CN103908671A - Alprostadil combinatorial drug - Google Patents
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- CN103908671A CN103908671A CN201410026700.8A CN201410026700A CN103908671A CN 103908671 A CN103908671 A CN 103908671A CN 201410026700 A CN201410026700 A CN 201410026700A CN 103908671 A CN103908671 A CN 103908671A
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Abstract
The invention provides an alprostadil combinatorial drug. The alprostadil combinatorial drug is characterized in that the alprostadil combinatorial drug is prepared from alprostadil, vitamin C, folic acid and glycine as active ingredients according to a weight part ratio of alprostadil, vitamin C, folic acid to glycine is 70-150: 20-35: 5-20: 30-60. The alprostadil combinatorial drug is superior to the drug prepared by the prior art in safety, stability and curative effects and can be prepared by an energy-saving and eco-friendly preparation method.
Description
Technical field
The present invention relates to a kind of composition of medicine and compound method thereof of Alprostadil.
Background technology
Alprostadil is the bioactive substance being extensively present in body, the mechanism for the treatment of diabetic neuropathy: 1, improve hematodinamics, by increasing the CAMP content in vascular smooth muscle cell, bring into play its vasodilative effect, reduce Peripheral resistance; 2, improve hemorheology, PGE1 can suppress platelet aggregation, reduces hematoblastic high reaction and thromboxane A 2 (TXA 2) level, can suppress platelet activation, promote the platelet that thrombosis has activated to reverse around, improve erythrocyte deformability; 3, PGE1, can activate lipoprotein lipase and promote triglyceride hydrolysis, reduces blood fat and blood viscosity; 4, PGE1, can stimulate vascular endothelial cell to produce the fine soluble substance of tectotype (t-PA), has certain direct thrombolytic effect.5, by suppressing the Free Ca z of vascular smooth muscle cell, suppress blood vessel SNE and discharge norepinephrine, make to relax the VSM, improve microcirculation.At present, under greenhouse, preserve unstablely due to injection Alprostadil, while meeting the external force such as light, heat, water, oxidation, very easily go to pot, brought greatly inconvenience therefore to storage and transportation, also increased the product cost of storage and cost of transportation.In addition, there is drug allergy person and the untoward reaction such as gastrointestinal tract, liver system and drug fever are reacted;
In order to overcome existing technological deficiency; a kind of composition of medicine of Alprostadil of best proportioning is provided; oxidation and peroxidating with the combined protection Alprostadil of vitamin C, folic acid and glycine in manufacture, storage, transportation, use, body; untoward reaction is alleviated greatly; and vitamin C, folic acid and glycine make not superfluous Alprostadil and damaging in body of liver, kidney, play protect the liver, the effect of kidney.
Summary of the invention
In order to overcome the defect of prior art, the invention provides composition of medicine of a kind of Alprostadil and preparation method thereof;
Invent a kind of composition of medicine of Alprostadil, made by effective active ingredient of following parts by weight:
Alprostadil 70-150
Vitamin C 20-35
Folic acid 5-20
Glycine 30-60
The method of described Alprostadil composition of medicine, method and step that it is prepared are as follows:
(1). getting weight is the water for injection of 5-15 times of described Alprostadil weight, under stirring, respectively described Alprostadil, vitamin C, folic acid, glycine is dissolved completely, obtains the composition of medicine solution of Alprostadil;
(2). with molecular cut off be the medicinal liquid that 6000D ultrafilter membrane ultrafiltration step (1) obtains, the membrane ultrafiltration that filtrate is 2000D with molecular cut off, filtrate regulates pH value 6.1-6.5 with 8% hydrochloric acid solution solution;
(3). the medicinal liquid that step (2) obtains was 121 ℃ of steam sterilizations 20 minutes;
(4). when the medicinal liquid after sterilizing is cooled to 20-22 ℃, with 8% hydrochloric acid solution solution, under stirring, be added drop-wise in medicinal liquid, the pH value of adjusting medicinal liquid is 6.1-6.5, then filters through the membrane filtration of 0.22 μ m, obtains composition of medicine solution;
(5). the composition of medicine medicinal liquid that above-mentioned step (4) is made is made the acceptable dosage form of Alprostadil on pharmaceutics;
A. press the dosage of the Alprostadil of pharmaceutics permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in cillin bottle, partly jump a queue, routinely, in the freeze drying box of freezer dryer, lyophilization, makes residual moisture≤2% in composition of medicine solid, tamponade, roll lid, make the lyophilized injection of Alprostadil composition of medicine;
B. press the dosage of the Alprostadil of meterological permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in 316L rustless steel pallet, lyophilization, make moisture≤2% in composition of medicine solid, pulverize composition of medicine solid to 60-80 order, measure Alprostadil content, be mixed with again 0.9% sodium chloride injection of Alprostadil or the Alprostadil composition of medicine of 5% glucose injection or 10% glucose injection or oral formulations or spray dosage form by well-established law.
