TW201223560A - Drug-loaded emulsion and the preparation method thereof - Google Patents

Abstract

The present invention provides a method to prepare drug-loaded emulsion which can decrease the degradation of drug during the preparation. The present method includes such steps as followings: First, prepare non-self emulsifying oil-in-water emulsion containing no drugs. Second, add therapeutic drug into the oil-in-water emulsion and make the drug across the membrane into the inner oil phase of the emulsion by adjusting the pH value. The present preparation process is simple, avoiding the use of organic solvents and applicable to mass production.

Description

201223560 VI. Description of the Invention: [Technical Field] The present invention relates to a method for preparing a non-self-emulsifying 0/W type drug-loaded emulsion, in particular to prepare a non-self-emulsifying 〇/w type drug-loaded emulsion by adding a drug to a blank emulsion Methods. [Prior Art] The clinical application of the emulsion is very extensive. Among them, as a carrier for parenteral administration, the application of fat emulsion has been used for more than 40 years. Its characteristics include: improving the stability of the drug, reducing the side effects, and slowing down the drug. Controlled release or dryness. In recent years, based on the preparation method of fat emulsion ripening, research on drug-loaded emulsions has attracted more and more attention. 'The drug-loaded products can achieve therapeutic effects and provide energy for patients. It is more conducive to the recovery of patients' health. In the prior art, self-emulsified microemulsion technology is used to prepare drug-loaded emulsions, such as Li Xiujuan and Zhang Liwei, using the self-emulsified microemulsion method to prepare aspirin W/0 type microemulsion (《Chemical Research and Application》2008年月20第第第3 _ 352-355 pages). The self-emulsified emulsion can spontaneously form an emulsion of less than 1 〇〇〇 nanometer (nm) under mild agitation, so the drug can be added to the system during the preparation of the aqueous phase or the oil phase, and is conveniently packaged. In the internal phase of the emulsion, but the amount of the emulsifier in the self-emulsified emulsion is large, and it is usually necessary to add a co-emulsifier ("organic solvent") in the preparation, so that the self-emulsification agent is used, especially when injected. The drug is more toxic. In order to reduce the toxicity of emulsifiers and co-emulsifiers in self-emulsified emulsions, it is usually necessary to use high-speed semi-high pressure homogenization or micro-jet to overcome the strong interface tension between oil and water. 3 95060 201223560

