CN1739525A - A Novel Polyethylene Glycol Derivatized Phospholipid Encapsulated Nanoparticle Drug Delivery System of Prostaglandin E1 - Google Patents

Abstract

The invention provides a prostaglandin E1 nano particle drug delivery system for intravenous injection, which contains therapeutically effective dose of prostaglandin E1, polyethylene glycol derivatized phospholipids, and pharmaceutically acceptable auxiliary agents. It is prepared by encapsulating medicine in the formed nano particles to prepare an injectable prostaglandin E1 delivery system. The nanoparticle drug delivery system of the present invention can be in the form of liposome, microemulsion, micelle, or a mixture thereof. After the nanoparticles are formed, their polyethylene glycol long chains can be distributed on the surface of the nanoparticles to form a hydrophilic protective film, which prevents the mutual aggregation of the nanoparticles on the one hand, and on the other hand, avoids being recognized by the reticuloendothelial system in the body, Phagocytosis prolongs the retention time of the microparticle drug delivery system in the blood circulation; in addition, the drug is encapsulated in the hydrophobic core, which can protect the drug from damage by external factors (water, oxygen, light), and greatly improve the stability of the drug during storage.

Description

A Novel Polyethylene Glycol Derivatized Phospholipid Encapsulated Nanoparticle Drug Delivery System of Prostaglandin E1

technical field

The invention relates to a prostaglandin E1 (PGE1) nano particle delivery system for intravenous injection.

Background technique

Prostaglandin E1 (PGE1) is an endogenous drug that was first approved by the United States as a drug for marketing in 1981. It can be synthesized in normal human tissue cells and is an important substance that regulates cell function. It exists in almost all physiological phenomena of the human body, has a wide range of treatments, does not accumulate in the body, does not produce drug-resistant organisms, is non-toxic, has no harmful side effects, and has exact therapeutic effects. Therefore, it is widely used clinically in cardiovascular and cerebrovascular diseases, respiratory Systemic disease, limb vascular disease, liver disease, diabetes and its complications, pulmonary hypertension caused by various reasons, acute pancreatitis, cerebral infarction, extracorporeal circulation to protect platelets, arteriography, vascular reconstruction, etc. Especially for middle-aged and elderly cardiovascular disease treatment has a unique effect. However, PGE1 will be rapidly metabolized and inactivated by enzymes in the body. Therefore, it is necessary to use large doses for frequent or long-term continuous administration in clinical application to maintain effective blood drug concentrations, and long-term large-dose administration often leads to some unexpected results. Unexpected side effects. The use of certain preparation methods can prolong the circulation time of the drug in the body and prolong the curative effect of the drug. For example, Mizishuma et al (J. Rheumatol 14: 97 (1987)) and Hoshi et al (Drug. Exptl. Clin. Res 12 (8): 681 (1986)) have studied a kind of technology of preparing PGE1 lipid microsphere, However, Mizishuma et al (US Pat No 4,493,847) and Imagawa et al (US Pat No 4,493,847) revealed that it is actually a fat emulsion, which encapsulates PGE1 in emulsion droplets formed by soybean oil, thereby protecting the drug from in vivo Enzyme metabolism, while improving drug distribution and prolonging drug action time. Robert Plenk used phospholipids to prepare PGE1 into liposomes to prolong the drug's action time.

Liposomes and microemulsions have been proven to improve the stability of drugs in blood circulation and prolong the drug action time (U.S. Pat. Nos4837028 and 4920016). In addition, by changing their particle size and particle size distribution, drugs can be delivered to specific cells and tissues (U.S. Pat. Nos 5527528 and 5620689). At present, mature preparations of liposomes and microemulsions are on the market, such as adriamycin liposomes, amphotericin liposomes, paclitaxel liposomes, PGE1 lipid microspheres (actually microemulsions), etc. .

"Micelles", when the concentration of amphiphilic molecules in water exceeds the critical micelle concentration, they can spontaneously aggregate to form micelles. Using this property, certain preparation methods can be used to encapsulate drugs in micelles and deliver drugs to the body. For example, Kun et al published an article entitled "Polymer Micelles—A Novel Drug Carrier", which reviewed the application of micelles as drug carriers (Adv.Drug.Del.Rev.21: 107-116 (1976 ). As a drug delivery system, micelles can achieve the purpose of sustained release and long circulation, which has attracted great interest. Yokoyama et al used polymers capable of forming micelles to encapsulate anti-tumor drugs, and studied its Activity and toxicity against solid tumors, and its long-term circulation in the blood (Cancer res.51: 3229-3236 (1991). Trubetskoy et al described the use of polyethylene-phospholipids as a carrier for entrapment of therapeutic and diagnostic drugs (Adv Drug Del Rev.16:311-320 (1995). Micelles have been used clinically as a drug delivery system (Brodin et al, Acta Pharm Suec.19 267-284 (1982)), and are also used in Targeted drug preparations (Supersaxo et al.Pharm Res.8:1286-1291 (1991)) and drugs for the treatment of cancer (Fung et al.Biomater.Aritif.Cell.Aritif.Organs16:439et.Seq.(1988; Yokoyama et al., Cancer Res.51:3229-3236 (1991)). Lasic (Nature Vol.335, pp.379-380, (1992)) also studied the mixed micelle preparation prepared by phospholipid and a living drug.

