine fumarate using these water-soluble polymer compound solubilizing agents and surfactants. As a result, we found the following findings regarding the solubility of clemastine fumarate. I got it.
ｆｌ） ｐ Ｈ変化によるフマル酸クレマスチンの溶解
性フマル酸クレマスチン１ ｍｇをリン酸塩緩衝液９０
ｍ１ｌ 、ツイーン８００．０５ ｄ、ポリビニルピロ
リドン５ｇの混液に溶解させ、５％リン酸でｐＨを夫々
７６、帆 ７，０．および８．０に調整し、全量１００
−の試験溶液を夫々作り、これら溶液を室温で放置し、
液状を観察しな結果下表の如き結果が得られた。fl) Solubility of clemastine fumarate by pH change 1 mg of clemastine fumarate was added to 90% of phosphate buffer.
ml, Tween 800.05 d, and 5 g of polyvinylpyrrolidone, and the pH was adjusted to 76 with 5% phosphoric acid, and the pH was adjusted to 7.0. and adjusted to 8.0, total amount 100
- prepare test solutions, leave these solutions at room temperature,
After observing the liquid state, the results shown in the table below were obtained.
６．０ 無色澄明 無色澄明 微黄色澄明
微黄色澄明沈殿なし 沈殿なし 沈殿なし
沈殿なし７．０ 同上 同上
同上 同上面ｐＨが８．０をこえると溶液の
白濁が増大し、また沈殿物の析出が認められた。6.0 Colorless clear Colorless clear Slight yellow clear
Slight yellow clear No precipitate No precipitate No precipitate
No precipitation 7.0 Same as above Same as above
Same as above When the pH of the upper surface exceeded 8.0, the cloudiness of the solution increased, and precipitation of a precipitate was observed.
以上により緩衝液溶液のｐＨは６．０〜８．０特に好ま
しくは６．０〜７．０の範囲内が良好な結果を与えるこ
とが判明した。From the above, it has been found that the pH of the buffer solution within the range of 6.0 to 8.0, particularly preferably 6.0 to 7.0, gives good results.
（２）加熱の溶解性に及ぼず影響
フマル酸りレマチン１ ｍｇ、ツイーン帆０５ｍｋｌ、
ポリビニルピロリドン５ｇおよび帆０５Ｍリン酸塩緩衝
液（Ｎａ３ＰＯ４１２Ｈ１２０１９，Ｏｇを蒸留水１β
に溶解）９０ｍｌｌｌを混合し、加熱溶解させた溶液（
１００ｄ ）のｐＨを５％リン酸で７．５に調整した試
料Ｎｏ、１；フマル酸クレマスチン１ｍｇ、リン酸緩衝
液９０ｍＱ。(2) Heating does not affect the solubility of fumaric acid lematin 1 mg, Tween sail 05 mkl,
5g polyvinylpyrrolidone and 05M phosphate buffer (Na3PO412H12019,Og) in distilled water 1β
Mix 90ml of (dissolved in) and heat to dissolve the solution (
Sample No. 1 whose pH was adjusted to 7.5 with 5% phosphoric acid; Clemastine fumarate 1 mg, phosphate buffer 90 mQ.
ツイーン０．０５ｍＱを混合加熱し、次にポリビニルピ
ロリドン５ｇを加え全量ｌＯＯｍＱの溶液を得、さらに
５％リン酸でｐＨを７．５に調整した試料Ｎｔｔ ２
＋およびフマル酸クレマスチン１ｍｇ、 リン酸塩緩衝
液９０−、ツイーン８０ ０．０５ｍＲ，ポリビニルピ
ロリドン５ｇを加熱することなく撹拌混合し、１０ｆＪ
ｍｕの溶液を得、５％リン酸でｐＨ７，５に調整した試
料Ｎｎ、３を各々作り、各試料溶液を室温放置し、液状
を観察した結果、下記の如き結果を得た。Sample Ntt 2 in which 0.05 mQ of Tween was mixed and heated, then 5 g of polyvinylpyrrolidone was added to obtain a solution with a total volume of 100 mQ, and the pH was further adjusted to 7.5 with 5% phosphoric acid.
