KR810001164B1 - Process for preparing stable water-soluble salts of dehydroepiandrosterone sulfate - Google Patents
Process for preparing stable water-soluble salts of dehydroepiandrosterone sulfate Download PDFInfo
- Publication number
- KR810001164B1 KR810001164B1 KR7602232A KR760002232A KR810001164B1 KR 810001164 B1 KR810001164 B1 KR 810001164B1 KR 7602232 A KR7602232 A KR 7602232A KR 760002232 A KR760002232 A KR 760002232A KR 810001164 B1 KR810001164 B1 KR 810001164B1
- Authority
- KR
- South Korea
- Prior art keywords
- dha
- water
- dehydroepiandrosterone sulfate
- macrogol
- soluble salts
- Prior art date
Links
Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
본 발명은 안정한 디히드로 에피안드로스테론 설페이트 수용성염의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of stable dihydro epiandrosterone sulfate water soluble salts.
디히드로 에피안드로스테론 설페이트(이하"DHA-S라 한다)는 스테로이드홀몬의 한분비물 형태인 것으로 알려졌고, 인체의 오줌에서 나트륨염으로 발견되었다. DHA-S는 인체속에서 DHA-S로서 생동 순환하는 유리(遊離)디히드로 에피안드로스테론으로 부터 생성된다.Dehydroepiandrosterone sulfate (hereinafter referred to as DHA-S) is known to be a secreted form of steroid hormones and has been found as sodium salt in human urine. DHA-S is produced from free dihydroepiandrosterone, which circulates in the human body as DHA-S.
다량의 DHA-S가 태아의 부신(副腎)으로부터 분비되며, 이는 정상적인 임신을 하는데 중요한 역할을 하는 것이다.Large amounts of DHA-S are secreted from the adrenal gland of the fetus, which plays an important role in normal pregnancy.
DHA-S는 난소집에서도 생성되며 체액으로 분비된다.DHA-S is also produced in ovarian colonies and secreted into body fluids.
최근에, DHA-S를 임신 37내지 39주에 임산부에 주사하면, 출산관의 자궁 근육의 옥시로신(oxytocin)에 대한 민감성을 증진시켜, 안전하고 정상적인 분만으로 인도할 수 있음이 발견되었다.Recently, it has been found that injection of DHA-S in pregnant women 37 to 39 weeks of pregnancy enhances the sensitivity of the uterine muscles to oxytocin in the birth canal, leading to safe and normal delivery.
이리하여 DHA-S의 임상적용은 매우 중요하게 되었다. 그런데 불행하게도 DHA-S의 수용성염은 물의 존재하에서는 매우 불안정한 것이다. 즉 예로 DHA-S의 나트륨은, 실온에서 수용액에 저장되었을 때는 짧은 시간 동안에도 부분적으로 가수분해되어 유리 디히드로에피안드로 스테론으로 되어진다.Thus, the clinical application of DHA-S has become very important. Unfortunately, the water-soluble salts of DHA-S are very unstable in the presence of water. That is, for example, sodium of DHA-S, when stored in an aqueous solution at room temperature, is partially hydrolyzed even for a short time to become free dihydroepiandrosterone.
따라서 그 투약형태는, 각 사용시에 멸균수에 재용해되는 용기에 포장된 멸균 건조결정, 또는 동결 건조(凍結乾燥)된 분말이어야 한다.Thus, the dosage form should be sterile dried crystals or lyophilized powder packaged in a container which is redissolved in sterile water at each use.
상기 형태는 결정이 사용시에 물에 용해되는데 긴시간이 걸리고, 동결건조된 분말은 실온에서 충분한 수명을 못가지므로써 다 만족할만한 것이 못된다.This form takes a long time for the crystals to dissolve in water when in use, and the lyophilized powder does not have sufficient life at room temperature and thus is not satisfactory.
