WO2016021975A1 - Method for preparing sublingual spray containing pde-5 inhibitor, and composition for sublingual spraying prepared thereby - Google Patents

Method for preparing sublingual spray containing pde-5 inhibitor, and composition for sublingual spraying prepared thereby Download PDF

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Publication number
WO2016021975A1
WO2016021975A1 PCT/KR2015/008274 KR2015008274W WO2016021975A1 WO 2016021975 A1 WO2016021975 A1 WO 2016021975A1 KR 2015008274 W KR2015008274 W KR 2015008274W WO 2016021975 A1 WO2016021975 A1 WO 2016021975A1
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pde
inhibitor
sublingual
sublingual spray
solution
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PCT/KR2015/008274
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French (fr)
Korean (ko)
Inventor
김신규
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주식회사 다림바이오텍
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Publication of WO2016021975A1 publication Critical patent/WO2016021975A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams

Definitions

  • the present invention relates to a method for preparing a sublingual spray comprising a PDE-5 inhibitor and a composition for sublingual spray prepared by the present invention, and specifically, a sildenafil, tadalafil, vardenafil, oil used as a phosphodiesterase (PDE) inhibitor.
  • PDE phosphodiesterase
  • Vardenafil, sildenafil, tadalafil, and udenafil which are currently commercially available PDE-5 inhibitors, are tablets of oral administration that are absorbed via the stomach along with foods ingested with a content of 10 to 100 mg per party. 80 ⁇ 85% of the administered medicines are lost while going through the digestive tract, and the remaining 15 ⁇ 20% are absorbed to express the medicinal effect.It takes 60 ⁇ 90 minutes after taking until the medicinal effect is expressed and reaches the highest blood concentration. do.
  • the oral drug is dissociated and lost during the passage through various organs in the body, and the remaining ingredients are pharmacologically expressed, and various side effects are shown in the digestive organs during this process.
  • the sirenapi, vardenafil, tadalafil, udenafil, etc. which are used as PDE-5 inhibitors, are difficult to be easily absorbed and excreted in the body because they have a high molecular weight and are poorly soluble in water.
  • Korean Patent Publication No. 2010-0052453 discloses a technique using an excipient to improve the solubility of tadalafil
  • Korean Patent Publication No. 2009-0049883 to deliver citric acid syndenafil transdermally
  • the present invention discloses a controlled drug carrier and a transdermal patch containing the same
  • Korean Patent Application Publication No. 2007-0100023 discloses a fast-dissolving type that rapidly dissolves in the oral cavity in a solubilized form of a PDE-5 inhibitor.
  • Korean Laid-Open Patent Publication No. 2002-526319 discloses a technique for spraying a composition containing a film-forming polymer locally.
  • the present invention has a high body absorption rate can express the drug effect within 5 to 8 minutes, and a method for producing a sublingual spray agent for treating erectile dysfunction can minimize the side effects due to the active ingredient It is an object to provide a composition for spraying.
  • the present invention is to prepare a PDE-5 inhibitor solution by adding a PDE-5 inhibitor comprising at least one of sildenafil, tadalafil, vardenafil, udenafil to the solvent, the PDE Preparing a PDE-5 inhibitor solid by extracting the inhibitor solution at low temperature under reduced pressure, and extracting an active ingredient from the PDE-5 inhibitor solid using an extraction solvent, and then filtering the extract to prepare a sublingual spray agent stock solution; It provides a method for preparing a sublingual spray containing a PDE-5 inhibitor comprising a.
  • the preparation step of the PDE-5 inhibitor solution it is preferable that a mixed solvent of alcohol and alkaline ionized water is used.
  • citric acid or glycyrrhizinic acid is preferably added to the PDE-5 inhibitor solution.
  • the extraction solvent preferably contains alkaline ionized water.
  • an acid aqueous solution or citric acid is further added to the extraction solvent.
  • the extraction of the active ingredient is preferably stirred for 10 to 60 minutes at 30 to 40 °C, then left for 6 to 24 hours at room temperature.
  • an artificial sweetener or glucose is further added to the sublingual spray solution.
  • the manufacturing method is further comprising the step of filling the spray container with a single spray amount of 0.1 ⁇ 1ml of the sublingual spray solution.
  • the method of preparing the sublingual spraying agent may further include filling the spray container with the stock solution, preferably, spraying the spray container so that the spray amount is 0.1 to 1 ml.
  • the present invention for achieving the above object provides a composition for sublingual spraying comprising a PDE-5 inhibitor prepared by the above method
  • the sublingual spraying composition is any one or more of casualty or Eumyang extract, myrrh and peppermint oil It may be further included, and preferably may further include any one or more of filamentous or Yinyang extract 2-100ml, myrrh 0.01-0.3mg and peppermint oil 0.01-0.3mg per 100ml of the stock solution.
  • Sublingual spraying agent containing PDE-5 inhibitor prepared according to the present invention is absorbed more than 95% can express the drug effect within 5 to 8 minutes even with 1/5 ⁇ 1/7 of the conventional tablets, do not go through the digestive system Because the drug is directly delivered into the blood, side effects due to the active ingredient can be minimized, and the antioxidant activity and excretion promoting effect of free radicals produced in the body can be obtained.
  • the sublingual spraying agent comprising the PDE-5 inhibitor of the present invention is prepared by adding a PDE-5 inhibitor including at least one of sildenafil, tadalafil, vardenafil, and udenafil to a solvent to prepare a PDE-5 inhibitor solution.
  • the PDE-5 inhibitor solution is concentrated at low temperature under reduced pressure to prepare a PDE-5 inhibitor solid, and the active ingredient is extracted from the PDE-5 inhibitor solid using an extraction solvent. It may be prepared through the step of preparing.
  • PDE-5 inhibitor solution is prepared by first adding a PDE-5 inhibitor including at least one of sildenafil, tadalafil, vardenafil, and udenafil to a solvent.
  • the solvent is preferably a mixed solvent of alcohol and alkaline ionized water, more preferably 1 to 200 ml of a mixed solvent of alcohol and alkaline ionized water per 100 mg of PDE-5 inhibitor.
  • Room Lena field is generally, used as a PDE-5 inhibitor (C 22 H 30 N 6 O 4 S, MW 474), vardenafil (C 23 H 32 N 6 O 4 S, MW 488), tadalafil (C 22 H 19 N 3 O 4 , MW 389) and udenafil (C 20 H 35 N 5 O 4 S, MW 441) and the like are all difficult to be easily absorbed and excreted in the body because of their high molecular weight and poor water solubility.
