KR0137206B1 - Spray gel base and spray gel preparation thereof - Google Patents
Spray gel base and spray gel preparation thereofInfo
- Publication number
- KR0137206B1 KR0137206B1 KR1019900004562A KR900004562A KR0137206B1 KR 0137206 B1 KR0137206 B1 KR 0137206B1 KR 1019900004562 A KR1019900004562 A KR 1019900004562A KR 900004562 A KR900004562 A KR 900004562A KR 0137206 B1 KR0137206 B1 KR 0137206B1
- Authority
- KR
- South Korea
- Prior art keywords
- gel
- spray
- viscosity
- spraying
- wax
- Prior art date
Links
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- 238000002360 preparation method Methods 0.000 title claims description 5
- 238000005507 spraying Methods 0.000 claims description 50
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- 206010022000 influenza Diseases 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 32
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- 239000007922 nasal spray Substances 0.000 claims description 11
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- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
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- 238000010998 test method Methods 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- MLCGWPUVZKTVLO-UHFFFAOYSA-N traxanox Chemical compound C=1C(C(C2=CC=CN=C2O2)=O)=C2C(Cl)=CC=1C=1N=NNN=1 MLCGWPUVZKTVLO-UHFFFAOYSA-N 0.000 description 1
- 229950011638 traxanox Drugs 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229960004747 ubidecarenone Drugs 0.000 description 1
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Abstract
내용없음No content
Description
본 발명은 분무에 적합한 겔(Gel) 기제(基劑) (이하 분무용 겔 기재 라 함) 및 상기한 분무용 겔 기제를 활성 약물과 균일하게 혼합하여 제조된 분무에 적합한 겔제(gel preparation) (이하 분무용 겔제라 함)에 관한 것이다. 더욱 상세하게는 카르복시비닐 폴리머(carboxyvinyl polymer)(이하 CVP라 함) 수용액을 수용성 염기성 물질로 점성을 증대시켜 제조된 전착성(展着性)이 우수한 분무용 겔 기제 및 이 기제에 활성 약물을 균일하게 혼합하여 된 분무용 겔제에 관한 것이다.The present invention relates to a gel preparation suitable for spraying (hereinafter referred to as gel base for spraying) and a gel preparation suitable for spraying prepared by uniformly mixing the above-mentioned spraying gel base with an active drug (hereinafter for spraying Gel). More specifically, an electrodepositionable gel base having excellent electrodeposition properties, prepared by increasing the viscosity of an aqueous solution of a carboxyvinyl polymer (hereinafter referred to as CVP) with a water-soluble basic substance and uniformly dispensing the active drug thereon. It relates to a gel for spraying by mixing.
분사제로서 플루오르화 탄화수소 (hydrocarbon fluoride) [즉, 프레온 (Freon), 듀폰사의 상품명]를 이용한 에어로졸 (aerosol) 등의 분무제 및 수동 가압에 의한 활성 약물 수용액의 분무제 등이 현재 공지되어 있다. 이들 중에서 분사제로서 플루오르화 탄화수소 (프레온)를 사용하는 에어로졸은; (1) 분무된 활성 약물 또는 활성 약물을 함유하는 분말은 분무 부위에서 용해되어 약리 작용을 발휘하여야 하나 잘 용해되지 않으므로 에어로졸은 약리 작용을 최대한으로 발휘하는데 있어서 활성 약물 수용액으로 된 분무제 보다 뒤떨어지고. (2) 더욱이 플루오르화 탄화수소 자체와 가스 분무압 때문에 분무 부위에 대하여 물리적 자극이 있으며, (3) 그리고 플루오르화 탄화수소가 성층권 내에서의 오존(ozone) 함유량에 심각한 영향을 주므로, 사용 규제의 대상이 되고 있기 때문에 바람직하지 못하다.Sprays, such as aerosols and the like, using a fluorocarbon fluoride (i.e., Freon, a product of DuPont) as the propellant, and an active drug aqueous solution by manual pressurization, and the like are now known. Among these, aerosols using fluorinated hydrocarbons (freons) as propellants; (1) The sprayed active drug or powder containing the active drug must dissolve at the spray site to exert its pharmacological action, but it does not dissolve well, so the aerosol is inferior to the nebulizer of the active drug solution in order to maximize the pharmacological action. (2) furthermore, there is a physical irritation at the spray site due to the fluorinated hydrocarbons themselves and the gas atomization pressure, and (3) and because the fluorinated hydrocarbons have a severe effect on the ozone content in the stratosphere, It is not preferable because it becomes.
한편, 활성 약물의 수용액을 수동 가압으로 분무하는 분무제가 에어로졸에서의 상기한 결점을 가지고 있지 않더라도 다른 여러 가지 결점들이 있다. 즉, 활성약물 수용액의 분무가 전착성이 불량하므로 분무 부위에서부터 활성 약물 수용액이 흘러떨어지기 때문에 사용할 때에 불안감이 있게 되며, 고정된 부위에 활성 약물의 소요량을 투여할 수가 없고, 활성 약물이 물에 용해하지 않을 경우에는 활성 약물을 함유하는 제제를 균일하게 제조할 수가 없다On the other hand, there are a number of other drawbacks, although the nebulizer for spraying an aqueous solution of the active drug by manual press does not have the drawbacks mentioned above in the aerosol. In other words, the spray of the active drug solution has poor electrodeposition properties, so the active drug solution flows down from the spray site, resulting in anxiety when used, and the active drug cannot be administered to the fixed site. If not dissolved, the formulation containing the active drug cannot be prepared uniformly.
상기한 상황하에서 예컨대, 분무기의 분무 노즐의 크기를 최소화하여 분무시 입자크기를 훨씬 작게 하는 등의 몇가지 수단에 의해 액체 방울이 떨어지지 않도록 시도하고 있다. 그러나, 이러한 수단에 의해서도 액체 방울이 흘러떨어지는 문제는 아직도 해결되지 않고 있으므로 액체 방울이 흘러떨어지는 일이 없이 분무 부위에서 적절하게 소요량의 활성 약물을 유지할 수 있는 수단을 개발하고자 하는 연구가 수행되어 왔다.Under the above circumstances, for example, attempts have been made to prevent the liquid droplets from dropping by some means such as minimizing the size of the spray nozzle of the sprayer to make the particle size much smaller when spraying. However, the problem of the liquid drop still being solved by such means has not been solved. Therefore, studies have been conducted to develop a means for maintaining the required amount of the active drug properly at the spray site without the liquid drop flowing.
분무시에 활성 약물 수용액으로 된 분무제의 전착성을 개선하기 위해서는 일반적으로 증점제 (增粘濟)로서 널리 사용되고 있는 수용성 고분자 화합물, 예를 들어, 히드록시프로필 셀룰로오스, 히드록시프로필 메틸셀룰로오스, 폴리비닐 알코올, 폴리비닐 피롤리돈, 젤라틴, 알긴산 나트륨 등을 사용하면 상기한 활성 약물 수용액의 점도를 높이는데 효과적이다. 그러나, 본 발명자들의 연구에 따르면 이들 종래의 증점제들을 사용할 때는 활성 약물의 수용액은 분무기로부터 분사될 수 없거나, 그것이 분사될 수 있다 하더라도 그 분사액은 안개 같은 형태가 되지 않고 물기둥 같이 되므로 상기한 문제점은 이러한 수단으로서는 미해결인 채로 되어 있다.In order to improve the electrodeposition property of the spray agent which is an aqueous solution of the active drug at the time of spraying, a water-soluble high molecular compound generally used as a thickener, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol , Polyvinyl pyrrolidone, gelatin, sodium alginate and the like are effective in increasing the viscosity of the aqueous active drug solution. However, according to the researches of the present inventors, when using these conventional thickeners, the aqueous solution of the active drug cannot be sprayed from the sprayer, or even if it can be sprayed, the sprayed liquid does not become a misty form and becomes a water column. It remains unresolved as such a means.
