CN107137351B - Stable alprostadil emulsion injection - Google Patents
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- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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Abstract
The invention relates to a stable alprostadil emulsion injection which has uniform and stable particle size distribution, has more stable particle size and distribution in blood plasma for heat sterilization, reduces degradation and oxidation of oil for injection, and reduces the generation of lysophospholipid, thereby improving the stability and safety of the medicament and reducing the toxic and side effects of the medicament.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a stable alprostadil emulsion injection.
Background
Currently, alprostadil, namely prostaglandin E1, is widely applied to clinical treatment, such as treatment of cardiovascular diseases including arterial occlusive diseases, coronary heart diseases, angina pectoris, heart failure, peripheral vascular diseases and the like, treatment of cerebrovascular diseases including acute cerebral infarction, cerebral infarction and vascular spasm after subarachnoid hemorrhage and the like, respiratory diseases, digestive system diseases including hepatitis and the like, renal function diseases including renal insufficiency and the like, diabetes and erectile dysfunction.
In addition, after intravenous administration, the biological stability of the alprostadil in vivo is poor, and in order to maintain effective blood concentration, large dose of the alprostadil needs to be continuously administered intravenously for a long time, so that local blood vessels are excessively stimulated, and the side effect of phlebitis is caused. Under the action of 15-hydroxy-prostaglandin dehydrogenase, alprostadil firstly forms 15-keto-alprostadil in vivo, and then forms a metabolic end product under the action of a series of enzymes, wherein the 15-hydroxy-prostaglandin dehydrogenase is widely present in tissues such as lung, liver, kidney, fat and the like, and the lung is a main metabolic site, so that 60-90% of the dosage of alprostadil loses pharmacological activity due to metabolism after the alprostadil circulates through the lung, and the clinical potency of the alprostadil is greatly influenced. In order to solve the problems of the alprostadil traditional preparation intravenous preparation, the alprostadil injection emulsion which is developed and applied to clinic has the following advantages: (1) the targeted and efficient injection emulsion is easy to gather at the site of vasculitis, and the concentration of the medicine at the lesion site can reach 10-20 times of that of the traditional preparation, so that the toxic and side effects of the whole body are reduced; (2) the alprostadil injection emulsion for reducing the metabolic inactivation of the medicine dissolves and disperses medicine molecules in an inner oil phase and an oil-water interface of the emulsion, so that the direct contact between the medicine molecules and pulmonary enzymes can be avoided to a certain extent, and the metabolic inactivation of the medicine molecules in the lung is further reduced.
Except for easy metabolism of 15-hydroxy-prostaglandin dehydrogenase in vivo, the alprostadil is unstable in chemical property, and the chemical structure of the alprostadil contains β -hydroxyketone, the alprostadil is easy to dehydrate under acid and alkali conditions to generate prostaglandin A1, and is continuously rearranged under alkali conditions to generate prostaglandin B1 so as to lose pharmacological activity.
The existing alprostadil preparation relates to various dosage forms such as liposome, injection emulsion, microsphere, micelle, gel, nasal powder, freeze-dried preparation, external emulsion and the like.
In the aspect of liposome dosage form, the drug is usually wrapped in a formed lipid bilayer membrane to prepare a prostaglandin E1 liposome delivery system for injection, such as the common liposome preparation of alprostadil reported in U.S. Pat. No. 3, 94/12579, and the long-circulating alprostadil nano delivery system prepared by adding polyethylene glycol-derivatized phospholipid is disclosed in CN1739525, and the system can prolong the circulation time of liposome in vivo, but has poor encapsulation effect. CN101108188 also discloses a long-circulating alprostadil nano liposome drug delivery system prepared by adding polyethylene glycol-derived phospholipid, and the encapsulation efficiency is improved by increasing the phospholipid dosage and cholesterol, but the stability condition is not described.
A microsphere preparation mainly adopts high molecular polymers as carriers, such as polylactic acid, glycolide-lactide copolymer, polyethylene glycol-polylactic acid copolymer, polyethylene glycol-glycolide-lactide copolymer and phospholipid substances to jointly encapsulate alprostadil, such as CN101088493, but the preparation cannot easily reach corresponding effective blood concentration, and the technology and cost required by the degradable polymers in vivo are higher.
Micelle preparation, which is amphiphilic molecule, can spontaneously polymerize to form micelle when the concentration of the amphiphilic molecule in aqueous solution exceeds Critical Micelle Concentration (CMC), and the micelle is different from liposome and does not have bilayer, and has a structure that a hydrophobic part is inward to form a hydrophobic core, and a hydrophilic part is outward to form a hydrophilic surface. For example, CN101278913 discloses a prostaglandin E1 micelle preparation with high encapsulation efficiency and low initial release for intravenous injection, which contains prostaglandin E1, PEG-derivatized phospholipid, hydrogenated phospholipid and pharmaceutically acceptable auxiliary agents such as water for injection in a therapeutically effective amount, and CN101439037 also discloses an alprostadil lipid complex and a micelle composition for injection thereof, wherein the alprostadil lipid complex and the micelle composition for injection thereof consist of alprostadil, phospholipid, cholesterol sulfate or/and similar cholesterol derivative, additive and water for injection in a therapeutically effective amount. However, the micelle preparation has relatively low drug loading, which is not favorable for clinical administration of alprostadil.