The advantage of a kind of Alprostadil composition of medicine of the present invention has:
1. composition of medicine provided by the invention is to Vasculocardiology Deparment, vascular surgery, myocardial infarction, vasculitis, the therapeutic effect of atherosclerotic occlusive disease is higher than Alprostadil preparation in prior art and other treatment Vasculocardiology Deparment, vascular surgery, myocardial infarction, vasculitis, the medicine of atherosclerotic occlusive disease;
2. the present invention separates thermal source with the ultrafilter membrane of the molecular weight 2000D that dams, both specific activity charcoal except thermal source technique thorough, also separate thoroughly than the ultrafilter membrane with the molecular weight 2500D that dams, although heat source substance molecular weight is greater than 2500D, this research also finds that the heat source substance molecule fragment of 2500D also has pyrogen reaction, so must separate the pyrogen sheet segment molecule of 2500D molecular weight.So it is thorough that the present invention separates pyrogen, apyrogeneity reaction;
3. glycine has another name called glycine, for non-human essential amino acids, in molecule, there is acidity and basic functionality simultaneously, it in aqueous solution, is strong electrolyte, in intensive polar solvent, dissolubility is larger, substantially be insoluble to non-polar solven, and there is higher Boiling points and melting points, can make glycine present different molecular conformations by the adjusting of aqueous solution Acidity of Aikalinity, can be used as stabilizing agent simultaneously, vitamin C is had to Stabilization, and methyl parahydroxybenzoate, can prevent the microbial contamination of medicine receipts, microorganism is harmful to human body great majority, therefore played and ensured drug quality and bacteriostasis, under the interaction of glycine and methyl parahydroxybenzoate, stability and the safety of Alprostadil are guaranteed,
4. composition of medicine medicinal liquid, the solid after lyophilization is the dispersed system that is molecularity, makes corresponding preparation, the uniformity of dosage units of each composition is higher more than 20% than traditional coating mixing and high-speed stirred wet mixing technique.
