CN102133182A - Epoprostenol liposome and preparation method thereof - Google Patents
Epoprostenol liposome and preparation method thereof Download PDFInfo
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- CN102133182A CN102133182A CN 201010622976 CN201010622976A CN102133182A CN 102133182 A CN102133182 A CN 102133182A CN 201010622976 CN201010622976 CN 201010622976 CN 201010622976 A CN201010622976 A CN 201010622976A CN 102133182 A CN102133182 A CN 102133182A
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- epoprostenol
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- phospholipid
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Abstract
The invention relates to epoprostenol liposome and a preparation method thereof. In the liposome, the weight ratio of the epoprostenol to a phospholipid material is 1:4 to 1:200. A membrane dispersion-high pressure homogenizing method is adopted for preparation, the prepared liposome not only solves the stability problem of a medicament, but also reduces the irritation of intravenous administration, thus improving the safety in clinical medication.
Description
Technical field
The present invention relates to a kind of epoprostenol liposome and preparation method thereof, the invention still further relates to dosage form that contains described liposome and preparation method thereof.
Background technology
Epoprostenol has another name called prostacyclin (PGX), prostaglandin I
2(PGI
2), being the arachidonic acid metabolite that vascular endothelial cell produces, the energy anticoagulant has strong diastole effect to arteria coronaria, whole body blood vessel and lung blood vessel.Be used for unstable angina pectoris, myocardial infarction, intractable heart failure, periperal vascular spasm and pulmonary hypertension clinically.Its antiplatelet aggregative activity can be used for preventing thrombosis.(more safer than heparin) is as anticoagulant when being used for the treatment of some cardiovascular disease and hemodialysis; Peripheral vascular disease such as raynaud disease obviously reduce attack times and duration of seizure after the medication; Also be used for the platelet consumption syndrome and reduce platelet in the loss of extracorporeal circulation etc.The epoprostenol half-life is short, generally uses infusion pump to continue the infusion administration by central venous catheter.Initial dose is 2ng/ (kgmin), if can tolerate, continue after can increase 2ng/kg at every turn, reach required dosage gradually.After being recommended in 6 months, its mean dose can reach 20 to 40ng/ (kgmin), and some patient's final dose need be increased to 200ng/ (kgmin), even more.Untoward reaction: when quiet notes speed surpasses per minute 10ng/kg, headache, abdominal discomfort, hypertension etc. can occur, when surpassing 20ng/kg, blood pressure drops, decreased heart rate can occur, even faint.Adverse reaction rate is relevant with dosage: untoward reaction has flush, headache, uneasiness, anxiety, vomiting, abdominal discomfort, hypotension and bradycardia etc. in the time of quiet.
The unstable chemcial property of epoprostenol, especially potential hydrolytic instability makes it be difficult to research and develop into stabilization formulations.PGI
2The vinyl ethers of-Na partly by buffering under alkalescence (pH＞8.8) condition in solution stabilisation.
International Application PCT/US2007/002948 discloses epoprostenol at 23 ℃, and therefore the degraded 50% in following 10 hours of pH 9.3 conditions, is developed to the stability problem that stable formulation need at first solve epoprostenol with it.The pharmaceutical composition of the alkalizing agent of a kind of pH＞11 is provided in this application, and under high pH condition, epoprostenol solution still kept down 90% epoprostenol not degrade in 24 to 48 hours at 15 to 30 ℃.The dosage form of having gone on the market at present is injectable powder Flolan (Glaxo Smith Kline), and every lyophilizing bottle comprises 0.5mg or 1.5mg epoprostenol, 3.76mg glycine, 2.93mg sodium chloride and 50mg mannitol.Also sodium hydroxide can be added so that regulate pH.Also be furnished with sterile diluent in addition, contain the 94mg glycine, 73.5mg sodium chloride, sodium hydroxide (regulating pH), an amount of water for injection is to the vial of 50ml.Reconfigure Flolan solution and have 10.2 to 10.8 pH.The pH scope 4 to 9 of intravenously administrable, pH is too high or too low all to cause zest easily, though there is the potential safety hazard of intravenously administrable in above-mentioned solution by regulating the stability problem that pH value has solved epoprostenol to a certain extent.