  • the present invention is characterized in that the PDE-5 inhibitor solution is concentrated under reduced pressure and concentrated to dryness to prepare a solid first, then to extract the active ingredient from the solid with alkaline ionized water as a solvent to prepare a sublingual spraying stock solution. .
  • a mixed solvent containing alcohol and alkaline ionized water of pH 7.5-10.5, preferably pH 8.0-8.5 is used as a solvent.
  • the alcohol and the alkaline ionized water is preferably mixed in a ratio of 9: 1 to 5: 5.
  • the alkaline ionized water (pH 7.5 ⁇ 10.5) is composed of 6 units of cluster (cluster) is smaller in size than water that forms a hydrogen bond in 13 to 15 units, the penetration is good, and the thermal conductivity is high even at a relatively low temperature Elution is not only efficient, but also excellent in absorbency, which is effective in increasing the solubility and absorption of the PDE-5 inhibitor of the present invention.
  • the hydrogen contained in the alkaline ionized water removes free radicals and acts as an antioxidant, thereby reducing the side effects of the PDE-5 inhibitor.
  • the metabolism becomes excessively active, increasing the levels of lactic acid, pyruvic acid, and oxalic acid in the blood, causing unnecessary waste to accumulate in the cells and in the blood.
  • Hydrogen contained in alkaline ionized water rapidly penetrates into cells and rapidly releases the side effects causing substances produced by the PDE-5 inhibitor to the outside of the body, thereby preventing various symptoms caused by the side effects of the PDE-5 inhibitor. It can be minimized.
  • citric acid may be further added to the PDE-5 inhibitor solution.
  • the citric acid serves to further increase the solubility by inducing a PDE-5 inhibitor as a salt component, it is preferred that 1 to 10mg per 100mg of PDE-5 inhibitor.
  • glycyrrhizinic acid may be additionally added to the PDE-5 inhibitor solution.
  • the bitter taste is not detected during sublingual spraying, but after 2-3 minutes after sublingual spraying, the PDE-5 inhibitor is in contact with the taste buds of the snow due to saliva secretion Can be.
  • the glycyrrhizin acid may not only eliminate the bitter taste of the PDE-5 inhibitor as a main component of licorice, but also have a detoxifying effect, thereby reducing side effects caused by taking the PDE-5 inhibitor.
  • the glycyrrhizin acid and the PDE-5 inhibitor are preferably mixed in a ratio of 1: 2 to 3.
  • the solution is concentrated under reduced pressure at low temperature to prepare a PDE-5 inhibitor solid.
  • the mixed solvent in which the PDE-5 inhibitor is dissolved is reacted for 60 minutes to 70 ° C. under a CO 2 stream for 10 minutes to 1 hour, and then concentrated under reduced pressure and drying at low temperature.
  • the molecular compound of can be obtained.
  • the PDE-5 inhibitor solid thus obtained is subjected to a step of preparing a stock solution by extracting the active ingredient using an extracting solvent and then filtering.
  • the extraction solvent may include alkaline ionized water having a pH of 7.5 to 10.5, preferably pH 8.0 to 8.5, and preferably 10 to 20 ml of alkaline ionized water per 100 mg of PDE-5 inhibitor solids.
  • the alkaline ionized water is smaller in size than the water in which the alkaline ionized water is hydrogen-bonded, so that the penetration power is good, the thermal conductivity is high, and the component dissolution is efficiently performed even at a relatively low temperature.
  • an acid aqueous solution may be further added to the extraction solvent.
  • the acid aqueous solution may be a variety of acids, including hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citric acid, amino acids, citric acid, folic acid, ascorbic acid, pyruvic acid, and the like, in one embodiment, 0.3 per 100 mg of PDE-5 inhibitor solids 0.1-1 ml of% aqueous hydrochloric acid solution can be added.
  • 1 ml of the extracted alkaline ionized water solvent contains about 10 to 20 mg of the active ingredient of the PDE-5 inhibitor solid.
  • citric acid in order to further increase the solubility of the active ingredients, may be further added to the extraction solvent.
  • the citric acid serves to increase the solubility by inducing the active ingredients into the salt component, it is preferable to dissolve by adding an additional 1 ⁇ 10mg of citric acid per 100ml of the extraction solvent.
  • the citric acid may play a role of increasing the solubility by inducing the active ingredients into the salt component.
  • Extraction of the active ingredient may be made by various methods, but preferably, PDE-5 inhibitor solids may be added to the extraction solvent, stirred for 10 to 60 minutes at 30 to 40 ° C, and left at room temperature for 6 to 24 hours. have. The extract is filtered to obtain a final stock solution.
  • the stock solution may be used as a sublingual spray by filling in a spray container manufactured to have a spray amount of 0.1 to 1 ml. 3 ml, myrrh 0.01-0.3 mg, and peppermint oil may further include any one or more.
  • sildenafil solid To 100 mg of the sildenafil solid, 0.6 ml of citric acid and 0.3 ml of hydrochloric acid were added to 10 ml of alkaline ionized water (PH 8.5), and a solution was added. The solution was stirred at 30 to 40 ° C. for 20 minutes and left at room temperature for 6 to 12 hours, followed by filtration. To prepare a stock solution. The stock solution was confirmed that the active ingredient 15mg of sildenafil solids dissolved per 1ml of alkaline ionized water solvent.
  • Table 1 below shows the drug expression time and the presence of side effects when the stock solution prepared in the above example was sprayed 2.0 ml once daily for 8 healthy males 40 to 55 years old, and the control group was used in a commercial pharmacy. Purchased tablets were used.
  • Drug expression (minutes) 1 ⁇ 2 2 ⁇ 3 3 ⁇ 4 4 ⁇ 5 5 ⁇ 6 6 ⁇ 7 7-8 8-9 9-10 10-11 11-12 take over One 2 3 4 5 6 7 8 8 8 8 8 Spray amount (ml) 2 2 2 2 2 2 2 2 2 2 2 2 2 Side Effect headache vertigo flushing sickness rash Muscle pain colic diarrhea Ocular hyperemia Indigestion Arthralgia The presence or absence radish radish radish U radish radish radish radish U radish contrast U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U
  • sublingual spraying agent containing the PDE-5 inhibitor of the present invention can be confirmed that not only the drug expression is made within 8 minutes compared to the general tablets but also very few side effects.

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Abstract

The present invention relates to a method for preparing a sublingual spray containing a PDE-5 inhibitor, and a composition for sublingual spraying prepared thereby and, specifically, to: a method for preparing a sublingual spray for treating erectile dysfunction, capable of quickly exhibiting the efficacy of a medicine by allowing an active ingredient to be absorbed into the sublingual mucosa so as to be quickly delivered into blood through the carotid artery by preparing sildenafil, tadalafil, vardenafil, udenafil and the like, which are used as a phosphodiesterase (PDE) inhibitor, in the dosage form of a sublingual spray; and a composition for sublingual spraying prepared thereby.