Polyethylene glycol (PEG) is a water-soluble polymer that can exist stably under physiological conditions. Because its spatial structure can prevent plasma proteins from approaching, it has been widely used to change the properties of phospholipids and protein drugs. , in the microparticle drug delivery system, the PEG long chain can form a hydrophilic protective layer on the surface of the microparticles, which can prevent the aggregation of the microparticles, and avoid being recognized and swallowed by the reticuloendothelial system in the body, thereby prolonging the retention of the drug in the blood circulation Time to achieve the purpose of long cycle.

The nanoparticle drug delivery system based on PEG-derivatized phospholipids not only has the advantages of general nanoparticle delivery systems: the particle size is small, basically between 10nm and 1000nm, and it is a kinetically stable system. On the one hand, it avoids other particles. Drug delivery systems, such as liposomes, are prone to agglomeration; on the other hand, it is easier to penetrate into the lesion, improve drug distribution, and improve drug efficacy. Using PEG derivatized phospholipids as carrier materials, PEG chains can form a hydrophilic protective layer on the surface of particles, which can further take advantage of the nanoparticle drug delivery system. As we have previously introduced about the pharmacological characteristics of PGE1, it is of positive significance to prepare it into a nanoparticle drug delivery system to exert its medicinal effect and reduce toxic and side effects.

Contents of the invention

The object of the present invention is to provide a prostaglandin E1 nanoparticle drug delivery system, which is a kinetically stable system with good stability, and has a targeting effect in the body, increases the distribution of drugs in the lesion, and improves the drug delivery system. Drug efficacy and reduce side effects.

The invention provides a prostaglandin E1 nano particle drug delivery system for intravenous injection, which contains therapeutically effective dose of prostaglandin E1, polyethylene glycol derivatized phospholipids, and pharmaceutically acceptable auxiliary agents.

The main content of the present invention is to use polyethylene glycol (PEG) derivatized phospholipids as the main auxiliary material, and adopt appropriate pharmacy means to prepare PGE1 nanoparticle drug delivery system. The nanoparticle drug delivery system referred to in the present invention includes liposomes , microemulsion, micelles.

In order to better understand the content of the present invention, we first explain some technical terms as follows.

"Microemulsion" refers to a non-uniform dispersion system in which one or more than one liquid is dispersed in another incompatible liquid continuous phase in the form of small droplets. The small droplet size of the "microemulsion" is 10-1000nm.

Molecules such as "liposomes" and phospholipids can spontaneously arrange into bilayers in aqueous solution, forming single-layer or multilayer bilayer vesicles.

"Micelle" means that when the concentration of amphiphilic molecules in aqueous solution exceeds the critical micelle concentration (CMO), it can spontaneously polymerize to form micelles. Unlike liposomes, micelles do not have a bilayer, and their structure is that the hydrophobic part faces inward. , form a hydrophobic core, and the hydrophilic part forms a hydrophilic surface outward. The micellar particle size is small (less than 200nm), and the average particle size is about 20-30nm, so it is not only a thermodynamically stable system, but also a kinetically stable system. Micellar particles are not easy to aggregate and stratify, and have a high loading capacity. At low concentrations, they can load a higher amount of drug.

"Phospholipid", the molecular structure of phospholipid is similar to that of fat, the difference is that there are only two fatty acids attached to the glycerol molecule, while the third hydroxyl of phospholipid is combined with phosphoric acid to form a lipid, and there is a nitrogenous base combined with phosphoric acid . This structure of phospholipids makes it an amphiphilic molecule. One end of its phosphoric acid and nitrogenous base is polar, easy to absorb with water, forming the hydrophilic head of phospholipid molecule, and its fatty acid end is non-polar, not absorbing with water, forming the head of phospholipid molecule For the hydrophobic tail, the phospholipids involved in the present invention are often used in combination of several phospholipids including polyethylene glycol derivatized phospholipids.

"Therapeutically effective amount" refers to the amount of prostaglandin E1 that produces a therapeutic effect. According to the present invention, the unit dose of prostaglandin E1 is 1-1000 ug, preferably 5-100 ug, and the optimal unit dose is 10 ug, and the dose will be adjusted according to the needs of each special individual.

The nanoparticle drug delivery system of prostaglandin E1 of the present invention is mixed with polyethylene glycol (PEG) derivatized phospholipids, which can protect the nanoparticle drug delivery system from being swallowed by the reticuloendothelial system in the body, and prolong the nanoparticle in the blood circulation. At the same time, it improves the pharmacokinetic properties of the drug distribution in the body and enhances the efficacy of the drug.