The emulsion comprises emulsion injection and emulsion freeze-dried preparation, is the current clinical mainstream preparation of alprostadil, and is also the preparation most researched in relevant technology, and is generally prepared from oil-phase vegetable oil, emulsifier phospholipid, cholesterol, auxiliary emulsifier poloxamer, oleic acid and the like, and water phase, for example, CN101496787A discloses a charged prostaglandin E1 lipid microsphere injection and a preparation method thereof, wherein medicinal auxiliary materials comprise 5-20 parts by weight of injection oil, 0.2-5 parts by weight of emulsifier, 0-5 parts by weight of auxiliary emulsifier, 0.5-3 parts by weight of isoosmotic adjusting agent, a proper amount of antioxidant, a proper amount of pH adjusting agent and a proper amount of injection water, and the emulsion injection can be used together with 10-20m L of glucose, sodium chloride or sterile pyrogen-free quality-controllable fat emulsion injection in clinical application, all indexes meet requirements after the mixture are matched, no obvious difference exists, the physiological compatibility is good, more than 85% of the medicines can be wrapped in the oil-phase and the oil/water interface membrane phase, the medicine free in the water phase is not 15%, the stability of the emulsion injection is improved, and the average particle size range is 500-200 nm.
CN101664390 discloses a preparation method of alprostadil microspheres, which is prepared from alprostadil, oil for injection, emulsifier, stabilizer, isotonic agent and water for injection. The medicine and the phospholipid are dissolved in a proper solvent, the solvent is removed, and then the oil phase is added, so that the encapsulation rate of the prepared product is obviously improved, the encapsulation rate of the medicine is over 97 percent, the content of free alprostadil in water is less than 5 percent, and the generation of degradation products is reduced.
CN103655485 discloses an alprostadil lipid microsphere preparation and a preparation method thereof, the alprostadil lipid microsphere preparation is prepared from alprostadil and/or salts thereof, oil for injection, an emulsifier, an auxiliary emulsifier, an osmotic pressure regulator, a metal complexing agent, an antioxidant, a pH value regulator and water for injection, the encapsulation rate is more than 93 percent, the degradation rate of the alprostadil during hot-pressing sterilization is between 6.8 percent and 8.5 percent, and the degradation rate at high temperature is about 50 percent.
CN101091890 discloses a compound emulsifier and an emulsion prepared by using the same, the compound emulsifier can be combined by two or three or more emulsifiers, the concentrations of the components in the emulsifier are respectively: 0-5% lecithin w/v, 0-5% poloxamer w/v, 0-5% Solutol HS15w/v, 0-5% vitamin E polyethylene glycol succinate w/v, 0-5% DSPE-PEG w/v, wherein the molecular weight of PEG is 1000-10000. Has heat resistance and freeze-thaw stability, and has average particle size of 50-100 nm.
CN101332182 discloses an emulsion containing alprostadil for intravenous infusion, which comprises: the alprostadil injection is characterized by comprising alprostadil, oil for injection 5, an emulsifier, a stabilizer, an isotonic agent, an antioxidant, a proper amount of pH regulator and water for injection, wherein the oil for injection is one or a mixture of more than two of soybean oil, olive oil, fish oil, palm oil, sesame oil and tea oil, and the emulsifier is one or a mixture of more than two of egg yolk lecithin, soybean lecithin and poloxamer; the stabilizer is one or a mixture of more than two of oleic acid, sodium oleate and cholic acid; the isotonic agent is selected from glycerol. The emulsion prepared at 60-80 deg.C has uniform particle size and high stability.
CN101474150 discloses a stable alprostadil injection emulsion, which contains alprostadil as an active ingredient, and is prepared by adding pharmaceutically acceptable oil for injection, emulsifier, glycerin for injection and water for injection through an emulsification technology. The emulsifier contains 1883-30 g of poloxamer and 1-6 g of lecithin for injection, and compared with the existing alprostadil injection emulsion, the thermal stability of the alprostadil can be obviously enhanced, the effective period of the alprostadil injection emulsion is prolonged, and the degradation of the alprostadil in the lung can be obviously reduced.
CN101829054 discloses an alprostadil submicron emulsion for injection, which is prepared from alprostadil, oil for injection, an emulsifier, a stabilizer and a freeze-drying protective agent. The prepared alprostadil submicron emulsion for injection has uniform and stable particle size, the degradation product is reduced to 10 percent, and the effective period is prolonged to 24 months. The pH value of the solution before the submicroemulsion is freeze-dried and after redissolution is 6.0-7.5, and the average particle size range of the submicroemulsion is 120-280 nm.