본 발명에 의하면, 수용성DHA-S의 주사제의 안정한 제조는, 덱스트란, 마크로골(macrogol), 중성아미노산, 염기성 아미노산, 약산의 알카리금속염, 고체아민, 및 그들의 혼합물의 군으로부터 선택된 화합물을 함유하는 수용액에 상기 염을 용해시키고, 그 결과 얻어진 혼합물을 동결건조시킴에 의해 얻어질 수 있는 것이다. 그 결과 얻어진 분말은 저장에 있어서는 긴시간 동안 안정하며 사용에 있어 정맥주사 또는 근육주사와 같은 주사를 위해 멸균수에 쉽게 용해되는 것이다.According to the present invention, stable preparation of water-soluble DHA-S injections contains compounds selected from the group of dextran, macrogol, neutral amino acids, basic amino acids, alkali metal salts of weak acids, solid amines, and mixtures thereof. It can be obtained by dissolving the salt in an aqueous solution and lyophilizing the resulting mixture. The resulting powder is stable for a long time in storage and readily soluble in sterile water for injection such as intravenous or intramuscular injection in use.
본 발명은 실시하는데 사용될 수 있는 DHA-S의 수용성염은, 나트륨염 또는 칼륨염과 같은 알카리금속염, 암모늄염, 및 L-라이신염 또는 L-아르기닌염과 같은 아민염이다.Water-soluble salts of DHA-S that can be used in the present invention are alkali metal salts such as sodium salts or potassium salts, ammonium salts, and amine salts such as L-lysine salts or L-arginine salts.
본 발명에 의해 첨가될 수 있는 화합물은, 일본약전 제8판(JP)의 덱스트란 40(평균 M.W=40,000)과 덱스트란 70(평균 M.W=70,000)과 같은 30,000내지 100,000의 평균 분자량을 갖는 덱스트란, 마크로골 1,500,JP,마크토콜 4,000 JP, 및 마크로골 ; 6,000 JP와 같은 마크로골 ; 글리신, 알라닌, 루신, 아르기닌, 히스티딘, 라이신, 오르니틴(ornithine)과 같은 중성 혹은 염기성 아미노산(D-, L-또는 DL-형) ; 구연산, 주석산, 숙신산, 초산, 인산, 봉산, 및 탄산의 칼륨 염과 나트륨염 같은 약 유기산이나 무기산의 알칼리금속염 ; 및 트리스(히드록시메틸)아미노메틸과 같은 고체아민이다.Compounds that can be added by the present invention are dextran having an average molecular weight of 30,000 to 100,000, such as dextran 40 (average MW = 40,000) and dextran 70 (average MW = 70,000) of the JP Eighth Edition (JP). Tran, Macrogol 1,500, JP, Macrotocol 4,000 JP, and Macrogol; Macrogol such as 6,000 JP; Neutral or basic amino acids (D-, L- or DL-type) such as glycine, alanine, leucine, arginine, histidine, lysine and ornithine; Alkali metal salts of weak organic and inorganic acids such as potassium and sodium salts of citric acid, tartaric acid, succinic acid, acetic acid, phosphoric acid, bongsan, and carbonic acid; And solid amines such as tris (hydroxymethyl) aminomethyl.
아미노산, 약산의 알칼리금속염 및 고체아민은 완충제로서 알려졌다.Amino acids, alkali metal salts of weak acids and solid amines are known as buffers.
안정제의 량은 DHA-S의 수용성염의 중량에 대해 적어도 10%, 바람직하게는 20%내지 200%이다.The amount of stabilizer is at least 10%, preferably 20% to 200% by weight of the water soluble salt of DHA-S.
DHA-S의 용해도는, 덱스트란, 마크로골 및 아미노산의 존재에 의해 현저하게 증가됨을 알았다.It was found that the solubility of DHA-S was markedly increased by the presence of dextran, macrogol and amino acids.
예로, 실온에서 DHA-S 나트륨의 담수에 대한 용해도는 1.4%이나, 2%의 글리신 수용액에서는 3.0%이다.For example, the solubility of DHA-S sodium in fresh water at room temperature is 1.4%, but 3.0% in 2% aqueous glycine solution.