Description

PDE-5 저해제를 포함하는 설하분무제의 제조방법 및 이에 의하여 제조된 설하분무용 조성물Method for producing a sublingual spray containing a PDE-5 inhibitor and a composition for sublingual spray prepared thereby
본 발명은 PDE-5 저해제를 포함하는 설하분무제의 제조방법 및 이에 의하여 제조된 설하분무용 조성물에 관한 것으로서, 자세하게는 포스포디에스테라제(PDE) 저해제로 사용되고 있는 실데나필, 타달라필, 바데나필, 유데나필 등을 설하분무 제형으로 제조하여 유효성분이 설하점막으로 흡수되어 경동맥을 통하여 신속하게 혈액 속으로 전달되도록 함으로써, 약효를 빠르게 발현시킬 수 있는 발기부전 치료용 설하분무제의 제조방법 및 이에 의하여 제조된 설하분무용 조성물에 대한 것이다.The present invention relates to a method for preparing a sublingual spray comprising a PDE-5 inhibitor and a composition for sublingual spray prepared by the present invention, and specifically, a sildenafil, tadalafil, vardenafil, oil used as a phosphodiesterase (PDE) inhibitor. Method of preparing a sublingual spray agent for treating erectile dysfunction that can express medicinal effects by making dennafil and the like into a sublingual spray formulation so that the active ingredient is absorbed into the sublingual mucosa and rapidly delivered into the blood through the carotid artery. It relates to a sublingual spray composition.
약재는 제형에 따라 체내 흡수율에 차이가 있으며, 일반적으로 정제와 환제는 10%, 캅슐제는 20%, 패치제는 40%, 수액제는 50%, 근육주사제는 90%, 정맥주사제는 100%가 흡수되는 것으로 알려져 있다. There are differences in the absorption rate of medicines depending on the dosage form.In general, tablets and pills are 10%, capsules are 20%, patchs are 40%, fluids are 50%, intramuscular injections are 90%, intravenous injections are 100% It is known to be absorbed.
현재 일반적으로 상용화되고 있는 PDE-5 저해제인 바데나필, 실데나필, 타달라필, 유데나필 등은 매 정당 성분 함량이 10~100mg로서 섭취한 음식물과 함께 위장을 경유하여 흡수되는 경구투여 방식의 정제로 제조되고 있으며, 투여한 약재의 80~85%가 소화기관을 거치는 동안 소실되고 나머지 15~20%가 흡수되어 약효가 발현되며, 약효가 발현하여 최고혈중 농도에 이르기까지는 복용 후 60~90분이 소요된다. Vardenafil, sildenafil, tadalafil, and udenafil, which are currently commercially available PDE-5 inhibitors, are tablets of oral administration that are absorbed via the stomach along with foods ingested with a content of 10 to 100 mg per party. 80 ~ 85% of the administered medicines are lost while going through the digestive tract, and the remaining 15 ~ 20% are absorbed to express the medicinal effect.It takes 60 ~ 90 minutes after taking until the medicinal effect is expressed and reaches the highest blood concentration. do.
이와 같이 경구투여 약물은 생체 내에서 여러 가지 기관을 경유하는 동안 분해 소실되고 남는 성분들이 약효발현을 하게 되며, 이러한 과정 중에서 소화기관에 다양한 부작용을 나타내게 된다. 특히, PDE-5 저해제로 사용되는 실레나필, 바데나필, 타달라필, 유데나필 등은 모두 분자량이 크고 물에 난용성이기 때문에 체내에서 쉽게 흡수 배설되기가 어렵다. As described above, the oral drug is dissociated and lost during the passage through various organs in the body, and the remaining ingredients are pharmacologically expressed, and various side effects are shown in the digestive organs during this process. In particular, the sirenapi, vardenafil, tadalafil, udenafil, etc., which are used as PDE-5 inhibitors, are difficult to be easily absorbed and excreted in the body because they have a high molecular weight and are poorly soluble in water.
따라서, 이러한 문제점을 해결하기 위하여 약품의 활성에 영향을 주지 않는 범위 내에서 약효성분을 유,무기산염으로 유도하는 방법, 용해 보조제를 이용하는 방법, 용매와의 접촉면적을 증가시키는 방법 등 약재의 체내흡수율을 높이기 위한 다양한 연구들이 이루어지고 있다.Therefore, in order to solve these problems, the method of inducing the active ingredient into organic and inorganic salts, the method of using a dissolving aid, increasing the contact area with the solvent within the range that does not affect the activity of the drug, etc. Various studies have been made to increase the absorption rate.
일 실시예로, 한국공개특허 제2010-0052453호는 타달라필의 용해도를 개선하기 위하여 부형제를 사용하는 기술이 개시되어 있으며, 한국공개특허 제2009-0049883호는 구연산 신데나필을 경피로 전달하기 위한 조절약물 전달체 및 이를 포함하는 경피패치제가 개시되어 한국있고, 공개특허 제2007-0100023호는 PDE-5 저해제의 경구용 속용제형으로 가용화된 형태로 구강에서 신속하게 용해되는 속용제형을 개시하고 있으며, 한국공개특허 제2002-526319호는 필름형성 폴리머를 함유한 조성물을 국부에 분사하는 기술을 개시하고 있다In one embodiment, Korean Patent Publication No. 2010-0052453 discloses a technique using an excipient to improve the solubility of tadalafil, Korean Patent Publication No. 2009-0049883 to deliver citric acid syndenafil transdermally The present invention discloses a controlled drug carrier and a transdermal patch containing the same, and Korean Patent Application Publication No. 2007-0100023 discloses a fast-dissolving type that rapidly dissolves in the oral cavity in a solubilized form of a PDE-5 inhibitor. Korean Laid-Open Patent Publication No. 2002-526319 discloses a technique for spraying a composition containing a film-forming polymer locally.
상기 선행기술들을 살펴보면 주로 약효를 속히 발현시키는 수단으로 정제를 구강과 위장 속에서 빠르게 분해되도록 하는 방법, 약재를 필름에 도포 건조하여 피부 표층으로부터 흡수시키는 방법, 추출된 약재를 국부에 도말 또는 분무하는 방법 등을 개시하고 있다.Looking at the prior arts mainly to the rapid disintegration of the drug in the oral cavity and gastrointestinal means as a means of quickly expressing the drug, the method of applying and drying the medicine on the film to absorb from the skin superficial layer, smearing or spraying the extracted medicine locally Methods and the like are disclosed.