The PGE1 nanoparticle drug delivery system involved in the present invention can be in the form of a solution or in a freeze-dried form as required.

In the prostaglandin E1 nanoparticle drug delivery system of the present invention, the particle size range of the particles is 10-1000 nm, preferably 10 nm-200 nm. The dosage of prostaglandin E1 is 1μg/ml-1000μg/ml preparation, preferably 10μg/ml-200μg/ml, and the dosage of polyethylene glycol derivatized phospholipid is 0.01mM-50mM, preferably 1mM-20mM.

In the present invention, the polyethylene glycol derivatized phospholipid is formed by combining polyethylene glycol molecules with nitrogen-containing bases on the phospholipid molecules through covalent bonds.

The phospholipid used in the present invention is a PEG derivatized phospholipid, and the fatty acid in the phospholipid part of the structure contains 10 to 24 carbon atoms, preferably 12, 14, 16, 18, 20, 22, 24 carbon atoms, The fatty acid chain can be saturated or partially saturated. The fatty acids that need to be pointed out in particular are lauric acid (12 carbons), myristic acid (14 carbons), palmitic acid (16 carbons), stearic acid or oleic acid or linoleic acid. Oleic acid (18 carbons), eicosic acid (20 carbons), behenic acid (22 carbons), lignocerate (24 carbons).

Polyethylene glycol derivatized phospholipids, the phospholipid part can be phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylserine (PS) diphosphatidylglycerol, Phospholipids, lysophosphatidylcholine (LPC), lysoethanolamine phospholipids (LPE), etc.

Polyethylene glycol derivatized phospholipid, its polyethylene glycol molecular weight range is 200～20000 (relevant with the quantity of ethoxyl group on the polyethylene glycol long chain), preferably polyethylene glycol molecular weight range is 500-～10000, more The preferred range is 1000-10000 (the number of ethoxy groups is 22-220), and the most preferred molecular weight of polyethylene glycol is 2000.

The PGE1 nanoparticle system of the present invention uses PEG derivatized phospholipids as a carrier, and is used in conjunction with other nano-preparation materials. Through certain pharmaceutical means, a therapeutic amount of PGE1 is wrapped in the formed nanoparticles. Certain antioxidants, osmotic pressure regulators, and pH value regulators need to be added.

The drug delivery system according to the invention is in the form selected from liposomes, microemulsions or micellar formulations, or a mixture of two or three of the above forms.

According to the present invention, different nanoparticle preparations can be obtained by using different additives, such as adjusting the ratio of PEG derivatized phospholipids to other phospholipids to obtain liposomes and micelles or their mixtures in different ratios. If an oil phase material is used in the formulation, microemulsions can be obtained, where polyethylene glycol derivatized phospholipids are distributed on the surface of oil droplets as emulsifiers,

The delivery system according to the present invention may be a liposome containing prostaglandin E1, polyethylene glycol derivatized phospholipids, other phospholipid materials that facilitate liposome formation, and pharmaceutically acceptable antioxidants, osmotic Pressure regulator, pH regulator. Wherein said other phospholipid materials include soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, hydrogenated lecithin, especially mentioned in the present invention is hydrogenated lecithin.

In the liposome preparation according to the present invention, the molar ratio of the PEG derivatized phospholipids to the total phospholipids ranges from 1% to 20%. The molecular ratio of PGE1 and phospholipid contained in the preparation (drug lipid ratio) is 1:1-1:100, preferably 1:5-1:20.

The liposome formulation according to the present invention can be in the form of solution or in the form of lyophilized powder. When in solution form, the concentration range of PGE1 is 1μg/ml-1000μg/ml, the concentration of total phospholipids is 0.01mM-50mM, and the concentration of other additives is 0.01%-10%. When in the form of freeze-dried powder, the PGE1 concentration is 0.01%-10% (weight percent), the total phospholipid concentration is 10%-95% (weight percent), and the concentration of other additives is 10%-80% (weight percent).

During the preparation of liposomes, the formation of some microemulsions and micelles is not excluded.

The drug delivery system according to the present invention can be a microemulsion, which contains prostaglandin E1, polyethylene glycol derivatized phospholipids, other phospholipid materials that are conducive to the formation of microemulsions, emulsifiers, oil phase materials, and pharmaceutically acceptable antioxidants. agent, osmotic pressure regulator, pH value regulator. Wherein, the other phospholipid materials include soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, hydrogenated lecithin, etc., and the oil phase material includes refined soybean oil. .

In the microemulsion of the present invention, the ratio of the oil phase to the water phase is 5:95˜50:50. The concentration range of PGE1 is 1μg/ml-1000μg/ml, the concentration of total phospholipid is 0.01mM-50mM, and the concentration of other additives is 0.01%-10%.

During the preparation process of the microemulsion, the formation of some liposomes and micelles is not excluded.