CN101843594 discloses an alprostadil freeze-dried emulsion for injection, which adopts cyclodextrin substances and polysaccharide substances as freeze-drying protective agents to prepare the alprostadil freeze-dried emulsion with high stability, and also comprises an oily solvent, an emulsifier, an auxiliary emulsifier, a freeze-drying protective agent, an isotonic regulator and a pH regulator, and the level of free PGE1 in the alprostadil freeze-dried emulsion for injection is reduced before or after freeze drying, so that the degradation of the alprostadil is further reduced.
CN102038639 discloses an alprostadil injection preparation, which comprises alprostadil, soybean oil, phospholipid, glycerol and oleic acid. Adjusting pH value of the primary emulsion to 5.4-6.0, and passing through a nanometer machine for 5 times under 50MPa to obtain lipid microsphere with uniform particle diameter and average particle diameter of 100-280 nm. The encapsulation efficiency of the drug gradually increases with the decrease of the pH value, but the Zeta potential absolute value decreases, which is not beneficial to the stability of the preparation. The pH value is set to be 5.4-6.0, so that the drug encapsulation efficiency is ensured to be more than 90%, the appropriate Zeta potential value is maintained, and the stability of the emulsion is increased.
CN 102178650A discloses an alprostadil injection, which comprises the following components: (a) the concentration range of the alprostadil serving as a main drug is 5-15 mug/ml; (b) the oil phase is soybean oil, and the concentration ranges of the soybean oil and the soybean oil are respectively 10.0-12.0%; (c) the emulsifier is selected from soybean phospholipid and poloxamer 188, and the concentration ranges of the soybean phospholipid and the poloxamer 188 are 1.0-1.8% and 0.02% -0.2%, respectively; (d) a pH adjusting agent citric acid with a concentration ranging from 5mM to 50mM and a pH ranging from 5.0 to 6.0; (e) the osmotic pressure regulator glycerin has the concentration ranges of 2.0-2.5%; the rest is water for injection. The degradation rate of the alprostadil after autoclaving is between 11 and 12 percent.
CN103599066 discloses an alprostadil injection and a preparation method thereof, and the injection is prepared from the following raw materials in proportion: every 1000ml of injection contains 5mg of alprostadil, 90-110 g of soybean oil, 15-20 g of phospholipid, 2-3 g of oleic acid, 22.1-25g of isotonic agent and a proper amount of pH regulator, and the pH is regulated to 5.0-6.0; after 12 months of storage, the content and the encapsulation rate are both above 90 percent, and the content of related substances is lower than 0.5 percent.
CN103610640 discloses an alprostadil medium-long chain fat emulsion for injection, which is composed of 0.01-0.1 parts by weight of alprostadil, 10-100 parts by weight of long chain triglyceride, 10-100 parts by weight of medium chain triglyceride, 1-20 parts by weight of phospholipid, 0.01-1 part by weight of oleic acid, 5-20 parts by weight of glycerol and 300-2500 parts by weight of water for injection. The medium-chain triglyceride and the long-chain triglyceride are effectively combined, so that the encapsulation rate of the medium-chain and long-chain fat emulsion of the alprostadil is high, the vascular irritation of the alprostadil injection is obviously reduced, the particle size of the medium-chain and long-chain fat emulsion is 50-200 nm, the medium-chain and long-chain fat emulsion has good stability in the range of pH value of 5.0-8.0, and the contents of degradation products prostaglandin A1 and prostaglandin B1 of the alprostadil are measured to be below 1% by adopting a high performance liquid chromatography.
CN105287376 discloses an alprostadil injection, which comprises alprostadil, oil for injection, oleophilic type emulsifier, isotonic agent for injection and stabilizer, wherein the oleophilic type emulsifier is selected from one or more of span substances (such as span 60, span 80 and the like), lecithin, soybean lecithin and agar, wherein the alprostadil injection contains alprostadil particles with the average particle size of between 100 and 300nm and D90 of between 150 and 350nm, and the change of the particle size of the alprostadil injection after being placed at 2-8 ℃ for 12 months is less than or equal to 10%.
CN1872072 discloses an alprostadil nano-emulsion injection and a preparation method thereof, and the injection comprises: (1) oil for injection; (2) a hydrophilic emulsifier; (3) an oleophilic emulsifier; (4) an isotonic agent; (5) a stabilizer. The hydrophilic emulsifier is preferably poloxamer 188 or polyethylene glycol-vitamin E succinate; the oleophilic emulsifier is preferably lecithin or soybean lecithin.
CN102764240 discloses an alprostadil freeze-dried microemulsion, which comprises the following components in percentage by weight: 0.001-0.1% of alprostadil, 1.0-10.0% of grease, 1.0-20.0% of emulsifier, 1.0-20.0% of auxiliary emulsifier, 0.3-1.6% of stabilizer, 50.0-90.0% of freeze-drying protective agent and 0.005-5.0% of pH regulator. Therefore, the appearance, particle size, reconstitution, pH and content of the lyophilized PGE1-ME formulation were almost unchanged after three months of storage at 4 ℃ and 25 ℃, mainly due to the fact that the lyophilized formulation was a solid formulation, there were no various instability problems with emulsion liquid formulations, and sterilization was not performed by heat sterilization. CN103301076 also discloses similar freeze-dried emulsions.