분무용 제제에 대한 철저한 연구에서 본 발명자들은 수용성의 염기성 물질로 CVP 수용액의 점도를 증가시켜 제조된 겔 기제가 분무기에서의 분무성이 양호한 반면, 이렇게하여 제조된 겔 기제는 상기한 종래의 증점제를 사용하여 제조된 용액과 비교하여 높은 점도를 가지며, 또한 액의 흘러떨어짐도 생체에 적용하는 경우를 제외하고 상기한 겔 기제를 사용함으로써 방지할 수 있다는 것을 발견하였다. 그러나, 본 발명자들은 CVP로부터 만든 상기한 겔 기제에서 다음과 같은 결점을 발견하였다. 즉, 분무 전에 높은 CVP 용액의 점도는 분무를 함으로써 어느 정도 저하하게 되고, 점막이나 피부와 같은 생체에 적용하면 용액의 점도는 분무 부위에서 급격히 감소하여 액의 흘러떨어짐이나 함유된 소요량의 활성 약물을 적절하게 유지할 수 있다. 이상에서 말한 결점을 해결하기 위하여 본 발명자들은 CVP를 높은 비율로 사용함으로써 활성 약물 용액의 점도를 증가시키고자 시도하였으나 이 경우에 있어서 그것을 분무하는 데는 높은 분무압이 필요하였고, 적용 부위에서 높은 분무암으로 인해 자극이 있었다.In a thorough study of spray formulations, the inventors found that gel bases prepared by increasing the viscosity of a CVP aqueous solution with water-soluble basic materials have good sprayability in the sprayer, whereas the gel bases prepared in this way employ the conventional thickeners described above. It has been found that it has a high viscosity compared to the solution prepared in the above, and that the dripping of the liquid can also be prevented by using the gel base described above except in the case of application to a living body. However, the present inventors have found the following drawbacks in the above-described gel base made from CVP. That is, the viscosity of the high CVP solution before spraying is somewhat lowered by spraying, and when applied to a living body such as mucous membranes or skin, the viscosity of the solution decreases rapidly at the spraying site, and the liquid drips or contains the required amount of active drug. It can be maintained properly. In order to solve the above-mentioned drawbacks, the present inventors attempted to increase the viscosity of the active drug solution by using CVP at a high rate, but in this case, high spraying pressure was required to spray it, and high spraying cancer at the application site. There was a stimulus.
더욱이, 이러한 높은 점도를 가진 용액을 강제로 분무하면 용액의 입자 크기는 대단히 크게 되며,Moreover, forced spraying of such high viscosity solutions results in very large particle sizes of the solution,
용액의 점도가 더욱 높아지면 분무할 수 없게 된다.A higher viscosity of the solution makes it impossible to spray.
상기한 사정하에서 본 발명자들은 더욱 더 강도 높은 연구를 거듭한 결과, 비교적 높은 농도의 CVP를 함유하는 수용액을 수용성 염기물질로 점도를 증대시켜 비교적 높은 점도의 겔 (gel)을 얻은 다음 그 점도를 점도 조정제로 500-5,000 센티포이즈 (cp) (centipoise) 범위로 조정하면, 우수한 성질을 가진 소용의 분무용 겔 기제를 얻을 수 있다는 것을 뜻밖에 발견하였다. 즉, 상기한 방법으로 제조한 분무용 겔 기제는 분무 전후 사이에 점도변화가 작고 우수한 성질을 가진 소요의 분무용 겔 기제를 얻을 수 있다는 것을 뜻밖에 발견하였다. 즉, 상기한 방법으로 제조한 분무용 겔 기제는 분무 전후 사이에 점도변화가 작고 우수한 전착성을 나타내므로 그것을 점막이나 피부 같은 생체에 적용할 경우 적용 부위로부터 흘러떨어지는 일이 없다. 더욱이, 본 발명자들은 활성 약물과 상기한 겔 기제를 혼합하여 제조한 분무용 겔제는 또한 대단히 우수한 특성을 가지고 있어 점막이나, 피부 같은 생체에 대하여 계속해서 활성 약물을 방출할 수 있다는 것을 발견하였다.Under the circumstances described above, the inventors have made more and more intense studies and, as a result, the aqueous solution containing a relatively high concentration of CVP is increased to a water-soluble base material to obtain a gel having a relatively high viscosity, and then the viscosity is increased. It was unexpectedly found that by adjusting the range to 500-5,000 centipoise (cp) as a modifier, a useful spray gel base with good properties could be obtained. That is, it was unexpectedly found that the gel base for spraying prepared by the above-described method was able to obtain the required gel base for spraying having a small viscosity change and excellent properties between before and after spraying. In other words, the gel base for spraying prepared by the above-described method has a small viscosity change and excellent electrodeposition property between before and after spraying, so that when applied to a living body such as mucous membrane or skin, it does not flow from the application site. Furthermore, the present inventors have found that spray gels prepared by mixing the active drug with the gel bases described above also have very good properties and can continue to release the active drug against living organisms such as mucous membranes and skin.
본 발명의 목적은 수용성의 염기성 물질로 비교적 고농도의 CVP함유 수용액의 점도를 증대시킨 다음 증점된 용액의 점도를 점도 조정제로써 일정한 범위로 조정하여 제조되는 우수한 전착성과 생체 적용시 흘러내림이 없는 분무용 겔 기제를 제공함이 있다. 본 발명의 기타 목적은 생체에 적용했을 때 활성 약물의 우수한 흡수력을 가진 활성 약물과 상기한 겔 기제를 균일하게 혼합하여 제조한 분무용 겔제를 제공함에 있다. 본 발명의 여러 가지 목적과 장점들은 다음 설명에서부터 명백해질 것이다.It is an object of the present invention to increase the viscosity of a relatively high concentration of aqueous solution containing CVP with a water-soluble basic material, and then to adjust the viscosity of the thickened solution to a certain range as a viscosity modifier to prepare a good electrodeposition and spray-free spray gel in vivo application It provides a mechanism. Another object of the present invention to provide a spray gel prepared by uniformly mixing the active drug and the above-described gel base with an active drug having excellent absorption of the active drug when applied to a living body. Various objects and advantages of the present invention will become apparent from the following description.
본 발명은 CVP를 0.2-1.5 wt. % 함유하는 수용액을 수용성 염기물질로써 점도를 증대시키고, 그 점도를 점도 조정제로써 500-5,000 cp 범위내로 조정하여 분무 후의 분무 입도(粒度) 분포가 20-100 ㎕ 의 범위에서 80% 이상이 되게 한 활성 약물과 분무용 겔 기제 함유의 우수한 전착성을 가진 분무용 겔 기제를 제공한다.The present invention provides a CVP of 0.2-1.5 wt. The aqueous solution containing% was used to increase the viscosity with a water-soluble base material, and the viscosity was adjusted within the range of 500-5,000 cp with a viscosity modifier so that the spray particle size distribution after spraying was 80% or more in the range of 20-100 μl. Provided is a spray gel base having good electrodeposition properties comprising an active drug and a spray gel base.
이하, 본 발명을 더욱 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 분무용 겔 기제에서 사용된 CVP 는 아크릴산을 주(主)단량체 성분으로 하여 종합하여 제조되는 친수성 폴리머이고, 종래의 카아보폴(Carbopol) 934,934P, 940 및 941 [미합중국의 (Goorich사에서 시판)] 등을 포함한다. 본 발명에서 사용된 CVP 수용액의 농도는 일반적으로 0.2-1.5 wt. % 범위내에 있다.The CVP used in the spray gel base of the present invention is a hydrophilic polymer prepared by synthesizing acrylic acid as the main monomer component, and is manufactured by conventional Carbopol 934,934P, 940 and 941 [commercially available from Goorich, USA. )] And the like. The concentration of the CVP aqueous solution used in the present invention is generally 0.2-1.5 wt. It is in the range of%.
본 발명에서 사용된 수용성 염기물질은 CVP수용액을 증점(增粘)시켜 그의 점도를 증대시킬 목적으로 사용된다. 본 발명의 수용성 염기물질의 적절한 예로서는 무기 기제 (예 : 수산화 나트륨, 수산화 칼륨, 암모니아 등)와 유기 기제 [예 : 알칼아민 (예 : 메틸아민, 에틸아민, 프로필아민 등), 디알킬아민 (예 : 디메틸아민, 디에틸아민, 디프로필아민 등), 트리알킬아민 (예 : 트리메틸아민, 트리에틸아민, 트리프로필아민 등), 알칸올아민 (예 : 메탄올아민, 에탄올아민, 프로판올아민 등), 디알칸올아민 (예 : 디메탄올아민, 디에탄올아민, 디프로판올아민 등), 트리알칸올아민 (예: 트리메탄올아민, 트리에탄올아민, 트리프로판올아민 등), 아미노산 (예 아르기닌, 리신, 오르니틴 등)등]를 포함한다. 이들 수용성 염기들은 CVP수용액의 pH 값을 소망하는 pH 값으로 조정하기 위한 중성화에 필요한 양으로 사용된다.The water-soluble base material used in the present invention is used for the purpose of thickening the CVP aqueous solution to increase its viscosity. Suitable examples of the water-soluble base material of the present invention include inorganic bases (e.g. sodium hydroxide, potassium hydroxide, ammonia, etc.) and organic bases [e.g. alkalamines (e.g. methylamine, ethylamine, propylamine, etc.), dialkylamines (e.g. : Dimethylamine, diethylamine, dipropylamine, etc.), trialkylamines (such as trimethylamine, triethylamine, tripropylamine, etc.), alkanolamines (such as methanolamine, ethanolamine, propanolamine, etc.), Dialkanolamines (e.g. dimethanolamine, diethanolamine, dipropanolamine, etc.), trialkanolamines (e.g. trimethanolamine, triethanolamine, tripropanolamine, etc.), amino acids (e.g. arginine, lysine, ornithine, etc.) ), Etc.]. These water soluble bases are used in amounts necessary for neutralization to adjust the pH value of the CVP aqueous solution to the desired pH value.
