CN101669904A - Epoprostanol lipid nanoparticle and preparation method thereof - Google Patents
Epoprostanol lipid nanoparticle and preparation method thereof Download PDFInfo
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- CN101669904A CN101669904A CN200910093402A CN200910093402A CN101669904A CN 101669904 A CN101669904 A CN 101669904A CN 200910093402 A CN200910093402 A CN 200910093402A CN 200910093402 A CN200910093402 A CN 200910093402A CN 101669904 A CN101669904 A CN 101669904A
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- epoprostenol
- lipid nanoparticle
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- lipid
- water
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- 239000008354 sodium chloride injection Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Abstract
The invention relates to an epoprostanol lipid nanoparticle and a preparation method thereof, the weight ratio of epoprostanol to lipid material to surfactant is 1:5-50:2-20. The nanoparticle is prepared by a fusing emulsification and high-pressure homogenization method, and the prepared nanoparticle not only solves the problem of medicine stability, but also reduces the excitation of the vein injection, and improves the safety of clinical medication.
Description
Technical field
The present invention relates to a kind of epoprostenol lipid nanoparticle and preparation method thereof, contain dosage form of this lipid nanoparticle and preparation method thereof.
Background technology
Epoprostenol has another name called prostacyclin (PGX), prostaglandin I
2(PGI
2), this product is a kind of natural prostaglandins that blood vessel endothelium produces.Have vasodilator, bring high blood pressure down and effect that antiplatelet aggregation, tampon form.Be 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.Its clinical indication is: be used for unstable angina pectoris, myocardial infarction, intractable heart failure, periperal vascular spasm and pulmonary hypertension.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 outbreak persistent period after the medication; Also be used for the platelet consumption syndrome and reduce platelet in the loss of extracorporeal circulation etc.When the quiet notes speed of untoward reaction surpasses per minute 10 μ g/kg, headache, abdominal discomfort, hypertension etc. can occur, when surpassing 20 μ g/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 dosage form of having gone on the market at present is injectable powder Flolan, 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 10.2～10.8 pH.
The epoprostenol facile hydrolysis, especially more unstable under lower pH condition, according to the disclosed data of patent application 200780011395.3 Instructions Page 4 tables 1, epoprostenol is at 23 ℃, the degraded 50% in following 10 hours of pH9.3 condition, therefore, it is developed to the stability problem that stable formulation need at first solve epoprostenol.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 keeps after 24～48 hours down 90% epoprostenol not degrade at 15～30 ℃.
The pH scope 4～9 of intravenously administrable, pH is too high or too low all to cause zest easily, though there is the safety hidden danger of intravenously administrable in above-mentioned solution by regulating the stability problem that pH has solved epoprostenol to a certain extent.Therefore, be necessary to develop a kind of novel form of stable and suitable intravenously administrable.
Nanoparticulate carriers is a kind of submicron pharmaceutical carrier induction system.Drug encapsulation in submicron, can be changed in vivo distribution of medicine, regulates drug release rate, improves bioavailability, increases medicine to biomembranous permeability etc., thereby improve curative effect, reduce toxic and side effects.(solid lipid nanoparticles is to be that the particle diameter that carrier is made is about 50 to 1000nm solid micelle drug delivery system with solid-state natural or synthetic lipid SLN) to solid lipid nanoparticle.With the compatible high-melting-point lipid of physiology (as fatty glyceride, stearic acid, mixing lipid) is the SLN of framework material preparation, at room temperature be solid-state usually, therefore both possessed polymer nanoparticle physical stability height, the slow advantage of drug leakage, the advantage that the toxicity that has had liposome, Emulsion again concurrently is low, can large-scale production is a kind of extremely promising novel drug-supplying system.Nano-lipid carrier (Nano-structruedlipid carries; NLC) be on the solid lipid nanoparticle basis; in solid lipid, add fluid oil, nanoparticle is existed with crystal defect type or undefined structure, can avoid effluxing and the decline of envelop rate of put procedure Chinese medicine.Among the present invention, with solid lipid nanoparticle, nano-lipid carrier is referred to as lipid nanoparticle.
Do not provide in the above-mentioned prior art epoprostenol is made the relevant technology enlightenment of lipid nanoparticle.