따라서 100mg의 DHA-S 나트륨염을 함유하는 앰플용액은 2%글리신 수용액5ml를 배합하므로써 얻어지는 반면에, 만약 DHA-S 나트륨염을 용해시키기 위해 담수를 사용한다면 10ml가 필요하게 된다.Thus, an ampoule solution containing 100 mg of DHA-S sodium salt is obtained by combining 5 ml of a 2% glycine aqueous solution, whereas 10 ml is required if fresh water is used to dissolve the DHA-S sodium salt.
이것은 동결건조시 제거해야 할 물의 량과, 또 동결건조 하는데 필요한 시간을 현격히 감소시킨다. 실시에 있어서 DHA-S의 수용성염은 안정제의 용액속에 용해되며, 용액은 종래방법으로 여과하므로 멸균된다.This significantly reduces the amount of water to be removed during lyophilization and the time required for lyophilization. In practice, the water-soluble salt of DHA-S is dissolved in the solution of the stabilizer, and the solution is sterilized by filtration by conventional methods.
용액은, 앰플이나 바이얼(vial)같은 용기에 분배된 다음 종래의 방법으로 동결 건조된다. 최종적으로 용기는 밀봉된다.The solution is dispensed in a container such as an ampoule or vial and then lyophilized by conventional methods. Finally the container is sealed.
사용시에는 충분한 량의 멸균수를 가함에 의해 용기내의 내용물은 제용해 둔다. 본 발명을 하기 실시예에 따라 상세히 설명한다. 실시예 1.In use, the contents in the container are removed by adding a sufficient amount of sterile water. The invention is described in detail in accordance with the following examples. Example 1.
100 ml의 DHA-S나트륨염을 각 중량의 마크로골 4,000, JP와 혼합했다. 혼합물을 각기 5ml이 멸균수에 용해시켰다.100 ml of DHA-S sodium salt was mixed with each weight of Macrogol 4,000, JP. 5 ml each of the mixture was dissolved in sterile water.
이 용액을 멸균조건하에서 앰플에 충전한다음 동결건조시켰다. 앰플은 50°C에서 10일간, 20일간, 30일간, 각기 저장했고 그리고 DHA-S 나트륨의 잔량을 측정했다. 얻어진 결과는 표-1에 표시했다.This solution was filled into ampoules under sterile conditions and then lyophilized. The ampoules were stored at 50 ° C. for 10 days, 20 days and 30 days, respectively, and the residual amount of DHA-S sodium was measured. The results obtained are shown in Table-1.
[표 1]TABLE 1
표 1로부터 DHA-S 나트륨은 20mg내지 150mg의 마크로골의 첨가에 의해 근본적으로 안정되며, 상기와 같은 적당시간에 용해됨을 알게 될 것이다. 실시예 2It will be seen from Table 1 that DHA-S sodium is fundamentally stabilized by the addition of 20 mg to 150 mg of macrogol and dissolves in such a suitable time. Example 2
[실시예 2]Example 2
DHA-S 나트륨과 마크로골 4,000대신에 DHA-S L-히스티딘염과 마크로골 6,000,JP를 사용하는 것외에는 실시예 1의 방법과 마찬가지로 반복했다.The same procedure as in Example 1 was repeated except that DHA-S L-histidine salt and macrogol 6,000, JP were used instead of 4,000 DHA-S sodium and macrogol.
표2에는 표시된 바와같이 20mg내지 150mg의 마크로골 6,000으로 만족스러운 결과를 얻었다.As shown in Table 2, satisfactory results were obtained with macrogol 6,000 of 20 mg to 150 mg.
[표 2]TABLE 2
[실시예 3]Example 3
마크로골 4,000대신에 덱스트할 40,JP를 사용한 외에는 실시예 1의 방법과 마찬가지로 반복했다.The procedure was repeated in the same manner as in Example 1 except that 40, JP to be dexted instead of 4,000 macrogols was used.