+ and 1 mg of clemastine fumarate, phosphate buffer 90-, Tween 80 0.05 mR, and 5 g of polyvinylpyrrolidone were stirred and mixed without heating, and 10 fJ
Samples Nn and 3 were prepared by obtaining a solution of mu and adjusting the pH to 7.5 with 5% phosphoric acid. Each sample solution was left at room temperature, and the liquid state was observed. As a result, the following results were obtained.
（以 下 余 白）
試料 初日 ３日後 ７日後
１４４日後 無色半透明 微黄色半澄明 微黄
色半澄明 微黄色半澄明油状沈殿少量 結晶沈殿少量
結晶沈殿物 結晶沈殿物２ 無色澄明 微黄
色半澄明 微黄色半澄明 微黄色澄明沈殿なし 沈
殿なし 結晶沈殿少量 結晶沈殿物３ 無色澄
明 微黄色澄明 微黄色澄明 微黄色澄明沈殿
なし 沈殿なし 沈殿なし 沈殿なし以上
により加熱しない方が良好な結果を与えることが判明し
た。(Margin below) Sample First day 3 days later 7 days later
After 144 days Colorless and translucent Slight yellow semi-clear Slight yellow semi-clear Slight yellow semi-clear Small amount of oily precipitate Small amount of crystal precipitate
Crystal precipitate Crystal precipitate 2 Colorless clear Slight yellow semi-clear Slight yellow semi-clear Slight yellow clear No precipitate No precipitate A small amount of crystal precipitate Crystal precipitate 3 Colorless clear Slight yellow clear Slight yellow clear Slight yellow clear No precipitate No precipitate No precipitate No precipitate From the above, it was found that not heating gave better results.
、（３）ポリビニルピロリドン添加量の影響フマル酸ク
レマスチン１００ｍｇ、リン酸塩緩衝液９５ｍＱ、ツイ
ーン０．０５ｍＲにポリビニルピロリドンＩｇ２ｇ、３
ｇ、４ｇ、あるいは５ｇ、を加え、全量１００ａｌｌの
溶液５種を作り、各々５％リン酸でｐＨを７．０に調整
した。これら溶液の保存時の液状をしらへ下記の結果を
得た。, (3) Effect of added amount of polyvinylpyrrolidone Clemastine fumarate 100mg, phosphate buffer 95mQ, Tween 0.05mR, polyvinylpyrrolidone Ig 2g, 3
5 g, 4 g, or 5 g were added to make five types of solutions with a total volume of 100 all, and the pH of each solution was adjusted to 7.0 with 5% phosphoric acid. The following results were obtained regarding the liquid state of these solutions during storage.
（以 下 余 白）
試ｈ 初日 ５日後 １２日を麦
臣旦春１−−−−１ 無色澄明
無色澄明 無色澄明 無色澄明白色油状沈
殿物 白色油状沈殿物 白色油状沈殿物 白色油状沈殿
物２ 同上 同上 同上
同上３ 同」−同上 同上
同−Ｆ４ 同上 同上 同
上 同上但 沈殿物少量 但 沈殿物少量
但 沈殿物少量 但 沈殿物少量以上より、ポリビニル
ピロリドン添加量は５％以上必要であることが判明した
。(Left below) Trial h First day 5 days later Mugi on the 12th Shintan Spring 1 ---- 1 Colorless clear light
Colorless clear Colorless clear Colorless clear Light colored oily precipitate White oily precipitate White oily precipitate White oily precipitate 2 Same as above Same as above Same as above
Same as above 3 Same as above” - Same as above Same as above
Same as above - F4 Same as above Same as above Same as above However, a small amount of sediment However, a small amount of sediment
However, a small amount of precipitate However, from the small amount of precipitate, it was found that the amount of polyvinylpyrrolidone added was required to be 5% or more.