Chinese patent application CN200910093402 discloses a kind of epoprostenol lipid nanoparticle and preparation method thereof, but used solid lipid material lacks the injection rank, and needing to add the exhibiting high surface activating agent to improve preparation stability, this makes preparation toxicity increase, and has potential safety hazard.Therefore, be necessary to develop a kind of novel form of stable and suitable intravenously administrable.
Liposome (Liposome) or title lipoid bead, liquid crystal microcapsule are a kind of targeted drug carriers, belong to the novel form of a kind of similar microencapsulation of targeting drug delivery system.1971, people such as Britain Rymen began liposome as pharmaceutical carrier.It has the class cellularity, enter the autoimmune function that is mainly activated body in the animal body by reticuloendothelial system phagocytic, and the interior distribution of the body that changes encapsulated medicine, drug main will be put aside in histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the toxicity of the therapeutic dose and the reduction medicine of medicine.Liposome technology be described as " biological missile " the 4th generation the target administration technology, also be present the most popular in the world pharmaceutical technology.
Summary of the invention
Technical problem to be solved by this invention is the stability that significantly improves epoprostenol.
One object of the present invention is to provide a kind of epoprostenol liposome, and the weight ratio of epoprostenol, phospholipid material is 1: 4 to 1: 200 in the wherein said liposome, is preferably 1: 20 to 1: 100.
Described phospholipid material is selected from Ovum Gallus domesticus Flavus lecithin, soybean phospholipid, phosphoglyceride, hydrogenated soya phosphatide, hydrolecithin, hydrogenating glycerol phospholipid, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE or its combination, preferred soybean phospholipid, Ovum Gallus domesticus Flavus lecithin.In the context of the invention, described phospholipid does not comprise cholesterol.
In one embodiment of the invention, described phospholipid is soybean phospholipid.
In another embodiment of the invention, described phospholipid is Ovum Gallus domesticus Flavus lecithin.
In another embodiment of the invention, described phospholipid is hydrolecithin.
Preferably, in described epoprostenol liposome, add the cholesterol that helps liposome to form.Described cholesterol consumption is pressed the C/PL weight ratio and is calculated, and amount ranges is 1: 0.2 to 1: 20, is preferably 1: 1 to 1: 10, most preferably is 1: 2 to 1: 6.
In one embodiment of the invention, the weight ratio of described C/PL is 1: 0.2.
In another embodiment of the invention, the weight ratio of described C/PL is 1: 4.
In another embodiment of the invention, the weight ratio of described C/PL is 1: 10.
In another embodiment of the invention, the weight ratio of described C/PL is 1: 20.
Another object of the present invention is to provide the preparation method of described epoprostenol liposome, may further comprise the steps:
1) with phospholipid, optional cholesterol, epoprostenol organic solvent dissolution, uniform mixing is removed organic solvent, obtains to contain the adipose membrane of epoprostenol;
2) with the described adipose membrane aquation of step 1), high pressure homogenize obtains the epoprostenol liposome.
Wherein,
Organic solvent in the described step 1) is selected from ethanol, isopropyl alcohol, dichloromethane, chloroform, methanol and combination thereof.
Described step 2) the mesohigh homogenization pressure is 600 to 2000bar, and the homogenizing number of times is 3 to 10 times.
Another object of the present invention is to provide the dosage form of epoprostenol liposome, and described dosage form is injectable powder or aqueous injection.
In one embodiment of the invention, the dosage form of described epoprostenol liposome is an aqueous injection.
In another embodiment of the invention, the dosage form of described epoprostenol liposome is an injectable powder, it is characterized in that containing proppant.Described proppant is selected from trehalose, sucrose, lactose, maltose, glucose, mannitol, sorbitol or its combination.Preferably, described proppant is sucrose, lactose, mannitol, trehalose.More preferably, described proppant is lactose, trehalose.
In one embodiment of the invention, described proppant is a sorbitol.
In another embodiment of the invention, described proppant is a lactose.