The drug delivery system according to the present invention may be micelles, which contain prostaglandin E1, amphiphilic molecules, and pharmaceutically acceptable antioxidants, osmotic pressure regulators, pH value regulators. The amphiphilic molecules are PEG derivatized phospholipids and other phospholipids. Other phospholipid materials include soybean phospholipids, phosphatidylcholine, phosphatidylethanolamine, hydrogenated lecithin, and the like.

In the micelle preparation of the present invention, the molar ratio of PEG derivatized phospholipids to the total phospholipids ranges from 10% to 100%, preferably 50% to 70%.

The final micellar preparation can be in the form of a solution, containing 1 μg/ml-1000 μg/ml prostaglandin E1 and 0.01 mM-50 mM total phospholipids. The concentration of other additives is 0.01% to 10%.

The final preparation of micelles can be in the form of lyophilized powder, containing 0.01% to 10% (percentage by weight) of prostaglandin E1, 10% to 90% (percentage by weight) of total phospholipids and 10% to 90% (percentage by weight) of other additive.

Because PGE1 and phospholipids are all easily oxidized, as required, the PGE1 micellar preparation of the present invention also contains antioxidants, such as water-soluble antioxidants (corbic acid, sodium bisulfite, EDTA, consumption range 0.01～1.0%) (weight percent) and fat-soluble antioxidant (tocopherol, BHA, propyl gallate, consumption range 0.01～1.0% (weight percent).

According to needs, the drug delivery system of the present invention can be added with a pH regulator (various buffer systems such as citric acid-sodium citrate, acetic acid-sodium acetate, phosphate, etc.), the dosage range is 1mM～100mM, and the pH of the medicinal solution is adjusted to 3.0～ 8.0. The optimum pH range is 3.0-5.0.

According to needs, the drug delivery system of the present invention can add osmotic pressure regulators (sodium chloride, glucose, mannitol). The osmotic pressure regulator refers to various pharmaceutically acceptable salts and carbohydrates used to adjust isotonicity, and adjusts the osmotic pressure to the human body isotonic or hypertonic (body fluid osmotic pressure range 290-310mmol/L) .

The invention also provides a preparation method of the prostaglandin E1 nano particle delivery system, which comprises wrapping the prostaglandin E1 in the nano particle formed by polyethylene glycol derivatized phospholipids, and preparing the prostaglandin E1 drug delivery system for intravenous injection.

Specifically, the micellar drug delivery system of the present invention is prepared by the following preparation method: PGE1, phospholipids, and fat-soluble additives are dissolved in an organic solvent, placed in an eggplant-shaped bottle, and a rotary evaporator is used. Evaporate the organic solvent to form a thin and uniform phospholipid film on the surface of the eggplant-shaped bottle, dissolve the water-soluble additive (water-soluble antioxidant, osmotic pressure regulator, pH value regulator) in water, and add the aqueous solution to the eggplant-shaped bottle. In the bottle, oscillate for hydration, ultrasonically disperse, pass through a membrane to adjust the particles, and finally pass through a 0.22um microporous membrane to filter and sterilize, and prepare a PGE1 nanoparticle preparation for intravenous injection. The particle size of the formed nanoparticles ranges from 10 -1000nm, available in solution or freeze-dried form as needed.

The preparation method of the liposome drug delivery system of the present invention is similar to the preparation method of the above-mentioned micellar drug delivery system, except that the proportion of PEG derivatized phospholipids in the total phospholipids in the prescription is relatively low.

Microemulsion preparation method of the present invention: PGE1, phospholipid, fat-soluble additive are dissolved in refined soybean oil, and water-soluble additive (water-soluble antioxidant, osmotic pressure regulator, pH value regulator) is dissolved in water, The two are mixed, and the milk is repeatedly homogenized by a high-pressure homogenizer to form a nano-microemulsion.

As mentioned above, after ordinary PGE1 injection is injected into the body, the drug can be quickly metabolized and inactivated by the enzymes in the body. Therefore, in clinical application, it is necessary to use a large dose of frequent or long-term continuous administration, which limits the clinical application and curative effect. Prepared as a common nanoparticle drug delivery system (liposome, microemulsion, etc.), it can be swallowed by the reticuloendothelial system in the body, so that the drug can be quickly cleared from the blood. Moreover, general liposomes and microemulsions also have disadvantages such as easy aggregation and precipitation, and easy leakage of medicines. In order to overcome the disadvantages of the above dosage forms, the present invention uses polyethylene glycol derivatized phospholipids as the main carrier, supplemented by other materials for preparing nanoparticles, to prepare PGE1 nanoparticle drug delivery preparations. The main technical advantage of the present invention is that polyethylene glycol derivatized phospholipids are mixed into the material for preparing nanoparticles. The reticuloendothelial system in the body recognizes and phagocytizes, prolonging the circulation time of micelles in the body; on the other hand, the drug is encapsulated in nanoparticles, which can protect the drug from the damage of external factors (water, oxygen, light), and greatly improve the storage capacity of the drug. In addition, the nanoparticle drug delivery system can improve the pharmacokinetic properties of the drug distribution in the body, increase the distribution of the drug in the lesion, and improve the efficacy of the drug.