CN103961356 discloses an alprostadil freeze-drying composition for injection and a preparation method thereof, wherein the composition comprises the following components in parts by weight: 0.001-0.05 part of alprostadil; emulsifier: 1-50 parts of polyethylene glycol hydroxystearate, a mixture of polyethylene glycol hydroxystearate and phospholipid; 1-50 parts of medium-chain triglyceride; 10-200 parts of other medicinal auxiliary materials. The alprostadil freeze-dried solid preparation can be stored in a shade place for 2 years, and the content of PGA1 is lower than 10 percent; the particle size change before and after freeze-drying is small, the appearance is transparent or slightly opalescent after redissolution, visible foreign matters can be detected, the average particle size is between 10 and 100nm, and emulsion drops larger than 1 mu m are not contained.
CN106176600 discloses an alprostadil freeze-dried microemulsion, the raw material composition of which comprises 0.1-10 mg/100m L of alprostadil, 0.5-20 g/100m L of oil, 0.5-30 g/100m L of emulsifier, 0.5-2 g/100m L of co-emulsifier, 5-40 mg/100m L of stabilizer and 5-20 g/100m L of freeze-drying protective agent, wherein the emulsifier is polyethylene glycol dodecahydroxy fatty acid ester or a composite emulsifier consisting of polyethylene glycol dodecahydroxy fatty acid ester and one or more of egg yolk lecithin, soybean lecithin, pegylated lecithin and hydrogenated lecithin.
US2008234376 discloses an emulsified composition of prostaglandin E1 comprising prostaglandin E1, a high purity phospholipid and a non-proton providing surfactant which enhances the stability of PGE 1. The use of a non-proton donating surfactant as a co-emulsifier in place of oleic acid in the emulsified composition at a concentration of at least about 1.6% (w/w) of the oil base in the emulsified composition results in improved stability of PGE1 in the emulsified composition.
In addition, prostaglandin E1 emulsions in the european and american countries are primarily used for topical treatment of male erectile dysfunction, and US2002045665 discloses prostaglandin compositions and methods for treating male erectile dysfunction that include vasoactive prostaglandins, permeation enhancers, shear-thinning polysaccharides, lipophilic compounds, and acidic buffer systems.
The administration of alprostadil by japanese pharmaceutical companies has further been developed into emulsion injection, for example JP5890599 discloses a stable fat emulsion containing prostaglandin E1, which contains 5 μ g of a compound having prostaglandin E1 activity, 100mg of refined soybean oil, 18mg of highly refined egg yolk lecithin, 2.4mg of oleic acid and 22.1mg of concentrated glycerol in 1m L of fat emulsion.
JP5193870 discloses a prostaglandin fat emulsion containing a prostaglandin as an active ingredient and a phospholipid containing phosphatidylcholine PC and phosphatidylglycerol PG, wherein the ratio of PC to PG in the phospholipid is 85:15 to 99.7:0.3, and free higher fatty acids or salts thereof can be substantially not contained because the phospholipid is excellent in stability and emulsification stability. The emulsion stability was improved by the presence of PE in the phospholipid, but the reduction of PGE1 was increased.
JP2012214430 discloses a prostaglandin-containing fat emulsion which is a fat emulsion having a pH of 4.5 to 6.0 and comprising a prostaglandin, an oil component, lecithin in an amount of 0.15 times the mass of the oil component, a water-soluble acid or a salt thereof having a dissociable group and having a pKa of 4.0 to 6.0, and water, the water-soluble acid being citric acid. Is favorable for improving the stability of prostaglandin and the stability of emulsion.
Although the stability of the medicines and the emulsion is improved to a certain extent by the current injection emulsion of alprostadil, a plurality of problems still exist, although the injection oil in the patent technology mentions that vegetable oil is adopted, soybean oil is also adopted, factors of automatic oxidation of the soybean oil, such as light, heat, oxygen and metal ions, as well as emulsifying agents, pH regulators and the like adopted in the system can generate complex influence on the stability of the soybean oil, and the soybean oil is used as a main component of the injection emulsion, so that the adverse effects can directly influence the stability and potential adverse side effects of the injection; in addition, the current emulsifier mainly adopts lecithin or the lecithin and other emulsification aids are compounded, however, in JP5193870, different phospholipids have different effects on the stability of drugs and emulsifiers, lecithin is also susceptible to hydrolysis under acidic conditions, and may cause rupture of the phospholipid membrane of emulsion droplets to allow oil droplets to leak out, meanwhile, the current research considers that most of alprostadil in the alprostadil emulsion is distributed in the interface phase of the emulsion, and only a small amount of alprostadil is distributed in the oil phase and the water phase, so that the emulsion drops are broken and combined, or other external substances or heat easily breaks the balance of the oil-water interface, such as the current deviation of the distribution uniformity of the size of emulsion droplets, is a factor for reducing the stability, how to achieve better stability, how to make the substances in the emulsion system compatible with each other and how to ensure the safety of the drug application still remain the problems to be solved at present.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a stable alprostadil emulsion injection which has uniform and stable particle size distribution, has more stable particle size and distribution in blood plasma after being heated and sterilized, reduces the degradation and oxidation of oil for injection and reduces the generation of lysophospholipid, thereby improving the stability and safety of the medicine and reducing the toxic and side effects of the medicine.