본 발명의 점도 조정제는 CVP를 0.2-1.5 wt. % 함유하는 수용액을 수용성 염기물질로 증점시켜 제조된 비교적 고점성의 겔의 점도를 조정하여 분무 후의 분무 입도 분포가 20∼100㎛의 범위에서 80% 이상이 되도록 할 목적으로 사용된다. 본 발명의 적절한 점도 조정제는 예를 들어 염화 나트륨, 염화 칼륨, 염화 칼슘 같은 것들을 포함한다. 본 발명의 점도 조정제는 모든 성분의 총량에 대하여 0.01-10.2wt. % 의 비율로 사용되는 것이 바람직하다. 한편, 점막에 적용될 경우 점도 조정제의 양은 점도 조정제로 인한 삼투압의 변화를 고려하여 결정하여야 한다.The viscosity modifier of the present invention is a CVP 0.2-1.5 wt. It is used for the purpose of adjusting the viscosity of a relatively high viscosity gel prepared by thickening the aqueous solution containing% with a water-soluble base material so that the spray particle size distribution after spraying is 80% or more in the range of 20 to 100 µm. Suitable viscosity modifiers of the invention include, for example, sodium chloride, potassium chloride, calcium chloride and the like. The viscosity modifier of the present invention is 0.01-10.2 wt.% With respect to the total amount of all components. It is preferable to use it in the ratio of%. On the other hand, when applied to the mucosa, the amount of viscosity modifier should be determined in consideration of the change in osmotic pressure due to the viscosity modifier.
본 발명의 분무용 겔 기제의 점도를 조정함에 있어서 분무 후의 분무 입도 분포가 20-100㎛의 범위 안에서 80% 이상이 되도록 하는 것이 바람직하다. 분무 후의 분무 입도 분포가 상기한 범위내에 있는 경우에서만 본 발명의 분무용 겔 기제는 우수한 전착성을 가지며, 그 점도는 분무 전후에서 변하지 않는다.In adjusting the viscosity of the gel base for spraying of this invention, it is preferable to make the spray particle size distribution after spraying be 80% or more in the range of 20-100 micrometers. Only when the spray particle size distribution after spraying is in the said range, the spray gel base of this invention has the outstanding electrodeposition property, and the viscosity does not change before and behind spraying.
본 발명의 분무용 겔 기제는 교반하에 CVP를 0.2-1.5wt. % 함유하는 수용액에 수용성 염기물질을 첨가하고, 이 혼합물을 균일하게 혼합하여 점성겔을 제조한 다음 교반하에 점도 조정제를 첨가하여 소요의 점도를 얻음으로써 제조할 수 있다. 점도 조정제가 결정형태인 때에는 그대로 첨가할 수도 있으나, 수용액의 형태로 첨가되는 것이 더욱 바람직하다. 왜냐하면 수용액 형태로 첨가되면 점도의 급격한 변화가 없고 점도가 균일하게 변화하기 때문이다.The spray gel base of the present invention contains 0.2-1.5 wt. It can be prepared by adding a water-soluble base material to the aqueous solution containing%, uniformly mixing the mixture to prepare a viscous gel, and then adding a viscosity modifier under stirring to obtain the required viscosity. When a viscosity modifier is a crystalline form, it can also add as it is, but it is more preferable to add in the form of aqueous solution. This is because when added in the form of an aqueous solution, there is no sudden change in viscosity and the viscosity changes uniformly.
본 발명의 분무용 겔 기제의 pH 값은 활성 약물의 안정성 또는 흡수성을 고려하여 수용성 염기물질 또는 기타 pH 조정제로 조정한다.The pH value of the spray gel base of the present invention is adjusted with a water soluble base material or other pH adjuster taking into account the stability or absorbency of the active drug.
본 발명의 분무용 겔제는 CVP를 0.2-1.5 wt.% 함유하는 수용액을 수용성 염기물질로 증점시킨 다음, 활성 약물과 균일하게 혼합한 후 상기한 분무용 겔 기제와 같은 방법으로 혼합물의 점도를 조정하여 제조한다. 더욱이 활성 약물의 종류에 따라 본 발명의 분무용 겔제는 CVP를 0.2-1.5 wt.% 함유하는 수용액 중에 활성 약물을 먼저 용해 또는 분산시킨 다음 교반하에 수용성 염기물질을 첨가하여 균일하게 혼합한 후 상기와 같은 방법으로 혼합물의 점도를 조정하여 제조한다.The spray gel of the present invention is prepared by thickening an aqueous solution containing 0.2-1.5 wt.% CVP with a water-soluble base material, then uniformly mixing the active drug and adjusting the viscosity of the mixture in the same manner as the spray gel base described above. do. Furthermore, according to the type of active drug, the spray gel of the present invention first dissolves or disperses the active drug in an aqueous solution containing 0.2-1.5 wt.% Of CVP, and then uniformly mixes the same by adding a water-soluble base material under stirring. It is prepared by adjusting the viscosity of the mixture by the method.
수용성 및 수불용성의 약물 두가지를 본 발명의 활성 약물로서 사용할 수 있으나, 제제중에서, 즉 수용액 중에서 안정한 약물을 사용하는 것이 더욱 바람직하다. 본 발명의 적절한 활성 약물의 예로서는 최면제와 진정제 (예 : 그루테티미드, 클로랄 수화물, 니트라제팜, 아모바르비탈, 페노바르비탈 등), 해열, 진통 및 소염제 (예 : 아스피린, 아세트아미노펜, 이부프로펜, 플루르비프로펜, 인도메타신, 케토프로펜, 티클로페낙 나트륨, 염산 티알아미드, 피록시캉, 플루페남산, 메페남산, 펜타조신 등), 국소 마취제 (예 : 메틸 아미노벤조에이트, 리도카인 등), 국소 혈관수축제 (예: 질산 나파졸린, 질산 테트라졸린, 염산 옥시메타존, 염산 트라미졸린 등), 항알레르기제 (예 : 크로모글리크산이나트륨, 옥사토미드, 염산 아젤라스틴, 프마르산 케토티펜, 트락사녹스 나트륨, 암렉사녹스 등), 강심제 (예 : 염산 도파민, 유비데카레논 등), 항부정맥제 (예 :염산 프로프라놀롤, 핀드롤, 페니토인, 디소피라미드 등), 관상혈관 확장제 (예 : 질산 이소소르비드, 니페디핀, 염산 딜티아젬, 디피리다몰 등), 소화기관의 약 (예 : 돔페리돈 등), 부신피질 홀몬제 (예 : 트리암시놀론 아세토니드, 덱사메타존, 베타메타존소듐 포스페이트, 아세트산 프레도니솔론, 플루오시노니드, 프로피온산베클로메타존, 플루니솔리드 등), 항프라스민제 (예 : 트라넥삼산등), 항진균제 (예 : 클로트리마졸, 질산 미코나졸, 케토코나졸 등), 항악성종양제 (예 : 테가푸르, 플루오로우라실, 메르캅토푸린 등), 항생물질 (에 : 아목시실린, 암피실린, 세팔렉신, 세팔로틴 나트륨, 세프티족심 나트륨, 에리트로마이신, 염산 옥시테트라사이클린 등), 생리활성 펩티드 (예 : 인슐린, 연어 칼시토닌 등의 칼시토닌류, 병아리 칼시토닌 및 엘카토닌, 우로키나제, TRA, 인테페론 등), 왁진류 (예: 인플루엔자 왁진, 돼지 보르데텔라 감염증 예방 확진, B형 감염 왁진 등) 같은 것들을 포함한다. 본 발명의 분무용 겔제에서 사용된 활성 약물의 양은 약물의 종류에 따라 달라지나 활성 약물을 소용의 약리학적 활성을 발휘하는데 충분한 양으로 사용한다.Both water-soluble and water-insoluble drugs can be used as the active drugs of the present invention, but it is more preferable to use drugs which are stable in the preparation, ie in aqueous solution. Examples of suitable active drugs of the present invention include hypnotics and sedatives (e.g., glutetimides, chloral hydrates, nitrazepam, amobarbital, phenobarbital, etc.), antipyretic, analgesic and anti-inflammatory agents (e.g. aspirin, acetaminophen, ibuprofen, flur) Bipropene, Indomethacin, Ketoprofen, Thiclofenac Sodium, Thialamide, Pyroxycane, Flufenacic Acid, Mefenamic Acid, Pentazosin, etc., Local Anesthetics (e.g. Methyl Aminobenzoate, Lidocaine, etc.) ), Local vasoconstrictors (e.g. napazoline nitrate, tetrazoline nitrate, oxymetazone hydrochloride, tramizoline hydrochloride, etc.), anti-allergic agents (e.g. disodium chromoglycolate, oxatomid, azelastine hydrochloride, fructose Ketoxifene, sodium traxanox, amlexanox, etc.), cardiac agents (e.g., dopamine hydrochloride, ubidecarenone, etc.), antiarrhythmic agents (e.g., propranolol, pindrol, phenytoin, disopyramid, etc.), coronary blood Dilators (e.g. isosorbide nitrate, nifedipine, diltiazem hydrochloride, dipyridamole, etc.), drugs of the digestive system (e.g. domperidone, etc.), corticosteroids (e.g. triamcinolone acetonide, dexamethasone, betametha Zonsodium phosphate, predonisolone acetate, fluorinide, fluoropropionate beclomethasone, flunisolide, etc., antipramine (e.g., tranexamic acid), antifungal agents (e.g. clotrimazole, nitrate myconazole, ketoconazole Etc.), anti-malignant neoplastic agents (e.g. tegapur, fluorouracil, mercaptopurine, etc.), antibiotics (e.g. amoxicillin, ampicillin, cephalexin, cephalotin sodium, ceftizone sodium, erythromycin, hydrochloric acid) Oxytetracycline, etc.), bioactive peptides (e.g., calcitonins such as insulin, salmon calcitonin, chick calcitonin and elcatonin, urokinase, TRA, inteferon, etc.), waxes (e.g., influenza wax, swine) Reude include those such telra infection prevention confirmed, B-type infection wakjin etc.). The amount of active drug used in the spray gel of the present invention varies depending on the type of drug, but the active drug is used in an amount sufficient to exert a useful pharmacological activity.
