CN110721155B - Long-acting drug-loaded fat emulsion preparation and preparation method thereof - Google Patents
Long-acting drug-loaded fat emulsion preparation and preparation method thereof Download PDFInfo
- Publication number
- CN110721155B CN110721155B CN201810703107.0A CN201810703107A CN110721155B CN 110721155 B CN110721155 B CN 110721155B CN 201810703107 A CN201810703107 A CN 201810703107A CN 110721155 B CN110721155 B CN 110721155B
- Authority
- CN
- China
- Prior art keywords
- oil
- emulsion
- injection
- preparation
- lecithin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Abstract
The invention discloses a long-acting drug-loaded fat emulsion preparation which comprises, by mass, 0.5-10% of phospholipid or fatty acid of polyethylene glycol, 0.6-20% of emulsifier, 0.5-10% of solubilizer, 0-6% of co-emulsifier, 8-30% of oil for injection, 2-8% of isotonic agent and the balance of water for injection. The fat emulsion preparation prepared by the invention changes the prescription, reduces the particle size, is suitable for the medicine which is easy to damage at high temperature, increases the step of dissolving the solvent, and is suitable for the medicine which can be dissolved in the solvent and is difficult to dissolve in water or oil; the phospholipid or fatty acid of the polyethylene glycol is increased, and the in vivo long-acting effect is generated. The stability of the injection is improved, the drug effect of the preparation is improved, the safety of the medicine is ensured, the preparation process is simpler, the time and the cost are saved, and the injection is suitable for large-scale production. In addition, the formula composition and the preparation method of the fat emulsion are obtained through scientific screening, so that beneficial effects are produced.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to long-acting medicine-carrying fat emulsion and a preparation method thereof.
Background
Intravenous injection is a rapid and effective administration mode, and the medicine entering the body does not pass through the gastrointestinal tract and is not influenced by digestive juice and food, so the effect is reliable and rapid. However, due to the particularity of the administration route, the intravenous injection not only has strict limitations on the excipients, but also requires good solubility, and thus, the development of the hydrophobic drug injection has certain difficulty and challenge. At present, whether the monomer compound obtained by separating and purifying natural medicines or the synthetic medicines obtained by synthesis, the solubility of most medicines is lower than 0.1mg/L, and the implementation of injection administration is prevented due to the limitation of the solubility of the medicines. The main methods for improving the dissolution problem of drugs in intravenous injections are: the mixed solvent method is used for preparing micelle and liposome, cyclodextrin inclusion compound, o/w type intravenous injection emulsion and the like. However, the main disadvantage of using mixed solvents is that the organic solutions used are mostly toxic; the research on the preparation of the micelle is more at present, but the preparation is the micelle in vitro, and the structure of the micelle can be changed due to the dilution of blood when the preparation is injected into the body, so that the aim of designing the preparation cannot be achieved by destroying the micelle; the liposome preparation process is complex, and the actual large-scale production has certain difficulty and high cost; and the cyclodextrin inclusion auxiliary material can cause adverse reaction, splenomegaly, ataxia and the like.
The O/W type intravenous injection emulsion is started from the research and development of nutritional type intravenous injection emulsion, is firstly used as a safe energy supply agent, and is successfully developed into intravenous fat emulsion Intralipid in Sweden in 1962, so that the preparation is widely applied. With the increasing need of clinical treatment and the intensive research of related research, the intravenous injection emulsion is also increasingly widely used as a drug carrier, especially for a poorly soluble drug. Poorly soluble drugs often have a certain lipophilicity, and are dispersed in a dispersion of microparticles, which are dissolved or solubilized in a suitable oil phase, using fatty oils as a matrix, and encapsulated by a phospholipid membrane. Medicated fat emulsions have a number of unique advantages: the solubility of the fat-soluble medicine is improved, and the preparation is suitable for preparing the insoluble medicine into a preparation type for injection administration; the emulsion has small drug toxicity and good safety due to the wrapping effect on the drug; the process is simple, and the industrialized mass production is feasible; the preparation can resist high pressure steam sterilization; the drug loading can reduce the irritation of intravenous administration to blood vessels; the used auxiliary materials for injection mainly comprise refined vegetable oil and lecithin, and are higher than liposomes for human. Therefore, the drug-containing fat emulsion has wide application prospect as a novel drug delivery carrier. At present, various medicament-carrying fat emulsion preparations are sequentially marketed at home and abroad, the clinical curative effect is good, and the main varieties comprise alprostadil E1, diazepam, perfluorocarbon, propofol, etomidate, amphotericin, acyclovir, tirapazate, paclitaxel, coix seed oil, brucea javanica oil and the like. In order to further improve the stability of the fat emulsion, expand the drug loading range and develop a novel emulsifier, pharmaceutical researchers have conducted many studies with great effect in recent years, and the development of the drug-loaded fat emulsion is promoted.