The following examples are mainly used to further illustrate the present invention, but not to limit the scope of the present invention.

Detailed ways

Embodiment 1: Preparation of PGE1 micellar preparation

See Table 1 for the prescription:

Table 1 embodiment 1PGE1 micelle preparation prescription Concentration (mM) Content (mg) PGE1 0.564 0.2 PEG2000-DSPE 3.0 8.4 HSPCs 3.0 2.28 VE 2.115 1.0 VC 56.77 10.0 EDTA 2.69 1.0 water 1.0ml

Preparation process: Weigh PGE1, polyethylene glycol 2000 derivatized distearoyl phosphatidylcholine (PEG2000-DSPE), and hydrogenated phospholipid (HSPC) according to the above prescription ratio, dissolve them in an appropriate amount of chloroform, and place them in a 100ml eggplant-shaped bottle , using a rotary evaporator to evaporate the organic solvent to form a thin and uniform phospholipid film on the surface of the eggplant-shaped bottle, dissolve water-soluble additives (VC, VE, EDTA) in water, and add the aqueous solution to the eggplant-shaped bottle for 60 Oscillate for hydration at ℃, ultrasonically disperse, pass through a 0.1 μm membrane for sizing (pay attention to nitrogen protection during the preparation process).

The appearance of the obtained sample is milky, the average particle size is 23.3nm, the particle size distribution is between 12.0nm and 31.9nm, the Zeta potential is +3.1, and the encapsulation efficiency is greater than 90%.

The preparation of embodiment 2PGE1 mixed micelle preparation

See Table 2 for the prescription:

Table 2 embodiment 2PGE1 mixed micelle preparation prescription Concentration (μM) Content (mg) PGE1 56.4 0.1 PEG2000-DSPE 300 4.2 HSPCs 300 1.14 VE 211.5 0.5 VC 5677 5.0 EDTA 269 0.5 water 5.0ml

Preparation process: Weigh PGE1, PEG2000-DSPE, and HSPC according to the above prescription proportions, dissolve them in an appropriate amount of chloroform, place them in a 100ml eggplant-shaped bottle, and use a rotary evaporator to evaporate the organic solvent to form a thin and uniform layer on the surface of the eggplant-shaped bottle. For the phospholipid film, dissolve the water-soluble additives (VC, VE, EDTA) in water, add the aqueous solution into an eggplant-shaped bottle, hydrate by shaking at 60°C, and disperse by ultrasonic (pay attention to nitrogen protection during the preparation process).

The appearance of the obtained sample is milky, and it is a mixed micelle preparation. The main particle size is distributed in two regions, and 26.3nm～39.3nm (average particle diameter 29.4nm) is a region, accounting for 78.7% of the volume ratio, 130.6nm～ 238.1nm (average particle diameter 174.9nm) is a region, accounting for 9.3% of the volume, and the encapsulation efficiency is greater than 90%.

The preparation of embodiment 3PGE1 mixed micelles preparation

See Table 3 for the prescription:

Table 3 embodiment 3PGE1 mixed micelle formulation prescription Concentration (mM) Content (mg) PGE1 0.564 0.2 PEG2000-DSPE 1.2 3.36 HSPCs 4.8 3.648 VE 2.115 1.0 VC 56.77 10.0 EDTA 2.69 1.0 water 1.0ml

Preparation process: Weigh PGE1, PEG2000-DSPE, and HSPC according to the above prescription proportions, dissolve them in an appropriate amount of chloroform, place them in a 100ml eggplant-shaped bottle, and use a rotary evaporator to evaporate the organic solvent to form a thin and uniform layer on the surface of the eggplant-shaped bottle. phospholipid film, dissolve water-soluble additives (VC, VE, EDTA) in water, add the aqueous solution into an eggplant-shaped bottle, vibrate at 60°C for hydration, ultrasonically disperse (pay attention to nitrogen protection during the preparation process), and filter through a filter of 0.4 μm Film whole grain.

The appearance of the obtained sample is milky, and it is a mixed micelle preparation. The main particle size is distributed in two regions, 17.9nm～40.0nm (average particle size 24.3nm) is a region, accounting for 64.1% by volume, and 361.7nm～ 59.7nm (average particle diameter 172.2nm) is a region, accounting for 35.9% of the volume, Zeta potential is -17.8, and the encapsulation efficiency is greater than 90%.

The preparation of embodiment 4PGE1 mixed micelle preparation

See Table 4 for the prescription:

Table 4 embodiment 4PGE1 mixed micelle preparation prescription Concentration (mM) Content (mg) PGE1 0.564 0.2 PEG2000-DSPE 2.0 5.6 HSPCs 4.0 3.04 VE 2.115 1.0 VC 56.77 10.0 EDTA 2.69 1.0 water 1.0ml

Preparation process: with embodiment 3.