본 발명에서 수불용성 약물을 사용하면 분무용 겔제는 백색으로 탁해지게 되나 활성 약물은 침강하지는 않고, 일상적인 투약에는 지장이 없다. 그러나 본 발명의 분무용 겔제를 피부 같은 것에 적용하여 생체에의 흡수가 고형보다 용액형에서 더 잘 될 경우에 있어서는 수용성 유기용매내에 미리 수불용성 약물을 용해하거나 용해제를 사용하여 분무용 겔제를 제조하는 것이 바람직하다. 적절한 수용성 유기용매로는 예를 들어 저급 알코올 (예: 에탄올, 이소프로판올 등), 글리콜류 (예:프로필렌글리콜, 1,3-부틸렌글리콜, 분자량 300-500의 폴리에틸렌글리콜 등) 같은 것을 포함한다. 적절한 용해제는 활성 약물의 용해도에 따라 여러 가지 계면활성제, 크로타미톤, 살리실화 글리콜 에스테르, 살리실산 메틸, 박하유, 벤질 알코올 등으로 구성된 군으로부터 선택된다.In the present invention, when the water-insoluble drug is used, the spray gel becomes cloudy in white, but the active drug does not settle, and there is no problem in daily administration. However, when the spray gel of the present invention is applied to a skin or the like and the absorption into the living body is better in a solid form than the solid, it is preferable to dissolve the water-insoluble drug in a water-soluble organic solvent or prepare a spray gel using a dissolving agent. Do. Suitable water soluble organic solvents include, for example, lower alcohols (eg ethanol, isopropanol, etc.), glycols (eg propylene glycol, 1,3-butylene glycol, polyethylene glycol having a molecular weight of 300-500, etc.). Suitable solubilizers are selected from the group consisting of various surfactants, crotamiton, salicylate glycol esters, methyl salicylate, peppermint oil, benzyl alcohol, and the like, depending on the solubility of the active drug.
한편, 본 발명에서 사용된 활성 약물은 적당한 현탁화제를 사용함으로써 현탁시킬 수가 있다. 적절한 현탁화제는 여러 가지 계면활성제가 포함되는데, 예컨대 수크로오스 지방산 에스테르, 폴리옥실 스테아레이트 40, 폴리옥시에틸렌 수소첨가 피마자유 60, 폴리소르베이트 80, 글리세린 모노스테아레이트, 소리비탄 모노스테아레이트, 소르비탄모노스테아레이트, 소르비탄 모노팔미테이트 같은 것들을 포함한다.On the other hand, the active drug used in the present invention can be suspended by using a suitable suspending agent. Suitable suspending agents include various surfactants, such as sucrose fatty acid esters, polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil 60, polysorbate 80, glycerin monostearate, voicebita monostearate, sorbitan Monostearate, sorbitan monopalmitate and the like.
본 발명의 분무용 겔 기제와 분무용 겔제의 점도를 염화 나트륨, 염화 칼륨, 염화 칼슘 등의 점도 조정제로 500-5,000cp의 범위내로 조정하는 것이 바람직하다. 본 발명의 분무용 겔 기제 또는 분무용 겔제의 점도가 500cp 이하이면 유동성이 너무 높기 때문에 점막이나 피부에 적용될 경우 액이 흘러떨어지게 된다. 한편, 본 발명의 분무용 기제 또는 분무용 겔제의 점도가 5,000cp 이상이면 분무 후의 입자 크기가 불규칙하고 크기 때문에 활성 약물의 소망한 효력을 잘 나타내기에는 부적합하다. 본 발명의 분무용 기제 또는 분무용 겔제의 점도는 800-3,000cp 범위 이내인 것이 더욱 바람직하다.It is preferable to adjust the viscosity of the spray gel base and the spray gel of the present invention within the range of 500-5,000 cps with a viscosity modifier such as sodium chloride, potassium chloride or calcium chloride. When the viscosity of the spray gel base or spray gel of the present invention is 500 cps or less, the fluidity is too high, and when applied to mucous membranes or skin, the liquid flows down. On the other hand, when the viscosity of the spray base or spray gel of the present invention is 5,000 cps or more, the particle size after spraying is irregular and large, which is not suitable for showing the desired effect of the active drug well. More preferably, the viscosity of the spray base or spray gel of the present invention is within the range of 800-3,000 cp.
본 발명의 분무용 겔제는 종래의 방법에 따라 비강점막, 구강점막, 질점막 및 피부에 적용될 수 있다. 점도 조정제를 쓰지 않고 제조된 겔제 또는 CVP 겔 기제 혹은 종래의 수용성 고분자 화합물을 사용하여 제조된 제제와 비교하면 본 발명의 분무용 겔 기제와 분무용 겔제는 입자크기가 훨씬 균일하고 분무 전후 사이의 점도의 변화가 적기 때문에 전착성이 우수하고 분무후 액이 흘러떨어지는 일이 없다.Spray gel of the present invention can be applied to the nasal mucosa, oral mucosa, vaginal mucosa and skin according to the conventional method. Compared with gels prepared without the use of viscosity modifiers or with CVP gel bases or formulations prepared using conventional water-soluble polymer compounds, the spray gel bases and spray gels of the present invention have a much more uniform particle size and change in viscosity between before and after spraying. Because of the small amount, the electrodepositability is excellent and the liquid does not flow down after spraying.
더욱이, 본 발명의 분무용 겔제는 의료용에도 유용하다. 예를 들어서, 본 발명에 따라 제조된 인플루엔저 왁진의 분무용 겔저를 비강 점막에 적용할 수가 있으며 종래의 인플루엔자 왁진의 투약 형태보다 더욱 바람직하다.Moreover, the spray gel of the present invention is also useful for medical use. For example, spray gels of influenza wax prepared according to the present invention can be applied to the nasal mucosa and are more preferred than the dosage forms of conventional influenza waxes.
이제까지 인플루엔저 왁진은 피하주사로 투여되어 왔는데, 그 이유는 인플루엔자 왁진은 고분자량의 폴리펩티드이어서 막투과성이 불량하고, 소화관내에서 분해되는 경향이 있으며, 생체에 흡수되기 어렵고, 더욱이 경구 투여시 인플루엔저 왁진의 접종은 혈액내의 항균 항체의 생성 (체액 면역)에 목적을 두고 있기 때문이다.Until now, influenza waxes have been administered by subcutaneous injection, because influenza waxes are high molecular weight polypeptides, which have poor membrane permeability, tend to degrade in the digestive tract, are difficult to be absorbed by living bodies, and moreover, influenza when administered orally This is because the inoculation of Luenzer wax is aimed at the production of antimicrobial antibodies in the blood (fluid immunity).
근본적으로 인플루엔저균은 호흡관의 점막에서만 감염 (국소 감염)을 하므로 혈액내에서 항체를 생성하는 것보다 호흡관의 점막에 항체 (I gA 항체)를 생성하는 것이 더욱 효과적이다. 그러나, 종래의 피하접종에서는 호흡관의 점막은 자극되지 않으므로 분비 I gA를 얻어질 수 있다. 또한, 피하접종은 그 부작용으로 인해 사용이 제한되어 있으며, 감염예방에 충분항 양의 인플루엔저 왁진을 접종할 수 없기 때문에 항체반응 레벨은 적절하지 않고 그 지속시간도 짧다.Essentially, influenza bacteria infect only the mucous membrane of the respiratory tract (local infection), so it is more effective to produce antibodies (I gA antibodies) on the mucous membrane of the respiratory tract than to produce antibodies in the blood. However, in conventional subcutaneous inoculation, secretion I gA can be obtained since the mucous membrane of the respiratory tract is not irritated. In addition, subcutaneous vaccination is limited in use due to its side effects, and the antibody response level is not appropriate and the duration is short, because a sufficient amount of influenza wax cannot be inoculated to prevent infection.