The technical scheme for solving the technical problem is as follows:
the invention provides an alprostadil emulsion injection which comprises alprostadil, glutamic acid, lecithin, 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid, oil for injection and water for injection.
The injection is nanoemulsion.
The injection does not contain one or more of oleic acid, antioxidants, EDTA, preferably does not contain oleic acid and antioxidants, preferably does not contain oleic acid and EDTA, preferably does not contain antioxidants and EDTA.
The injection also comprises one or more of medium chain triglyceride and glycerol, preferably medium chain triglyceride and glycerol.
Wherein the weight ratio of the glutamic acid to the 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid is 1: 1.
The lecithin is selected from egg yolk lecithin or soybean lecithin, the oil for injection is selected from one or more of soybean oil, sesame oil or peanut oil, and soybean oil is preferred.
The injection is prepared from alprostadil, glutamic acid, lecithin, 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid, oil for injection, medium chain triglyceride, glycerol and water for injection.
Each 1000ml of injection contains 0.1-10mg of alprostadil, 80-150 g of oil for injection, 10-30g of medium chain triglyceride, 10-20 g of lecithin, 0.1-3 g of 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid, 0.1-3 g of glutamic acid, 10-30g of glycerol and water for injection. Preferably, the injection contains 5mg of alprostadil, 100g of oil for injection, 20g of medium chain triglyceride, 15g of lecithin, 1g of 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid, 1g of glutamic acid and 20g of glycerol in each 1000ml of injection, and the injection water is added to 1000 ml.
The injection is sterilized by heating, preferably at 121 deg.C for 10-15 min, preferably 12 min. After heat sterilization, the average particle size is between 105 and 130nm, preferably 110, 111, 112, 113, 114, 115, 116, 117 and 118 nm; the polydispersity index of the particle size is between 0.1 and 0.2, preferably 0.11, 0.12, 0.13, 0.14, 0.15, 0.16.
The peroxide value of the injection is less than 0.8, preferably less than 0.7, 0.6, 0.5 and 0.4 after being placed at 25 ℃ for 0-6 months, the peroxide value of the injection is less than 0.4 after being placed at 25 ℃ for 1 month, the peroxide value of the injection is less than 0.4 after being placed at 25 ℃ for 2 months, the peroxide value of the injection is less than 0.4 after being placed at 25 ℃ for 3 months, and the peroxide value of the injection is less than 0.4 after being placed at 25 ℃ for 6 months.
The injection is placed in a constant-temperature and constant-humidity environment at the temperature of 2-8 ℃ for 24 months, and the content of the alprostadil is 95-99.9%, preferably 95% and 96%.
The invention further provides a preparation method of the alprostadil emulsion injection, which comprises the following steps:
(1) adding lecithin, alprostadil, medium chain triglyceride and 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid into oil for injection to form an oil phase;
(2) adding glycerol and glutamic acid into water for injection to form a water phase;
(3) slowly adding the oil phase into the water phase to form primary emulsion;
(4) supplementing water for injection to full dose, and homogenizing under high pressure;
(5) and (4) after filling, heating and sterilizing.
Wherein, the step (1) is to form an oil phase by high-speed shearing dispersion for 1 to 30 minutes, preferably 10, 15, 20 and 25 minutes under a high-shear dispersion emulsifier;
step (2), under a high-shear dispersion emulsifying machine, shearing and dispersing for 1-20 minutes, preferably 10, 15 and 20 minutes, and forming a water phase;
step (3), under a high-shear dispersion emulsifying machine, shearing and dispersing for 1-30 minutes, preferably 10, 15, 20 and 25 minutes to form primary emulsion;
homogenizing for 3 times under high pressure in step (4).
The invention has the beneficial effects that:
1. the injection is nanoemulsion, has the average particle size of between 100 and 130 nanometers, is more stable, and has uniform and stable particle size distribution.
2. Has stable particle size and uniform distribution after sterilization at 121 ℃.
3. Also in vitro plasma mixing experiments, stable particle size and uniform distribution were obtained.
4. The emulsion injection system reduces the oxidative degradation of the oil for injection, and the peroxide value of the emulsion injection system is less than 0.4 after the emulsion injection system is placed at 25 ℃ for 6 months.
5. The emulsion injection system of the invention reduces the generation of lysophospholipid, can be stably stored for 24 months at the temperature of 2-8 ℃, has no obvious hemolysis phenomenon and has small irritation to blood vessels.