An emulsion having a particle size of less than 10 nm and a + A 01 having good kinetic stability and vascular permeability was obtained. At present, the general preparation method of non-self-receiving/householding and pulverizing emulsion is: first step, preparation and mixing of oil-water two-phase; second step, preparation of colostrum. third step, by means of the aforementioned severe conditions to reduce The particle size of the emulsion is prepared as a final emulsion. The method of adding the drugs in the first step or the second step is as follows. 1. If the drug is dissolved in the oil phase, the drug may be first dissolved in the oil phase to be made into an emulsion; The drug is soluble in the aqueous phase, and the drug can be dissolved in water and then f-formed into an emulsion; 3. If the drug is insoluble in the oil phase and insoluble in water (4), the drug, oil phase or/and emulsifier can be dissolved in a suitable time. The emulsion is removed, and the organic solvent is removed to prepare an emulsion. For example, in the prior art, Chinese patent application CN1399959A "Preparation method of relying on vinegar fat emulsion injection, cn1546〇16a" natural vitamin E nano preparation and preparation method thereof,, (3)163·α "--a new intravenous injection Paclitaxel emulsion and preparation method thereof, (3) (4) Shan "Stabilized oil-in-water emulsion for intravenous culture for intravenous use, preparation method thereof, CN1732936A nimodipine emulsion injection and preparation method", CN1947720A clarithromycin lipid Microsphere injection and preparation method thereof, CN1861085A sheath disc fat isolated fat emulsion and preparation method thereof are added to the preparation of the first step oil-water two-phase preparation. Chinese Patent Application CN1771954A "Changchun Ruibin Lipid Microsphere Injection and Its Preparation Method" is to add a drug during the preparation of the second step of colostrum. According to the general preparation method of the prior art drug-loading agent, if the drug is dissolved in the water phase Or in the oil phase, usually in the first step or the second step mentioned above, that is, the drug is added in the system and is present in the system. On the one hand, 4 95060 201223560 is retained in the system for a longer period of time. It is necessary to homogenize with other substances in the system to form an emulsion. For some unstable drugs, long-term retention and multiple homogenization, especially the high shear force produced by the preparation of the homogenization conditions High temperature, high temperature, will increase the strength + their denaturation, inactivation, space structure damage or the probability of producing degradation products. If the drug is insoluble in the oil phase and is not soluble in the water phase, usually use organic, 'agent or other drugs to increase solubility Additives or additives, so that the organic solvent residue or the entire emulsion formulation is complicated, and the potential agent - Lu sex problem. The case CN brain_disclosed is a method of making a micro-dissolved or difficult-to-solve active ingredient into a dispersion, and grinding the active ingredient emulsion to form an active ingredient mainly distributed in the aqueous phase, the same as the internal phase. The oil droplets and the dispersion system of the active ingredient crystals are added to and dissolved in the high-phase oil droplets of the knives and the bulk line such as 15Q()bar, 5 ..., έ 均 ^ 固 1 solid homogenized loop After adding the blank 0/* type emulsion to the solvent, it has a shrinkage time. The retention time in the system is <^ type_2 = the drug is dissolved, and the drug is added to the blank less than 1000. The drug is subjected to ultrafine pulverization to make the particle size high == dissolve into the emulsion and use a relatively emulsion oil: dissolve the drug into another with strong mechanical energy. This method is not suitable for drugs with poor stability. The preparation of the preparation uses a solvent-promoting organic solvent, but it has a high requirement for the production of a large amount of energy. 95060 5 201223560 Gong Mingtao, Zhang Yunshou, etc. China Natural Medicine, Vol. 3, No. j, 2005, 41_43 ), although the drug is added after the preparation of the empty nano-milk, the drug is added to the blank nano-milk at a temperature exceeding the phase transition temperature of the emulsion (70 〇, and the drug is packaged by the phase change process of the emulsion) The internal phase of the emulsion. 2 In this method, _ is added above the phase transition temperature, so this method has certain limitations for the heat-labile drug. [Summary of the Invention] In order to overcome the prior art, the preparation of the drug-loaded emulsion Insufficient methods, especially = chemical drugs 'or drugs that are insoluble in water or oil or oil and water' are present when preparing emulsions, especially when preparing emulsions with an average particle size of less than 10 nm. The drug is unstable or poorly soluble, resulting in a decrease in the quality of the preparation. The present invention employs an active drug-loading technique to achieve a method for producing a high drug-loaded non-self-emulsified milk #1 under mild conditions, especially if the particle size of the emulsion is less than 1〇〇.高nm high-loading non-self-emulsion emulsion, the method comprises the following steps: gas non-self-emulsifying 0/W blank emulsion containing no drug component; preferably non-self-cultivating 〇/w blank emulsion The diameter is below 1000 nm; a therapeutically effective amount of the drug is added to the blank emulsion, pH 2' is adjusted, and the drug is transferred to the emulsion oil droplet by mixing to prepare a drug-loaded emulsion, and the pH value is appropriately adjusted to make the oil-water distribution of the drug The coefficient is increased; the preferred embodiment of the invention includes no need to change the temperature after adding the drug to change the phase transition temperature of the sword or to perform high energy homogenization treatment. The method of the present invention is to first prepare a non-self-elected blank 〇/W type emulsion through a conventional emulsion preparation method, so that the particle size of the emulsion satisfies the needs of the clinical use of 6 95060 201223560 medicine, such as a particle size of less than lOOOnm, and then Add the drug to the white alpha agent to dissolve or disperse the drug in the external water of the 0/W blank emulsion = medium 3. Then adjust the pH of the external phase solution to make the drug dissolved in the external aqueous phase turn to be more fat soluble. Strong free molecules and other forms, increase the oil-water partition coefficient lgP of the drug, so that the drug can spontaneously enter the internal phase oil droplets of the 0/W emulsion from the external phase water solution driven by the concentration difference, in mild conditions. — Active loading of objects. The non-self-emulsifying blank 0/W type emulsion of the present invention refers to a non-self-emulsifying 0/W type emulsion which does not contain a therapeutically effective amount of the drug, the emulsion particle size and the most final drug-loaded emulsion. The particle size is consistent, which is equivalent to the blank terminal milk in the prior art, that is, the invention adds the drug after the final emulsion of the general drug-loading preparation method, instead of adding the drug to the oil phase, the water phase or the colostrum. Therefore, the time for the drug to remain in the system can be reduced, and the drug is added to the emulsion after the blank terminal milk is prepared, and the preparation method does not need to reduce the particle size of the emulsion by vigorous conditions, so that the conventional emulsion preparation can be effectively avoided. In the process, the high temperature, high pressure and high shear force generated by the high-speed secret, high-pressure homogenization and the like which must be adopted for the low emulsion particle size are required to destroy the molecular structure and stability of the sensitive drug. In addition, the method used in the present invention is The drug is added to the blank terminal milk, and then the pH value of the external phase solution is adjusted, so that the drug dissolved in the external water phase is converted into a form of free molecules which are more soluble in the month, thereby increasing the oil-water distribution of the drug. The difference between the internal phases of the emulsion forms a difference in drug concentration. This concentration shifts the drug from the aqueous phase of the external phase into the internal phase oil droplets of the human (4) emulsion, thus also reducing the dissolution and encapsulation of the drug. The external mechanical energy required to reach the internal phase of 95060 7 201223560 can improve the encapsulation efficiency of the drug on the one hand, and achieve the internal phase oil of the emulsion into the 〇/w^ emulsion through a mild mixing method. The purpose of preparing the non-self-emulsifying blank 0/W emulsion of the present invention can be the preparation method of the emulsion known in the prior art, such as mechanical method, two-phase alternating addition method, phase transformation temperature method, phase transformation method. For example, in the mechanical method, the preparation of the non-self-emulsifying blank 0/W emulsion comprises the following steps: (1) preparing an oil phase; preparing an aqueous phase; (3) mixing oil and water into two phases, uniformly dispersing and then using an emulsification mechanism. The 0/W blank emulsion 'emulsification machine can be a mortar, a blender, a colloid mill, a ultrasonic emulsifying device, a high pressure homogenizer or a micro jet. ^