더욱이 인플루엔저균은 향원변위를 일으키면서 유행하기 때문에 왁진 중의 항원종류가 유행하는 균의 항원 종류와 상이하면 왁진의 예방 효과는 감소된다.In addition, because influenza bacteria are prevalent as they cause fragrance displacement, if the types of antigens in waxes are different from those of prevalent bacteria, the prevention effect of waxes is reduced.
종래의 인플루엔저 왁진의 투여제형의 상기한 결점을 개량하기 위하여 그의 새로운 유형의 왁진 또는 그 투여제형을 개발하려고 노력하여 왔다. 비강(코구멍)으로의 투여는 하나의 감염 루우트인 호흡관에서 분비 I gA항체를 유도 하는 것이 될 수 있으며 감염저지에 유효하다.In order to ameliorate the above drawbacks of conventional influenza wax dosage forms, efforts have been made to develop new types of waxes or dosage forms thereof. Administration into the nasal cavity (nasal cavity) may induce secretory I gA antibodies in the respiratory tract, one infectious route and is effective in preventing infection.
그러나 인플루엔저 왁진을 단독으로 또는 인플루엔저 왁진 수용액을 분무하여 호흡관에서 높은 레벨의 분비 I gA를 얻는다는 것은 어렵다. 그 이유는 인플루엔저 왁진은 고분자량의 폴리펩티드이기 때문에 호흡관 점막에서의 침투성이 낮고, 그리고 점액분비, 상피마모, 융모(villus)운동 등의 호흡관 점막의 정화 메카니즘에 의한 호흡관 점막에서의 인플루엔저 왁진의 흡수가 곤란하기 때문이다.However, it is difficult to obtain high levels of secreted I gA in the respiratory tract by spraying the influenza wax alone or by spraying the influenza wax aqueous solution. The reason is that because influenza wax is a high molecular weight polypeptide, it has low permeability in the respiratory tract mucosa, and in respiratory tract mucosa due to the purifying mechanism of the respiratory tract mucosa such as mucus secretion, epithelial wear, villius movement, etc. This is because absorption of influenza wax is difficult.
본 발명의 인플루엔저 왁진의 비강 분무용 겔제는 위에서 설명한 분무용 겔 기제와 인플루엔저 왁진을 혼합하여 제조할 수 있다. 본 발명에서 사용된 인플루엔저 왁진은 독성 약화된 왁진 또는 그의 비활성 왁진 중의 어느 것이라도 좋다.The nasal spray gel of the influenza wax of the present invention may be prepared by mixing the spray gel base and the influenza wax described above. The influenza wax used in the present invention may be either a toxic weakened wax or an inactive wax thereof.
독성 약화된 왁진을 사용할 때는 에테르 처리에 의하여 지방질 성분을 제거하여 만든 HA왁진이거나, 에테르 처리하지 않은 바이러스 입자 왁진이어도 좋다.When using toxic weakened wax, it may be H A wax made by removing fat component by ether treatment or viral particle wax without ether treatment.
더욱이, 본 발명에서 사용한 인플루엔저 왁진은 신형인 한랭적응 생왁진, 인공막왁진, 유전자 조작 왁진, 펩티드 왁진 같은 것들을 포함한다.Moreover, influenza waxes used in the present invention include those such as new cold-adapted fresh waxes, artificial waxes, genetically modified waxes, and peptide waxes.
본 발명에 따라 제조된 인플루엔저 왁진의 비강 분무용 겔제는 인플루엔저 왁진과 함께 사용될 수 있는 적당한 활성 약물, 살균제, 방부제, 계면 활성제, 안정제 등을 함유할 수 있다.Nasal spray gels of influenza waxes prepared according to the present invention may contain suitable active drugs, fungicides, preservatives, surfactants, stabilizers and the like that can be used with influenza waxes.
본 발명을 다음의 실시예에, 참고예 및 실험예에 따라 더욱 상세하게 설명하게 될 것이나, 거기에 한정되는 것으로 생각해서는 안 된다. 다음의 실험예나 참고예와 실시예에서는 점도는 20℃에서 C형 점도계 [일본국의 Tokyo Keiki(주)제]로 측정하였다.The present invention will be described in more detail in the following examples with reference examples and experimental examples, but should not be construed as being limited thereto. In the following experimental example, the reference example, and the Example, the viscosity was measured with C-type viscosity meter [made by Tokyo Keiki Co., Ltd. of Japan] at 20 degreeC.
실험예Experimental Example
다음의 여러 가지 증점제와 정제수를 사용하여 제조한 여러 가지 기제에서 분무 시험을 하였고, 기제의 특성은 분무상태, 점도 유지율, 전착성, 피부 전착성으로 측정하였다. 그 결과는 제 1표에 나와 있다.The spray test was carried out on various bases prepared using the following various thickeners and purified water, and the properties of the bases were measured by spray state, viscosity retention, electrodeposition, and skin electrodeposition. The results are shown in Table 1.
[표 1]TABLE 1
HPMC : 히드록시프로필 메틸셀룰로오스HPMC: hydroxypropyl methylcellulose
HPC : 히드록시프로필 셀룰로오스HPC: Hydroxypropyl Cellulose
PVA : 폴리비닐 알코올PVA: Polyvinyl Alcohol
PVP : 폴리비닐 피롤리돈PVP: Polyvinyl Pyrrolidone
*) 분무상태는 다음 기준에 따라 평가하였음.*) Spray condition was evaluated according to the following criteria.
불량 1: 분무기에서 분출 않음Poor 1: No ejection from sprayer
불량 2: 분무기에서 분출한 용액상태는 입자가 아니고 물기둥 이었음.Poor 2: The solution from the sprayer was not a particle but a column of water.
불량 3: 분무기에서 분출하였으나, 입자가 너무 큼.Poor 3: Ejected from sprayer, but too large particles.
양호 : 분무기에서 균일하게 분출하였고, 입자가 작음.Good: Uniformly ejected from the sprayer, small particles.
**) 점도 유지율은 다음 식에 따라 구하였음.**) Viscosity retention was calculated according to the following equation.
***) 전착성 시험은 다음 방법으로 하였다.***) The electrodeposition test was carried out in the following manner.
생리식염수 (1.5g)를 침투시킨 여과지 6호 (직경 : 110 ㎜)를 각도 40도의 경사판에 붙인 다음 30㎜ 떨어진 거리에서 분무기의 내용물 (600 ㎎)을 여과지의 중심을 향하여 분무한 후, 액이 흘러떨어지기 시작할 때까지의 시간 (초)을 측정하였다. 액의 흘러떨어지지 않았을 때는 무변화로 평가하였다.Filter paper No. 6 (diameter: 110 mm) infiltrated with saline solution (1.5 g) was attached to an inclined plate at an angle of 40 degrees, and then sprayed the contents of the sprayer (600 mg) toward the center of the filter paper at a distance of 30 mm, and then the liquid The time (seconds) until starting to flow was measured. When the liquid did not flow out, it was evaluated as no change.
****)피부 전착성은 다음 방법으로 평가하였다.****) Skin electrodeposition was evaluated by the following method.
분무기의 내용물 (180㎎)을 사람의 상부 팔뚝 안쪽에다 30㎜ 거리에서 분무한 후 10초 내에 액이 흘러떨어졌을 경우에는 흘러떨어짐 이라고 평가하였고, 분무후 10초 동안 액이 흘러떨어지지 않았을 경우에는 점착 (粘着)함으로 평가하였다.After spraying the contents of the sprayer (180mg) inside the upper forearm of a person at a distance of 30mm, if the liquid spilled within 10 seconds, it was regarded as dripping, and if the liquid did not flow for 10 seconds after spraying, Evaluated by
제 1표에서 명백한 바와 같이, 본 발명 (CVP 0.4 % + NaCl 0.27% 및 CVP 0.6 + NaCl 0.45%)에 따라 제조된 겔 기제만이 분무상태, 점도 유지율, 판과 인간피부에 대한 전착성이 모두 양호하였다.As is clear from Table 1, only the gel base prepared according to the present invention (CVP 0.4% + NaCl 0.27% and CVP 0.6 + NaCl 0.45%) has all spraying state, viscosity retention, electrodeposition to plate and human skin. It was good.
실시예 1Example 1
케토프로펜 (Ketoprophen)의 분무용 겔제 :Gel gel for spraying of ketoprophen:
케토프로펜의 분무용 겔제는 다음과 같은 양의 성분을 사용하여 제조하였다.Ketoprofen spray gel was prepared using the following amounts of ingredients.