Summary of the invention
Technical problem solved by the invention is the poor stability at epoprostenol in the prior art, provides a kind of and can significantly improve its stable preparation, and the preparation method of said preparation.
Technical scheme of the present invention is as follows:
The invention provides a kind of epoprostenol lipid nanoparticle, it is characterized in that, epoprostenol in this lipid nanoparticle, the weight ratio of matrix material and surfactant is 1: 5～50: 2～20.
Epoprostenol lipid nanoparticle of the present invention is characterized in that, described matrix material is a solid lipid material Glyceryl Behenate, tristerin, tripalmitin, glyceryl palmitostearate, glycol stearate, Palmic acid glycol ester, Ethylene Glycol Palmitostearate, white beeswax, Cera Flava, microwax, Brazil wax, Synthetic Spermacet, stearic acid, lanoline, stearyl alcohol, one or more in the vaseline lanonol.
Epoprostenol lipid nanoparticle of the present invention is characterized in that, described matrix material is solid lipid and liquid fatty mixture, the weight ratio of solid lipid and liquid fatty is 1: 1～9: 1, and described liquid fatty is a soybean oil, Oleum Gossypii semen, Oleum Brassicae campestris, Oleum sesami, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Helianthi, coix seed oil, vitamin e succinate, medium chain triglyceride, one or more in the fish oil.
Described medium chain triglyceride is meant one or more triglyceride or its mixture with medium-chain fatty acid of about 8～18 carbon atom length.
Epoprostenol lipid nanoparticle of the present invention; it is characterized in that; described surfactant is a soybean phospholipid; Ovum Gallus domesticus Flavus lecithin; poloxamer; polyethylene glycol 1000 vitamin E succinic acid ester (TPGS); Polyethylene Glycol 660-12-hydroxy stearic acid ester (HS-15), polyoxyethylene-8-caprylic/capric glyceride (Labrasol), Polyethylene Glycol distearyl ethanolamine (PEG-DSPE); ethylene glycol monomethyl ether (Transcutol); dihexyl succinic acid acyl sodium sulfonate (Aerosol OT), polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol; cholic acid and salt thereof, one or more in deoxycholic acid and the salt thereof.
The preparation method of epoprostenol lipid nanoparticle of the present invention is characterized in that, may further comprise the steps:
(1) the matrix material heating is 60～80 ℃, adds the epoprostenol mix homogeneously, gets oil phase;
(2) surfactant dissolves is heated to 60～80 ℃ in water, gets water;
(3) water is joined in the oil phase, 60～80 ℃ of temperature controls, high speed shear is disperseed, and gets colostrum;
(4) the gained colostrum becomes nano-emulsion through high pressure homogenize;
(5) the gained nano-emulsion is quickly cooled to below 4 ℃, forms epoprostenol lipid nanoparticle suspension.
The preparation method of epoprostenol lipid nanoparticle of the present invention, it is characterized in that, the dispersive shear rate of the described high speed shear of step (3) is to be 10～60 minutes 1000～5000rpm time, and the described pressure of step (4) is 600～2000bar, homogenize number of times 3～6 times.
The dosage form of epoprostenol lipid nanoparticle of the present invention is characterized in that, the dosage form that acceptable auxiliary is made on this lipid nanoparticle and the medicament.
The dosage form of epoprostenol lipid nanoparticle of the present invention is characterized in that, described dosage form is an injectable powder.
The preparation method of epoprostenol lipid nanoparticle injectable powder of the present invention is characterized in that, may further comprise the steps:
(1) the matrix material heating is 60～80 ℃, adds the epoprostenol mix homogeneously, gets oil phase;
(2) surfactant dissolves is heated to 60～80 ℃ in water, gets water;
(3) water is joined in the oil phase, 60～80 ℃ of temperature controls, high speed shear is disperseed, and shear rate is to be 10～60 minutes 1000～5000rpm time, gets colostrum;
(4) the gained colostrum is through high pressure homogenize, and pressure is 600～2000bar, and homogenize number of times 3～6 times gets nano-emulsion;
(5) the gained nano-emulsion is quickly cooled to below 4 ℃, forms epoprostenol lipid nanoparticle suspension;
(6) the lipid nanoparticle suspension is added freeze drying protectant, aseptic subpackaged through 0.22 μ m filtering with microporous membrane, lyophilization, promptly.