The medicament of the present invention may be a drug which is water-soluble, fat-soluble, slightly soluble or slightly soluble or slightly dissolved in the oil phase and/or the aqueous phase. Slightly soluble refers to solute 1 transport (^ can be dissolved in solvent 30 to less than 100ml; slightly soluble solute lg (mi) can be transferred in solvent 1GG to less than l_ml towel; _ dissolve refers to f ^ (4)) can be in solvent surface The drug may be present in the 〇/w type emulsion of the present invention in a state in which the drug is dissolved in the sputum-in-situ, and is formed into an emulsion formed of a heterogeneous dispersed emulsion. The water-soluble drug == phase PH value, then the water-soluble drug is converted into a fat-soluble drug, (4) means to complete the transmembrane, wrapped in the emulsion droplet, micro: = τ dispersed emulsion formed by the emulsion. Slightly soluble or slightly soluble or extremely ==/ or the drug in the aqueous phase, a part of which is dissolved in the oil phase, and the heterogeneous octylene crystal form is in the form of a milk, which is obtained by the preparation side =:=; Emulsion. The drug-loaded emulsion of the present invention has a fat solubility which changes with pH value. 95060 8 201223560 A drug, a water-soluble drug, a drug which is slightly soluble or slightly soluble or slightly dissolved in an oil phase and/or an aqueous phase. The medicine according to the present invention is an active ingredient for treating diseases of human or animal body, and may be selected from the group consisting of an anti-tumor medicine, a cardiovascular medicine, an anti-infective medicine, an anti-fungal medicine, an anti-viral medicine, an anti-allergic medicine, an anti-inflammatory medicine, and an endocrine medicine. , psychotropic drugs, antibiotics, immunosuppressants, vitamins or anesthetics, may be paclitaxel, docetaxel, vinorelbine, Changchun new test, Jingjixi test, oxaliplatin, prostaglandin E1, Nemo Dipine, cyclosporine, itraconazole, amphotericin, acyclovir, dexamethasone, dexamethasone palmitate, indomethacin, diazepam, clarithromycin, pingyangmycin, poly Respiratory stars, vitamin A, vitamin D2, vitamin E, vitamin K, bupivacaine, propofol, relying on p-methanol, flurbiprofen ethoxylated α-ethyl ester, and the like. The drug may be added to the blank emulsion in powder form, in the form of a pharmaceutical solution, or as a pharmaceutical suspension. After the drug is added to the blank emulsion, the pH of the outer aqueous phase is adjusted, and the mixture is uniformly mixed, and the volume is fixed, filtered, dispensed, and sterilized. $ As mentioned above, the mixing at this time is not for the purpose of reducing the particle size of the emulsion, but an auxiliary mechanical means for the drug to enter the internal oil phase driven by the difference in concentration. The mixing mode may be mechanical agitation, high-speed shearing, ultrasonic wave. Emulsifying, high-pressure homogenization and micro-jet, etc., are commonly used in the art, and mechanical agitation and high-speed shearing are preferred. Due to the pH adjustment of the blank emulsion system added with the drug during the preparation of the drug-loaded emulsion of the invention, the oil-water partition coefficient of the drug is improved, and the drug is actively entrained into the internal oil phase under the driving of the concentration difference. And the distribution in the oil phase is easier. Therefore, the mixing at this time is a supplementary manipulator that allows the drug to enter the internal oil phase driven by the concentration difference. 9 95060 201223560, is a mixture that does not require high energy or a relatively high energy. condition. Even with a violent blending method, such as ultrasonic emulsification, high pressure homogenization or microjet, it also controls certain parameters. For example, ultrasonic emulsification can reduce the ultrasonic frequency or shorten the processing time, and the high disk homogenizes the control pressure and The number of loops, the blending energy provided by the rubber is reduced, and the adverse effects of high-energy treatment on the drug are avoided while the auxiliary drug enters the emulsion. The sterilization method can be selected by hot pressing sterilization or filtration sterilization. Emulsion sterilization commonly used in the field. The drug-loaded emulsion of the present invention contains a drug, a solvent oil, a surfactant, and water. Depending on the physical and chemical properties of the drug, the drug-loaded emulsion may also have one or more of a stabilizer, a penetration enhancer, a co-solvent, a metal chelating agent, an osmotic pressure adjusting agent, an antioxidant, or a preservative residue. The