面別の試験から、ポリビニルアルコール、ポリエチレン
グリコールでは約３％程度で有効であること、これら溶
解補助剤の上限は実用的見地ならびに効果の点より約６
％であることも見出されている。From side-by-side tests, it was found that polyvinyl alcohol and polyethylene glycol are effective at about 3%, and the upper limit of these solubilizers is about 6% from a practical standpoint and effectiveness.
It has also been found that %.
１４１ツイ一ン界面活性剤の有無における溶解性フマル
酸クレマスチン１００＋＋＋ｇ、リン酸塩＃ｊｌ衝液９
５ｍＱ、ポリビニルピロリドン５ｇおよびツイーン８０
０．０５ ｍＱを混合しｐＨを７．０に調整した試料Ｎ
ｎ、 １ 、および上記配合よりツイーン８０を除いて
同様にｐ Ｈを７．０に調整した試料Ｎ（Ｌ ２を作り
、それらの保存試験を行ない下記の結果を得た。141 Soluble clemastine fumarate 100 +++ g in the presence and absence of twinning surfactant, phosphate #jl buffer solution 9
5mQ, polyvinylpyrrolidone 5g and Tween 80
Sample N mixed with 0.05 mQ and adjusted to pH 7.0
Sample N (L2) was prepared by removing Tween 80 from the above formulation and adjusting the pH to 7.0, and a storage test was conducted on them to obtain the following results.
以」−によりツイーンを添加しないと白色油状沈殿物か
のこり、また白濁するためツイーンの添加が必須である
ことが判明した。As a result, it was found that the addition of Tween was essential because if Tween was not added, a white oily precipitate remained and the mixture became cloudy.
別の一連の試験によりツイーンの添加量は０．０１〜０
．５％か必要であることも判明しな。Another series of tests showed that the amount of Tween added was between 0.01 and 0.
．． It turns out that 5% is necessary.
これら各種試験よりフマル酸クレマスチンの安定水溶液
を得るためには、３〜６％のポリビニルピロリドン、ポ
リエチレングリコールあるいはポリビニルアルコールと
、０．０１〜０．５％のツイーン２０、ツイーン６０あ
るいはツイーン８０を含むリン酸緩衝液にフマル酸クレ
マスチンを溶解させ、ｐＨを５．５〜８．５に調整する
ことが必須であることを見出し、本発明を完成させたも
のである。From these various tests, in order to obtain a stable aqueous solution of clemastine fumarate, it is necessary to contain 3-6% polyvinylpyrrolidone, polyethylene glycol or polyvinyl alcohol and 0.01-0.5% Tween 20, Tween 60 or Tween 80. The present invention was completed based on the discovery that it is essential to dissolve clemastine fumarate in a phosphate buffer and adjust the pH to 5.5 to 8.5.
以下実施例により本発明を説明する。The present invention will be explained below with reference to Examples.
実施例１
フマル酸クレマスチン０．１ｇをポリビニルピロリドン
５ｇ、界面活性剤０．０５ｍ１ｌを加えたリン酸緩衝液
（ｐＨ８，０） ９０−に加え、リン酸でｐ Ｈを７．
０に調節し、水を加えて １００ｍ１ｌとする。Example 1 0.1 g of clemastine fumarate was added to phosphate buffer (pH 8.0) 90-90 containing 5 g of polyvinylpyrrolidone and 0.05 ml of surfactant, and the pH was adjusted to 7.0 with phosphoric acid.
Adjust to 0 and add water to make 100ml.