The specific embodiment
Embodiment 1
The composition of medicine of a kind of Alprostadil of the present invention, made by effective active ingredient of following parts by weight:
Alprostadil 70
Vitamin C 20
Folic acid 5
Glycine 30
The method of described Alprostadil composition of medicine, method and step that it is prepared are as follows:
(2). getting weight is the water for injection of 5-15 times of described Alprostadil weight, under stirring, respectively described Alprostadil, vitamin C, folic acid, glycine is dissolved completely, obtains the composition of medicine solution of Alprostadil;
(2). with molecular cut off be the medicinal liquid that 6000D ultrafilter membrane ultrafiltration step (1) obtains, the membrane ultrafiltration that filtrate is 2000D with molecular cut off, filtrate regulates pH value 6.1-6.5 with 8% hydrochloric acid solution solution;
(3). the medicinal liquid that step (2) obtains was 121 ℃ of steam sterilizations 20 minutes;
(4). when the medicinal liquid after sterilizing is cooled to 20-22 ℃, with 8% hydrochloric acid solution solution, under stirring, be added drop-wise in medicinal liquid, the pH value of adjusting medicinal liquid is 6.1-6.5, then filters through the membrane filtration of 0.22 μ m, obtains composition of medicine solution;
(5). the composition of medicine medicinal liquid that above-mentioned step (4) is made is made the acceptable dosage form of Alprostadil on pharmaceutics;
A. press the dosage of the Alprostadil of pharmaceutics permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in cillin bottle, partly jump a queue, routinely, in the freeze drying box of freezer dryer, lyophilization, makes residual moisture≤2% in composition of medicine solid, tamponade, roll lid, make the lyophilized injection of Alprostadil composition of medicine;
B. press the dosage of the Alprostadil of meterological permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in 316L rustless steel pallet, lyophilization, make moisture≤2% in composition of medicine solid, pulverize composition of medicine solid to 60-80 order, measure Alprostadil content, be mixed with again 0.9% sodium chloride injection of Alprostadil or the Alprostadil composition of medicine of 5% glucose injection or 10% glucose injection or oral formulations or spray dosage form by well-established law.
Embodiment 2
The composition of medicine of a kind of Alprostadil of the present invention, made by effective active ingredient of following parts by weight:
Alprostadil 85
Vitamin C 24
Folic acid 8
Glycine 35
The method of described Alprostadil composition of medicine, method and step that it is prepared are as follows:
(3). getting weight is the water for injection of 5-15 times of described Alprostadil weight, under stirring, respectively described Alprostadil, vitamin C, folic acid, glycine is dissolved completely, obtains the composition of medicine solution of Alprostadil;
(2). with molecular cut off be the medicinal liquid that 6000D ultrafilter membrane ultrafiltration step (1) obtains, the membrane ultrafiltration that filtrate is 2000D with molecular cut off, filtrate regulates pH value 6.1-6.5 with 8% hydrochloric acid solution solution;
(3). the medicinal liquid that step (2) obtains was 121 ℃ of steam sterilizations 20 minutes;
(4). when the medicinal liquid after sterilizing is cooled to 20-22 ℃, with 8% hydrochloric acid solution solution, under stirring, be added drop-wise in medicinal liquid, the pH value of adjusting medicinal liquid is 6.1-6.5, then filters through the membrane filtration of 0.22 μ m, obtains composition of medicine solution;
(5). the composition of medicine medicinal liquid that above-mentioned step (4) is made is made the acceptable dosage form of Alprostadil on pharmaceutics;
A. press the dosage of the Alprostadil of pharmaceutics permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in cillin bottle, partly jump a queue, routinely, in the freeze drying box of freezer dryer, lyophilization, makes residual moisture≤2% in composition of medicine solid, tamponade, roll lid, make the lyophilized injection of Alprostadil composition of medicine;
B. press the dosage of the Alprostadil of meterological permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in 316L rustless steel pallet, lyophilization, make moisture≤2% in composition of medicine solid, pulverize composition of medicine solid to 60-80 order, measure Alprostadil content, be mixed with again 0.9% sodium chloride injection of Alprostadil or the Alprostadil composition of medicine of 5% glucose injection or 10% glucose injection or oral formulations or spray dosage form by well-established law.