그러나, 상기 방법들 모두 체내 흡수율 향상에 한계가 있으며, 홍조, 두통, 어지러움, 오심, 복통, 비충혈, 소화불량, 발진, 관절통, 안충혈, 근육통, 설사 등의 이상반응 등의 부작용이 나타나기 쉽다. However, all of the above methods are limited in improving the absorption rate in the body, and side effects such as flushing, headache, dizziness, nausea, abdominal pain, nasal congestion, indigestion, rash, arthralgia, nystagmus, myalgia, diarrhea, and the like are likely to occur. .
상기와 같은 문제점을 해결하기 위하여, 본 발명은 높은 체내 흡수율을 가져 약효를 5~8분 이내에 발현시킬 수 있으며, 약효성분으로 인한 부작용을 최소화할 수 있는 발기부전 치료용 설하분무제의 제조방법 및 설하분무용 조성물을 제공하는 것을 목적으로 한다.In order to solve the above problems, the present invention has a high body absorption rate can express the drug effect within 5 to 8 minutes, and a method for producing a sublingual spray agent for treating erectile dysfunction can minimize the side effects due to the active ingredient It is an object to provide a composition for spraying.
상기 목적을 달성하기 위하여, 본 발명은 실데나필, 타달라필, 바데나필, 유데나필 중 적어도 어느 하나 이상을 포함하는 PDE-5 저해제를 용매에 첨가하여 PDE-5 저해제 용액을 제조하는 단계, 상기 PDE-5 저해제 용액을 저온 감압 농축하여 PDE-5 저해제 고형물을 제조하는 단계, 및 상기 PDE-5 저해제 고형물로부터 추출용매를 사용하여 유효성분을 추출한 후, 추출액을 여과하여 설하분무제 원액을 제조하는 단계;를 포함하는 PDE-5 저해제를 포함하는 설하분무제의 제조방법을 제공한다.In order to achieve the above object, the present invention is to prepare a PDE-5 inhibitor solution by adding a PDE-5 inhibitor comprising at least one of sildenafil, tadalafil, vardenafil, udenafil to the solvent, the PDE Preparing a PDE-5 inhibitor solid by extracting the inhibitor solution at low temperature under reduced pressure, and extracting an active ingredient from the PDE-5 inhibitor solid using an extraction solvent, and then filtering the extract to prepare a sublingual spray agent stock solution; It provides a method for preparing a sublingual spray containing a PDE-5 inhibitor comprising a.
상기 PDE-5 저해제 용액의 제조단계에서, 알코올과 알칼리 이온수의 혼합용매가 사용되는 것이 바람직하다. 또한, 상기 PDE-5 저해제 용액에는 구연산 또는 글리시리진산(glycyrrhizinic acid)이 추가로 첨가되는 것이 바람직하다. In the preparation step of the PDE-5 inhibitor solution, it is preferable that a mixed solvent of alcohol and alkaline ionized water is used. In addition, citric acid or glycyrrhizinic acid is preferably added to the PDE-5 inhibitor solution.
그리고, 상기 추출용매는 알칼리 이온수를 포함하는 것이 바람직하다. 또한, 상기 추출용매에 산 수용액 또는 구연산이 추가로 첨가되는 것이 바람직하다. In addition, the extraction solvent preferably contains alkaline ionized water. In addition, it is preferable that an acid aqueous solution or citric acid is further added to the extraction solvent.
또한, 상기 유효성분의 추출은 30~40℃에서 10~60 분간 교반한 후, 실온에서 6~24시간 방치하여 이루어지는 것이 바람직하다. In addition, the extraction of the active ingredient is preferably stirred for 10 to 60 minutes at 30 to 40 ℃, then left for 6 to 24 hours at room temperature.
그리고, 상기 설하분무제 원액에는 인공감미제 또는 포도당이 추가로 첨가되는 것이 바람직하다.In addition, it is preferable that an artificial sweetener or glucose is further added to the sublingual spray solution.
또한, 상기 제조방법은 상기 설하분무제 원액을 1회 분무량이 0.1~1㎖인 분무용기에 충입하는 단계;를 추가로 포함하는 것이 바람직하다. In addition, the manufacturing method is further comprising the step of filling the spray container with a single spray amount of 0.1 ~ 1ml of the sublingual spray solution.
상기 설하분무제의 제조방법은 원액을 분무용기에 충입하는 단계, 바람직하게는 1회 분무량이 0.1~1㎖가 되도록 제작된 분무용기에 충입하는 단계를 추가로 포함할 수 있다. The method of preparing the sublingual spraying agent may further include filling the spray container with the stock solution, preferably, spraying the spray container so that the spray amount is 0.1 to 1 ml.
한편, 상기 목적을 달성하기 위한 본 발명은 상기 방법들에 의하여 제조된 PDE-5 저해제를 포함하는 설하분무용 조성물을 제공하며, 상기 설하분무용 조성물은 사상자 또는 음양곽 추출액, 몰약 및 박하유 중 어느 하나 이상을 추가로 포함할 수 있으며, 바람직하게는 원액 100㎖당 사상자 또는 음양곽 추출액 2~3㎖, 몰약 0.01~0.3㎎ 및 박하유 0.01~0.3㎎ 중 어느 하나 이상을 추가로 포함할 수 있다.On the other hand, the present invention for achieving the above object provides a composition for sublingual spraying comprising a PDE-5 inhibitor prepared by the above method, the sublingual spraying composition is any one or more of casualty or Eumyang extract, myrrh and peppermint oil It may be further included, and preferably may further include any one or more of filamentous or Yinyang extract 2-100ml, myrrh 0.01-0.3mg and peppermint oil 0.01-0.3mg per 100ml of the stock solution.
본 발명에 따라 제조된 PDE-5 저해제를 포함하는 설하분무제는 95% 이상 흡수되어 기존 정제의 1/5~1/7 양으로도 약효를 5~8분 이내에 발현시킬 수 있으며, 소화기관을 거치지 않고 직접 혈액 속으로 약이 전달되기 때문에 약효성분으로 인한 부작용을 최소화할 수 있으며, 체내에서 생성된 자유 라디칼의 항산화작용과 배설 촉진 효과를 얻을 수 있다.Sublingual spraying agent containing PDE-5 inhibitor prepared according to the present invention is absorbed more than 95% can express the drug effect within 5 to 8 minutes even with 1/5 ~ 1/7 of the conventional tablets, do not go through the digestive system Because the drug is directly delivered into the blood, side effects due to the active ingredient can be minimized, and the antioxidant activity and excretion promoting effect of free radicals produced in the body can be obtained.