The prior medicine carrying prescription solves the problem of difficult-soluble medicines, and has complex treatment process, for example, the SolEmul technology needs to micronize the main medicines and then homogenize the main medicines with prepared blank fat emulsion under high pressure, so that the emulsion is easily mixed unevenly or the layering phenomenon is generated. In addition, the retention time of the common fat emulsion drug carrier in blood is short, and most fat emulsions are enriched in macrophages and reticulocytes, so that the drug dosage is increased, and additional side effects are caused to patients with hyperlipidemia and liver insufficiency. In order to effectively solve the problem, vitamin E and sodium bisulfite are added into the prescription of the preparation as antioxidants, but the vitamin E and the sodium bisulfite can still be degraded after being placed for a long time. Chinese patent 200710017684.6 discloses a high-stability long-circulation fat emulsion drug-loaded preparation for intravenous injection, wherein the prescription contains vitamin E as antioxidant, although the antioxidant is added to prolong the shelf life of the medicine, the medicine can be degraded after long-term storage, and the drug-loaded prescription of the patent is difficult to solve the problem of the medicine which can be dissolved in solvent and is difficult to dissolve in water or oil; in addition, high temperature sterilization is required in order to ensure the sterility requirement in the production process, and the high temperature condition aggravates the instability of the product quality, thereby causing the quality control of the product in the production and storage processes to be difficult.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a long-acting drug-loaded fat emulsion preparation and a preparation method thereof.
In order to realize the purpose, the technical scheme is as follows:
the long-acting drug-loaded fat emulsion preparation comprises, by mass, 0.5-10% of phospholipid or fatty acid of polyethylene glycol, 0.6-20% of an emulsifier, 0.5-10% of a solubilizer, 0-6% of an auxiliary emulsifier, 8-30% of oil for injection, 2-8% of an isotonic agent and the balance of water for injection.
Preferably, the phospholipid or fatty acid of the polyethylene glycol is one of a polyethylene glycol-cholesterol derivative, a polyethylene glycol fatty acid ester derivative and a polyethylene glycol fatty acid glyceride derivative. The phospholipid of the polyethylene glycol or the phospholipid of the derivative in the fatty acid has fat solubility and can be well matched with the vegetable oil, so that the polyethylene glycol is coated on the surface of the fat emulsion. The phospholipid or fatty acid of the polyethylene glycol can increase the retention time of the drug in blood to generate the effect of long-acting in vivo, thereby solving the problem of short retention time of the common drug-loaded fat emulsion drug carrier in blood.
Preferably, the emulsifier is a mixture of lecithin PC and phosphatidylglycerol PG or phosphatidylserine PS, and the phospholipid PC is selected from one of dioleoyl lecithin DOPC, dimyristoyl lecithin DMPC, distearoyl phosphatidylcholine DSPC, dicaprylyl lecithin DEPC, dipalmitoyl lecithin DPPC, hydrogenated soybean lecithin HSPC; the phosphatidyl glycerol PG is one of dioleoyl phosphatidyl glycerol DOPG, dipalmitoyl phosphatidyl glycerol DPPG, egg yolk phosphatidyl glycerol EPG and distearoyl phosphatidyl glycerol DSPG; phosphatidylserine PS is dimyristoyl lecithin DMPC.
Preferably, the solubilizer is one of absolute ethyl alcohol, dichloromethane and diethyl ether.
Preferably, the coemulsifier is one of sodium oleate, potassium oleate and oleic acid.
Preferably, the oil for injection is a mixture of soybean oil, chinaroot greenbrier seed oil and ganoderma lucidum spore oil.
The meadowfoam seed oil is the most stable vegetable oil in nature, the meadowfoam seed oil contains 18 percent of docosadienoic acid C22:2, docosahexaenoic acid is DHA necessary for human bodies, C22:2 is omega-6, the effect on the human bodies is greater than that of C18:1, and the carbon chain of C22:2 is longer than that of C18: 1. The white Potentilla seed oil mainly contains unsaturated higher alcohol and fatty acid, and has good stability and excellent oxidation resistance. In addition, the meadowfoam seed oil also contains abundant vitamins; the ganoderma lucidum spores are spores continuously released from the lower part of a pileus in the mature period of the ganoderma lucidum; the Ganoderma spore oil is a hydrophobic oil substance extracted from Ganoderma spore, and mainly contains fatty acid, sterol, terpenes, vitamins, etc. Has great advantages in improving immunity and resisting tumor in vegetable oil. The soybean oil contains 7-10% of palmitic acid, 2-5% of stearic acid, 1-3% of arachidic acid, 22-30% of oleic acid, 50-60% of linoleic acid and 5-9% of linoleic acid. The soybean oil has good fatty acid composition, contains rich linoleic acid, has obvious effects of reducing serum cholesterol content and preventing cardiovascular diseases, contains a large amount of vitamin E, vitamin D and rich lecithin, and is very beneficial to human health. In addition, the human body digestibility of the soybean oil is as high as 98%, so the soybean oil is also an excellent edible oil with high nutritive value. However, the soybean oil has poor oxidation resistance, and is mixed with the meadowfoam seed oil and the ganoderma lucidum spore oil to form the composite vegetable oil, so that the stability of the fat emulsion can be effectively improved, and the meadowfoam seed oil can replace an antioxidant to play an oxidation resistance role, so that the use of the antioxidant is reduced.