표-3에 표시된 바와같이, 20mg내지 150mg의 덱스트란 40으로 만족스러운 결과를 얻었다.As shown in Table-3, satisfactory results were obtained with 20 mg to 150 mg of dextran 40.
[표 3]TABLE 3
[실시예 4]Example 4
마트로골 4,000대신에 마크로골 4,000,JP와 텍스트란 70, JP와의 1 : 1혼합물을 사용하는 외에는 실시예 1의 방법과 마찬가지로 반복했다.The same procedure as in Example 1 was repeated except that a 1: 1 mixture of macrogol 4,000, JP, text field 70, and JP was used instead of 4,000 of romatrogol.
표-4에 표시된 바와같이, 20mg내지 150mg의 마크로골 4,000과 덱스트란 70과의 혼합물로 만족스러운 결과를 얻었다.As shown in Table-4, satisfactory results were obtained with a mixture of 20 to 150 mg of macrogol 4,000 and dextran 70.
[표 4]TABLE 4
[실시예 5]Example 5
40g의 글리신을 2리터들이 용기에서 증류수에 용해했다. 용액에 40g의 DHA-S 나트륨염을 가온에 의해 첨가했다. 증류수로서 용액의 전용량이 2리터가 되도록 했다. 용액은 종래의 방법의 여과에 의해 멸균하고, 유리앰플에 각 5ml씩 나눠 넣었다. 그 다음 용액을 종래의 방법으로 동결 건조시켜 밀봉했다.40 g of glycine was dissolved in distilled water in a 2 liter container. 40 g of DHA-S sodium salt was added to the solution by warming. As distilled water, the total amount of the solution was set to 2 liters. The solution was sterilized by filtration according to the conventional method, and each 5 ml was divided into glass ampoules. The solution was then lyophilized and sealed by conventional methods.
각 앰플은 100mg의 DHA-S 나트륨과 100mg의 글리신을 함유한다. 상기 방법을 글리신의 각종량으로 반복했다.Each ampoule contains 100 mg of DHA-S sodium and 100 mg of glycine. The method was repeated with various amounts of glycine.
DHA-S 나트륨염의 잔량은 실시예 1과 마찬가지로 측정했다. 얻어진 결과는 표-5에 표시했다.The residual amount of DHA-S sodium salt was measured in the same manner as in Example 1. The results obtained are shown in Table-5.
[표 5]TABLE 5
[실시예 6]Example 6
글리신 대신에 L-아르기닌(유리염기)을 사용한 외에는 실시예 5와 마찬가지로 반복했다.The procedure was repeated as in Example 5 except that L-arginine (free base) was used instead of glycine.
저장시험에서 DHA-S의 나트륨염의 잔량은 표-6에 표시했다.The residual amount of sodium salt of DHA-S in the storage test is shown in Table-6.
[표 6]TABLE 6
[실시예 7]Example 7
글리신 대신에 주석산 나트륨을 사용한 외에는 실시예 5와 마찬가지로 반복했다.The same procedure was followed as in Example 5 except that sodium stannate was used instead of glycine.
저장시험에서의 DHA-S 나트륨의 잔량은 표-7에 표시했다.The residual amount of DHA-S sodium in the storage test is shown in Table-7.
[표 7]TABLE 7
[실시예 8]Example 8
글리신 대신에 인산수소칼륨을 사용한 외에는 실시예 5와 마찬가지로 반복했다.The procedure was repeated as in Example 5 except that potassium hydrogen phosphate was used instead of glycine.
저장시험에서의 DHA-S 나트륨염의 잔량은 표-8에 표시했다.The residual amount of DHA-S sodium salt in the storage test is shown in Table-8.
[표 8]TABLE 8
[실시예 9]Example 9
글리신 대신에 DL- 알라닌을 사용한 외에는 실시예 5와 마찬가지로 반복했다.The procedure was repeated as in Example 5 except that DL-alanine was used instead of glycine.