이하 본 발명에 따른 바람직한 실시예를 상세히 설명하기로 한다. 이에 앞서, 본 명세서 및 청구범위에 사용된 용어나 단어는 통상적이거나 사전적인 의미로 한정해서 해석되어서는 아니 되며, 본 발명의 기술적 사상에 부합하는 의미와 개념으로 해석되어야 한다.Hereinafter, preferred embodiments of the present invention will be described in detail. Prior to this, terms or words used in the present specification and claims should not be construed as being limited to ordinary or dictionary meanings, but should be construed as meanings and concepts consistent with the technical spirit of the present invention.
먼저, 본 발명의 PDE-5 저해제를 포함하는 설하분무제는 실데나필, 타달라필, 바데나필, 유데나필 중 적어도 어느 하나 이상을 포함하는 PDE-5 저해제를 용매에 첨가하여 PDE-5 저해제 용액을 제조하는 단계, 상기 PDE-5 저해제 용액을 저온 감압 농축하여 PDE-5 저해제 고형물을 제조하는 단계, 및 상기 PDE-5 저해제 고형물로부터 추출용매를 사용하여 유효성분을 추출한 후, 추출액을 여과하여 설하분무제 원액을 제조하는 단계를 통하여 제조될 수 있다. First, the sublingual spraying agent comprising the PDE-5 inhibitor of the present invention is prepared by adding a PDE-5 inhibitor including at least one of sildenafil, tadalafil, vardenafil, and udenafil to a solvent to prepare a PDE-5 inhibitor solution. The PDE-5 inhibitor solution is concentrated at low temperature under reduced pressure to prepare a PDE-5 inhibitor solid, and the active ingredient is extracted from the PDE-5 inhibitor solid using an extraction solvent. It may be prepared through the step of preparing.
각 단계를 자세히 살펴보면, 먼저 실데나필, 타달라필, 바데나필, 유데나필 중 적어도 어느 하나 이상을 포함하는 PDE-5 저해제를 용매에 첨가하여 PDE-5 저해제 용액을 제조한다. Looking at each step in detail, PDE-5 inhibitor solution is prepared by first adding a PDE-5 inhibitor including at least one of sildenafil, tadalafil, vardenafil, and udenafil to a solvent.
이때, 상기 용매는 알코올과 알칼리 이온수의 혼합용매가 사용되는 것이 바람직하며, 더욱 바람직하게는 PDE-5 저해제 100㎎당 알코올과 알칼리 이온수의 혼합용매 1~200㎖를 용매로 사용하는 것이 바람직하다. At this time, the solvent is preferably a mixed solvent of alcohol and alkaline ionized water, more preferably 1 to 200 ml of a mixed solvent of alcohol and alkaline ionized water per 100 mg of PDE-5 inhibitor.
일반적으로, PDE-5 저해제로 사용되는 실레나필(C22H30N6O4S, MW 474), 바데나필(C23H32N6O4S, MW 488), 타달라필(C22H19N3O4, MW 389), 유데나필(C20H35N5O4S, MW 441) 등은 모두 분자량이 크고 물에 난용성이기 때문에 체내에서 쉽게 흡수 배설되기가 어렵다. 이에, 본 발명은 PDE-5 저해제가 용해된 용액을 저온 감압농축 건조하여 고형물을 먼저 제조한 후, 알칼리 이온수를 용매로 하여 상기 고형물로부터 유효성분을 추출하여 설하분무용 원액을 제조하는 것을 특징으로 한다.Room Lena field is generally, used as a PDE-5 inhibitor (C 22 H 30 N 6 O 4 S, MW 474), vardenafil (C 23 H 32 N 6 O 4 S, MW 488), tadalafil (C 22 H 19 N 3 O 4 , MW 389) and udenafil (C 20 H 35 N 5 O 4 S, MW 441) and the like are all difficult to be easily absorbed and excreted in the body because of their high molecular weight and poor water solubility. Thus, the present invention is characterized in that the PDE-5 inhibitor solution is concentrated under reduced pressure and concentrated to dryness to prepare a solid first, then to extract the active ingredient from the solid with alkaline ionized water as a solvent to prepare a sublingual spraying stock solution. .
본 발명은 난용성 물질인 PDE-5 저해제의 용해도를 증가시키기 위하여, 용매로서 알코올과 pH 7.5~10.5, 바람직하게는 pH 8.0~8.5의 알칼리 이온수를 포함하는 혼합용매를 사용하는 것을 특징으로 하며, 이때 상기 알코올과 알칼리 이온수는 9:1~5:5의 비율로 혼합하는 것이 바람직하다.In order to increase the solubility of the PDE-5 inhibitor which is a poorly soluble substance, a mixed solvent containing alcohol and alkaline ionized water of pH 7.5-10.5, preferably pH 8.0-8.5 is used as a solvent. At this time, the alcohol and the alkaline ionized water is preferably mixed in a ratio of 9: 1 to 5: 5.
상기 알칼리 이온수(pH 7.5~10.5)는 분자 집단(cluster)이 6개 단위로 구성되어 13~15개 단위로 수소 결합을 이루고 있는 물보다 크기가 작아 침투력이 좋고, 열전도가 높아 비교적 낮은 온도에서도 성분 용출이 효율적으로 이루어질 뿐 아니라 흡수력 또한 우수하여 본 발명의 PDE-5 저해제의 용해도 및 흡수력을 높이는 데 효과적이다.The alkaline ionized water (pH 7.5 ~ 10.5) is composed of 6 units of cluster (cluster) is smaller in size than water that forms a hydrogen bond in 13 to 15 units, the penetration is good, and the thermal conductivity is high even at a relatively low temperature Elution is not only efficient, but also excellent in absorbency, which is effective in increasing the solubility and absorption of the PDE-5 inhibitor of the present invention.