Preferably, the mass ratio of the soybean oil to the meadowfoam seed oil to the ganoderma lucidum spore oil is 2:1: 1.
In a large number of experiments, the applicant unexpectedly finds that the prepared fat emulsion preparation is most stable when the mass ratio of the soybean oil to the meadowfoam seed oil to the ganoderma lucidum spore oil is 2:1: 1.
Preferably, 10% of polyethylene glycol fatty acid ester derivative, 5% of dimyristoyl lecithin DMPC, 7% of egg yolk phosphatidyl glycerol EPG, 10% of diethyl ether, 2% of oleic acid, 10% of soybean oil, 5% of white pond flower seed oil, 5% of ganoderma lucidum spore oil, 8% of sucrose, and water for injection are added to 100%. The applicant has found, surprisingly in a large number of experiments, that, at this specific weight ratio, the effect of the composition of the invention is optimal,
the preparation method of the long-acting drug-loaded fat emulsion preparation is characterized by comprising the following steps:
1) dissolving the insoluble drug in solubilizer, mixing with emulsifier, phospholipid or fatty acid of polyethylene glycol, and oil for injection, and rotary evaporating under reduced pressure at 30-45 deg.C to remove solubilizer; continuously stirring for 1-5min under 50-100KHz water bath ultrasonic condition to dissolve to form oil phase, and keeping temperature in 40-70 deg.C water bath;
2) and (3) mixing the isotonic agent, the co-emulsifier and the water for injection at 40-80 ℃ to form a water phase mixture.
3) Mixing the water phase mixture obtained in the step 2 with the oil phase mixture obtained in the step 1 under the protection of nitrogen, then dispersing at a high speed for 5-30min at the temperature of 40-70 ℃ under the condition of 6500-24000rpm, adjusting the pH to 6.0-9.0 by using 0.1mol/L NaOH or HCL, and homogenizing for 1-2 times under the pressure of 90-110 MPa to obtain uniform primary emulsion;
4) repeatedly homogenizing the primary emulsion for 3-20 times at 3-18 Kpsi pressure by microfluidizer to obtain final emulsion;
5) sealing by fusing and sterilizing: passing the final emulsion through 0.22-0.8 μm microporous filter membrane, subpackaging in ampoule bottle, charging nitrogen gas, sealing, and sterilizing at 100-121 deg.C for 15-30min to obtain fat emulsion.
Has the advantages that:
1. the fat emulsion preparation prepared by the invention changes the prescription, reduces the particle size, is suitable for the medicine which is easy to damage at high temperature, increases the step of dissolving the solvent, and is suitable for the medicine which can be dissolved in the solvent and is difficult to dissolve in water or oil; the phospholipid or fatty acid of the polyethylene glycol is increased, and the in vivo long-acting effect is generated.
2. The invention improves the stability of the injection, improves the drug effect of the preparation, ensures the safety of the medicine, has simpler preparation process, saves time and cost, and is suitable for large-scale production. In addition, the formula composition and the preparation method of the fat emulsion are obtained through scientific screening, so that beneficial effects are produced.
Detailed Description
The present invention will be further described with reference to the following examples. It should be understood that the following examples are illustrative only and are not intended to limit the scope of the present invention. Therefore, all equivalent changes or modifications made according to the principle of the method described in the claims of the present invention are included in the scope of the present invention.
The invention discloses a long-acting drug-loaded fat emulsion preparation which comprises, by mass, 0.5-10% of phospholipid or fatty acid of polyethylene glycol, 0.6-20% of emulsifier, 0.5-10% of solubilizer, 0-6% of co-emulsifier, 8-30% of oil for injection, 2-8% of isotonic agent and the balance of water for injection.
The water for injection of the invention is realized by adopting the prior art, and refers to water which meets the requirements specified in the Chinese pharmacopoeia water for injection.
The phospholipid or fatty acid of the polyethylene glycol is one of polyethylene glycol-cholesterol derivative, polyethylene glycol fatty acid ester derivative and polyethylene glycol fatty glyceride derivative;
the emulsifier is a mixture of lecithin PC and phosphatidylglycerol PG or phosphatidylserine PS, and the phospholipid PC is one of dioleoyl lecithin DOPC, dimyristoyl lecithin DMPC, distearoyl phosphatidylcholine DSPC, dicaprylyl lecithin DEPC, dipalmitoyl lecithin DPPC and hydrogenated soybean lecithin HSPC; the phosphatidyl glycerol PG is one of dioleoyl phosphatidyl glycerol DOPG, dipalmitoyl phosphatidyl glycerol DPPG, egg yolk phosphatidyl glycerol EPG and distearoyl phosphatidyl glycerol DSPG; phosphatidylserine PS is dimyristoyl lecithin DMPC.