solvent oil of the present invention includes one or more of mineral oil, vegetable oil, animal oil, and synthetic oil. The vegetable oil may be selected from the group consisting of soybean oil, safflower oil, corn oil, coconut oil, castor oil, gall bladder oil, palm oil, medium chain fatty acid triglyceride, peanut oil, cottonseed oil or a mixture thereof; From fish 4, cetyl oil or a mixture thereof. The appropriate solvent oil can be selected depending on the drug to be administered and the route of administration of the emulsion. The solvent oil comprises from 2 to 4 Å w/v% of the emulsion. The surfactant of the present invention comprises a squama, a nonionic surfactant or a mixture thereof, and the surfactant may be dissolved in the oil phase or may be dispersed in the aqueous phase. The phosphonium of the present invention may be selected from the group consisting of egg yolk lecithin, soybean phospholipid, hydrogenated egg yolk lecithin, hydrogenated large lecithin or synthetic phospholipid; non-95060 10 201223560 ionic surfactant may be selected from Tween 20, Tween. 40, Tween 60, Tween 80, Tween 85, Span 20, Span 40, Span 60, Span 80, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearate , poloxamer 188, polyethylene glycol stearate 15, polyethylene glycol-vitamin E succinate or a mixture thereof. The surfactant is 0.5 to 50 w/v % of the emulsion. The antioxidant of the present invention may be selected from the group consisting of a water-soluble antioxidant and an oil-soluble antioxidant, and the water-soluble antioxidant is dissolved in the aqueous phase. The oil-soluble antioxidant is dissolved in the Φ oil phase, wherein the water-soluble antioxidant may be selected from sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, ascorbic acid, sodium ascorbate, L-cysteine or a mixture thereof; The antioxidant may be selected from the group consisting of tocopherol, alpha-tocopherol tocopherol, alpha-tocopherol succinate, tert-butyl p-hydroxyanisole (oxime), di-tert-butyl-p-nonylphenol (oxime) or mixtures thereof; The metal chelating agent may be selected from the group consisting of ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid disodium salt, ethylenediaminetetraacetic acid dicalcium salt or a mixture thereof. I The osmotic pressure adjusting agent of the present invention may be selected from the group consisting of glycerin, sorbitol, mannitol, glucose, sodium chloride or a mixture thereof. The stabilizer of the present invention may be selected from the group consisting of oleic acid, sodium oleate, cholesterol, cholic acid, sodium cholate, deoxycholic acid, sodium deoxycholate or a mixture thereof. The preservative according to the present invention may be selected from the group consisting of clove oil, propylene glycol, sorbitol, sorbic acid, citric acid, p-hydroxybenzoic acid esters, calcium butyl paraben, sodium methyl p-hydroxybenzoate, One or more of sodium propyl paraben, benzoquinone, and benzoic acid. The co-solvent according to the present invention may be selected from the group consisting of ethyl oleate, benzyl benzoate, 11 95060 201223560 benzene f-alcohol, ethyl lactate, ethanol, 1> 2-propanediol, polyethylene or a plurality. j - The drug-loaded emulsion of the present invention can be used as a topical, oral or parenteral administration for intravenous, intradermal, subcutaneous, intramuscular, and intra-articular or intra-abdominal administration. In the case of intravenous administration, the average particle size of the emulsion in the drug-loaded emulsion is less than 100 Ornn. Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The invention changes the oil-water partition coefficient of the medicine by pH adjustment, so that the distribution ratio of the music in the oil-water two-phase of the blank emulsion is changed, and by a mild mixing method, The transmembrane transport of the drug is achieved and distributed in the oil phase, thereby avoiding the use of the organic solvent, so that the drug-loaded emulsion has no problem of residual organic solvent; 2. Compared with the general drug-loaded emulsion method The medicine of the invention is added after the preparation of the Gongbai 0/W type emulsion, which reduces the retention time of the medicine in the system, and no longer warms or high energy of the system during the process of adding the medicine or after the medicine is added. Mechanically mixed/homogenized, thus reducing or avoiding the degradation of the drug during preparation of the preparation; 曰3, the method of the invention is simple, the special emulsion preparation equipment is not required, and the equipment of the eucalyptus emulsification function is provided, which is advantageous for large-scale industrialization. produce. [Embodiment], ""