또한, 상기 알칼리 이온수에 함유된 수소는 체내 활성산소를 제거하여 항산화 작용을 하며 그에 따라 PDE-5 저해제의 부작용을 감소시키는 역할을 하게 된다. 자세히 설명하면 PDE-5 저해제 약품을 복용하고 성관계를 하는 경우 신진대사가 과하게 활발해지면서 혈액 중에 피로물질인 젖산, 피류빅산, 옥살산 등이 증가하며 불필요한 노폐물들이 세포 사이와 혈액 속에 축적되게 된다. 알칼리 이온수에 함유된 수소는 세포 속에 빠르게 침투하여 상기 PDE-5 저해제로 인하여 생성되는 부작용 유발물질들을 신속하게 체외로 배출하는 역할을 하게 되며, 이를 통하여 PDE-5 저해제 부작용으로 발생하는 여러 가지 증상들을 최소화할 수 있다.In addition, the hydrogen contained in the alkaline ionized water removes free radicals and acts as an antioxidant, thereby reducing the side effects of the PDE-5 inhibitor. In detail, when taking PDE-5 inhibitors and having sex, the metabolism becomes excessively active, increasing the levels of lactic acid, pyruvic acid, and oxalic acid in the blood, causing unnecessary waste to accumulate in the cells and in the blood. Hydrogen contained in alkaline ionized water rapidly penetrates into cells and rapidly releases the side effects causing substances produced by the PDE-5 inhibitor to the outside of the body, thereby preventing various symptoms caused by the side effects of the PDE-5 inhibitor. It can be minimized.
그리고, PDE-5 저해제의 용해도를 더욱 높이기 위하여, 상기 PDE-5 저해제 용액에는 구연산이 추가로 첨가될 수 있다. 상기 구연산은 PDE-5 저해제를 염 성분으로 유도하여 용해도를 더욱 높이는 역할을 하며, PDE-5 저해제 100㎎당 1~10mg 사용되는 것이 바람직하다. In order to further increase the solubility of the PDE-5 inhibitor, citric acid may be further added to the PDE-5 inhibitor solution. The citric acid serves to further increase the solubility by inducing a PDE-5 inhibitor as a salt component, it is preferred that 1 to 10mg per 100mg of PDE-5 inhibitor.
한편, 상기 PDE-5 저해제 용액에는 PDE-5 저해제의 쓴맛을 최소화하기 위하여 PDE-5 저해제외에도 글리시리진산(glycyrrhizinic acid)이 추가로 첨가될 수 있다. 일반적으로 설하에는 맛을 감지하는 미뢰가 없기 때문에 설하 분무시 쓴맛이 감지되지 않으나, 설하분무 후 2~3분이 경과하면 침 분비로 인하여 상기 PDE-5 저해제가 설상의 미뢰와 접촉하여 쓴 맛이 감지될 수 있다. Meanwhile, in order to minimize the bitter taste of the PDE-5 inhibitor, glycyrrhizinic acid may be additionally added to the PDE-5 inhibitor solution. In general, because there is no taste taste sensory in the sublingual, the bitter taste is not detected during sublingual spraying, but after 2-3 minutes after sublingual spraying, the PDE-5 inhibitor is in contact with the taste buds of the snow due to saliva secretion Can be.
상기 글리시리진산은 감초의 주성분으로서 상기 PDE-5 저해제의 쓴맛을 없앨 뿐만 아니라 해독 효과를 가져 PDE-5 저해제의 복용으로 인한 부작용을 감소시킬 수 있다. 이때, 상기 글리시리진산과 PDE-5 저해제는 1:2~3의 비율로 혼합되는 것이 바람직하다. The glycyrrhizin acid may not only eliminate the bitter taste of the PDE-5 inhibitor as a main component of licorice, but also have a detoxifying effect, thereby reducing side effects caused by taking the PDE-5 inhibitor. At this time, the glycyrrhizin acid and the PDE-5 inhibitor are preferably mixed in a ratio of 1: 2 to 3.
상기 PDE-5 저해제 용액이 준비되면, 상기 용액을 저온 감압 농축하여 PDE-5 저해제 고형물을 제조한다. 바람직하게는 상기 PDE-5 저해제가 용해된 혼합용매는 CO₂기류 하에서 60~70℃, 10분~1시간 동안 반응시킨 후 저온 감압농축 및 건조하는 과정을 거치게 되며, 이러한 과정을 통해 최종적으로 담황색 고형물의 분자화합물을 얻을 수 있다.When the PDE-5 inhibitor solution is prepared, the solution is concentrated under reduced pressure at low temperature to prepare a PDE-5 inhibitor solid. Preferably, the mixed solvent in which the PDE-5 inhibitor is dissolved is reacted for 60 minutes to 70 ° C. under a CO 2 stream for 10 minutes to 1 hour, and then concentrated under reduced pressure and drying at low temperature. The molecular compound of can be obtained.
이와 같이 얻어진 PDE-5 저해제 고형물은 추출용매를 사용하여 유효성분을 추출한 후 여과하여 원액을 제조하는 단계를 거치게 된다. 상기 추출용매는 pH 7.5~10.5, 바람직하게는 pH 8.0~8.5의 알칼리 이온수를 포함할 수 있으며, 바람직하게는 PDE-5 저해제 고형물 100㎎당 알칼리 이온수 10~20ml을 사용할 수 있다. The PDE-5 inhibitor solid thus obtained is subjected to a step of preparing a stock solution by extracting the active ingredient using an extracting solvent and then filtering. The extraction solvent may include alkaline ionized water having a pH of 7.5 to 10.5, preferably pH 8.0 to 8.5, and preferably 10 to 20 ml of alkaline ionized water per 100 mg of PDE-5 inhibitor solids.
상기 알칼리 이온수는 앞서 살펴본 바와 같이 알칼리 이온수가 수소 결합을 이루고 있는 물보다 크기가 작아 침투력이 좋고, 열전도가 높아 비교적 낮은 온도에서도 성분 용출이 효율적으로 이루어질 뿐 아니라 흡수력 또한 우수하다. As described above, the alkaline ionized water is smaller in size than the water in which the alkaline ionized water is hydrogen-bonded, so that the penetration power is good, the thermal conductivity is high, and the component dissolution is efficiently performed even at a relatively low temperature.
이때, 유효성분의 용출이 더욱 효과적으로 이루어지기 위하여, 추출용매에 산 수용액을 추가로 첨가할 수 있다. 상기 산 수용액은 염산, 황산, 질산, 아세트산, 시트르산, 아미노산, 구연산, 엽산, 아스코르빈산, 피루브산 등을 포함하는 다양한 종류의 산이 사용될 수 있으며, 일 실시예로, PDE-5 저해제 고형물 100mg 당 0.3% 염산 수용액을 0.1~1ml 첨가할 수 있다. 이와 같이 추출된 알칼리 이온수 용매 1ml에는 PDE-5 저해제 고형물의 유효성분이 10~20mg 정도 함유되는 것이 바람직하다. In this case, in order to more effectively elute the active ingredient, an acid aqueous solution may be further added to the extraction solvent. The acid aqueous solution may be a variety of acids, including hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citric acid, amino acids, citric acid, folic acid, ascorbic acid, pyruvic acid, and the like, in one embodiment, 0.3 per 100 mg of PDE-5 inhibitor solids 0.1-1 ml of% aqueous hydrochloric acid solution can be added. Thus, it is preferable that 1 ml of the extracted alkaline ionized water solvent contains about 10 to 20 mg of the active ingredient of the PDE-5 inhibitor solid.