Embodiment 3
The composition of medicine of a kind of Alprostadil of the present invention, made by effective active ingredient of following parts by weight:
Alprostadil 96
Vitamin C 28
Folic acid 12
Glycine 40
The method of described Alprostadil composition of medicine, method and step that it is prepared are as follows:
(4). getting weight is the water for injection of 5-15 times of described Alprostadil weight, under stirring, respectively described Alprostadil, vitamin C, folic acid, glycine is dissolved completely, obtains the composition of medicine solution of Alprostadil;
(2). with molecular cut off be the medicinal liquid that 6000D ultrafilter membrane ultrafiltration step (1) obtains, the membrane ultrafiltration that filtrate is 2000D with molecular cut off, filtrate regulates pH value 6.1-6.5 with 8% hydrochloric acid solution solution;
(3). the medicinal liquid that step (2) obtains was 121 ℃ of steam sterilizations 20 minutes;
(4). when the medicinal liquid after sterilizing is cooled to 20-22 ℃, with 8% hydrochloric acid solution solution, under stirring, be added drop-wise in medicinal liquid, the pH value of adjusting medicinal liquid is 6.1-6.5, then filters through the membrane filtration of 0.22 μ m, obtains composition of medicine solution;
(5). the composition of medicine medicinal liquid that above-mentioned step (4) is made is made the acceptable dosage form of Alprostadil on pharmaceutics;
A. press the dosage of the Alprostadil of pharmaceutics permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in cillin bottle, partly jump a queue, routinely, in the freeze drying box of freezer dryer, lyophilization, makes residual moisture≤2% in composition of medicine solid, tamponade, roll lid, make the lyophilized injection of Alprostadil composition of medicine;
B. press the dosage of the Alprostadil of meterological permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in 316L rustless steel pallet, lyophilization, make moisture≤2% in composition of medicine solid, pulverize composition of medicine solid to 60-80 order, measure Alprostadil content, be mixed with again 0.9% sodium chloride injection of Alprostadil or the Alprostadil composition of medicine of 5% glucose injection or 10% glucose injection or oral formulations or spray dosage form by well-established law.
Embodiment 4
The composition of medicine of a kind of Alprostadil of the present invention, made by effective active ingredient of following parts by weight:
Alprostadil 120
Vitamin C 33
Folic acid 16
Glycine 50
The method of described Alprostadil composition of medicine, method and step that it is prepared are as follows:
(5). getting weight is the water for injection of 5-15 times of described Alprostadil weight, under stirring, respectively described Alprostadil, vitamin C, folic acid, glycine is dissolved completely, obtains the composition of medicine solution of Alprostadil;
(2). with molecular cut off be the medicinal liquid that 6000D ultrafilter membrane ultrafiltration step (1) obtains, the membrane ultrafiltration that filtrate is 2000D with molecular cut off, filtrate regulates pH value 6.1-6.5 with 8% hydrochloric acid solution solution;
(3). the medicinal liquid that step (2) obtains was 121 ℃ of steam sterilizations 20 minutes;
(4). when the medicinal liquid after sterilizing is cooled to 20-22 ℃, with 8% hydrochloric acid solution solution, under stirring, be added drop-wise in medicinal liquid, the pH value of adjusting medicinal liquid is 6.1-6.5, then filters through the membrane filtration of 0.22 μ m, obtains composition of medicine solution;
(5). the composition of medicine medicinal liquid that above-mentioned step (4) is made is made the acceptable dosage form of Alprostadil on pharmaceutics;
A. press the dosage of the Alprostadil of pharmaceutics permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in cillin bottle, partly jump a queue, routinely, in the freeze drying box of freezer dryer, lyophilization, makes residual moisture≤2% in composition of medicine solid, tamponade, roll lid, make the lyophilized injection of Alprostadil composition of medicine;
B. press the dosage of the Alprostadil of meterological permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in 316L rustless steel pallet, lyophilization, make moisture≤2% in composition of medicine solid, pulverize composition of medicine solid to 60-80 order, measure Alprostadil content, be mixed with again 0.9% sodium chloride injection of Alprostadil or the Alprostadil composition of medicine of 5% glucose injection or 10% glucose injection or oral formulations or spray dosage form by well-established law.