The invention is further illustrated by the following examples, which are not to be construed as limiting. X Example 1 Vinorelbine tartrate 0. 05% 95060 12 201223560 Soybean oil 5% Egg yolk fat filling 2%

Add water to 1000 mL of water for injection under inert gas protection, weigh 50 g of soybean oil, preheat to 75 ° C; add 20 g of egg yolk lecithin to an appropriate amount of water for injection, stir to form an aqueous phase, preheat to 75 ° C; 5克的调pH参参。 The high-speed stirring, the aqueous phase was added to the oil phase, and the mixture was homogenized and homogenized by a high-pressure homogenizer to form a 0/W type blank emulsion having a particle size of less than 100 °m, adding vinorelbine tartrate 0. 5g, adjusting the pH value To 8. 0, mechanical stirring, constant volume to 1000ml, 0. 22# m filter membrane sterilization, filling, nitrogen filling, sealing. Example 2 Bupivacaine hydrochloride 0.1% said sesame oil 10% large denier 2% anhydrous sodium sulfite 0.2% glycerin water for injection 2. 5%

Add to 1000mL Under the protection of inert gas, weigh 100g of castor oil and preheat it to 60°C. Add 20g of soybean fat, 2g of anhydrous sodium sulfite and 25g of glycerin to the appropriate amount of water for injection, stir to form an aqueous phase, preheat to 60 ° C; Under high-speed agitation, the oil phase and the water phase are uniformly mixed, and homogenized by a high-pressure homogenizer to form a 0/W type blank emulsion having a particle diameter of less than 100 nm, and bupivacaine hydrochloride is added to adjust the pH value. To 7. 0, mechanical stirring, constant volume to 1000ml, 0. 22 / zm filter membrane sterilization, filling, nitrogen filling, sealing. 。。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. 5。 The composition of the same as the pH value of 5.0. Example 5 Formulation Composition Same as Example pH value to 6. 〇. Example 6 Formulation composition same as Example pH value to 8. 〇. The content and related substances are 2 to 6, and the results are shown in Tables 1 and 2. Table 1 The difference in the measurement results in the preparation method is that the adjustment in the preparation method is that the adjustment in the preparation method is the same in the preparation method. Encapsulation ratio and particle size are indicators for adjusting the adjustment example

Example (pH 7.0) Example (pH 4. Q) (pH 5.0) Example (pH 6.0) Example 6 (pH 8. 0) Η 95060 201223560 Table 2 Acceleration 1 month measurement result (25〇C) Particle size (nm) content 〇〇 0.72 Example 2 (pH 7. 0) 131.2 98.9 ------ 87.2 Example 3 JpH4. 0) 132.4 99.0 ------ 36. 4 ~-'- 0.48 - --——__ Example 4 139.2 ---- -------- (pH5. 0) 98.8 51.8 0.54 - Example 5 130.2 ------- _ (PH6. 0) 98.4 69.5 0.62 Example 6 (pH 8. 0) 129.5 98.6 —— -------- 95.9 0.82 It can be seen from the above Examples 2 to 6 that the oil-water partition coefficient of bupivacaine hydrochloride is changed by adjusting the pH of the emulsion. , which significantly affects the drug encapsulation efficiency. The lower the pH value, the lower the oil-water partition coefficient of the drug, the smaller the amount of transmembrane entering the inner phase of the emulsion, the lower the encapsulation efficiency, and the encapsulation efficiency of the emulsion increases with the increase of pH value. After 1 month of acceleration, the particle size, content and related substances of different prescriptions will have different changes. For the reason of analysis, when the pH is low, bupivacaine hydrochloride is mostly in the form of water-soluble hydrochloride, and the oil-water partition coefficient Low, the stability is slightly higher than the fat-soluble free base, so the prescription of the substance is slightly lower than the pH. The change in pH has no significant effect on the content and particle size. Example 7 Irinotecan Hydrochloride 0.05% Soybean Oil 10% Egg Yolk Lecithin 2% 15 95060 201223560