The appearance of the obtained sample is milky, and it is a mixed micelle preparation. The main particle size is distributed in two regions, 19.2nm～28.7nm (average particle diameter 23.7nm) is a region, accounting for 81.6% of the volume ratio, 116.4nm～ 212.2nm (average particle diameter 155.5nm) is a region, occupying a volume ratio of 18.4%, Zeta potential is -3.2, and encapsulation efficiency is greater than 90%.

The preparation of embodiment 5PGE1 mixed micelle preparation

See Table 5 for the prescription:

Table 5 embodiment 5PGE1 mixed micelle preparation prescription Concentration (mM) Content (mg) PGE1 0.564 0.2 PEG2000-DSPE 3.6 5.6 HSPCs 2.4 3.04 VE 2.115 1.0 VC 56.77 10.0 EDTA 2.69 1.0 water 1.0ml

Preparation process: with embodiment 3.

The appearance of the obtained sample is milky, and it is a mixed micelle preparation. The main particle size is distributed in two regions, 18.1nm～27.1nm (average particle size 22.4nm) is a region, accounting for 72.3% by volume, and 134.4nm～ 245.0nm (average particle diameter 162.5nm) is a region, accounting for 8.2% of the volume, Zeta potential is -29.1, and the encapsulation efficiency is greater than 90%.

The preparation of embodiment 6 PGE1 micelle preparation

See Table 6 for the prescription:

Table 6 embodiment 6PGE1 micelle preparation prescription Concentration (mM) Content (mg) PGE1 0.564 2.0 PEG2000-DSPE 4.0 112 HSPCs 2.0 15.2 VE 2.115 10.0 VC 56.77 100.0 EDTA 2.69 10.0 water 50ml

Preparation process: Weigh PGE1, PEG2000-DSPE, and HSPC according to the above prescription proportions, dissolve them in an appropriate amount of chloroform, put them in a 100ml eggplant-shaped bottle, and use a rotary evaporator to evaporate the organic solvent to form a thin and uniform layer on the surface of the eggplant-shaped bottle. phospholipid film, dissolve water-soluble additives (VC, VE, EDTA) in water, add the aqueous solution into an eggplant-shaped bottle, vibrate at 60°C for hydration, ultrasonically disperse (pay attention to nitrogen protection during the preparation process), and filter through a filter of 0.4 μm Membrane granulation, the resulting solution was divided into 2ml vials, each divided into 0.25ml, and freeze-dried.

Before freeze-drying: the appearance of the sample is milky, and the particle size is distributed in two areas, one area is 14.6nm-40.5nm (average particle size 32.nm), accounting for 92% of the volume, and the other area is 94.8nm-187.2 nm (average particle diameter 134.7nm), the volume ratio is 8%, the average Zeta potential is -30.8, and the encapsulation efficiency is greater than 90%.

The appearance of the sample after lyophilization was white loose lumps, and after reconstitution with water, the measured particle size distribution was 13.5nm-34.3nm (average particle size 21.2nm).

After freeze-drying, the sample was placed at room temperature and illuminated (4500lx), and samples were taken in 5 days and 10 days respectively, and the changes of the various indicators of the samples were observed. The results are shown in Table 7.

Method for measuring the pH value: take a sample, add water to make a drug solution containing 10 μg per 1 ml, and measure it with a pH meter.

Table 7 The variation of each index of the stability investigation sample Exterior PH value Average particle size (m) content(%) Encapsulation rate (%) 0 days white loose lumps 3.92 21.2 100.0% Encapsulation rate greater than 90% High temperature 25℃ for 5 days white loose lumps 3.96 22.7 95.1% Encapsulation rate greater than 90% High temperature 25℃ for 10 days white loose lumps 3.97 23.3 90.0% Encapsulation rate greater than 90% Strong light (4500lx) for 5 days white loose lumps 3.96 25.1 95.4% Encapsulation rate greater than 90% Strong light (4500lx) 10 days white loose lumps 3.90 23.4 89.2% Encapsulation rate greater than 90%

The preparation of embodiment 8PGE1 liposome

See Table 8 for the prescription:

The prescription of table 8 embodiment 8PGE1 liposome preparation Concentration (mM) Content (mg) PGE1 0.564 0.6 PEG2000-DSPE 0.3 2.52 HSPCs 5.7 12.996 VE 2.115 3.0 VC 56.77 30.0 EDTA 2.69 3.0 water 3.0ml

Preparation process: Weigh PGE1, PEG2000-DSPE, and HSPC according to the above prescription proportions, dissolve them in an appropriate amount of chloroform, put them in a 100ml eggplant-shaped bottle, and use a rotary evaporator to evaporate the organic solvent to form a thin and uniform layer on the surface of the eggplant-shaped bottle. phospholipid film, dissolve water-soluble additives (VC, VE, EDTA) in water, add the aqueous solution into an eggplant-shaped bottle, vibrate at 60°C for hydration, ultrasonically disperse (pay attention to nitrogen protection during the preparation process), and filter through a filter of 0.4 μm Membrane granulation, to obtain a solution sample, the appearance is milky, the particle size distribution is divided into two regions, 34.4nm ~ 54.5nm (average particle size 43.9nm) is a region, accounting for 50.4% of the volume, 108.8nm ~ 273.3nm (average particle diameter 180.0nm) is a region, accounting for 49.1% of the volume, and the encapsulation efficiency is greater than 90%.