実施例２
フマル酸クレマスチン０．１ｇをポリエチレンクリコー
ル３ｇ、界面活性剤０．０５ｍＱを加えたリン酸緩衝液
（ｐＨ８，０） ９０ｍＱに加え、リン酸でｐＨを７．
０に調節し、水を加えて １００ ｍＱとする。Example 2 0.1 g of clemastine fumarate was added to 90 mQ of phosphate buffer (pH 8.0) containing 3 g of polyethylene glycol and 0.05 mQ of surfactant, and the pH was adjusted to 7.0 with phosphoric acid.
Adjust to 0 and add water to make 100 mQ.
実施例３
フマル酸クレマスチン０．４ｇをポリビニルアルコール
３ｇ、界面活性剤０．０５ｍＭを加えたリン酸緩衝Ｍ
（ｐｉｔ ８．０＞ ９０ｍｇに加え、リン酸でｐＨを
８．０に調節し、水を加えて １００ｄとする。Example 3 Phosphate buffer M containing 0.4 g of clemastine fumarate, 3 g of polyvinyl alcohol, and 0.05 mM surfactant
(Pit 8.0> Add to 90 mg, adjust the pH to 8.0 with phosphoric acid, and add water to make 100 d.
実施例試験液の安定性の確認試験 （１）室温に放置した実施例の各溶液を一ヶ月。Confirmation test for stability of example test solution (1) Each solution of the example was left at room temperature for one month.
三ケ月及び六ケ月に、フレマスチン及びフマル酸の確認
の為に、日本薬局方第十−改正の方法に従って薄層クロ
マトグラフ法を用いて試験した結果、フレマスチン及び
フマル酸が水溶液中に存在していることが確認された。At the 3rd and 6th month, tests using thin layer chromatography according to the method of the Japanese Pharmacopoeia 10th revision were conducted to confirm the presence of flemastine and fumaric acid in the aqueous solution. This was confirmed.
（２）試験液のフレマスチン含有率の試験は紫外線吸光
試験法を用い、標準フレマスチンを試験液と同じ組成と
なるように調製し、測定することにより確認したが、力
価の低下は認められなかった。(2) The flemastine content of the test liquid was tested using an ultraviolet absorption test method, and standard flemastine was prepared to have the same composition as the test liquid and measured, but no decrease in titer was observed. Ta.
特許出願代理人patent application agent
Claims (1)
ドン、ポリエチレングリコールおよびポリビニルアルコ
ールからなる群より選ばれる水溶性高分子化合物および
０．０１〜０．５％のツイーン２０、ツイーン６０およ
びツイーン８０からなる群より選ばれる界面活性剤を含
むリン酸緩衝液に加え、ｐＨを５．５〜８．５に調節し
て得られる安定なフマル酸クレマスチン水溶液Clemastine fumarate, 3 to 6% of a water-soluble polymer compound selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol and polyvinyl alcohol, and 0.01 to 0.5% of the group consisting of Tween 20, Tween 60 and Tween 80. A stable clemastine fumarate aqueous solution obtained by adding to a phosphate buffer containing a surfactant selected from the above and adjusting the pH to 5.5 to 8.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2121797A JPH0418015A (en) | 1990-05-10 | 1990-05-10 | Stable aqueous solution of clemastine fumarate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2121797A JPH0418015A (en) | 1990-05-10 | 1990-05-10 | Stable aqueous solution of clemastine fumarate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0418015A true JPH0418015A (en) | 1992-01-22 |
Family
ID=14820157
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2121797A Pending JPH0418015A (en) | 1990-05-10 | 1990-05-10 | Stable aqueous solution of clemastine fumarate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0418015A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999004818A1 (en) * | 1997-07-24 | 1999-02-04 | Eisai Co., Ltd. | Preparation composition and process for producing the same |
| EP0956014A1 (en) * | 1996-11-13 | 1999-11-17 | Nastech Pharmaceutical Company, Inc. | Method for increasing the solubility of clemastine and pharmaceutical compositions prepared therefrom |
| US6576677B1 (en) | 1998-08-28 | 2003-06-10 | Eisai Co., Ltd. | Medicinal compositions with relieved bitterness |
| GB2446953A (en) * | 2007-02-24 | 2008-08-27 | Agt Sciences Ltd | Aqueous pharmaceutical formulations |
| JP2010111589A (en) * | 2008-11-04 | 2010-05-20 | Lion Corp | Solid preparation comprising clemastine fumarate and method for inhibiting lowering of clemastine fumarate content |
| US7727548B2 (en) | 2000-03-01 | 2010-06-01 | Eisai R&D Management Co., Ltd. | Rapidly disintegrable tablet containing polyvinyl alcohol |
| US7727552B1 (en) | 1997-03-28 | 2010-06-01 | Eisai R&D Management Co., Ltd. | Oral pharmaceutical preparations decreased in bitterness by masking |
| WO2013129319A1 (en) * | 2012-02-27 | 2013-09-06 | ロート製薬株式会社 | Ophthalmic composition |
| US8784789B2 (en) * | 2002-07-31 | 2014-07-22 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparations and light-stabilized aqueous liquid preparations |
| US8877168B1 (en) | 2002-07-31 | 2014-11-04 | Senju Pharmaceuticals Co., Ltd. | Aqueous liquid preparations and light-stabilized aqueous liquid preparations |
-
1990
- 1990-05-10 JP JP2121797A patent/JPH0418015A/en active Pending
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0956014A1 (en) * | 1996-11-13 | 1999-11-17 | Nastech Pharmaceutical Company, Inc. | Method for increasing the solubility of clemastine and pharmaceutical compositions prepared therefrom |
| EP0956014A4 (en) * | 1996-11-13 | 2001-03-07 | Nastech Pharm Co | Method for increasing the solubility of clemastine and pharmaceutical compositions prepared therefrom |
| US7727552B1 (en) | 1997-03-28 | 2010-06-01 | Eisai R&D Management Co., Ltd. | Oral pharmaceutical preparations decreased in bitterness by masking |
| WO1999004818A1 (en) * | 1997-07-24 | 1999-02-04 | Eisai Co., Ltd. | Preparation composition and process for producing the same |
| US6576677B1 (en) | 1998-08-28 | 2003-06-10 | Eisai Co., Ltd. | Medicinal compositions with relieved bitterness |
| US7727548B2 (en) | 2000-03-01 | 2010-06-01 | Eisai R&D Management Co., Ltd. | Rapidly disintegrable tablet containing polyvinyl alcohol |
| US8263123B2 (en) | 2000-03-01 | 2012-09-11 | Eisai R&D Management Co., Ltd. | Rapidly disintegrating tablet containing polyvinyl alcohol |
| US8784789B2 (en) * | 2002-07-31 | 2014-07-22 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparations and light-stabilized aqueous liquid preparations |
| US8877168B1 (en) | 2002-07-31 | 2014-11-04 | Senju Pharmaceuticals Co., Ltd. | Aqueous liquid preparations and light-stabilized aqueous liquid preparations |
| US8883825B2 (en) | 2002-07-31 | 2014-11-11 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparations and light-stabilized aqueous liquid preparations |
| US9849121B2 (en) | 2002-07-31 | 2017-12-26 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparations and light-stabilized aqueous liquid preparations |
| GB2446953A (en) * | 2007-02-24 | 2008-08-27 | Agt Sciences Ltd | Aqueous pharmaceutical formulations |
| JP2010111589A (en) * | 2008-11-04 | 2010-05-20 | Lion Corp | Solid preparation comprising clemastine fumarate and method for inhibiting lowering of clemastine fumarate content |
| WO2013129319A1 (en) * | 2012-02-27 | 2013-09-06 | ロート製薬株式会社 | Ophthalmic composition |
| JP5345745B1 (en) * | 2012-02-27 | 2013-11-20 | ロート製薬株式会社 | Ophthalmic composition |
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