Poloxamer 2% Glycerin 2. 5% Water for injection to 1000 mL Under the protection of an inert gas, weigh 100 g of soybean oil, as an oil phase, and add 20 g of egg yolk lecithin, 20 g of poloxamer and 25 g of glycerol to the appropriate amount. In water, stir to form an aqueous phase. Under high-speed agitation, the oil phase and the water phase are uniformly mixed, and homogenized by a high-pressure homogenizer to form a 0/W blank emulsion having a particle diameter of less than 1 OOOnm, and irinotecan hydrochloride is added. 0.5g, adjusted pH value of 8. 0, emulsified in a micro-jet instrument, constant volume to 1000ml, filling, nitrogen filling, melt sealing, rotary sterilization is obtained.

Example 8 vinorelbine 0. 2% soybean oil 5% egg yolk egg 1 fat 2% water for injection to lOOOmL Under the protection of inert gas, weigh 50g of soybean oil, preheat to 75 ° C; another egg yolk lecithin 20g is added to the appropriate amount of water for injection, stirred to form an aqueous phase, preheated to 75 ° C; under high-speed agitation, the aqueous phase is added to the oil phase, mixed uniformly, and homogenized by a high-pressure homogenizer to make the particle size below lOOOnm 0/W blank emulsion, adding vinorelbine 2g, adjusting the pH to 8.0, mechanically stirred, constant volume to 1000ml, 0.22μπι filter membrane sterilization, filling, nitrogen filling, sealing. Example 9 Docetaxel 0. 05% 16 95060 201223560 Medium chain oil 15% egg yolk phospholipid 2% Tween-80 0. 53⁄4 oleic acid 0. 4% glycerin 2. 5% VE 〇. 05% water for injection To 1000mL Under inert gas protection, stir the medium chain oil and Tween-80 5g into oil phase % "«八迥置>王射水, preheat to 7〇 °C; ride evenly into the water phase, At high speed, the oil phase and the water phase are mixed σ uniformly and homogenized by the same pressure homogenizer to form a 〇/, type blank riting agent with a particle size smaller than _〇nm, adding Docetaxel, adjusting value 5 』, micro-grass in the instrument of Lihua 'Shibuya to 1 〇〇〇 ml, filling, nitrogen filling, solution sealing, rotary sterilization is available.

Example 10 10% 2% 0. 1% 2. 5% 〇. 01% amphotericin B fish oil egg yolk lecithin sodium oleate glycerol ethylenediaminetetraacetic acid disodium

Spray water to lOOOOmL Under the protection of h gas, weigh the fish oil 1QQg to preheat. c; another 17 95060 201223560 20g of egg yolk lecithin, sodium oleate lg, disodium edetate 0. lg, glycerin 25g added to the appropriate amount of water for injection, preheated to 70 ° C; stirred evenly into an aqueous phase, in Under high-speed agitation, the oil phase and the water phase are uniformly mixed, and homogenized by a high-pressure homogenizer to form a 0/W blank emulsion, amphotericin B 2g is added, the pH value is adjusted to 7.0, and the volume is adjusted to 1000 ml, and the mixture is emulsified in a high-pressure homogenizer. To the particle size less than 100Onm, filling, filling with nitrogen, sealing, sterilization by rotary sterilization cabinet. Example 11 Prostaglandin E1 0. 001% Soybean Oil 10% Egg Yolk Egg Scale 1.2% Oleic Acid 0.1% Glycerin 2.5%

Add water to 1000mL under the protection of inert gas, soy oil l〇〇g, oleic acid lg, stir evenly into an oil phase; another 12 grams of egg yolk lecithin, glycerol 25g into the appropriate amount of water for injection, stir to form an aqueous phase; The high-pressure homogenization is carried out under high-speed agitation, the oil phase and the water phase are uniformly mixed, and homogenized by a high-pressure homogenizer to form a 0/W type blank emulsion having a particle diameter of less than 1000 nm, and a prostaglandin El 10 mg is added to adjust the pH value of 5.0. Emulsified in the machine, constant volume to 1000ml, filling, nitrogen filling, melt sealing, rotary sterilization. Example 12 Diazepam 0.1% Soybean Oil 10% Egg Yolk Lecithin 1.2% 18 95060 201223560 Sodium oleate 0.05% Glycerin 2. 5%