CVP 4%수용액에 교반하면서 수산화 나트륨 2% 수용액을 서서히 첨가하고 겔이 될 때까지 혼합물을 교반하였다. 혼합물에 디소디움 에데테이트 (disodiumedetate) 1%수용액을 첨가한 다음, 케토프로펜을 폴리소트베이트 80과 정제수에 현탁시킨 현탁액을 서서히 첨가하여 균일하게 교반하였다. 이 혼합물의 점도를 염화 나트륨 10% 수용액으로 조정한 다음 이 혼합물을 균일히 교반하고 잘 혼합함으로써 케토프로펜의 분무용 겔제 (3%, pH : 6.8, 점도 : 3,800 cp)를 제조하였다.To the CVP 4% aqueous solution was slowly added an aqueous 2% sodium hydroxide solution while stirring and the mixture was stirred until it became a gel. A 1% aqueous solution of disodiumedetate was added to the mixture, followed by the slow addition of a suspension in which ketoprofen was suspended in polysorbate 80 and purified water, and then stirred uniformly. Kerosene spray gel (3%, pH: 6.8, viscosity: 3,800 cps) was prepared by adjusting the viscosity of this mixture with an aqueous 10% sodium chloride solution and then stirring the mixture uniformly and mixing well.
실시예 2Example 2
질산 테트라졸린 분무용 겔제 :Gel for spraying nitrate tetrazoline:
질산 테트라졸린 분무용 겔제는 다음과 같은 양의 성분을 사용하여 제조하였다.Gel for spray tetranitrate nitrate was prepared using the following amounts of ingredients.
CVP 4% 수용액에 교반하면서 L-아르기닌 2% 수용액을 서서히 첨가하고, 이 혼합물을 겔이 되기까지 교반하였다. 정제수에 용해된 질산 테트라졸린을 서서히 첨가하고 이 혼합물을 균일히 교반한 후, 이 혼합물의 점도를 염화 나트륨 10% 수용액으로 조정하고, 이 혼합물을 균일하게 교반 혼합하여 질산 테트라졸린의 분무용 겔제 (0.1 %, pH : 5.8, 점도 : 4,500 cp)를 제조하였다.To the CVP 4% aqueous solution was slowly added a 2% aqueous solution of L-arginine, and the mixture was stirred until it became a gel. Tetrazoline nitrate dissolved in purified water was slowly added and the mixture was stirred uniformly, and then the viscosity of the mixture was adjusted to 10% aqueous sodium chloride solution, and the mixture was stirred and mixed uniformly to spray gel of tetrazoline nitrate (0.1 %, pH: 5.8, viscosity: 4,500 cps).
실시예 3Example 3
크로모글리크산 이나트륨의 분무용 겔제 :Gel for spraying disodium chromoglycolate:
크로모글리크산 이나트륨의 분무용 겔제를 다음과 같은 양의 성분을 사용하여서 제조하였다.Spray gels of disodium chromoglycolate were prepared using the following amounts of ingredients.
CVP 4% 수용액에 교반하면서 2% 수산화 나트륨 2% 수용액을 서서히 첨가하고, 이 혼합물을 겔이 될 때까지 교반하였다. 혼합물에 디소디움 에데테이트 1% 수용액을 첨가하고, 글리세린과 정제수에 크로모글리크산 이나트륨을 첨가하여서 된 용액을 가하여 균일하게 교반하였다. 이 혼합물의 점도를 10% 염화 나트륨, 10% 수용액으로 조정하고 균일하게 교반 혼합하여 크로모글리크산 이나트륨의 분무용 겔제 (2%, pH : 6.0, 점도 : 1,500cp)를 제조하였다.2% aqueous sodium hydroxide 2% solution was slowly added to the CVP 4% aqueous solution while stirring, and the mixture was stirred until it became a gel. A 1% aqueous solution of disodium edetate was added to the mixture, and a solution obtained by adding sodium chromoglycolate to glycerin and purified water was added and stirred uniformly. The viscosity of this mixture was adjusted to 10% sodium chloride, 10% aqueous solution, and uniformly stirred and mixed to prepare a gel for spraying disodium chromoglycolate (2%, pH: 6.0, viscosity: 1500cp).
실시예 4Example 4
옥사토미드이 분무용 겔제 :Oxatomide spray gel:
옥사토미드의 분무용 겔제를 다음과 같은 양의 성분을 사용하여 제조하였다.A spray gel of oxatomid was prepared using the following amounts of ingredients.
CVP 4%수용액에 교반하면서 L-아르기닌 2% 수용액을 서서히 첨가하고, 이 혼합물이 겔이 될 때까지 교반하였다. 이 혼합물이 폴리소르베이트 80과 정제수에 옥사토미드를 가해서 된 현탁액을 서서히 첨가하여 균일하게 교반하였다. 혼합물의 점도를 염화 나트륨 10% 수용액으로 조정하고 균일하게 교반 혼합하여 옥사토미드의 분무용 겔제 (0.01%, pH : 5.1, 점도 : 1,500 cp )를 제조하였다.To the CVP 4% aqueous solution, an aqueous 2% aqueous solution of L-arginine was slowly added while stirring until the mixture became a gel. The mixture was added to polysorbate 80 and purified water, and the suspension obtained by adding oxatomid was gradually added and stirred uniformly. The viscosity of the mixture was adjusted with an aqueous 10% sodium chloride solution and uniformly stirred to prepare a gel for spraying oxatomide (0.01%, pH: 5.1, viscosity: 1500 cps).
실시예 5Example 5
프로피온산 베클로메타존 분무용 겔제 :Gel for spraying propionic acid beclomethasone:
프로피온산 베클로메타존의 분무용 겔제를 다음과 같은 양의 성분을 사용하여서 제조하였다.Spray gel of propionic acid beclomethasone was prepared using the following amount of components.
CVP 4% 수용액에 교반하면서 수산화 나트륨 2% 수용액을 서서히 첨가하고, 이 혼합물을 겔이 될 때까지Slowly add 2% aqueous sodium hydroxide solution to the CVP 4% aqueous solution, stirring until the mixture becomes a gel.
교반하였다. 혼합물에 서서히 폴리소르베이트 80, 진한 글리세린 및 정제수에 프로피온산 베클로메타존을 가해Stirred. Slowly add polysorbate 80, concentrated glycerin and beclometazone propionate to purified water
서 된 현탁액을 서서히 첨가하여 균일하게 교반하였다.The suspension was slowly added and stirred uniformly.
이 혼합물의 점도를 염화 나트륨 10% 수용액으로 조정하고, 균일하게 교반 혼합하여 프로피온산 베클로메타The viscosity of this mixture was adjusted to 10% aqueous sodium chloride solution, uniformly stirred and mixed, and propionate beclometa.
존의 분무용 겔제 (0.1%, pH : 6.0, 점도 : 2,500 cp )를 제조하였다.Zone spray gel (0.1%, pH: 6.0, viscosity: 2500 cps) was prepared.
실시예 6Example 6
폴니솔리드의 분무용 겔제 :Polyniside Spray Gel:
폴니솔리드의 분무용 겔제를 다음과 같은 양의 성분을 사용하여 제조하였다.Polynilide's spray gel was prepared using the following amounts of ingredients.
CVP 4% 수용액에 교반하면서, 수산화 나트륨 2% 수용액을 서서히 첨가하고 이 혼합물이 겔이 되기까지 교반하였다. 혼합물에 디소디움 에데테이트 1% 수용액과 염화 벨즈알코늄 0.1%수용액을 첨가한 다음 폴리소르베이트 80, 폴리에틸렌 글리콜 및 정제수에 폴니솔리드를 가해서된 용액을 서서히 첨가하고 균일하게 교반하였다.While stirring to a 4% aqueous solution of CVP, an aqueous 2% sodium hydroxide solution was slowly added and stirred until the mixture became a gel. A 1% aqueous solution of disodium edetate and 0.1% aqueous solution of belsalkonium chloride were added to the mixture, followed by the addition of polysorbate 80, polyglycolide to polyethylene glycol and purified water, and agitation.
혼합물의 점도를 염화 나트륨의 10%수용액으로 조정하고 이 혼합물을 균일하게 교반 혼합하여, 폴니솔리드의 분무용 겔제 (0.0255 %, pH : 5.1, 점도 : 2,200 cp )를 제조하였다.The viscosity of the mixture was adjusted to a 10% aqueous solution of sodium chloride and the mixture was stirred and mixed uniformly to prepare polynisole's spray gel (0.0255%, pH: 5.1, viscosity: 2,200 cps).
실시예 7Example 7
인슐린의 분무용 겔제 :Gel for spraying insulin:
인슐린의 분무용 겔제를 다음과 같은 양의 성분을 사용하여 제조하였다.Spray gels of insulin were prepared using the following amounts of ingredients.