The solubilizer is one of ethanol, dichloromethane and diethyl ether;
the auxiliary emulsifier is one of sodium oleate, potassium oleate and oleic acid;
the oil for injection is a mixture of soybean oil, chinaroot greenbrier seed oil and ganoderma lucidum spore oil;
the isotonic agent is sucrose.
The invention also provides a preparation method of the long-acting drug-loaded fat emulsion preparation, which comprises the following steps:
1) dissolving the insoluble drug in solubilizer, mixing with emulsifier, phospholipid or fatty acid of polyethylene glycol, and oil for injection, and rotary evaporating under reduced pressure at 30-45 deg.C to remove solubilizer; continuously stirring for 1-5min under 50-100KHz water bath ultrasonic condition to dissolve to form oil phase, and keeping temperature in 40-70 deg.C water bath;
2) and (3) mixing the isotonic agent, the co-emulsifier and the water for injection at 40-80 ℃ to form a water phase mixture.
3) Mixing the water phase mixture obtained in the step 2 with the oil phase mixture obtained in the step 1 under the protection of nitrogen, then dispersing at a high speed for 5-30min at the temperature of 40-70 ℃ under the condition of 6500-24000rpm, adjusting the pH to 6.0-9.0 by using 0.1mol/L NaOH or HCL, and homogenizing for 1-2 times under the pressure of 90-110 MPa to obtain uniform primary emulsion;
4) repeatedly homogenizing the primary emulsion for 3-20 times at 3-18 Kpsi pressure by microfluidizer to obtain final emulsion;
5) sealing by fusing and sterilizing: passing the final emulsion through 0.22-0.8 μm microporous filter membrane, subpackaging in ampoule bottle, charging nitrogen gas, sealing, and sterilizing at 100-121 deg.C for 15-30min to obtain fat emulsion.
Example 1
The composition of the ingredients is shown in table 1:
the preparation method of the long-acting drug-loaded fat emulsion preparation comprises the following steps:
1) dissolving magnolol in anhydrous alcohol, mixing with dioleoyl lecithin DOPC, dioleoyl phosphatidyl glycerol DOPG, polyethylene glycol-cholesterol derivative, soybean oil, white chingma flower seed oil, and Ganoderma spore oil, and removing solubilizer by rotary evaporation under reduced pressure at 30 deg.C; continuously stirring for 2min under 50KHz water bath ultrasonic condition to dissolve to form oil phase, and keeping temperature in 40 deg.C water bath for use;
2) sucrose, sodium oleate and water for injection were mixed at 40 ℃ to form an aqueous mixture.
3) Mixing the water phase mixture obtained in the step 2 with the oil phase mixture obtained in the step 1 under the protection of nitrogen, dispersing at high speed for 30min at the temperature of 40 ℃ under the condition of 6500rpm, adjusting the pH to 6.0 by using 0.1mol/L NaOH or HCL, and homogenizing for 1 time under the pressure of 90MPa to obtain uniform primary emulsion;
4) repeatedly homogenizing the primary emulsion for 20 times under 3Kpsi pressure by using a microfluidizer to obtain final emulsion;
5) sealing by fusing and sterilizing: sieving the final emulsion with 0.22 μm microporous membrane, subpackaging in ampoule bottle, charging nitrogen gas, sealing, and sterilizing at 100 deg.C for 30min to obtain fat emulsion.
And (3) stability testing: the stability determination method adopts freshly prepared fat emulsion, the fat emulsion is placed in a centrifuge tube with a plug, and after the fat emulsion is centrifuged at 4000rpm for 15min, no layering is found, and no drug precipitation is found. The emulsion is stored in shade at room temperature for one year, and the physicochemical properties such as the appearance, the grain diameter, the Zeta potential and the like and the content of the emulsion are not obviously changed, which shows that the emulsion is stable.
And (3) particle size testing: pH value of fat emulsion intravenous injection: 6.7, size and range of milk particles: the average particle size of the emulsion is less than 1 μm, 15% of the emulsion has a particle size of less than 100nm, 65% of the emulsion has a particle size of less than 350nm, and 99% of the emulsion has a particle size of less than 600 nm. Meets the relevant requirements of the fat emulsion for intravenous injection.
Example 2
The composition of the ingredients is shown in table 2:
the preparation method of the long-acting drug-loaded fat emulsion preparation comprises the following steps:
1) dissolving nimodipine as insoluble drug in dichloromethane, mixing with dimyristoyl lecithin DMPC, polyethylene glycol fatty acid ester derivative, soybean oil, white chinaberry seed oil and Ganoderma spore oil, and removing solubilizer by rotary evaporation under reduced pressure at 45 deg.C; continuously stirring for 1min under 100KHz water bath ultrasonic condition to dissolve to form oil phase, and keeping temperature in 70 deg.C water bath for use;
2) sucrose, co-emulsifier and water for injection were mixed at 80 ℃ to form an aqueous mixture.