Embodiment 5
The composition of medicine of a kind of Alprostadil of the present invention, made by effective active ingredient of following parts by weight:
Alprostadil 150
Vitamin C 35
Folic acid 20
Glycine 60
The method of described Alprostadil composition of medicine, method and step that it is prepared are as follows:
(6). getting weight is the water for injection of 5-15 times of described Alprostadil weight, under stirring, respectively described Alprostadil, vitamin C, folic acid, glycine is dissolved completely, obtains the composition of medicine solution of Alprostadil;
(2). with molecular cut off be the medicinal liquid that 6000D ultrafilter membrane ultrafiltration step (1) obtains, the membrane ultrafiltration that filtrate is 2000D with molecular cut off, filtrate regulates pH value 6.1-6.5 with 8% hydrochloric acid solution solution;
(3). the medicinal liquid that step (2) obtains was 121 ℃ of steam sterilizations 20 minutes;
(4). when the medicinal liquid after sterilizing is cooled to 20-22 ℃, with 8% hydrochloric acid solution solution, under stirring, be added drop-wise in medicinal liquid, the pH value of adjusting medicinal liquid is 6.1-6.5, then filters through the membrane filtration of 0.22 μ m, obtains composition of medicine solution;
(5). the composition of medicine medicinal liquid that above-mentioned step (4) is made is made the acceptable dosage form of Alprostadil on pharmaceutics;
A. press the dosage of the Alprostadil of pharmaceutics permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in cillin bottle, partly jump a queue, routinely, in the freeze drying box of freezer dryer, lyophilization, makes residual moisture≤2% in composition of medicine solid, tamponade, roll lid, make the lyophilized injection of Alprostadil composition of medicine;
B. press the dosage of the Alprostadil of meterological permission, composition of medicine medicinal liquid prepared by above-mentioned (4) step is aseptic subpackaged in 316L rustless steel pallet, lyophilization, make moisture≤2% in composition of medicine solid, pulverize composition of medicine solid to 60-80 order, measure Alprostadil content, be mixed with again 0.9% sodium chloride injection of Alprostadil or the Alprostadil composition of medicine of 5% glucose injection or 10% glucose injection or oral formulations or spray dosage form by well-established law.
Pharmacodynamics confirmatory experiment:
Animal is selected: 150 of the mices of the experimental model that selection is prepared by Experimental Animal Center, and body weight 18g-22g, male and female half and half, are divided into three groups at random, 50 of every treated animals.Be labeled as tri-groups of A, B, C;
Three groups of experiment mices are raised to 1 year with food higher fatty acid, high heat, and observe day by day the physiological conditions of mice, and note down;
After 1 year, all there is the heart and brain such as bradykinesia, tic infarction symptom in three groups of experiment mices.Then,, to the mice of A group, do not add any material and normally raise; To B group mice, the composition of medicine of injection Alprostadil; To C group mice, injection Alprostadil injection;
Above-mentioned three groups are continued to raise with identical food (not containing Alprostadil material), and observe day by day the physiological conditions of mice, and note down;
The method of experiment: be by observational method day by day, the upgrowth situation of statistics mice, then contrasts;
(6) mice of conclusion: according to observation day by day, after half a year: A group, small, it is still blunt to react, and twitches and often occurs, part dead mouse; B organizes mice, and build is larger, comparatively flexible, without dead; C organizes mice, and build is larger, and the phenomenon but part mice is had a convulsion, only has minority death.After 1 year, observing, A group mice is substantially dead, and B group mice only has minority death, and the mice of existence is still healthy; , still there is the heart and brain such as bradykinesia, tic infarction phenomenon in C group mice Mortality;
| Project | Upgrowth situation after half a year | Upgrowth situation after 1 year | Drug fever response rate (%) | Stomach and liver untoward reaction rate (%) |
| The A group of not administration | Small, it is still blunt to react, and twitches and often occurs, part dead mouse | Mice is substantially dead | —— | —— |
| The B group of injection Alprostadil composition of medicine injection | Build is larger, comparatively flexible, without dead | Mice only has minority death, and the mice of existence is still healthy | 23 | 16 |
| The C group of injection Alprostadil injection | Build is larger, and the phenomenon but part mice is had a convulsion, only has minority death | , still there is the heart and brain such as bradykinesia, tic infarction phenomenon in mice Mortality | 0 | 0 |
Visible, Alprostadil composition of medicine of the present invention is all better than Alprostadil injection prepared by prior art in safety, stability, curative effect comprehensively.