Epoprostenol lipid nanoparticle injectable powder of the present invention is characterized in that described freeze drying protectant is a trehalose, sucrose, maltose, one or more in the lactose.
Relative to existing technologies, the present invention makes lipid nanoparticle with epoprostenol, has not only solved the stability of drug problem, and has reduced the zest of intravenously administrable, has increased clinical application safety.The prepared epoprostenol lipid nanoparticle 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, prepared lipid nanoparticle in lipid carrier, prevents the hydrolysis of medicine with drug encapsulation, has improved the stability of product;
3, adopt the mixing lipid carrier, improved the drug loading of medicine.
The specific embodiment
With specific embodiment the present invention is elaborated below, but following examples must not be interpreted as the restriction to claim of the present invention of going up in all senses.
Embodiment 1
Prescription:
Epoprostenol 0.5g
Rikemal B 200 25g
Soybean phospholipid 5g
Poloxamer 5g
Make 1000ml
Preparation technology:
(1) Rikemal B 200 is heated to 70 ℃ of fusions, adds epoprostenol, and the soybean phospholipid mix homogeneously gets oil phase;
(2) poloxamer is soluble in water, is heated to 70 ℃, gets water;
(3) water is joined in the oil phase, 70 ℃ of temperature controls, high speed shear is disperseed, and shear rate is 10 minutes for the 3000rpm time, gets colostrum;
(4) the gained colostrum is through high pressure homogenize, and pressure is 600～1200bar, and homogenize 6 times gets nano-emulsion;
(5) the gained nano-emulsion is quickly cooled to 0～2 ℃, forms epoprostenol lipid nanoparticle suspension.
Embodiment 2
Prescription:
Epoprostenol 0.5g
Rikemal B 200 1.5g
Refined soybean oil 1.5g
Soybean phospholipid 0.5g
Poloxamer 0.5g
Make 1000ml
Preparation technology:
(1) Rikemal B 200 is heated to 80 ℃ of fusions, adds refined soybean oil, soybean phospholipid, and the epoprostenol mix homogeneously gets oil phase;
(2) poloxamer is soluble in water, is heated to 80 ℃, gets water;
(3) water is joined in the oil phase, 80 ℃ of temperature controls, high speed shear is disperseed, and shear rate is 45 minutes for the 1000rpm time, gets colostrum;
(4) the gained colostrum is through high pressure homogenize, and pressure is 1000～1500bar, and homogenize 4 times gets nano-emulsion;
(5) the gained nano-emulsion is quickly cooled to 0～2 ℃, forms epoprostenol lipid nanoparticle suspension.
Embodiment 3
Prescription:
Epoprostenol 0.5g
Stearic acid 15g
Ovum Gallus domesticus Flavus lecithin 5g
Poloxamer 2.5g
Sucrose 150g
Make 1000ml
Preparation technology:
(1) stearic acid is heated to 75 ℃ of fusions, adds Ovum Gallus domesticus Flavus lecithin, and the epoprostenol mix homogeneously gets oil phase;
(2) poloxamer is soluble in water, is heated to 75 ℃, gets water;
(3) water is joined in the oil phase, 75 ℃ of temperature controls, high speed shear is disperseed, and shear rate is 20 minutes for the 2000rpm time, gets colostrum;
(4) the gained colostrum is through high pressure homogenize, and pressure is 1000bar, and homogenize 5 times gets nano-emulsion;
(5) the gained nano-emulsion is quickly cooled to 0～2 ℃, forms epoprostenol lipid nanoparticle suspension;
(6) above-mentioned suspension adds sucrose, regulates pH value, filtration sterilization, and sterile filling, lyophilization gets injection epoprostenol lipid nanoparticle.
Embodiment 4
Prescription:
Epoprostenol 0.5g
Palmic acid glycol ester 9g
Refined soybean oil 1g
Soybean phospholipid 1.5g
Polyethylene glycol 1000 vitamin E succinic acid ester 0.5g
Trehalose 100g
Make 1000ml
Preparation technology:
(1) the Palmic acid glycol ester is heated to 65 ℃ of fusions, adds refined soybean oil, soybean phospholipid, and the epoprostenol mix homogeneously gets oil phase;
(2) the Polyethylene Glycol vitamin e succinate is soluble in water, is heated to 65 ℃, gets water;
(3) water is joined in the oil phase, 65 ℃ of temperature controls, high speed shear is disperseed, and shear rate is 10 minutes for the 5000rpm time, gets colostrum;
(4) the gained colostrum is through high pressure homogenize, and pressure is 1400～1800bar, and homogenize 3 times gets nano-emulsion;
(5) the gained nano-emulsion is quickly cooled to 0～2 ℃, forms epoprostenol lipid nanoparticle suspension;
(6) above-mentioned mixing entreated liquid adding trehalose, filtration sterilization, and sterile filling, lyophilization gets injection epoprostenol lipid nanoparticle.