3) Mixing the water phase mixture obtained in the step 2 with the oil phase mixture obtained in the step 1 under the protection of nitrogen, then dispersing at high speed for 5min at the condition of 24000rpm at 70 ℃, adjusting the pH to 6.8 by using 0.1mol/L NaOH or HCL, and homogenizing for 2 times under the condition of 110MPa of pressure to obtain uniform primary emulsion;
4) repeatedly homogenizing the primary emulsion for 3 times under 18Kpsi pressure by using a microfluidizer to obtain final emulsion;
5) sealing by fusing and sterilizing: sieving the final emulsion with 0.8 μm microporous membrane, subpackaging in ampoule bottle, charging nitrogen gas, sealing, and sterilizing at 121 deg.C for 15min to obtain fat emulsion.
And (3) stability testing: the stability determination method adopts freshly prepared fat emulsion, the fat emulsion is placed in a centrifuge tube with a plug, and after the fat emulsion is centrifuged at 4000rpm for 15min, no layering is found, and no drug precipitation is found. The emulsion is stored in shade at room temperature for one year, and the physicochemical properties such as the appearance, the grain diameter, the Zeta potential and the like and the content of the emulsion are not obviously changed, which shows that the emulsion is stable.
And (3) particle size testing: pH value of fat emulsion intravenous injection: 6.8, size and range of milk particles: the average particle size of the emulsion is less than 1 μm, 15% of the emulsion has a particle size of less than 100nm, 70% of the emulsion has a particle size of less than 350nm, and 98% of the emulsion has a particle size of less than 600 nm. Meets the relevant requirements of the fat emulsion for intravenous injection.
Example 3
The composition is shown in table 3:
the preparation method of the long-acting drug-loaded fat emulsion preparation comprises the following steps:
1) dissolving the slightly soluble medicine artesunate in diethyl ether, mixing with dimyristoyl lecithin DMPC, egg yolk phosphatidyl glycerol EPG, polyethylene glycol fatty acid ester derivative, soybean oil, white Potentilla seed oil, and Ganoderma spore oil, and rotary evaporating at 35 deg.C under reduced pressure to remove diethyl ether; continuously stirring for 3min under 80KHz water bath ultrasonic condition to dissolve to form oil phase, and keeping temperature in 50 deg.C water bath for use;
2) sucrose, oleic acid and water for injection were mixed at 50 ℃ to form an aqueous mixture.
3) Mixing the water phase mixture obtained in the step 2 with the oil phase mixture obtained in the step 1 under the protection of nitrogen, dispersing at high speed for 30min at 50 ℃ under the condition of 6500rpm, adjusting the pH to 9.0 by using 0.1mol/L NaOH or HCL, and homogenizing for 1 time under the condition of 110MPa of pressure to obtain uniform primary emulsion;
4) repeatedly homogenizing the primary emulsion for 10 times under 10Kpsi pressure by using a microfluidizer to obtain final emulsion;
5) sealing by fusing and sterilizing: sieving the final emulsion with 0.3 μm microporous membrane, subpackaging in ampoule bottle, charging nitrogen gas, sealing, and sterilizing at 100 deg.C for 15min to obtain fat emulsion.
Stability test the stability determination method is to adopt the freshly prepared fat emulsion, place in a centrifuge tube with a plug, and centrifuge at 4000rpm for 15min, and no layering is found, and no drug precipitation is found. The emulsion is stored in shade at room temperature for one year, and the physicochemical properties such as the appearance, the grain diameter, the Zeta potential and the like and the content of the emulsion are not obviously changed, which shows that the emulsion is stable.
And (3) particle size testing: the pH value of the fat emulsion oral liquid is as follows: 9.0, size and range of milk particles: the average particle size of the emulsion is less than 1 μm, 14% of the emulsion has a particle size of less than 100nm, 65% of the emulsion has a particle size of less than 350nm, and 99% of the emulsion has a particle size of less than 600 nm. Meets the relevant requirements of the fat emulsion for intravenous injection.
Example 4
The composition is shown in table 4:
the preparation method of the long-acting drug-loaded fat emulsion preparation comprises the following steps:
1) dissolving the slightly soluble drug of docetaxel in absolute ethanol, mixing with dicaprylyl lecithin DEPC, distearoyl phosphatidyl glycerol DSPG, polyethylene glycol fatty acid ester derivatives, soybean oil, chingma seed oil and ganoderma lucidum spore oil, and performing reduced pressure rotary evaporation at 45 ℃ to remove the solubilizer; continuously stirring for 1min under 100KHz water bath ultrasonic condition to dissolve to form oil phase, and keeping temperature in 40 deg.C water bath for use;
2) sucrose, sodium oleate and water for injection were mixed at 80 ℃ to form an aqueous mixture.