6. The emulsion injection has higher encapsulation efficiency, and the encapsulation efficiency and the drug content are relatively stable, and the emulsion injection system effectively controls the degradation of the alprostadil.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1: formula of emulsion injection
Weighing the raw materials according to the formulas in tables 1 and 2, respectively, adding lecithin, alprostadil, medium-chain triglyceride and other fat-soluble components such as oleic acid, phospholipid derivatives, poloxamer and the like into vegetable oil, and then, carrying out high-speed shearing dispersion for 10-20 minutes under a high-shear dispersion emulsifying machine to form an oil phase. Glycerol, amino acid and other water-soluble substances EDTA are added into water for injection, and the mixture is subjected to shear dispersion for 10 minutes under a high-shear dispersion emulsifier to form a water phase. The oil phase was slowly added to the aqueous phase under high shear dispersion, and then high shear dispersion was continued for 20 minutes to form colostrum. Adding injectable water to full volume, homogenizing under high pressure for 3 times, packaging, and sterilizing at 121 deg.C for 12 min.
TABLE 1 compatibility of different injection prescriptions
TABLE 2 compatibility of different injection prescriptions
1.1 emulsion particle size and particle size uniformity
The particle size and particle size distribution of the emulsion were measured by using an L S230 laser particle size analyzer, which measures the particle size and particle size distribution by utilizing the principle that the particles are irradiated with light and are characterized by light scattering and light diffraction, and the principle that the scattering intensity and diffraction intensity of light are related to the particle size and optical characteristics.
TABLE 3 particle size and distribution before and after sterilization
Wherein the polydispersity index is used to measure the uniformity of the particle size distribution of the emulsion, and smaller values indicate that the more uniform and more concentrated the particle size distribution, the smaller the size difference of the particle size. From the above-mentioned test results, it can be found that the emulsion prepared by the formulas 1 to 16 has small particle size and small variation of average particle size before and after sterilization, but the uniform distribution of particle size of each formula has large difference and the uniform distribution of particle size before and after sterilization is also large, compared with other formulas, the emulsion of the formula 1 has concentrated particle size distribution, small particle size difference and still concentrated particle size distribution after heat sterilization.
1.2 in vitro plasma assay
0.2ml of the above emulsion of formula 1-14 was mixed with 0.9ml of human plasma in a microcentrifuge tube, the mixed sample was incubated at 37 ℃ for 6 hours, and the change in particle size before and after incubation was analyzed.
TABLE 4 particle size variation before and after cultivation
| Group of | Primary particle average particle diameter nm | 1 hour after the cultivation | 2 hours after the cultivation | 4 hours after the cultivation | 6 hours after the cultivation |
| Prescription 1 | 118.2 | 129.4 | 140.5 | 151.7 | 162.1 |
| Prescription 2 | 135.1 | 170.8 | 197.4 | 230.4 | 275.9 |
| Prescription 3 | 132.7 | 168.9 | 201.3 | 220.7 | 287.5 |
| Prescription 4 | 152.1 | 181.5 | 210.4 | 258.9 | 301.4 |
| Prescription 5 | 123.4 | 143.8 | 197.6 | 246.7 | 304.6 |
| Prescription 6 | 146.8 | 189.7 | 267.1 | 331.4 | 378.1 |
| Prescription 7 | 158.9 | 205.9 | 258.4 | 314.8 | 365.2 |
| Prescription 8 | 130.4 | 178.5 | 240.7 | 303.5 | 355.7 |
| Prescription 9 | 127.8 | 168.8 | 224.7 | 298.3 | 351.6 |
| Prescription 10 | 128.3 | 170.5 | 218.9 | 287.3 | 347.2 |
| Prescription 11 | 132.8 | 185.6 | 238.4 | 310.7 | 375.4 |
| Prescription 12 | 139.7 | 196.7 | 248.1 | 328.4 | 401.5 |
| Prescription 13 | 150.1 | 208.1 | 274.6 | 347.8 | 411.2 |
| Prescription 14 | 153.4 | 211.8 | 296.4 | 368.4 | 421.4 |
1.3 accelerated stability test
The samples of the prescriptions 1-14 are respectively placed at the temperature of about 25 ℃ for 6 months, and the envelope rate, the content of PGE1, the peroxide value, the sterility condition and other indexes are respectively sampled and detected at the end of 0, 1, 2, 3 and 6 months during the experiment.
The peroxide value measuring method comprises the steps of taking a proper amount of alprostadil emulsion injection, accurately weighing the alprostadil emulsion injection, placing the alprostadil emulsion injection in a 250ml iodine bottle to serve as a test sample, adding 30ml of trichloromethane-glacial acetic acid (2:3, v/v) mixed solution, shaking for dispersion, adding 0.5ml of potassium iodide test solution, shaking for 1 minute, adding 30ml of water, titrating with 0.01 mol/L sodium thiosulfate titration solution, slowly adding the titration solution, sufficiently shaking until the yellow color almost disappears, adding 5ml of starch indicator solution, continuously titrating, sufficiently shaking until the blue color disappears, and simultaneously performing a blank test, wherein in the blank test, the consumption of the sodium thiosulfate titration solution (0.01 mol/L) does not exceed 0.1ml, the peroxide value of the test sample is 10(A-B)/W, A represents the volume of the sodium thiosulfate titration solution (0.01 mol/L) consumed by the test sample, B represents the volume of the sodium thiosulfate titration solution (0.01 mol/L) consumed by the blank test sample, and W represents the weight g and g of the test sample.