Embodiment 5
Prescription:
Epoprostenol 0.5g
Glyceryl monostearate 10g
Ovum Gallus domesticus Flavus lecithin 3g
Polyethylene Glycol 660-12-hydroxy stearic acid ester 1g
Make 1000ml
Preparation technology:
(1) glyceryl monostearate is heated to 70 ℃ of fusions, adds Ovum Gallus domesticus Flavus lecithin, and the epoprostenol mix homogeneously gets oil phase;
(2) Polyethylene Glycol 660-12-hydroxy stearic acid ester is soluble in water, is heated to 70 ℃, gets water;
(3) water is joined in the oil phase, 70 ℃ of temperature controls, high speed shear is disperseed, and shear rate is 30 minutes for the 1500rpm time, gets colostrum;
(4) the gained colostrum is through high pressure homogenize, and pressure is 1000bar, and homogenize 5 times gets nano-emulsion;
(5) the gained nano-emulsion is quickly cooled to 0～2 ℃, forms epoprostenol lipid nanoparticle suspension.
Embodiment 6
Prescription:
Epoprostenol 0.5g
Glycerol trioleate 3g
Medium chain triglyceride 1g
Soybean phospholipid 2g
Polyoxyethylene-8 caprylic/capric glyceride 0.5g
Lactose 200g
Make 1000ml
Preparation technology:
(1) trioleate is heated to 60 ℃ of fusions, adds medium chain triglyceride, soybean phospholipid, and the epoprostenol mix homogeneously gets oil phase;
(2) polyoxyethylene-8 caprylic/capric glyceride is soluble in water, is heated to 60 ℃, gets water;
(3) water is joined in the oil phase, 60 ℃ of temperature controls, high speed shear is disperseed, and shear rate is 20 minutes for the 2000rpm time, gets colostrum;
(4) the gained colostrum is through high pressure homogenize, and pressure is 1400～1800bar, and homogenize 3 times gets nano-emulsion;
(5) the gained nano-emulsion is quickly cooled to 0～2 ℃, forms epoprostenol lipid nanoparticle suspension;
(6) above-mentioned suspension adds lactose, filtration sterilization, and sterile filling, lyophilization gets injection epoprostenol lipid nanoparticle.
Embodiment 7
Prescription:
Epoprostenol 0.5g
Spermol cetylate 4g
Oleum Gossypii semen 2g
Soybean phospholipid 2.5g
Polyethylene glycol 1000 vitamin E succinic acid ester 5g
Poloxamer 1g
Make 1000ml
Preparation technology:
(1) the spermol Palmic acid is heated to 70 ℃ of fusions, adds Oleum Gossypii semen, soybean phospholipid, and polyethylene glycol 1000 vitamin E succinic acid ester, the epoprostenol mix homogeneously gets oil phase;
(2) poloxamer is soluble in water, is heated to 70 ℃, gets water;
(3) water is joined in the oil phase, 70 ℃ of temperature controls, high speed shear is disperseed, and shear rate is 10 minutes for the 5000rpm time, gets colostrum;
(4) the gained colostrum is through high pressure homogenize, and pressure is 1400～1800bar, and homogenize 3 times gets nano-emulsion;
(5) the gained nano-emulsion is quickly cooled to 0～2 ℃, forms epoprostenol lipid nanoparticle suspension;
Embodiment 8
Particle size distribution measuring
Under the room temperature condition, get the SLN suspension, be diluted with water to suitable concentration, add in the sample cell of laser particle analyzer, measure size and distribution.
Embodiment 1～6 mean diameter
Comparing embodiment 1 medicine stability test
The method of referenced patent application 200780011395.3 Instructions Page 4s is measured the epoprostenol buffer salt solution, and the lipid nanoparticle stability of solution the results are shown in Table 1.The result shows, be made into lipid nanoparticle after, stability of drug is improved greatly.