The preparation of embodiment 9PGE1 microemulsion

See Table 9 for the prescription:

Table 9 embodiment 9PGE1 microemulsion formulation prescription Concentration (mM) Content (mg) PGE1 0.0564 6.0 PEG2000-DSPE 0.36 168.0 HSPCs 4.8 1824 VE 0.2115 300 Refined soybean oil 30ml VC 5.677 30.0 water 300ml

Preparation process: Weigh PGE1, PEG2000-DSPE, and HSPC according to the above prescription ratio and dissolve them in an appropriate amount of refined soybean oil, dissolve the water-soluble additive (VC) in water, mix the water phase and oil phase evenly, and repeatedly emulsify under high pressure for 30 minute.

The appearance of the sample is milky, the particle size distribution is 221.7nm-345.6nm (average particle size 289.3nm), and the encapsulation efficiency is greater than 90%.

The preparation of embodiment 10～embodiment 19PGE1 micelle

Prescription: See Table 10:

Table 10 Embodiment 10～Example 19 PGE1 micelle preparation prescription Concentration of raw materials and excipients (mM) 10 11 12 13 14 15 16 17 18 19 PGE1 0.564 0.564 0.564 0.564 0.564 0.564 0.564 0.564 0.564 0.564 PEG2000-DSPE 4.0 4.0 4.0 4.0 / / / / / / PEG500-DSPE / / / / 4.0 / / / / / PEG1000-DSPE / / / / / 4.0 / / / / PEG5000-DSPE / / / / / / 4.0 / / / PEG10000-DSPE / / / / / / / 4.0 / / PEG2000-DPPE / / / / / / / / 4.0 / PEG2000-DMPE / / / / / / / / / 4.0 DPPC 2.0 / / / / / / / / / DPPG / 2.0 / / / / / / / / DMPC / / 2.0 / / / / / / / egg phospholipids / / / 2.0 / / / / / / VE 2.115 2.115 2.115 2.115 2.115 2.115 2.115 2.115 2.115 2.115 VC 56.77 56.77 56.77 56.77 56.77 56.77 56.77 56.77 56.77 56.77 EDTA 2.69 2.69 2.69 2.69 2.69 2.69 2.69 2.69 2.69 2.69

Note: DPPC (16C, dipalmitoylphosphatidylcholine); PEG2000-DPPE (polyethylene glycol 2000 derivatized dipalmitoylphosphatidylethanolamine); DMPC (14C, dimyristoylphosphatidylcholine), PEG2000- DMPE (polyethylene glycol 2000 derivatized dimyristoylphosphatidylethanolamine).

The preparation process of the sample with reference to Example 1 is prepared according to the prescription process in Table 10. The test results show that when the molar ratio of PEG derivatized phospholipids in total phospholipids is high, a micelle system can be formed, and the particle size is below 200nm; and due to the presence of PGE1 Hydrophobic property, it is easy to be wrapped in the hydrophobic core of micelles, and the encapsulation efficiency is above 90%.

Claims (31)