저장시험에서의 DHA-S 나트륨염의 잔량은 표-9에 표시했다.The residual amount of DHA-S sodium salt in the storage test is shown in Table-9.
[표 9]TABLE 9
실시에 10 글리신 대신에 트리신(히드록시 메틸) 아미노메틸을 사용한 외에는 실시예 5와 마찬가지로 반복했다.It repeated like Example 5 except having used tricin (hydroxymethyl) aminomethyl instead of 10 glycine in the Example.
저장시험에서의 DHA-S 나트륨염의 잔량은 표-10에 표시했다.The residual amount of DHA-S sodium salt in the storage test is shown in Table-10.
[표 10]TABLE 10
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR7602232A KR810001164B1 (en) | 1976-09-10 | 1976-09-10 | Process for preparing stable water-soluble salts of dehydroepiandrosterone sulfate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR7602232A KR810001164B1 (en) | 1976-09-10 | 1976-09-10 | Process for preparing stable water-soluble salts of dehydroepiandrosterone sulfate |
Publications (1)
Publication Number | Publication Date |
---|---|
KR810001164B1 true KR810001164B1 (en) | 1981-09-25 |
Family
ID=19202670
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR7602232A KR810001164B1 (en) | 1976-09-10 | 1976-09-10 | Process for preparing stable water-soluble salts of dehydroepiandrosterone sulfate |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR810001164B1 (en) |
-
1976
- 1976-09-10 KR KR7602232A patent/KR810001164B1/en active
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US2980584A (en) | Parenteral magnesium oxytetracycline acetic or lactic acid carboxamide vehicle preparation | |
US3062717A (en) | Intramuscular calcium tetracycline acetic or lactic acid carboxamide vehicle preparation | |
US4866044A (en) | Solubilized composition of poorly-soluble pharmaceutical product | |
US3950513A (en) | Process of stabilizing therapeutically useful plasmin solutions | |
US4061744A (en) | Stable preparation of water-soluble salts of dehydroepiandrosterone sulfate for parenteral administration | |
JPH0347161A (en) | Stable liquid from of 5-aminosalicyclic acid | |
JP2514249B2 (en) | Stabilized calcitonin pharmaceutical composition | |
US4058623A (en) | Prostaglandin-containing lyophilized powders | |
CA1129344A (en) | Stabilized antibiotic formulations | |
KR810001164B1 (en) | Process for preparing stable water-soluble salts of dehydroepiandrosterone sulfate | |
US2970944A (en) | Parenteral solutions of steroid phosphates stabilized with creatinines | |
IL30594A (en) | Pharmaceutical compositions comprising salts of oestrone sulfate and oestradiol sulfate especially useful for treatment of climacteric disorders | |
US2644782A (en) | Aureomycin for injection | |
US4235900A (en) | Cephradine compositions | |
KR880002507A (en) | Lyophilized Pharmaceutical Compositions of Phenylquinoline Carboxylic Acid | |
EP0242653B1 (en) | Tpa-containing medical composition and use thereof | |
US4277461A (en) | Vaginal contraceptive | |
EP0180303B1 (en) | Parenteral composition | |
FI58072C (en) | FOERFARANDE FOER FRAMSTAELLNING AV ETT TORRPREPARAT AV ETT ALKALIMETALLSALT AV DEHYDROEPIANDROSTERONSULFAT FOER PARENTERAL ADMINISTRATION | |
US4088759A (en) | Injectable pharmaceutical solutions | |
US3133858A (en) | Stable thiobarbituric acid solution | |
BE845795A (en) | PROCESS FOR THE PREPARATION OF STABLE PREPARATIONS OF WATER-SOLUBLE SALTS OF DEHYDROEPIAND ROSTER SULPHATE FOR PARENTERAL ADMINISTRATION | |
US3161568A (en) | Parenteral solutions of hydroxocobalamin | |
US2213977A (en) | Pharmaceutical | |
US3075882A (en) | Estrone solubilized with n, n-dimethylacetamide |