3) Mixing the water phase mixture obtained in the step 2 with the oil phase mixture obtained in the step 1 under the protection of nitrogen, then dispersing at high speed for 10min at the condition of 24000rpm at 70 ℃, adjusting the pH to 7.5 by using 0.1mol/L NaOH or HCL, and homogenizing for 2 times under the condition of 110MPa of pressure to obtain uniform primary emulsion;
4) repeatedly homogenizing the primary emulsion for 3 times under 18Kpsi pressure by using a microfluidizer to obtain final emulsion;
5) sealing by fusing and sterilizing: sieving the final emulsion with 0.22 μm microporous membrane, subpackaging in ampoule bottle, charging nitrogen gas, sealing, and sterilizing at 121 deg.C for 15min to obtain fat emulsion.
And (3) stability testing: the stability determination method adopts freshly prepared fat emulsion, the fat emulsion is placed in a centrifuge tube with a plug, and after the fat emulsion is centrifuged at 4000rpm for 15min, no layering is found, and no drug precipitation is found. The emulsion is stored in shade at room temperature for one year, and the physicochemical properties such as the appearance, the grain diameter, the Zeta potential and the like and the content of the emulsion are not obviously changed, which shows that the emulsion is stable.
And (3) particle size testing: the pH value of the fat emulsion oral liquid is as follows: 6.8, size and range of milk particles: the average particle size of the emulsion is less than 1 μm, 9.5% of the emulsion has a particle size of less than 100nm, 53% of the emulsion has a particle size of less than 350nm, and 96% of the emulsion has a particle size of less than 600 nm. Meets the relevant requirements of the fat emulsion for intravenous injection.
Example 5
The composition is shown in table 5:
the preparation method of the long-acting drug-loaded fat emulsion preparation comprises the following steps:
1) dissolving the slightly soluble drug dicoumarin in anhydrous ethanol, mixing with hydrogenated soybean lecithin HSPC, distearoyl phosphatidyl glycerol DSPG, polyethylene glycol-cholesterol derivative, soybean oil, chingma chinensis seed oil and Ganoderma spore oil, and removing solubilizer by rotary evaporation under reduced pressure at 40 deg.C; continuously stirring for 5min under 80KHz water bath ultrasonic condition to dissolve to form oil phase, and keeping temperature in 60 deg.C water bath for use;
2) sucrose, sodium oleate and water for injection were mixed at 60 ℃ to form an aqueous mixture.
3) Mixing the water phase mixture obtained in the step 2 with the oil phase mixture obtained in the step 1 under the protection of nitrogen, then dispersing at high speed for 10min at 60 ℃ under the condition of 20000rpm, adjusting the pH value to 6.0 by 0.1mol/L NaOH or HCL, and homogenizing for 1 time under the condition of 90MPa of pressure to obtain uniform primary emulsion;
4) repeatedly homogenizing the primary emulsion for 20 times under 10Kpsi pressure by using a microfluidizer to obtain final emulsion;
5) sealing by fusing and sterilizing: sieving the final emulsion with 0.8 μm microporous membrane, subpackaging in ampoule bottle, charging nitrogen gas, sealing, and sterilizing at 121 deg.C for 30min to obtain fat emulsion.
And (3) stability testing: the stability determination method adopts freshly prepared fat emulsion, the fat emulsion is placed in a centrifuge tube with a plug, and after the fat emulsion is centrifuged at 4000rpm for 15min, no layering is found, and no drug precipitation is found. The emulsion is stored in shade at room temperature for one year, and the physicochemical properties such as the appearance, the grain diameter, the Zeta potential and the like and the content of the emulsion are not obviously changed, which shows that the emulsion is stable.
And (3) particle size testing: pH value of fat milk: 6.0, size and range of milk particles: the average particle size of the emulsion is less than 1 μm, the particle size of 10% of the emulsion is less than 10nm, the particle size of 50% of the emulsion is less than 350nm, and the particle size of 98% of the emulsion is less than 600 nm. Meets the relevant requirements of the fat emulsion for intravenous injection.
Comparative example 1
This comparative example is different from example 3 in that the oil for injection therein is 20 wt% of soybean oil.
Comparative example 2
The comparative example is different from example 3 in that the oil for injection is 10 wt% of soybean oil and 10 wt% of ganoderma lucidum spore oil.
Effect example 1
The fat emulsion preparations prepared in examples 1 to 5 of the present invention and comparative examples 1 to 2 were subjected to an accelerated stability test according to the guidelines on stability tests in the "second part of the chinese pharmacopoeia 2005 edition". The samples were placed in a constant temperature and humidity chamber at 40 ℃ and 75% relative humidity for 1, 2, 3 and 6 months, respectively, and the results are shown in Table 6:
as can be seen from Table 6, the clarity of comparative examples 1 to 2 does not meet the specification at 6 months acceleration, the pH value is obviously reduced, the content is also reduced, and the related substances are increased; however, the appearance of the 5 embodiments of the invention is not obviously changed, the solution is a milky clear solution, and the pH value, the content and related substances are not obviously changed. The stability of the samples prepared according to the invention is better.