Claims (3)
1. a composition of medicine for Alprostadil, is characterized in that, is made up of effective active ingredient of following parts by weight:
Alprostadil 70-150
Vitamin C 20-35
Folic acid 5-20
Glycine 30-60
The method of described Alprostadil composition of medicine, method and step that it is prepared are as follows:
(1). getting weight is the water for injection of 5-15 times of described Alprostadil weight, under stirring, respectively described Alprostadil, vitamin C, folic acid, glycine is dissolved completely, obtains the composition of medicine solution of Alprostadil;
(2). with molecular cut off be the medicinal liquid that 6000D ultrafilter membrane ultrafiltration step (1) obtains, the membrane ultrafiltration that filtrate is 2000D with molecular cut off, filtrate regulates pH value 6.1-6.5 with 8% hydrochloric acid solution solution;
(3). the medicinal liquid that step (2) obtains was 121 ℃ of steam sterilizations 20 minutes;
(4). when the medicinal liquid after sterilizing is cooled to 20-22 ℃, with 8% hydrochloric acid solution solution, under stirring, be added drop-wise in medicinal liquid, the pH value of adjusting medicinal liquid is 6.1-6.5, then filters through the membrane filtration of 0.22 μ m, obtains composition of medicine solution;
(5). the composition of medicine medicinal liquid that above-mentioned step (4) is made is made the acceptable dosage form of Alprostadil on pharmaceutics;
2. the composition of medicine of Alprostadil according to claim 1, it is characterized in that, on described pharmaceutics, the dosage form of acceptable Alprostadil is lyophilized injection, 0.9% sodium chloride injection, 5% glucose injection, 10% glucose injection, oral formulations, spray.
3. Alprostadil composition of medicine claimed in claim 1, is characterized in that, for myocardial infarction, and thromboangiitis, atherosclerosis obliterans etc.Also can be used for treating chronic arteria occlusion disease as the limbs chronic ulcer due to thromboangiitis obliterans, chronic arterial Atherosclerotic Agents, the extremity tranquillization pain due to blood capillary circulatory disturbance; And can be used as the treatment of the postoperative thromboembolism preventing of blood vessel transplantation; in order to suppress the relevant disease of thrombosis in grafting vessel; also protect Alprostadil in the process of manufacturing, store, transport, using; not oxidized and peroxidating; alleviate the untoward reaction such as headache, vomiting, diarrhoea, diarrhoea, abdominal distention, constipation; play simultaneously protect the liver, the effect of hepatoprotective, improved safety, stability and the health giving quality of composition of medicine.
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| CN201410026700.8A CN103908671A (en) | 2014-01-21 | 2014-01-21 | Alprostadil combinatorial drug |
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| CN201410026700.8A CN103908671A (en) | 2014-01-21 | 2014-01-21 | Alprostadil combinatorial drug |
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Citations (2)
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| CN1182592A (en) * | 1996-10-31 | 1998-05-27 | 新丰制药株式会社 | Stable prostaglandin E1-containing injectable composition |
| CN101822679A (en) * | 2010-02-02 | 2010-09-08 | 邓学峰 | Cefepime hydrochloride combined medicament |
-
2014
- 2014-01-21 CN CN201410026700.8A patent/CN103908671A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1182592A (en) * | 1996-10-31 | 1998-05-27 | 新丰制药株式会社 | Stable prostaglandin E1-containing injectable composition |
| CN101822679A (en) * | 2010-02-02 | 2010-09-08 | 邓学峰 | Cefepime hydrochloride combined medicament |
Non-Patent Citations (4)
| Title |
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| 张浩懿: "《家庭医学百科全书 上卷》", 31 December 1998 * |
| 王瑞云: "《对付乙肝没那么困难》", 31 January 2013 * |
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Application publication date: 20140709 |