In another embodiment of the invention, described proppant is a trehalose.
Another object of the present invention is to provide the preparation method of described epoprostenol liposome powder for injection, may further comprise the steps:
1) with phospholipid, optional cholesterol, epoprostenol organic solvent dissolution, uniform mixing is removed organic solvent, obtains to contain the adipose membrane of epoprostenol;
2) with the described adipose membrane aquation of step 1), high pressure homogenize obtains the epoprostenol liposome;
3) to step 2) add proppant in the epoprostenol liposome of gained, lyophilization obtains described epoprostenol liposome powder for injection.
Wherein,
Organic solvent in the described step 1) is selected from ethanol, isopropyl alcohol, dichloromethane, chloroform, methanol and combination thereof.
Described step 2) the high pressure homogenize pressure in is 600 to 2000bar, and the homogenizing number of times is 3 to 10 times.
Proppant in the described step 3) is selected from trehalose, sucrose, lactose, maltose, glucose, mannitol, sorbitol or its combination.Preferably, described proppant is sucrose, lactose, mannitol, trehalose.More preferably, described proppant is lactose, trehalose.
The prepared epoprostenol liposome of the present invention has the following advantages: (1) lipid carrier toxicity is low, and physiological compatibility is good, has reduced toxic and side effects, has improved the body toleration; (2) liposome easily accumulates in the lesion vessels place, has targeting; (3) prepared liposome in lipid carrier, can make medicine avoid the destruction of extraneous factor (water, oxygen, light) drug encapsulation, improve greatly medicine storage process stability; (4) prepared liposome in lipid carrier, can reduce renal excretion and metabolism and the holdup time of prolong drug in blood with drug encapsulation, makes medicine slowly discharge the action time of prolong drug in vivo.
Therefore, epoprostenol liposome powder for injection of the present invention has not only solved the stability of drug problem, and has reduced the zest of intravenously administrable, has increased clinical application safety.
The specific embodiment
Those of ordinary skills below in conjunction with embodiment the present invention are described in further detail, so that can more be expressly understood and implement the present invention.Yet, should be understood that the present invention is not limited to these embodiment.Any change that does not deviate from spirit and scope of the invention to the present invention did, revise and be equal to replacement, all fall within the scope of the present invention.
Embodiment 1
Prescription:
Epoprostenol 0.1g
Soybean phospholipid 1g
Cholesterol 5g
Water 200ml
Preparation technology:
1) with soybean phospholipid, cholesterol, epoprostenol 200ml anhydrous alcohol solution, uniform mixing, dry under 40 ℃ then, remove ethanol, obtain to contain the adipose membrane of epoprostenol;
2) above-mentioned adipose membrane is added aquation in the 200ml water, high pressure homogenize, pressure are 600bar, and homogenize 8 times obtains the epoprostenol liposome solutions.
Embodiment 2:
Prescription:
Epoprostenol 0.1g
Ovum Gallus domesticus Flavus lecithin 4g
Cholesterol 1g
Phosphate buffer (pH7.4) 200ml
Preparation technology:
1) Ovum Gallus domesticus Flavus lecithin, cholesterol, epoprostenol are dissolved with 200ml 95% isopropyl alcohol, mix homogeneously, dry under 45 ℃ then, remove isopropyl alcohol, obtain to contain the adipose membrane of epoprostenol;
2) above-mentioned adipose membrane is added aquation in the 200ml phosphate buffer, high pressure homogenize, pressure are 1200bar, and homogenize 6 times obtains the epoprostenol liposome solutions;
3) with above-mentioned liposome solutions through 0.22 μ m filtering with microporous membrane, aseptic embedding obtains epoprostenol liposome aqueous injection.
Embodiment 3:
Prescription:
Epoprostenol 0.1g
Soybean phospholipid 10g
Cholesterol 1g
Sorbitol 10g
Water 200ml
Preparation technology:
1) soybean phospholipid, cholesterol, epoprostenol are dissolved with 200ml methylene chloride (1: 1), uniform mixing, dry under 50 ℃ then, remove organic solvent, obtain to contain the adipose membrane of epoprostenol;
2) above-mentioned adipose membrane is added aquation in the 200ml water, high pressure homogenize, pressure are 2000bar, and homogenize 3 times obtains the epoprostenol liposome;
3) the epoprostenol liposome is added the recipe quantity sorbitol, lyophilizing obtains the epoprostenol liposome powder for injection.