또 다른 실시예로, 유효성분들의 용해도를 더욱 높이기 위하여, 상기 추출용매에 구연산을 추가로 첨가할 수 있다. 상기 구연산은 유효성분들을 염 성분으로 유도하여 용해도를 더욱 높이는 역할을 하며, 추출용매 100㎖ 당 구연산 1~10㎎을 추가로 첨가하여 용해시키는 것이 바람직하다. 상기 구연산은 유효성분들을 염 성분으로 유도하여 용해도를 더욱 높이는 역할을 할 수 있다. In another embodiment, in order to further increase the solubility of the active ingredients, citric acid may be further added to the extraction solvent. The citric acid serves to increase the solubility by inducing the active ingredients into the salt component, it is preferable to dissolve by adding an additional 1 ~ 10mg of citric acid per 100ml of the extraction solvent. The citric acid may play a role of increasing the solubility by inducing the active ingredients into the salt component.
상기 유효성분의 추출은 다양한 방식에 의하여 이루어질 수 있으나, 바람직하게는 PDE-5 저해제 고형물을 추출용매에 첨가하고 30~40℃에서 10~60 분간 교반한 후 실온에서 6~24시간 방치하여 이루어질 수 있다. 상기 추출액은 고형물을 여과하여 최종 원액을 얻게 된다.Extraction of the active ingredient may be made by various methods, but preferably, PDE-5 inhibitor solids may be added to the extraction solvent, stirred for 10 to 60 minutes at 30 to 40 ° C, and left at room temperature for 6 to 24 hours. have. The extract is filtered to obtain a final stock solution.
상기 원액은 1회 분무량이 0.1~1㎖가 되도록 제작된 분무용기에 충입하여 설하분무제로 사용될 수 있으며, 바람직하게는 발기부전 치료효과를 더욱 상승시키기 위하여, 원액 100㎖당 사상자 또는 음양곽 추출액 2~3㎖, 몰약 0.01~0.3㎎ 및 박하유 0.01~0.3㎎ 중 어느 하나 이상을 추가로 포함할 수 있다.The stock solution may be used as a sublingual spray by filling in a spray container manufactured to have a spray amount of 0.1 to 1 ml. 3 ml, myrrh 0.01-0.3 mg, and peppermint oil may further include any one or more.
이하 실시예를 통하여 본 발명의 효과를 상세하게 설명한다. 그러나 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 발명의 범위가 이들 실시예에 한정되는 것은 아니다. Hereinafter, the effects of the present invention will be described in detail through examples. However, these examples are intended to illustrate one or more embodiments by way of example and the scope of the invention is not limited to these examples.
[제조예] [Production example]
실데나필 189.6㎎와 글리시리진산 85.0㎎을 주정과 알칼리 이온수(pH 8.0)가 8:2의 비율로 혼합된 혼합용매 50㎖에 용해하고 CO₂기류 중에서 65℃에서 20분간 반응 후 저온 감압농축 건조하여 담황색 고형물 257.4㎎ 을 얻었다.Dissolve 189.6 mg of sildenafil and 85.0 mg of glycyrrhizin acid in 50 ml of a mixed solvent containing alcohol and alkaline ionized water (pH 8.0) at a ratio of 8: 2, and react for 20 minutes at 65 ° C. in a CO₂ stream. 257.4 mg was obtained.
상기 실데나필 고형물 100㎎에 알칼리 이온수(PH 8.5) 10㎖에 구연산 1㎎, 0.3% 염산을 0.6ml을 가하여 용해한 용액을 가하고 30~40℃에서 20분간 교반하고 실온에서 6~12시간 방치한 후 여과하여 원액을 제조하였다. 상기 원액은 알칼리 이온수 용매 1ml당 실데나필 고형물의 유효성분 15mg이 용해된 것을 확인할 수 있었다.To 100 mg of the sildenafil solid, 0.6 ml of citric acid and 0.3 ml of hydrochloric acid were added to 10 ml of alkaline ionized water (PH 8.5), and a solution was added. The solution was stirred at 30 to 40 ° C. for 20 minutes and left at room temperature for 6 to 12 hours, followed by filtration. To prepare a stock solution. The stock solution was confirmed that the active ingredient 15mg of sildenafil solids dissolved per 1ml of alkaline ionized water solvent.
이후, 원액 30㎖를 1회 분무시 0.2~0.3㎖의 원액이 분무되도록 설계 제작한 분무용기에 충입하여 제형화하였다. 타달라필, 바데나필, 유데나필 등의 원액 제도도 같은 방법으로 제형화한다. Thereafter, 30 ml of the stock solution was formulated by filling it into a spray container designed to spray 0.2-0.3 ml of the stock solution at one time of spraying. Stock solutions such as tadalafil, vardenafil and udenafil are also formulated in the same manner.
[실험예] Experimental Example
하기 표 1은 상기 제조예에서 제조한 원액을 40~55세 건강한 남성 8인을 대상으로 매일 1회씩 2.0㎖를 3일간 분무한 경우, 약효발현 시간 및 부작용 유무를 나타낸 것으로서, 대조군은 시중 약국에서 구입한 정제를 사용하였다.Table 1 below shows the drug expression time and the presence of side effects when the stock solution prepared in the above example was sprayed 2.0 ml once daily for 8 healthy males 40 to 55 years old, and the control group was used in a commercial pharmacy. Purchased tablets were used.
약효발현(분)Drug expression (minutes) 1~21 ~ 2 2~32 ~ 3 3~43 ~ 4 4~54 ~ 5 5~65 ~ 6 6~76 ~ 7 7~87-8 8~98-9 9~109-10 10~1110-11 11~1211-12
인수 take over 1One 22 33 44 55 66 77 88 88 88 88
분무량(㎖)Spray amount (ml) 22 22 22 22 22 22 22 22 22 22 22
부작용Side Effect 두통headache 현기vertigo 홍조flushing 메스꺼움sickness 발진rash 근육통Muscle pain 복통colic 설사diarrhea 안구충혈Ocular hyperemia 소화불량Indigestion 관절통Arthralgia
유·무The presence or absence 무radish 무radish 무radish 유U 무radish 무radish 무radish 무radish 무radish 유U 무radish
대 조contrast 유U 유U 유U 유U 유U 유U 유U 유U 유U 유U 유U
상기 표에서 볼 수 있듯이, 본 발명의 PDE-5 저해제를 포함하는 설하분무제는 일반 정제에 비해 약효발현이 8분 이내로 이루어질 뿐만 아니라 부작용이 매우 적은 것을 확인할 수 있다.As can be seen from the table, sublingual spraying agent containing the PDE-5 inhibitor of the present invention can be confirmed that not only the drug expression is made within 8 minutes compared to the general tablets but also very few side effects.