1. A prostaglandin E1 nanoparticle drug delivery system for intravenous injection, which contains a therapeutically effective amount of prostaglandin E1, polyethylene glycol derivatized phospholipids, and pharmaceutically acceptable adjuvants. 2. The drug delivery system according to claim 1, wherein the particle size of the particles in the drug delivery system ranges from 10-1000 nm, preferably from 10 nm to 200 nm. 3. The drug delivery system according to claim 1, wherein the dosage of the prostaglandin E1 is 1 μg/ml to 1000 μg/ml preparation, preferably 10 μg/ml to 200 μg/ml, and the dosage of the polyethylene glycol derivatized phospholipid is 0.01mM-50mM, preferably 1mM-20mM. 4. The drug delivery system according to claim 1, wherein the polyethylene glycol derivatized phospholipid is formed by combining polyethylene glycol molecules with nitrogenous bases on the phospholipid molecules through covalent bonds. 5. The drug delivery system according to claim 4, wherein the fatty acid in the phospholipid part of the polyethylene glycol derivatized phospholipid structure contains 10 to 24 carbon atoms, and the fatty acid chain is saturated or partially saturated, Preference is given to lauric acid, myristic acid, palmitic acid, stearic acid or oleic acid or linoleic acid, eicosic acid, behenic acid, or lignocerate. 6. The drug delivery system according to claim 4, wherein the phospholipid moieties in the polyethylene glycol derivatized phospholipid structure are phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, phosphatidylserine, Diphosphatidylglycerol, phospholipids, lysocholine phospholipids, or lysoethanolamine phospholipids. 7. The drug delivery system according to claim 4, wherein the polyethylene glycol molecular weight in the polyethylene glycol derivatized phospholipid structure is in the range of 200-20000, preferably 500-10000, more preferably 1000-10000, most preferably The molecular weight of polyethylene glycol is 2000. 8. The drug delivery system according to claim 4, wherein the polyethylene glycol derivatized phospholipid is polyethylene glycol 2000 derivatized distearoylphosphatidylethanolamine. 9. The drug delivery system according to claim 1, wherein the drug delivery system is in a solution form or a lyophilized form. 10. The drug delivery system according to claim 1, wherein the drug delivery system is in a form selected from liposome, microemulsion or micellar formulation, or a mixture of two or three of the above forms. 11. The drug delivery system according to claim 10, wherein the drug delivery system is a liposome, which contains prostaglandin E1, polyethylene glycol derivatized phospholipids, phospholipid materials that facilitate liposome formation, and agents Pharmaceutically acceptable antioxidants, osmotic pressure regulators, and pH value regulators. 12. The drug delivery system according to claim 11, wherein other phospholipid materials in the liposomal formulation include soybean phospholipids, phosphatidylcholine, phosphatidylethanolamine, hydrogenated lecithin, preferably hydrogenated lecithin. 13. The drug delivery system according to claim 11, wherein the molar ratio of PEG-derivatized phospholipids to the total phospholipids in the liposome formulation ranges from 1% to 20%. 14. The drug delivery system according to claim 11, wherein the molecular ratio of prostaglandin E1 to phospholipids in the liposome preparation is 1:1-1:100, preferably 1:5-1:20. 15. The drug delivery system according to claim 11, wherein the liposome preparation is in the form of a solution containing 1 μg/ml˜1000 μg/ml prostaglandin E1 and 0.01 mM˜50 mM total phospholipids. 16. The drug delivery system according to claim 11, wherein the liposome formulation is in the form of lyophilized powder, containing 0.01%-10% by weight of prostaglandin E1 and 10%-95% by weight of total phospholipids. 17. The drug delivery system according to claim 10, wherein the drug delivery system is a microemulsion containing prostaglandin E1, polyethylene glycol derivatized phospholipids, other phospholipid materials conducive to the formation of microemulsions, emulsifiers, Oil phase material and pharmaceutically acceptable antioxidant, osmotic pressure regulator, pH value regulator. 18. The drug delivery system of claim 16, wherein other phospholipid materials in the microemulsion include soybean phospholipids, phosphatidylcholine, phosphatidylethanolamine, and hydrogenated lecithin. 19. The drug delivery system according to claim 16, wherein the oil phase material in the microemulsion is refined soybean oil. 20. The drug delivery system according to claim 16, wherein the ratio of the oil phase to the water phase in the microemulsion is 5:95-50:50. 21. The drug delivery system according to claim 10, wherein the drug delivery system is a micelle containing prostaglandin E1, amphiphilic molecules, and pharmaceutically acceptable antioxidants, osmotic pressure regulators, pH value Conditioner. 22. The drug delivery system according to claim 21, wherein said amphiphilic molecules in micelles are PEG-derivatized phospholipids and other phospholipids. 23. The drug delivery system according to claim 22, wherein said other phospholipid materials in the micelles include soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, hydrogenated lecithin. 24. The drug delivery system according to claim 21, wherein the molar ratio of PEG-derivatized phospholipids to the total phospholipids in the micelles ranges from 10% to 100%, preferably 50% to 70%. 25. The drug delivery system according to claim 21, wherein the final micellar preparation is in the form of a solution, containing 1 μg/ml-1000 μg/ml prostaglandin E1 and 0.01 mM-50 mM total phospholipids. 26. The drug delivery system according to claim 21, wherein the final micellar preparation is in the form of lyophilized powder, containing 0.01%-10% by weight of prostaglandin E1 and 10%-90% by weight of total phospholipids. 27. The drug delivery system according to claim 11, 17 or 21, wherein said antioxidants include water-soluble antioxidants and fat-soluble antioxidants. 28. The drug delivery system according to claim 27, wherein said water-soluble antioxidant comprises ascorbic acid, sodium bisulfite, and EDTA, and the dosage ranges from 0.01 to 1.0% by weight. 29. The drug delivery system according to claim 21, wherein said fat-soluble antioxidant comprises tocopherol, BHA, and propyl gallate, and the dosage ranges from 0.01 to 1.0% by weight. 30. The drug delivery system according to claim 11, 17 or 21, wherein the pH regulator is selected from citric acid-sodium citrate, acetic acid-sodium acetate, or phosphate, and adjusts the pH of the solution to 3.0-8.0, Preferably 3.0-5.0. 31. The preparation method of the drug delivery system according to claim 1, comprising encapsulating prostaglandin E1 in nanoparticles formed by derivatized polyethylene glycol phospholipids to prepare a prostaglandin E1 drug delivery system for intravenous injection.