Embodiment 4:
Prescription:
Epoprostenol 0.1g
Hydrolecithin 20g
Cholesterol 1g
Lactose 20g
Phosphate buffer (pH7.4) 200ml
Preparation technology:
1) hydrolecithin, cholesterol, epoprostenol are dissolved with the 200ml chloroform, uniform mixing, dry under 60 ℃ then, remove chloroform, obtain to contain the adipose membrane of epoprostenol;
2) above-mentioned adipose membrane is added aquation in the 200ml phosphate buffer, high pressure homogenize, pressure are 1000bar, and homogenize 10 times obtains the epoprostenol liposome;
3) the epoprostenol liposome is added the recipe quantity lactose, lyophilizing obtains the epoprostenol liposome powder for injection.
Embodiment 5:
Prescription:
Epoprostenol 0.1g
Ovum Gallus domesticus Flavus lecithin 1g
Cholesterol 5g
Trehalose 3g
Water 200ml
Preparation technology:
1) Ovum Gallus domesticus Flavus lecithin, cholesterol, epoprostenol are dissolved with 200ml 75% isopropyl alcohol, mix homogeneously, dry under 55 ℃ then, remove isopropyl alcohol, obtain to contain the adipose membrane of epoprostenol;
2) above-mentioned adipose membrane is added aquation in the 200ml water, high pressure homogenize, pressure are 800bar, and homogenize 10 times obtains the epoprostenol liposome;
3) the epoprostenol liposome is added the recipe quantity trehalose, lyophilizing obtains the epoprostenol liposome powder for injection.
Embodiment 6:
Prescription:
Epoprostenol 0.5g
Ovum Gallus domesticus Flavus lecithin 2g
Cholesterol 8g
Lactose 10g
Phosphate buffer (pH7.4) 1000ml
Preparation technology:
1) hydrolecithin, cholesterol, epoprostenol are dissolved with the 200ml dichloromethane, uniform mixing, dry under 50 ℃ then, remove dichloromethane, obtain to contain the adipose membrane of epoprostenol;
2) above-mentioned adipose membrane is added aquation in the 1000ml phosphate buffer, high pressure homogenize, pressure are 1500bar, and homogenize 4 times obtains the epoprostenol liposome;
3) the epoprostenol liposome is added recipe quantity sucrose, lyophilizing obtains the epoprostenol liposome powder for injection.
Comparing embodiment 1 medicine stability test
The method of referenced patent application 200780011395.3 is measured epoprostenol buffer salt solution, liposome solutions stability, the results are shown in Table 1.The result shows, epoprostenol is made liposome after, stability of drug is improved greatly.
Table 1
Claims (10)
1. epoprostenol liposome, the weight ratio that it is characterized in that epoprostenol, phospholipid material in the described liposome is 1: 4 to 1: 200.
2. epoprostenol liposome according to claim 1, it is characterized in that, described phospholipid material is selected from Ovum Gallus domesticus Flavus lecithin, soybean phospholipid, phosphoglyceride, hydrolecithin, hydrogenated soya phosphatide, hydrogenating glycerol phospholipid, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE or its combination, preferred soybean phospholipid, Ovum Gallus domesticus Flavus lecithin.
3. epoprostenol liposome according to claim 1 and 2 is characterized in that, adds cholesterol in described epoprostenol liposome.
4. according to the described epoprostenol liposome of claim 3, it is characterized in that described cholesterol consumption is pressed the C/PL part by weight and calculated, amount ranges is 1: 0.2 to 1: 20, is preferably 1: 1 to 1: 10, most preferably is 1: 2 to 1: 6.