Effect example 2
The effect example considers the influence of the mass ratio of soybean oil, chinaroot greenbrier seed oil and ganoderma lucidum spore oil on the stability of the fat emulsion prepared by the invention, and we prepared the fat emulsion preparation according to the method of the example 1, wherein the components comprise, by mass, 0.5-10% of phospholipid or fatty acid of polyethylene glycol, 0.6-20% of emulsifier, 0.5-10% of solubilizer, 0-6% of co-emulsifier, 8-30% of oil for injection, 2-8% of isotonic agent and the balance of water for injection. The quality ratios of soybean oil, chinaroot greenbrier seed oil and ganoderma lucidum spore oil are shown in table 7:
stability determination test
The fat milks prepared in experimental groups 1 to 4 were stored under refrigeration and protection from light for 10 months, sampled at 0 th, 1 st, 2 nd, 3 th, 6 th, 8 th, and 10 th months, examined for their average particle diameter during storage, Zeta potential. The results are shown in Table 8:
TABLE 8 stability test results
It is seen from table 8 that the fat emulsion prepared by the invention is stored for a long time under the conditions of refrigeration and light shielding, the particle size and Zeta potential of the fat emulsion prepared by the experimental groups 1 to 4 are not significantly changed, and when the mass ratio of the soybean oil to the meadowfoam seed oil to the ganoderma lucidum spore oil is 2:1:1, the change is minimum, which indicates the most stable.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (1)
1. A preparation method of a long-acting drug-loaded fat emulsion preparation is characterized by comprising the following steps:
1) dissolving the insoluble drug in solubilizer, mixing with emulsifier, phospholipid or fatty acid of polyethylene glycol, and oil for injection, and rotary evaporating under reduced pressure at 30-45 deg.C to remove solubilizer; continuously stirring for 1-5min under 50-100KHz water bath ultrasonic condition to dissolve to form oil phase, and keeping temperature in 40-70 deg.C water bath;
2) mixing an isotonic agent, an auxiliary emulsifier and water for injection at 40-80 ℃ to form a water phase mixture;
3) mixing the water phase mixture obtained in the step 2) with the oil phase mixture obtained in the step 1 under the protection of nitrogen, then dispersing at a high speed for 5-30min at the temperature of 40-70 ℃ under the condition of 6500-24000rpm, adjusting the pH to 6.0-9.0 by using 0.1mol/L NaOH or HCL, and homogenizing for 1-2 times under the pressure of 90-110 MPa to obtain uniform primary emulsion;
4) repeatedly homogenizing the primary emulsion for 3-20 times at 3-18 Kpsi pressure by microfluidizer to obtain final emulsion;
5) sealing by fusing and sterilizing: passing the final emulsion through 0.22-0.8 μm microporous filter membrane, subpackaging in ampoule bottle, charging nitrogen gas, sealing, sterilizing at 100-121 deg.C for 15-30min to obtain fat emulsion;
wherein, except for the insoluble medicine, the other components are calculated according to the mass percentage: 0.5-10% of phospholipid or fatty acid of polyethylene glycol, 0.6-20% of emulsifier, 0.5-10% of solubilizer, 0-6% of co-emulsifier, 8-30% of oil for injection, 2-8% of isotonic agent and the balance of water for injection; the oil for injection is a mixture of soybean oil, chinaroot greenbrier seed oil and ganoderma lucidum spore oil, wherein the mass ratio of the soybean oil to the chinaroot greenbrier seed oil to the ganoderma lucidum spore oil is as follows: white Potentilla seed oil: ganoderma lucidum spore oil is 2:1: 1;
the emulsifier is at least two of lecithin PC, phosphatidyl glycerol PG and phosphatidyl serine PS, and the lecithin PC is one of dioleoyl lecithin DOPC, dimyristoyl lecithin DMPC, distearoyl phosphatidylcholine DSPC, dicapryoyl lecithin DEPC, dipalmitoyl lecithin DPPC and hydrogenated soybean lecithin HSPC; the phosphatidylglycerol PG is one of dioleoylphosphatidylglycerol DOPG, dipalmitoylphosphatidylglycerol DPPG, egg yolk phosphatidylglycerol EPG and distearoylphosphatidylglycerol DSPG; the phosphatidylserine PS is dimyristoyl lecithin DMPC; the solubilizer is one of ethanol, dichloromethane and diethyl ether; the auxiliary emulsifier is one of sodium oleate, potassium oleate and oleic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810703107.0A CN110721155B (en) | 2018-06-29 | 2018-06-29 | Long-acting drug-loaded fat emulsion preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810703107.0A CN110721155B (en) | 2018-06-29 | 2018-06-29 | Long-acting drug-loaded fat emulsion preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110721155A CN110721155A (en) | 2020-01-24 |