The water for injection is added to 1000 mL under the protection of an inert gas, and 100 g of soybean oil is weighed as an oil phase; and 12 g of egg yolk egg fat, 0.5 g of oleic acid, 25 g of glycerin are added to an appropriate amount of water for injection, and the mixture is uniformly mixed into an aqueous phase; The high-temperature turbulent mixing, the oil phase and the water phase are uniformly mixed, and homogenized by a high-pressure homogenizer to form a 0/W type blank emulsion having a particle diameter of less than 100 nm, adding diazepam 1 g, adjusting the pH value of 8. 0, Emulsified in high pressure homogenizer, constant volume to 1000ml, filling, nitrogen filling, sealing, rotation

The bacteria are available. Example 1 etomidate 0. 1% soybean oil 10% egg yolk printing fat 1. 2% glycerol 2. 5% water for injection added to 1000 mL under the protection of inert gas, weighed soybean oil 100g preheated to 50 ° C; In addition, add 12g of egg yolk egg fat and 25g of glycerin to the appropriate amount of water for injection, stir to form an aqueous phase, preheat to 50 ° C; mix the oil phase and water phase evenly under high speed stirring, and homogenize by high pressure homogenizer The 0/W type blank emulsion having a particle diameter of less than 100 nm is prepared, and the pH is adjusted to 5.0 by the support of 17 m S, and the emulsification is sterilized by high pressure homogenizer. Example 14, constant volume to 1000 ml, filling, nitrogen filling, solution sealing, 19 95060 201223560

ο. 1°/〇5% 5% 1. 2% 2. 5% Add to lOOOmL Propofol Soybean Oil Medium chain oil egg yolk 彡卩 Filling glycerin Water for injection Under the protection of inert gas, 50g of soybean oil, medium chain 50g of oil is evenly mixed into an oil phase, preheated to 60 ° C; another 12 g of egg yolk lecithin, 25 g of glycerin is added to an appropriate amount of water for injection, and the mixture is uniformly mixed into an aqueous phase, preheated to 60 ° C; under high-speed agitation, The oil phase and the water phase are uniformly mixed, and homogenized by a high-pressure homogenizer to form a 0/W type blank emulsion having a particle diameter of less than 100 nm, adding propofol lg, adjusting the pH value of 8.0, emulsification in a high-pressure homogenizer, and diluting to 1000 ml. , filling, nitrogen filling, melt sealing, rotary sterilization is available. Example 15 Cyclosporine 0.1% Medium Chain Oil 3% Polyoxyethylene Castor Oil 10% PEG-400 5% Sodium Chloride 0.4%

Add water to 1000 mL of water for injection under inert gas protection, and weigh 30 g of medium-chain oil to 60 ° C. Add another 10 μg of polyoxyethylene castor oil, 50 g of PEG-400, and 4 g of sodium chloride to the appropriate amount of water for injection. Stir well to form an aqueous phase, preheat to 60 ° C; mix the oil phase and water phase evenly under high-speed agitation, and homogenize by high-pressure homogenizer to make 20 95060 201223560 0/W blank emulsion with particle size less than lOOOnm , adding cyclosporine lg, adjusting the pH value of 7.4, high-speed shear emulsification, constant volume to ΙΟΟΟπα, 0. 22μιη filter membrane filtration, sterilization, filling, nitrogen filling, solution sealing. Example 16 Nimodipine 0. 1% Soybean oil 15% Soybean scale 1.2% Sodium oleate 0. 05% Glycerin 2. 25%

The sucrose is added to the appropriate amount of glycerol 22.5 g, sodium oleate 0. 5g, the appropriate amount of injection In water, stir to form an aqueous phase, preheat to 60 ° C; mix the oil phase and water phase evenly under high-speed stirring, and homogenize by high-pressure homogenizer to make 0/W blank emulsion with particle size less than 100 Onm , adding nimodipine lg, adjusting the pH value of 8.0, emulsification in a high-pressure homogenizer, constant volume to 1000ml, filling, nitrogen filling, melt sealing, rotary sterilization is obtained. Example 17 Vitamin D2 0. 5% Soybean oil 5% Soy fat filling 1.5% Glycerin 2. 25%