Determination of encapsulation efficiency: respectively injecting 20ul of alprostadil reference substance solution into a chromatograph as a reference; and taking 1ml of alprostadil emulsion injection, putting the alprostadil emulsion injection into a 5ml brown measuring flask, fixing the volume by using water, and shaking up. Adding 1ml of the above solution into an ultrafiltration tube (membrane molecular weight cut-off of 50KDa), performing centrifugal ultrafiltration at 4000 × g at 4 deg.C for 45min, injecting 20ul of filtrate into a chromatograph, recording peak area, and calculating the amount (W) of free drug by external standard method; taking 1ml of alprostadil emulsion injection, putting the alprostadil emulsion injection into a 5ml brown measuring flask, fixing the volume by methanol, shaking up, taking 20ul, injecting into a chromatograph, recording the peak area, and calculating the total dosage (W0) according to an external standard method, calculating the encapsulation rate according to the following formula:
EE% (1-W/W0) × 100%; wherein EE represents the encapsulation efficiency.
TABLE 5 accelerated stability test results
TABLE 6 accelerated stability test results (continuation)
Example 2
Prescription:
the preparation method comprises the following steps: weighing the raw materials according to the prescription respectively, adding lecithin, alprostadil, medium chain triglyceride and 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid into soybean oil, and then carrying out high-speed shearing and dispersion for 15 minutes under a high-shear dispersion emulsifying machine to form an oil phase. Adding glycerol and glutamic acid into water for injection, and shearing and dispersing for 15 minutes under a high-shear dispersion emulsifier to form a water phase. The oil phase was slowly added to the aqueous phase under high shear dispersion, and then high shear dispersion was continued for 20 minutes to form colostrum. Adding injectable water into the primary emulsion, homogenizing under high pressure for 3 times, packaging, and sterilizing at 121 deg.C for 15 min.
Example 3
Prescription:
the preparation method comprises the following steps: weighing the raw materials according to the prescription respectively, adding lecithin, alprostadil, medium chain triglyceride and 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid into soybean oil, and then, carrying out high-speed shearing dispersion for 20 minutes under a high-shear dispersion emulsifying machine to form an oil phase. Adding glycerol and glutamic acid into water for injection, and shearing and dispersing for 10 minutes under a high-shear dispersion emulsifier to form a water phase. The oil phase was slowly added to the aqueous phase under high shear dispersion, and then high shear dispersion was continued for 20 minutes to form colostrum. Adding injectable water into the primary emulsion, homogenizing under high pressure for 3 times, packaging, and sterilizing at 121 deg.C for 10 min.
Example 4
Prescription:
the preparation method comprises the following steps: weighing the raw materials according to the prescription respectively, adding lecithin, alprostadil, medium chain triglyceride and 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid into soybean oil, and then carrying out high-speed shearing and dispersion for 15 minutes under a high-shear dispersion emulsifying machine to form an oil phase. Adding glycerol and glutamic acid into water for injection, and shearing and dispersing for 15 minutes under a high-shear dispersion emulsifier to form a water phase. The oil phase was slowly added to the aqueous phase under high shear dispersion, and then high shear dispersion was continued for 20 minutes to form colostrum. Adding injectable water into the primary emulsion, homogenizing under high pressure for 3 times, packaging, and sterilizing at 121 deg.C for 10 min.
Example 5
Prescription:
the preparation method comprises the following steps: weighing the raw materials according to the prescription respectively, adding lecithin, alprostadil, medium chain triglyceride and 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid into soybean oil, and then, carrying out high-speed shearing dispersion for 20 minutes under a high-shear dispersion emulsifying machine to form an oil phase. Adding glycerol and glutamic acid into water for injection, and shearing and dispersing for 10 minutes under a high-shear dispersion emulsifier to form a water phase. The oil phase was slowly added to the aqueous phase under high shear dispersion, and then high shear dispersion was continued for 20 minutes to form colostrum. Adding injectable water into the primary emulsion, homogenizing under high pressure for 3 times, packaging, and sterilizing at 121 deg.C for 15 min.
Example 6
Prescription:
the preparation method comprises the following steps: weighing the raw materials according to the prescription respectively, adding lecithin, alprostadil, medium chain triglyceride and 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid into soybean oil, and then carrying out high-speed shearing and dispersion for 15 minutes under a high-shear dispersion emulsifying machine to form an oil phase. Adding glycerol and glutamic acid into water for injection, and shearing and dispersing for 15 minutes under a high-shear dispersion emulsifier to form a water phase. The oil phase was slowly added to the aqueous phase under high shear dispersion, and then high shear dispersion was continued for 20 minutes to form colostrum. Adding injectable water into the primary emulsion, homogenizing under high pressure for 3 times, packaging, and sterilizing at 121 deg.C for 10 min.