CVP 4% 수용액에 교반하면서 L-아르기닌 4% 수용액을 서서히 첨가하고, 이 혼합물을 겔이 될 때까지 교반하였다. 이 혼합물에 정제수에 인슐린을 가해서 된 용액을 서서히 첨가하여 균일하게 교반하였다. 이 혼합물의 점도를 염화나트륨 10% 수용액으로 조정하고, 균일하게 교반 혼합하여 인슐린의 분무용 겔제 (50 U/g pH: 7.3, 점도 : 550 cp)를 제조하였다.L-arginine 4% aqueous solution was added slowly, stirring to CVP 4% aqueous solution, and this mixture was stirred until it became a gel. To this mixture, a solution obtained by adding insulin to purified water was slowly added and stirred uniformly. The viscosity of this mixture was adjusted with an aqueous 10% sodium chloride solution and uniformly stirred to prepare a spray gel of insulin (50 U / g pH: 7.3, viscosity: 550 cps).
실시예 8Example 8
인플루엔저 HA왁진의 비강 분무용 겔제 :Gel for nasal spraying of influenza H A waxes:
인플루엔저 HA왁진의 비강 분무용 겔제를 다음과 같은 양의 성분을 사용하여 제조하였다.Nasal spray gels of influenza H A waxes were prepared using the following amounts of ingredients.
CVP 4% 수용액에 교반하면서 L-아르긴 4% 수용액을 서서히 첨가하고, 이 혼합물이 겔이 될 때까지 교반하였다. 이 혼합물에 인산 완충액에 인플루엔저 HA왁진을 가해서 된 용액을 서서히 첨가하여 균일하게 교반하였다.L-argin 4% aqueous solution was slowly added to the CVP 4% aqueous solution while stirring, and the mixture was stirred until it became a gel. To the mixture was slowly added a solution obtained by adding influenza H A wax to the phosphate buffer and stirred uniformly.
이 혼합물의 점도를 정제수에 염화 나트륨을 가해서 된 용액으로 조정하고 이 혼합물을 균일하게 교반 혼합하여 인플루엔저 HA왁진의 비강 분무용 겔제 (249 ㎍ 단백질/ml , pH : 7.2, 점도 : 2,900cp)를 제조하였다.The viscosity of this mixture was adjusted to a solution obtained by adding sodium chloride to purified water, and the mixture was uniformly stirred and mixed to obtain a nasal spray gel of influenza H A wax (249 μg protein / ml, pH: 7.2, viscosity: 2,900 cps). Was prepared.
실시예 9-11Example 9-11
인플루엔저 HA왁진 (A/야마가타/120/86)비강 분무용 겔제를 다음 제 2표에서의 성분량을 사용하여 제조하였다.Influenza H A wax (A / Yamagata / 120/86) Nasal spray gels were prepared using the amounts of ingredients in the following table.
[표 2]TABLE 2
*) A/야마가타/120/86, 500㎍ 단백질 /ml*) A / Yamagata / 120/86, 500µg Protein / ml
CVP 4% 수용액에 교반하면서 L-아르기닌 8% 수용액을 서서히 첨가하고, 이 혼합물이 겔이 될 때까지 교반하였다. 이 혼합물에 정제수에 염화 나트륨을 가해서 된 용액을 서서히 첨가하고, 균일하게 교반 혼합하여 분무용 기제를 제조하였다. 이렇게 제조된 분무용 겔 기제를 고압 증기 멸균처리 (121℃,20분 )한 다음 인플루엔저 HA왁진용액 (500㎍ 단백질/ ml)관 균일하게 혼합한 후 무균 조건하에서 농축하여 인플루엔저 HA왁진의 비강 분무용 겔제를 제조하였다.To the CVP 4% aqueous solution was slowly added an aqueous 8% aqueous solution of L-arginine and stirred until the mixture became a gel. A solution obtained by adding sodium chloride to purified water was slowly added to the mixture, followed by uniformly stirring to prepare a base for spraying. The spray gel base thus prepared was subjected to high pressure steam sterilization (121 ° C., 20 minutes), and then uniformly mixed with influenza H A wax solution (500 μg protein / ml) and concentrated under aseptic conditions to influenza H A. Wax nasal spray gels were prepared.
참고예 1Reference Example 1
인플루엔저 HA왁진 (A/야마가타/120/86)을 인산 완충액 (pH : 7.4)에 용해하여 인플루엔저 HA왁진의 비강Influenza Me H A wakjin (A / Yamagata / 120/86), a phosphate buffer solution (pH: 7.4) influenza that H A was dissolved in the wax spirit nasal
분무용 제제 (24㎍ 단백질/㎖)를 제조하였다.Spray formulations (24 μg protein / ml) were prepared.
참고예 2Reference Example 2
인플루엔저 HA왁진 (A/야마가타/120/86)은 인산 완충액 (pH : 7.3)에 용해하여, 인플루엔저 HA왁진의 비강 분무용 제제 (250㎍ 단백질/ ㎖)를 제조 하였다.Influenza H A wax (A / Yamagata / 120/86) was dissolved in phosphate buffer (pH: 7.3) to prepare a nasal spray formulation (250 μg protein / ml) of influenza H A wax.
약리학적 시험Pharmacological test
실시예 (8∼11)에서 제조된 인플루엔저 HA왁진의 비강 분무용 겔제와 참고예 1과 2에서 제조된 인플루엔저 HA왁진의 비강 분무용 제제를 사용하여 다음의 약리학적 시험을 하였다.The following pharmacological test was carried out using the nasal spray gel of the influenza H A waxes prepared in Examples (8 to 11) and the nasal spray formulations of the influenza H A waxes prepared in Reference Examples 1 and 2.
(방 법)(Way)
(1) 면역법 :(1) Immunology:
BALB/C마우스에 넴부탈 (Nembutal) 주사액 (소디움 페토바르비튜레이트, 15배희석액)을 복강내에 주사Intraperitoneal injection of Nembutal injection (sodium fetobarbiturate, 15-fold diluent) into BALB / C mice
(0.2-0.3㎖/마리)하여 마취시켰다.(0.2-0.3 ml / mar) and anesthetized.
마취된 BALB/C 마우스의 비강을 위쪽으로 돌려 비강의 하나에 제젤 투여 (20 ㎍마리)하였다.The nasal passages of anesthetized BALB / C mice were turned upward and gelled (20 μg) into one of the nasal passages.
(2) 샘플링법 :(2) Sampling Method:
면역후 3주째에 마우스로부터 혈구응집 반응 억제 항체값 (간단히 HI 항체값 이라 함)측정용 혈청을 채취 (전혈 채취)하고, 흉부를 절개하여 기관 (氣管)을 노출시켰다. 턱 아래의 기관의 정상부로부터 폐쪽을 향하여 항 IgA 항체의 희석액 (1 ㎖ )을 기관속으로 주입하여 서서히 흡안케하였다. 이러한 흡인과 주입을 반복하여 샘플들을 채취하였다.At 3 weeks post-immunization, blood serum was collected (whole blood) for measurement of hemagglutination inhibitory antibody value (hereinafter, simply referred to as HI antibody value), and the thoracic incision was exposed to trachea. Dilution of anti-IgA antibody (1 ml) was injected into the trachea from the top of the trachea under the jaw toward the lungs, and was slowly absorbed. Samples were taken by repeating this suction and injection.
(3) HI 항체값 측정법 :(3) HI antibody value measurement method:
혈청시료 (0.1 ㎖)를 수용체 파괴 효소 (RED) (뉴우라미니다아제, 0.3 ㎖)로 처리하여, 37℃에서 하룻밤 유지한 다음, 56℃에서 1시간 부동화 처리를 하였다. 여기에 닭의 적혈구를 한 방울 첨가하고, 이 혼합물을 진탕하여 실온에서 1시간 방치한 후, 원심 분리기 (2,000 rpm, 10분간)에서 상청액을 회수 하였다. 측정에 사용된 균주의 항원량을 16 HA로 조정하였다. 마이크로 플레이트 (microplate) 의 96웰 (well)위 첫 번째 웰을 제외하고, 전부에 인산 완충액 (0.025 ㎖)을 각각 주입하였다. 첫 번째 웰에는 시료 (0.05 ㎖)를 넣었다. 모든 웰 속의 샘플들을 자동 희석기로 희석하였다. 16 HA로 조종된 량의 항원액 (0.025 ㎖)을 마이크로플레이트의 모든 웰에 주입하고, 플레이트 믹서로 플레이트를 충분히 진탕한 후 1시간 방치하였다. 0.5%의 혈구 (0.05㎖)를 모든 웰에 첨가한 후, 다시 플레이트를 진탕한 후, 1시간 방치한 다음 각 웰 바닥의 형상을 관찰하였다.Serum samples (0.1 mL) were treated with receptor disrupting enzyme (RED) (neuuraminidase, 0.3 mL), kept at 37 ° C. overnight, followed by passivation at 56 ° C. for 1 hour. One drop of chicken red blood cells was added thereto, and the mixture was shaken and left at room temperature for 1 hour, after which the supernatant was collected in a centrifuge (2,000 rpm, 10 minutes). The antigen amount of the strain used for the measurement was adjusted to 16 H A. Phosphate buffer (0.025 mL) was injected into the whole, except for the first well above the 96 wells of the microplate. In the first well a sample (0.05 ml) was placed. Samples in all wells were diluted with an automatic dilutor. The amount of antigen solution (0.025 ml) steered to 16 H A was injected into all wells of the microplate, and the plate was shaken with a plate mixer for 1 hour. 0.5% of blood cells (0.05 ml) was added to all wells, then the plate was shaken again, left for 1 hour and the shape of each well bottom was observed.