| CN110721155B true CN110721155B (en) | 2022-04-05 |
Family
ID=69216827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810703107.0A Active CN110721155B (en) | 2018-06-29 | 2018-06-29 | Long-acting drug-loaded fat emulsion preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110721155B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022180199A1 (en) * | 2021-02-25 | 2022-09-01 | Exinov | Emulsion for use in the treatment of rosacea |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5330778A (en) * | 1988-09-19 | 1994-07-19 | Opta Food Ingredients, Inc. | Hydrophobic protein microparticles |
| CN101032467A (en) * | 2007-04-13 | 2007-09-12 | 西安力邦制药有限公司 | Superregulated long-cycled lipid emulsion carrying medicine reagent for mainline |
| CN101288642A (en) * | 2007-11-07 | 2008-10-22 | 中国人民解放军第二军医大学 | Taxanes medicine preparation for intravenous injection and preparation method thereof |
| CN102178651A (en) * | 2011-05-05 | 2011-09-14 | 山东大学 | Tretinoin fat emulsion injection and preparation method thereof |
| CN102772337A (en) * | 2012-08-17 | 2012-11-14 | 珀莱雅(湖州)化妆品有限公司 | Preparation method of composite whitening lipid nanoparticle emulsion |
-
2018
- 2018-06-29 CN CN201810703107.0A patent/CN110721155B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5330778A (en) * | 1988-09-19 | 1994-07-19 | Opta Food Ingredients, Inc. | Hydrophobic protein microparticles |
| CN101032467A (en) * | 2007-04-13 | 2007-09-12 | 西安力邦制药有限公司 | Superregulated long-cycled lipid emulsion carrying medicine reagent for mainline |
| CN101288642A (en) * | 2007-11-07 | 2008-10-22 | 中国人民解放军第二军医大学 | Taxanes medicine preparation for intravenous injection and preparation method thereof |
| CN102178651A (en) * | 2011-05-05 | 2011-09-14 | 山东大学 | Tretinoin fat emulsion injection and preparation method thereof |
| CN102772337A (en) * | 2012-08-17 | 2012-11-14 | 珀莱雅(湖州)化妆品有限公司 | Preparation method of composite whitening lipid nanoparticle emulsion |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110721155A (en) | 2020-01-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Klang et al. | Design and evaluation of submicron emulsions as colloidal drug carriers for intravenous administration | |
| EP2490678B1 (en) | Coated capsules and tablets of a fatty acid oil mixture | |
| US20100189596A1 (en) | Composite emulsifier, an emulsion prepared from it and the preparation method thereof | |
| EP2612655A1 (en) | Liquid compositions of insoluble drugs and preparation methods thereof | |
| CN110538148A (en) | Compositions comprising fatty acid oil mixtures and surfactants, methods and uses thereof | |
| CN104224711B (en) | Paclitaxel submicron emulsion taking steroid compound as intermediate vector | |
| US20230398072A1 (en) | Concentrate containing poorly soluble drug and emulsion prepared therefrom | |
| CN101829052B (en) | Self-emulsifying preparation of taxane compound and preparation method thereof | |
| US20130150335A1 (en) | Paclitaxel/steroidal complex | |
| WO2002083098A1 (en) | Coenzyme q10 containing microemulsion preconcentrates and microemulsions | |
| CN101524329B (en) | Bicyclo-ethanol submicron emulsion and preparation method thereof | |
| CN1706371B (en) | Efficient sword-like iris seed preparation and its preparation process | |
| CN110721155B (en) | Long-acting drug-loaded fat emulsion preparation and preparation method thereof | |
| CN109157549A (en) | EGCG G. lucidum spores Softgel and preparation method thereof | |
| CN101361711A (en) | Dihydroartemisinin emulsion for injection, freeze-dried emulsion and preparation method thereof | |
| CN108498455A (en) | A kind of water-soluble medicament nano crystalline substance of oiliness and preparation method thereof | |
| CN107095799A (en) | Complex liposome and its preparation method and application | |
| CN1957927A (en) | Fat micro sphere preparation of triterpenoid saponin and derivative, and fabricating method | |
| CN109260149B (en) | Nano emulsion containing gamma-tocotrienol and preparation method and application thereof | |
| CN109820820B (en) | Alprostadil injection and preparation method thereof | |
| CN112336705A (en) | Preparation method and application of artificial cannabidiol chyle | |
| CN101632635A (en) | Antitumor emulsion and preparation method thereof | |
| CN102228431A (en) | Self-emulsified medicinal composition for taxane compounds | |
| CN107519187B (en) | Preparation method of fat-soluble vitamin freeze-dried milk | |
| CN107412161A (en) | A kind of methoxyestradiol intravenous injection of self-emulsifying 2 and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |