KR100187603B1 - Famotidine solution for injection and lyophilized preparation thereof - Google Patents
Famotidine solution for injection and lyophilized preparation thereof Download PDFInfo
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- KR100187603B1 KR100187603B1 KR1019960060312A KR19960060312A KR100187603B1 KR 100187603 B1 KR100187603 B1 KR 100187603B1 KR 1019960060312 A KR1019960060312 A KR 1019960060312A KR 19960060312 A KR19960060312 A KR 19960060312A KR 100187603 B1 KR100187603 B1 KR 100187603B1
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
본 발명은 하기 구조식으로 표시되는 파모티딘의 가용화제로서 시트라말산 또는 키닌산을 함유하여 고도의 수용해성 및 적당한 pH를 갖는 파모티딘 주사 또는 주입 액제 및 이의 동결건조 제제에 관한 것이다.The present invention relates to pamotidine injection or infusion liquids and lyophilized preparations thereof containing citramal acid or chinic acid as a solubilizer of pamotidine represented by the following structural formula and having high water solubility and suitable pH.
Description
[발명의 명칭][Name of invention]
파모티딘의 주사용 액제 및 이의 동결건조 제제Injectable solutions of pamotidine and lyophilized preparations thereof
[발명의 상세한 설명]Detailed description of the invention
[발명의 목적][Purpose of invention]
본 발명의 목적은 하기 구조식으로 표시되는 수난용성 파모티딘의 개선된 주사 또는 주입 액제를 제공하는데 있다.It is an object of the present invention to provide an improved injection or infusion solution of poorly water-soluble pamotididine represented by the following structural formula.
[발명이 속하는 기술분야 및 그 분야의 종래기술][Technical field to which the invention belongs and the prior art in that field]
파모티딘은 [[[2-[(디아미노메틸렌)이미노]-4-티아졸릴]티오]-N2-설파모일프로리온아미딘의 화학명을 가지며 같은 약효군인 시메티딘, 라니티딘보다 우수한 약효를 보이며, 약동력학적으로 현재 시판되고 있는 약물들 중 우수한 약동력학적 성직을 나타내고 있다.Famotidine has the chemical name of [[[2-[(diaminomethylene) imino] -4-thiazolyl] thio] -N 2 -sulfamoylproionamidine and is superior to cimetidine and ranitidine. It shows pharmacokinetic orthodoxy among the currently marketed drugs.
일반적으로 약물은 경구투여 방식으로 인체에 투여하는 것이 가장 간편하지만 특별한 경우 경구투여는 그다지 바람직하지 않으며, 예를들면 인체의 세균성 전염병을 치료하기 위하여 특정 항생제의 높은 혈중농도가 요구될 때나 장기간에 걸쳐 특정한 혈중농도를 유지하기 위해 정맥주사 또는 점적주사할 때 또는 약물의 소화관에서의 불안정한 경우와 흡수가 불안전한 경우등이 있을 수 있다. 소아, 허약한 환자 또는 의식이 없는 환자를 치료할 때에 역시 근육 혹은 정맥 주사할 수 있다. 안정한 주사투여 형태 또는 사용전에 즉시 투여할 수 있는 주사용 약제는 최소한 피와 근육조직 등에 해가 없는 pH에서의 높은 수용해성, 상온 및 공기의 존재하에서 용액으로의 안정성, 첨가제와 함께 작용시 생체에 대해 독성을 나타내지 않는 등의 성질을 필요로 한다.In general, the drug is most easily administered to the human body by oral administration, but in particular cases, oral administration is not preferable, for example, when a high blood concentration of a certain antibiotic is required to treat a bacterial infectious disease in the human body or over a long period of time. Intravenous or drip injections to maintain a specific blood concentration, or instability of the drug in the digestive tract, and absorption may be unstable. Muscle or intravenous injections may also be used to treat pediatric, fragile or unconscious patients. A stable injectable form or an injectable agent which can be administered immediately before use has high solubility at a pH that is harmless to blood and muscle tissue, at least in stability in solution in the presence of room temperature and air, and when used with additives. It requires properties such as not toxic to the skin.
그러나 파모티딘은 물에 잘 녹지 않기 때문에(25℃ 물에 대한 용해도 1mg/ml 이하) 주사 또는 주입용액으로 사용하기에 곤란하다. 이러한 물에 불용성 약제를 녹이기 위한 많은 시도가 있었다. 그 결과로 파모티딘에 첨가하였을 때 주사 또는 주입하기에 적합한 농도에서 침전을 일으키지 않게 하는 물질들이 알려져 있다. 한국특허공고 제88-1632호에는 침전을 일으키지 않게 하는 산의 예로서 염산, 옥살산, 말론산, 석신산, 푸마르산, 시트르산, L-아스파르트산, L-글루탐산 등이 예시되어 있다. 이들 중 염산, 옥살산, 말론산, 석신산, 푸마르산 등은 용액 중의 안정성이 불량하여 24시간 방치시 침전이 형성되고, 시트르산, 침전은 형성하지 않으나 용액의 pH가 너무 낮으며 동결건조시 끈적거리는 럼프(lump)를 형성하는 등의 약제학적으로 많은 문제점이 있다. L-아스파르트산과 L-글루탐산의 경우에는 용해성 및 pH가 적당하여 실제 응용되고 있다.However, pamotididine is difficult to be used as an injection or injectable solution because it is poorly soluble in water (solubility in water of 25 ° C. or less than 1 mg / ml). Many attempts have been made to dissolve insoluble agents in such water. As a result, substances are known that when added to pamotididine do not cause precipitation at concentrations suitable for injection or infusion. In Korean Patent Publication No. 88-1632, hydrochloric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, citric acid, L-aspartic acid, L-glutamic acid and the like are exemplified as examples of acids which do not cause precipitation. Among them, hydrochloric acid, oxalic acid, malonic acid, succinic acid, and fumaric acid have poor stability in solution, and precipitate is formed when left for 24 hours, citric acid and precipitate are not formed, but the pH of the solution is too low and sticky during lyophilization. There are many pharmaceutical problems such as forming lumps. In the case of L-aspartic acid and L-glutamic acid, solubility and pH are suitable, and it is actually applied.
[발명이 이루고자 하는 기술적 과제][Technical problem to be achieved]
새로운 가용화제를 선정하여 파모티딘을 주사용 또는 주입용 액체로 투여하기에 충분한 정도의 수중 용해성 및 적당한 pH를 갖는 개선된 파모티딘 주사 또는 주입 액제의 개발이 요구된다.There is a need to select new solubilizers to develop improved pamotididine injection or infusion solutions that have a sufficient pH in water and adequate pH to administer pamotididine as an injection or infusion liquid.
[발명의 구성 및 작용][Configuration and Function of Invention]
본 발명자들은 놀랍게도 시트라말산 또는 키닌산의 유기산을 사용하여 파모티딘과의 염을 만들어 주면 파모티딘의 물에 대한 용해도가 크게 증가함을 발견하였다. 또한, 본 발명자들은 통상의 파모티딘 주사제 투여농도에서 투여하기에 적당한 pH를 가지고 안정성 면에서는 L-아스파르트산과 L-글루탐산과 비슷한 안정성을 가진다는 사실도 발견하였다.The inventors have surprisingly found that the solubility of pamotidine in water is greatly increased when salts with pamotidine are prepared using the organic acid of citramal acid or chinic acid. In addition, the inventors have found that they have a pH suitable for administration at a conventional pamotidine injectable concentration, and have stability similar to that of L-aspartic acid and L-glutamic acid in terms of stability.
따라서, 본 발명은 파모티딘과 가용화제로서 시트로말산 또는 키닌산을 함유함을 특징으로 하는 주사 또는 주입용 액제에 관한 것이다.Accordingly, the present invention relates to a solution for injection or infusion, characterized in that it contains cimomalic acid or chinic acid as pamotidine and a solubilizer.
본 발명에 따른 파모티딘의 액제는 pH가 3.0 내지 7.0이며, 바람직하게는 4.0 내지 6.0이다.The solution of pamotidine according to the present invention has a pH of 3.0 to 7.0, preferably 4.0 to 6.0.
또한, 본 발명에 따른 용액에 동결건조시에 통상적으로 사용되는 부형제를 첨가하여 동결 건조하였을 때, 안정적인 동결건조물을 얻을 수 있었으며 물과 재혼화하였을 때 재분산하여 맑은 용액을 얻을 수 있었다. 따라서, 본 발명에 의한 용액은 동결건조에 의해 제제화하여 사용하기에 적당하다.In addition, when the freeze-dried by adding the excipients commonly used during lyophilization to the solution according to the present invention it was possible to obtain a stable freeze-dried, and when remixed with water to obtain a clear solution. Thus, the solution according to the invention is suitable for use in formulating by lyophilization.
본 발명의 용액을 동결건조하는데 사용되는 부형제는 약제학 분야에서 통상적으로 사용되는 것중 어느 것도 가능하다. 본 발명에서 바람직하게 사용될 수 있는 것은 대표적으로 만니톨 또는 솔비톨과 같은 다가 알코올을 예로 들 수 있다.Excipients used to lyophilize the solutions of the invention can be any of those conventionally used in the pharmaceutical art. What can be preferably used in the present invention is typically a polyhydric alcohol such as mannitol or sorbitol.
하기 실시예로 본 발명을 구체적으로 예시한다. 그러나, 이들 실시예로 본 발명을 한정하는 것으로 이해되어서는 안된다.The following examples specifically illustrate the present invention. However, these examples should not be understood as limiting the invention.
[실시예 1]Example 1
파모티딘 1g에 시트라말산 440mg을 넣고 물 90ml을 가하여 교반하여 내용물을 녹인 후 총 용적이 100ml이 되도록 물을 가해 액량을 맞췄다.440 mg of citramal acid was added to 1 g of pamotidine, and 90 ml of water was added to the mixture to stir to dissolve the contents, and water was added to make the total volume 100 ml.
[실시예 2]Example 2
파모티딘 1g에 키닌산 570mg을 넣고 물 90ml을 가하여 교반하여 내용물을 녹인 후 총 용적이 100ml이 되도록 물을 가해 액량을 맞췄다.570 mg of kininic acid was added to 1 g of pamotididine, 90 ml of water was added thereto, the mixture was stirred to dissolve the contents, and water was added so that the total volume was 100 ml.
[실시예 3]Example 3
파모티딘 10g에 시트라말산 4.40g을 넣고 물 10ml을 가하여 충분히 교반하여 내용물을 녹인 후 총 용적이 100ml이 되도록 물을 가해 액량을 맞췄다.4.40 g of citramal acid was added to 10 g of pamotididine, 10 ml of water was added thereto, and the mixture was stirred sufficiently to dissolve the contents, and water was added so that the total volume was 100 ml.
[실시예 4]Example 4
파모티딘 10g에 키닌산 5.70g을 넣고 물 10ml을 가하여 충분히 교반하여 내용물을 녹인 후 총 용적이 100ml이 되도록 물을 가해 액량을 맞췄다.5.70 g of kininic acid was added to 10 g of pamotididine, 10 ml of water was added thereto, and the mixture was stirred sufficiently to dissolve the contents, followed by adding water so that the total volume was 100 ml.
[실시예 5]Example 5
파모티딘 1g에 시트라말산 440mg을 넣고 물 90ml을 가하여 교반하여 내용물을 녹인 후 만니톨 2g을 넣어 녹이고 총 용적이 100ml이 되도록 물을 가해 액량을 맞추고 얻어진 수용액을 동결건조하였다.440 mg of citramal acid was added to 1 g of pamotididine, 90 ml of water was added thereto, stirred, and the contents were dissolved. Then, 2 g of mannitol was dissolved, water was added so that the total volume was 100 ml, the amount of the solution was adjusted, and the obtained aqueous solution was lyophilized.
[실시예 6]Example 6
파모티딘 1g에 키닌산 570mg을 넣고 물 90ml을 가하여 교반하여 내용물을 녹인 후 만니톨 2g을 넣어 녹이고 총 용적이 100ml이 되도록 물을 가해 액량을 맞추고 얻어진 수용액을 동결건조하였다.570 mg of kininic acid was added to 1 g of pamotididine, 90 ml of water was added thereto, and the contents were stirred to dissolve the contents. Then, 2 g of mannitol was dissolved and water was added so that the total volume was 100 ml. The aqueous solution was lyophilized.
[발명의 효과][Effects of the Invention]
파모티딘 1% 용액의 pH와 고압증기멸균시(121℃, 1시간)의 약물의 잔여역가 및 25℃의 물에 대한 용해도 시험결과는 하기 표 1과 같다.The pH of the 1% solution of pamotididine, the residual titer of the drug at high pressure steam sterilization (121 ° C., 1 hour) and the solubility test results in water at 25 ° C. are shown in Table 1 below.
상기 결과로부터 시트라말산과 키닌산은 파모티딘에 탁월한 가용화효과를 나타냄을 알 수 있다.From the above results, it can be seen that citramal acid and chinic acid show an excellent solubilizing effect on pamotidine.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019960060312A KR100187603B1 (en) | 1996-11-30 | 1996-11-30 | Famotidine solution for injection and lyophilized preparation thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019960060312A KR100187603B1 (en) | 1996-11-30 | 1996-11-30 | Famotidine solution for injection and lyophilized preparation thereof |
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| Publication Number | Publication Date |
|---|---|
| KR19980041046A KR19980041046A (en) | 1998-08-17 |
| KR100187603B1 true KR100187603B1 (en) | 1999-06-01 |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1019960060312A KR100187603B1 (en) | 1996-11-30 | 1996-11-30 | Famotidine solution for injection and lyophilized preparation thereof |
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