(4) IgA 시험법 :(4) IgA test method:
다이나텍 임뮬론 II플랫바텀 플레이트 (Dynatech Immulon II Flatbottom Plates)를 사용하여 0.05M 탄산 수소염 완충액 (pH : 9.5 )으로 희석하여 , 최적농도 (약 1-10㎍/㎖)로 한 HANA항원을 100㎕의 량으로 상기한 플레이트의 각 웰에 주입한 다음 4℃에서 하룻밤 (약 18시간)방치하였다. 그 다음날, 플레이트를 0.05% Tween 20을 함유하는 0.01M 인산 완충액 (pH : 7.2)으로 3회 세척한 다음, 0.1% BSA (소혈청 알부민)을 함유하는 인산 완충액을 써서 37℃에서 1시간 처리함으로써 블로킹하여 항원 고형상을 만들었다. HANA 항원 대신에 혈청노액을 사용한 것을 제외하고 상기와 같은 방법으로 대조용 플레이트를 제조하였다.HANA antigen was diluted to 0.05 M carbonate buffer (pH: 9.5) using Dynatech Immulon II Flatbottom Plates to obtain an optimal concentration (approximately 1-10 μg / ml). The wells were injected into each well of the plates described above and left overnight at 4 ° C. (about 18 hours). The next day, the plates were washed three times with 0.01 M phosphate buffer (pH: 7.2) containing 0.05% Tween 20 and then treated at 37 ° C. for 1 hour with phosphate buffer containing 0.1% BSA (bovine serum albumin). Blocking made the antigen solids. A control plate was prepared in the same manner as above except that serum serum solution was used instead of HANA antigen.
샘플 (0.5% BSA와 0.05% Tween 20을 함유하는 0.01M 인산 완충액)에 대한 희석액 100㎕를 첨가하였다.100 μl of dilution for the sample (0.01 M phosphate buffer containing 0.5% BSA and 0.05% Tween 20) was added.
이 플레이트를 사란 랩 (Saran Wrap) (염화 폴리비닐리덴 필름)으로 싼 다음, 4℃에서 하룻밤 방치하였다. 그 다음날, 각 웰 속의 반응 혼합물을 제거하고, 각 웰을 세정액 (0.05% Tween 20을 함유하는 0.01M 인산 완충액)으로 3회 세정하였다.This plate was wrapped with Saran Wrap (polyvinylidene chloride film) and then left at 4 ° C. overnight. The next day, the reaction mixture in each well was removed and each well was washed three times with a wash (0.01 M phosphate buffer containing 0.05% Tween 20).
표지된 항체 (labelled antibody) (퍼옥시다아제로 표지된 항 마우스 IgA 항체)를 상기와 같은 샘플에 대한 동일한 희석액으로 최적농도로 희석하여, 100㎕를 플레이트의 웰 속에 주입하였다.Labeled antibodies (anti mouse IgA antibodies labeled with peroxidase) were diluted to optimal concentration with the same dilution for such samples and 100 μl was injected into the wells of the plate.
플레이트를 실온에서 2시간 반응시킨 다음, 상기한 세정액으로 3회 세정하였다.The plate was allowed to react at room temperature for 2 hours, and then washed three times with the above-mentioned washing liquid.
기질 용액 (0.1M 시트르산 완충액, pH : 4.9, 3.3㎎/㎖ 0-페닐렌디아민 함유, 0.02% H202) 100㎕씩을 각 웰에 주입하고 차광된 조건하에 실내온도에서 0.5-1.0시간 반응시킨 다음 1.5N 황산(100㎕)을 첨가하여 반응을 정지 시켰다. 흡광도 (492nm)를 마이크로플레이트에 대해 오토리이더(autoreader) 측정하였다.100 µl of substrate solution (0.1 M citric acid buffer, pH: 4.9, containing 3.3 mg / ml 0-phenylenediamine, 0.02% H202) was injected into each well, and reacted for 0.5-1.0 hours at room temperature under shaded conditions. N sulfuric acid (100 µl) was added to stop the reaction. Absorbance (492 nm) was measured by autoreader on a microplate.
(5) 결과 :(5) result:
그 결과는 다음 제 3 표에 나와 있다.The results are shown in the following third table.
[표 3]TABLE 3
상기한 결과로부터 명백한 바와 같이, 본 발명에 따라 제조된 인플루엔저 HA왁진의 비강 분무용 겔제가 투여된 마우스에 있어서, 투약된지 3주 후에 비강 세정액에서 항바이러스 IgA항체가 검출되었고, 또한 HI 항체가 혈증 농도가 높은 레벨로 검출되었다. 이에 반해서, 인산 완충액에 인플루엔저 HA왁진이 첨가된 용액 (참고예 1 및 2도 )이 투여된 마우스에 있어서 IgA항체는 미량 검출되었고 혈중 HI 항체는 같은 조건에서 저레벨로만 검출되었다.As is evident from the above results, in mice administered the nasal spray gel of the influenza H A wax prepared according to the present invention, antiviral IgA antibody was detected in the nasal lavage three weeks after administration, and also the HI antibody. Hyperemia concentrations were detected at high levels. In contrast, traces of IgA antibodies were detected in the mice to which the influenza H A wax was added to the phosphate buffer (Reference Examples 1 and 2 degrees) and blood HI antibodies were detected only at low levels under the same conditions.
Claims (12)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1086339A JPH0623094B2 (en) | 1989-04-05 | 1989-04-05 | Gel base for spraying and gel using the same |
JP1-86339 | 1989-04-05 |
Publications (2)
Publication Number | Publication Date |
---|---|
KR900015713A KR900015713A (en) | 1990-11-10 |
KR0137206B1 true KR0137206B1 (en) | 1998-04-25 |
Family
ID=13884095
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1019900004562A KR0137206B1 (en) | 1989-04-05 | 1990-04-03 | Spray gel base and spray gel preparation thereof |
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JP (1) | JPH0623094B2 (en) |
KR (1) | KR0137206B1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2007291073A (en) * | 2006-03-31 | 2007-11-08 | Daiichi Sankyo Healthcare Co Ltd | Nebulization pharmaceutical formulation for hemorrhoid |
CN104940943B (en) * | 2006-04-21 | 2019-01-04 | 东兴药品工业株式会社 | By spraying with the mucocutaneous attached type preparation of gel-type and the drug delivery system for using it |
WO2007123207A1 (en) | 2006-04-21 | 2007-11-01 | Toko Yakuhin Kogyo Kabushiki Kaisha | Fluid container and airless fluid dispensing system |
JP6401089B2 (en) * | 2015-03-20 | 2018-10-03 | 三粧化研株式会社 | Spray type skin cleanser |
JP7125862B2 (en) * | 2018-05-29 | 2022-08-25 | 小林製薬株式会社 | external composition |
CN115279364A (en) * | 2019-12-06 | 2022-11-01 | 东兴药品工业株式会社 | Pharmaceutical composition comprising a steroid and olopatadine |
CN114980881A (en) * | 2019-12-06 | 2022-08-30 | 东兴药品工业株式会社 | Nasal composition comprising olopatadine |
AU2022401207A1 (en) * | 2021-12-02 | 2024-06-06 | Toko Yakuhin Kogyo Co., Ltd. | Nasal vaccine-spraying formulation for simultaneously targeting nasal mucosa and nasopharynx |
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JPS5467022A (en) * | 1977-11-07 | 1979-05-30 | Toko Yakuhin Kogyo Kk | Topical agent and production thereof |
JPS61106509A (en) * | 1984-10-29 | 1986-05-24 | Fujisawa Pharmaceut Co Ltd | Pharmaceutical composition for nasal cavity application |
JPS63101318A (en) * | 1986-10-16 | 1988-05-06 | Toko Yakuhin Kogyo Kk | Collunarium |
-
1989
- 1989-04-05 JP JP1086339A patent/JPH0623094B2/en not_active Expired - Lifetime
-
1990
- 1990-04-03 KR KR1019900004562A patent/KR0137206B1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
JPH0623094B2 (en) | 1994-03-30 |
JPH02264714A (en) | 1990-10-29 |
KR900015713A (en) | 1990-11-10 |
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