5. the preparation method of each described epoprostenol liposome in the claim 1 to 4 is characterized in that, may further comprise the steps:
1) with phospholipid, optional cholesterol, epoprostenol organic solvent dissolution, uniform mixing is removed organic solvent, obtains to contain the adipose membrane of epoprostenol;
2) with the described adipose membrane aquation of step 1), high pressure homogenize obtains the epoprostenol liposome.
6. the preparation method of epoprostenol liposome according to claim 5 is characterized in that, the described organic solvent of step 1) is selected from ethanol, isopropyl alcohol, dichloromethane, chloroform, methanol or its combination; Step 2) described high pressure homogenize pressure is 600 to 2000bar, and the homogenizing number of times is 3 to 10 times.
7. an injectable powder that contains arbitrary described epoprostenol liposome in the claim 1 to 4 is characterized in that, contains proppant.
8. epoprostenol liposome powder for injection according to claim 7 is characterized in that described proppant is selected from trehalose, sucrose, and lactose, maltose, glucose, mannitol, sorbitol or its combination are preferably trehalose or lactose.
9. the preparation method of claim 7 or 8 described epoprostenol liposome powder for injection is characterized in that, may further comprise the steps:
1) with phospholipid, optional cholesterol, epoprostenol organic solvent dissolution, uniform mixing is removed organic solvent, obtains to contain the adipose membrane of epoprostenol;
2) with the described adipose membrane aquation of step 1), high pressure homogenize obtains the epoprostenol liposome;
3) with step 2) epoprostenol liposome adding proppant, lyophilization obtains the epoprostenol liposome powder for injection.
10. the preparation method of epoprostenol liposome powder for injection according to claim 9 is characterized in that, the described organic solvent of step 1) is selected from ethanol, isopropyl alcohol, dichloromethane, chloroform, methanol or its combination; Step 2) described high pressure homogenize pressure is 600 to 2000bar, and the homogenizing number of times is 3 to 10 times.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201010622976 CN102133182A (en) | 2010-12-30 | 2010-12-30 | Epoprostenol liposome and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201010622976 CN102133182A (en) | 2010-12-30 | 2010-12-30 | Epoprostenol liposome and preparation method thereof |
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| CN102133182A true CN102133182A (en) | 2011-07-27 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107693490A (en) * | 2017-10-25 | 2018-02-16 | 南京鼓楼医院 | A kind of nanometer formulation and its composition of the glucosyl group modification for treating pulmonary hypertension morbidity |
| CN107811970A (en) * | 2016-09-12 | 2018-03-20 | 江苏艾立康药业股份有限公司 | West pa lattice multivesicular liposome and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1207671A (en) * | 1995-12-15 | 1999-02-10 | 哈佛科学公司 | PGE-1 contg. lyophilized liposomes for use in treatment of erectile dysfunction |
| CN1449759A (en) * | 2002-04-10 | 2003-10-22 | 南阳普康集团化学制药厂 | Prostaglandin E1 liposome frozen dry powder injection and production technology thereof |
-
2010
- 2010-12-30 CN CN 201010622976 patent/CN102133182A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1207671A (en) * | 1995-12-15 | 1999-02-10 | 哈佛科学公司 | PGE-1 contg. lyophilized liposomes for use in treatment of erectile dysfunction |
| CN1449759A (en) * | 2002-04-10 | 2003-10-22 | 南阳普康集团化学制药厂 | Prostaglandin E1 liposome frozen dry powder injection and production technology thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《首都医药》 19981231 舒青等 前列腺素类药物的临床应用进展 20-21 1-10 第5卷, 第8期 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107811970A (en) * | 2016-09-12 | 2018-03-20 | 江苏艾立康药业股份有限公司 | West pa lattice multivesicular liposome and preparation method thereof |
| CN107811970B (en) * | 2016-09-12 | 2021-02-02 | 江苏艾立康药业股份有限公司 | Xilipaeg multivesicular liposome and preparation method thereof |
| CN107693490A (en) * | 2017-10-25 | 2018-02-16 | 南京鼓楼医院 | A kind of nanometer formulation and its composition of the glucosyl group modification for treating pulmonary hypertension morbidity |
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Application publication date: 20110727 |