Example 7
Prescription:
the preparation method comprises the following steps: weighing the raw materials according to the prescription respectively, adding lecithin, alprostadil, medium chain triglyceride and 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid into soybean oil, and then carrying out high-speed shearing and dispersion for 15 minutes under a high-shear dispersion emulsifying machine to form an oil phase. Adding glycerol and glutamic acid into water for injection, and shearing and dispersing for 15 minutes under a high-shear dispersion emulsifier to form a water phase. The oil phase was slowly added to the aqueous phase under high shear dispersion, and then high shear dispersion was continued for 20 minutes to form colostrum. Adding injectable water into the primary emulsion, homogenizing under high pressure for 3 times, packaging, and sterilizing at 121 deg.C for 15 min.
Experimental example 1
Long term stability study
The sample obtained from formulation 1 of example 1 was placed in a constant temperature and humidity environment at 2-8 ℃ for 24 months, and the average particle size, content and encapsulation efficiency were examined for changes, respectively, and the results are shown in Table 7.
TABLE 7 Long term stability results
| Test item | 0 month | 3 month | 6 month | 12 month | 18 months | 24 months |
| Average particle diameter of nm | 118.2 | 121.3 | 124.6 | 126.9 | 127.2 | 128.4 |
| Content% | 100.4 | 99.2 | 99.1 | 99.4 | 98.6 | 97.6 |
| Encapsulation efficiency% | 98.7 | 97.9 | 96.8 | 95.7 | 94.9 | 94.5 |
The above results show that the emulsion injection of the present invention can be stably stored at 2 to 8 ℃ for 24 months.
Experimental example 2 Special safety experiment
The blood vessel stimulation experiment comprises the steps of respectively fixing 8 healthy rabbits in a rabbit box, randomly dividing the rabbits into 2 groups, respectively dripping sodium chloride injection and the emulsion injection with the formula 1 into the left ear vein of 4 rabbits in each group, wherein the dripping speed is 2.8m L & min & lt-1 & gt, the static dripping amount of the rabbits is 25m L & kg & lt-1 & gt, dripping the mixture for 1 time every day for 3 days continuously, observing the ear vein stimulation reaction of the rabbits, and compared with the sodium chloride injection group, the ear vein of the 4 rabbits in the formula 1 has the advantages that the tube wall is complete, blood vessels are not obviously expanded, the tube wall and the periphery are not infiltrated by obvious inflammatory cells, and pathological changes such as thrombosis and the like are not seen in the tube wall.
Hemolytic test: after the formulations 1 to 9 of example 1 were left to stand in a constant temperature and humidity environment of 2 to 8 ℃ for 24 months, the hemolytic conditions were examined, respectively, and the phospholipid components therein may be further degraded into lysophospholipids and other degradation products may cause hemolysis during the storage. Preparing 2% erythrocyte suspension with 0.9% sodium chloride injection, using 0.9% sodium chloride solution as blank control group, using distilled water group as positive control group, and observing results after incubation for 0.5, 1, 2 and 3 hours at 37 ℃. And (4) judging the result: total hemolysis: the solution is clear red, and no cell residue exists at the bottom of the tube; partial hemolysis: the solution is clear red or brownish red, and a small amount of red blood cells are arranged at the bottom of the tube; has no hemolysis, red blood cells are all sunk, and supernatant fluid is milky white.
TABLE 8 Long term stability results
Therefore, the alprostadil emulsion injection of the invention has better medication safety.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.
Claims (8)
1. An alprostadil emulsion injection is characterized in that the injection is prepared from alprostadil, glutamic acid, lecithin, 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid, oil for injection, medium chain triglyceride, glycerol and water for injection; every 1000ml of injection contains 0.1-10mg of alprostadil, 80-150 g of oil for injection, 10-30g of medium chain triglyceride, 10-20 g of lecithin, 0.1-3 g of 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid, 0.1-3 g of glutamic acid, 10-30g of glycerol and water for injection; the lecithin is selected from egg yolk lecithin or soybean lecithin, and the injection is sterilized by heating.
2. The alprostadil emulsion injection of claim 1, wherein the oil for injection is selected from one or more of soybean oil, sesame oil or peanut oil.
3. The alprostadil emulsion injection according to claim 1, wherein the weight ratio of glutamic acid to 1, 2-dioleoyl-sn-glycero-3-phosphatidic acid is 1: 1.
4. The alprostadil emulsion injection according to claim 1, which comprises 5mg of alprostadil, 100g of oil for injection, 20g of medium chain triglyceride, 15g of lecithin, 1g of 1, 2-dioleoyl-sn-glycerol-3-phosphatidic acid, 1g of glutamic acid and 20g of glycerol per 1000ml of injection, and the volume of water for injection is increased to 1000 ml.
5. The alprostadil emulsion injection of claim 1, wherein after heat sterilization, the average particle size is between 105 and 130 nm; the polydispersity index of the particle size is between 0.1 and 0.2.
6. The alprostadil emulsion injection of claim 1, wherein the heat sterilization is sterilization at 121 ℃ for 10-15 minutes.
7. The alprostadil emulsion injection of claim 1, wherein the peroxide number is less than 0.4 after 3 months at 25 ℃.
8. The alprostadil emulsion injection of claim 1, wherein the injection is placed in a constant temperature and humidity environment of 2-8 ℃ for 24 months, and the content of the alprostadil is 95-99.9%.
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