The test of comparing embodiment 2 local irritations
6 of rabbit, female, 2.0～2.4kg is divided into two groups, and 3 every group, every left ear is given epoprostenol solution and embodiment 3 lipid nanoparticle suspensions respectively, and auris dextra is given and is waited capacity 0.9% sodium chloride injection.Each ear before injection with after the medical alcohol sterilization, auricular vein apart from the tip about 1cm place inserting needle, the slow injection tried thing, be administered once every day, for three days on end.Observe the injection site vein (blood vessel) and the irritant reaction of subcutaneous tissue gill epidermis on every side after each administration and before the administration next time, make itemized record.Mark by " vascular stimulation test standards of grading-macroscopy classification ".Put to death animal in 24 hours after the last administration, auricular concha about 5cm in clip injection site is long, after 10% formalin fixed, and censorship pathology.Last comprehensive naked eyes and histological score value evaluation test result.
Observe the injection site vein (blood vessel) and the irritant reaction of subcutaneous tissue gill epidermis on every side after each administration and before the administration next time, there is no significant change.Pathological examination results does not also see that blood vessel and surrounding tissue have significant change, by vascular stimulation standards of grading cumulative score is, lipid nanoparticle group score＜0.5 judges that thus the epoprostenol lipid nanoparticle does not have the blood vessel zest; Epoprostenol solution group must be divided into 2, slight zest.The result shows, make lipid nanoparticle after, local irritation reduces.
Claims (10)
1, a kind of epoprostenol lipid nanoparticle is characterized in that, epoprostenol in this lipid nanoparticle, and the weight ratio of matrix material and surfactant is 1: 5～50: 2～20.
According to the described epoprostenol lipid nanoparticle of claim 1, it is characterized in that 2, described matrix material is a solid lipid material Glyceryl Behenate, tristerin, tripalmitin, glyceryl palmitostearate, glycol stearate, Palmic acid glycol ester, Ethylene Glycol Palmitostearate, white beeswax, Cera Flava, microwax, Brazil wax, Synthetic Spermacet, stearic acid, lanoline, stearyl alcohol, one or more in the vaseline lanonol.
3, epoprostenol lipid nanoparticle according to claim 2 is characterized in that, described matrix material is solid lipid and liquid fatty mixture, the weight ratio of solid lipid and liquid fatty is 1: 1～9: 1, and described liquid fatty is a soybean oil, Oleum Gossypii semen, Oleum Brassicae campestris, Oleum sesami, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Helianthi, coix seed oil, vitamin e succinate, medium chain triglyceride, one or more in the fish oil.
4, epoprostenol lipid nanoparticle according to claim 3; it is characterized in that; described surfactant is a soybean phospholipid; Ovum Gallus domesticus Flavus lecithin; poloxamer; polyethylene glycol 1000 vitamin E succinic acid ester; Polyethylene Glycol 660-12-hydroxy stearic acid ester, polyoxyethylene-8-caprylic/capric glyceride, Polyethylene Glycol distearyl ethanolamine; ethylene glycol monomethyl ether; dihexyl succinic acid acyl sodium sulfonate, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol; cholic acid and salt thereof, one or more in deoxycholic acid and the salt thereof.
5, according to the preparation method of the described epoprostenol lipid nanoparticle of claim 1～4, it is characterized in that, may further comprise the steps:
(1) the matrix material heating is 60～80 ℃, adds the epoprostenol mix homogeneously, gets oil phase;
(2) surfactant dissolves is heated to 60～80 ℃ in water, gets water;
(3) water is joined in the oil phase, 60～80 ℃ of temperature controls, high speed shear is disperseed, and gets colostrum;
(4) the gained colostrum becomes nano-emulsion through high pressure homogenize;
(5) the gained nano-emulsion is quickly cooled to below 4 ℃, forms epoprostenol lipid nanoparticle suspension.
6, the preparation method of epoprostenol lipid nanoparticle according to claim 5, it is characterized in that, the dispersive shear rate of the described high speed shear of step (3) is to be 10～60 minutes 1000～5000rpm time, and the described pressure of step (4) is 600～2000bar, homogenize number of times 3～6 times.
7, a kind of dosage form that contains the arbitrary described epoprostenol lipid nanoparticle of claim 1 to 6 is characterized in that, the dosage form that acceptable auxiliary is made on this lipid nanoparticle and the medicament.
8, the dosage form of epoprostenol lipid nanoparticle according to claim 7 is characterized in that, described dosage form is an injectable powder.
9, the preparation method of epoprostenol lipid nanoparticle injectable powder according to claim 8 is characterized in that, may further comprise the steps:
(1) the matrix material heating is 60～80 ℃, adds the epoprostenol mix homogeneously, gets oil phase;
(2) surfactant dissolves is heated to 60～80 ℃ in water, gets water;
(3) water is joined in the oil phase, 60～80 ℃ of temperature controls, high speed shear is disperseed, and shear rate is to be 10～60 minutes 1000～5000rpm time, gets colostrum;
(4) the gained colostrum is through high pressure homogenize, and pressure is 600～2000bar, and homogenize number of times 3～6 times gets nano-emulsion;
(5) the gained nano-emulsion is quickly cooled to below 4 ℃, forms epoprostenol lipid nanoparticle suspension;
(6) the lipid nanoparticle suspension is added freeze drying protectant, aseptic subpackaged through 0.22 μ m filtering with microporous membrane, lyophilization, promptly.
10, epoprostenol lipid nanoparticle injectable powder according to claim 9 is characterized in that, described freeze drying protectant is a trehalose, sucrose, maltose, one or more in the lactose.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2925303A4 (en) * | 2012-11-30 | 2016-04-27 | Insmed Inc | Prostacylin compositions and methods for using the same |
| CN105687159A (en) * | 2016-01-04 | 2016-06-22 | 浙江大学 | Preparation and application of silymarin lipid nanoparticles |
| US10010518B2 (en) | 2013-10-25 | 2018-07-03 | Insmed Incorporated | Prostacyclin compounds, compositions and methods of use thereof |
| US10343979B2 (en) | 2014-11-18 | 2019-07-09 | Insmed Incorporated | Methods of manufacturing treprostinil and treprostinil derivative prodrugs |
| US11458098B2 (en) | 2019-04-29 | 2022-10-04 | Insmed Incorporated | Dry powder compositions of treprostinil prodrugs and methods of use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0707488B8 (en) * | 2006-02-03 | 2021-05-25 | Actelion One Sa | method for producing an epoprostenol composition, pharmaceutical composition and stable solution |
| CN1872072A (en) * | 2006-03-14 | 2006-12-06 | 广州中大创新药物研究与开发中心有限公司 | Nano emulsion injection of alprostadil and preparation method |
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|---|---|---|---|---|
| EP2925303A4 (en) * | 2012-11-30 | 2016-04-27 | Insmed Inc | Prostacylin compositions and methods for using the same |
| US10010518B2 (en) | 2013-10-25 | 2018-07-03 | Insmed Incorporated | Prostacyclin compounds, compositions and methods of use thereof |
| US10526274B2 (en) | 2013-10-25 | 2020-01-07 | Insmed Incorporated | Prostacyclin compounds, compositions and methods of use thereof |
| US10995055B2 (en) | 2013-10-25 | 2021-05-04 | Insmed Incorporated | Prostacyclin compounds, compositions and methods of use thereof |
| US11795135B2 (en) | 2013-10-25 | 2023-10-24 | Insmed Incorporated | Prostacyclin compounds, compositions and methods of use thereof |
| US10343979B2 (en) | 2014-11-18 | 2019-07-09 | Insmed Incorporated | Methods of manufacturing treprostinil and treprostinil derivative prodrugs |
| US11148997B2 (en) | 2014-11-18 | 2021-10-19 | Insmed Incorporated | Methods of manufacturing treprostinil and treprostinil derivative prodrugs |
| CN105687159A (en) * | 2016-01-04 | 2016-06-22 | 浙江大学 | Preparation and application of silymarin lipid nanoparticles |
| US11458098B2 (en) | 2019-04-29 | 2022-10-04 | Insmed Incorporated | Dry powder compositions of treprostinil prodrugs and methods of use thereof |
| US11759425B2 (en) | 2019-04-29 | 2023-09-19 | Insmed Incorporated | Dry powder compositions of treprostinil prodrugs and methods of use thereof |
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