본 발명은 상술한 특정의 실시예 및 설명에 한정되지 아니하며, 청구범위에서 청구하는 본 발명의 요지를 벗어남이 없이 당해 발명이 속하는 기술 분야에서 통상의 지식을 가진 자라면 누구든지 다양한 변형 실시가 가능하며, 그와 같은 변형은 본 발명의 보호 범위 내에 있게 된다.The present invention is not limited to the above specific embodiments and descriptions, and various modifications can be made by those skilled in the art without departing from the gist of the invention as claimed in the claims. Such variations are within the protection scope of the present invention.

Claims (12)

  1. 실데나필, 타달라필, 바데나필, 유데나필 중 적어도 어느 하나 이상을 포함하는 PDE-5 저해제를 용매에 첨가하여 PDE-5 저해제 용액을 제조하는 단계; Preparing a PDE-5 inhibitor solution by adding a PDE-5 inhibitor comprising at least one of sildenafil, tadalafil, vardenafil, and udenafil to a solvent;
    상기 PDE-5 저해제 용액을 저온 감압 농축하여 PDE-5 저해제 고형물을 제조하는 단계; 및Preparing a PDE-5 inhibitor solid by concentrating the PDE-5 inhibitor solution at low temperature; And
    상기 PDE-5 저해제 고형물로부터 추출용매를 사용하여 유효성분을 추출한 후, 추출액을 여과하여 설하분무제 원액을 제조하는 단계;Extracting an active ingredient from the PDE-5 inhibitor solids using an extraction solvent, and then filtering the extract to prepare a sublingual spray solution;
    를 포함하는 PDE-5 저해제를 포함하는 설하분무제의 제조방법.Method for producing a sublingual spray comprising a PDE-5 inhibitor comprising a.
  2. 제1항에 있어서, The method of claim 1,
    상기 PDE-5 저해제 용액의 제조단계에서, 알코올과 알칼리 이온수의 혼합용매가 사용되는 것을 특징으로 하는 PDE-5 저해제를 포함하는 설하분무제의 제조방법.In the preparation step of the PDE-5 inhibitor solution, a method for producing a sublingual spray containing a PDE-5 inhibitor, characterized in that a mixed solvent of alcohol and alkaline ionized water is used.
  3. 제1항에 있어서, The method of claim 1,
    상기 PDE-5 저해제 용액에 구연산이 추가로 첨가되는 것을 특징으로 하는 PDE-5 저해제를 포함하는 설하분무제의 제조방법.Method for producing a sublingual spray containing a PDE-5 inhibitor, characterized in that citric acid is further added to the PDE-5 inhibitor solution.
  4. 제1항에 있어서, The method of claim 1,
    상기 PDE-5 저해제 용액에 글리시리진산(glycyrrhizinic acid)이 추가로 첨가되는 것을 특징으로 하는 PDE-5 저해제를 포함하는 설하분무제의 제조방법.Method for producing a sublingual spray containing a PDE-5 inhibitor, characterized in that the glycyrrhizinic acid is further added to the PDE-5 inhibitor solution.
  5. 제1항에 있어서, The method of claim 1,
    상기 추출용매가 알칼리 이온수를 포함하는 것을 특징으로 하는 PDE-5 저해제를 포함하는 설하분무제의 제조방법.Method for producing a sublingual spray containing a PDE-5 inhibitor, characterized in that the extraction solvent comprises alkaline ionized water.
  6. 제1항에 있어서, The method of claim 1,
    상기 추출용매에 산 수용액이 추가로 첨가되는 것을 특징으로 하는 PDE-5 저해제를 포함하는 설하분무제의 제조방법.A method of producing a sublingual spray containing a PDE-5 inhibitor, characterized in that the addition of an aqueous acid solution to the extraction solvent.
  7. 제1항에 있어서, The method of claim 1,
    상기 추출용매에 구연산이 추가로 첨가되는 것을 특징으로 하는 PDE-5 저해제를 포함하는 설하분무제의 제조방법.Citric acid is added to the extraction solvent, the method for producing a sublingual spray comprising a PDE-5 inhibitor.
  8. 제1항에 있어서, The method of claim 1,
    상기 유효성분의 추출이 30~40℃에서 10~60 분간 교반한 후, 실온에서 6~24시간 방치하여 이루어지는 것을 특징으로 하는 PDE-5 저해제를 포함하는 설하분무제의 제조방법.The extraction of the active ingredient is stirred for 10 to 60 minutes at 30 ~ 40 ℃, and then left for 6 to 24 hours at room temperature manufacturing method of a sublingual spray containing a PDE-5 inhibitor.
  9. 제1항에 있어서, The method of claim 1,
    상기 설하분무제 원액에 인공감미제 또는 포도당이 추가로 첨가되는 것을 특징으로 하는 PDE-5 저해제를 포함하는 설하분무제의 제조방법Method for producing a sublingual spray containing a PDE-5 inhibitor, characterized in that artificial sweetener or glucose is added to the sublingual spray solution
  10. 제1항에 있어서, The method of claim 1,
    상기 설하분무제 원액을 분무용기에 충입하는 단계;를 추가로 포함하는 것을 특징으로 하는 PDE-5 저해제를 포함하는 설하분무제의 제조방법.The method of preparing a sublingual spray agent comprising a PDE-5 inhibitor, characterized in that it further comprises;
  11. 제1항 내지 제10항 중 어느 한 항의 방법에 의하여 제조된 PDE-5 저해제를 포함하는 설하분무용 조성물.Sublingual spray composition comprising a PDE-5 inhibitor prepared by the method of any one of claims 1 to 10.
  12. 제11항에 있어서, The method of claim 11,
    사상자 또는 음양곽 추출액, 몰약 및 박하유 중 어느 하나 이상을 추가로 포함하는 것을 특징으로 하는 PDE-5 저해제를 포함하는 설하분무용 조성물.Sublingual spray composition comprising a PDE-5 inhibitor, characterized in that it further comprises any one or more of casualty or Eumyang extract, myrrh and peppermint oil.
PCT/KR2015/008274 2014-08-07 2015-08-07 Method for preparing sublingual spray containing pde-5 inhibitor, and composition for sublingual spraying prepared thereby WO2016021975A1 (en)

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