5克。 Add water to 1000mL under the protection of an inert gas, soy oil 50g, soy fat 15g disturb 21 95060 201223560 mixed into an oil phase, preheated to 70 ° C; glycerol 22. 5g added to the appropriate amount of water for injection, stirring Uniformly into an aqueous phase, preheated to 70 ° C; under high-speed agitation, the oil phase and the water phase are uniformly mixed, and homogenized by a high-pressure homogenizer to form a 0/W blank emulsion having a particle size of less than 100 nm, and the vitamin 1 is added. 2 5g, adjust the pH value of 8. 0, emulsified in a high-pressure homogenizer, constant volume to 1000ml, filling, nitrogen filling, melt sealing, rotary sterilization. Example 18 Acyclovir 0.5% Soybean oil 10% Soy fat 2% Sodium oleate 0.05% Glycerol 2.25%

5克添加添加的水水,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Stir well to form an aqueous phase, preheat to 70 ° C; mix the oil phase and water phase evenly under high-speed agitation, and homogenize it to a 0/W blank emulsion with a particle size of less than 1000 nm. Ciclovir 5g, pH adjustment of 8. 0, emulsification in a high-pressure homogenizer, constant volume to 1000ml, filling, nitrogen filling, melt sealing, rotary sterilization. Example 19 The preparation method and the formulation excipient were the same as in Example 18 except that the drug was clarithromycin and the prescribed amount was 0.1%. Example 20 22 95060 201223560 The difference lies in the preparation method and the composition of the prescription excipient. The same example ΐδ music is dexamethasone, and the prescription amount is 0.1%. Example 21 - Preparation Method and Formulation Excipient Composition The same as Example 18' is that the drug is doxorubicin, which is prescribed in an amount of 0.1%. [Simple diagram description] None [Main component symbol description] Luit

23 95060

Claims (1)

201223560 VII. Patent application scope: 'Characterized by 1. A method for preparing non-self-emulsifying drug-loaded o/w emulsion The method comprises the following steps: preparing a non-self-emulsifying 〇/W type blank emulsion containing no drug component, The particle size of the non-self-emulsifying 0/W blank emulsion is below 1 〇〇〇 nm; a therapeutically effective amount of the drug is added to the blank emulsion, the pH is adjusted, and the drug is dissolved across the membrane to the emulsion oil droplet by mixing. In the preparation of a drug-loaded emulsion. 2. The method of claim 2, wherein the drug is present in the emulsion in a dissolved state, encapsulated in the emulsion droplets to obtain an emulsion formed by the heterogeneous dispersed emulsion droplets; or the medicament- Part of the emulsion is present in the form of highly dispersed nanocrystals, which are partially transferred to the oil phase, resulting in a co-presentation of the emulsion droplets and the drug crystals dispersed by the heterogeneous phase. 3. If you apply for a patent scope! The method of claim 7, wherein the drug is added to the empty form in the form of a powder, a drug solution, or a drug suspension. 4. 5. The method of claim 301, wherein the 5" sigma sigma mode is selected from the group consisting of mechanical picking, high speed shearing, or (four) flow. " = The method described in the item ii to 4 of the scope of the patent application, wherein the drug-loaded emulsion contains a drug, a solvent oil, a surfactant, and water. The method according to the fifth aspect, wherein the agent oil is selected from one or more of mineral oil, vegetable oil, animal oil, and synthetic oil. 95060 24 201223560 7. As claimed in claim 6th soybean oil, safflower oil, corn oil, method, wherein the vegetable oil is selected from the group consisting of palm oil, medium chain fatty acid glycerin, sesame oil, gallium oil, and the compound; The animal oil is selected from the group consisting of $-§ s, <raw oil, oil riding or its blending &<RTIgt; a method selected from the group consisting of a phospholipid, a non-ioning agent, and a method in which the surfactant agent is dissolved in the oil phase or dispersed in the aqueous phase. 9. The method of claim 8 to the fine mussel, wherein Phospholipids are selected from the group consisting of egg yolk phosphorus, soybean phospholipids, hydrogen sulphate, egg yolk lecithin, hydrogenated soybean egg phosphorus = phosphorus pentaphyllum; nonionic surfactants selected from Tween 20, Tween 40, Tween 60, Tween 8 〇, 5 Ί ^ β 吐 spit / dish 85, Spa 20, Span 40, two, Spa 80, polyoxygen, sesame oil, polyoxyethylene =, polyoxymethylene stearic acid brewing, moor (four) 188 , polyethylene glycol hard wide polyethylene glycol, raw E lyophilized vinegar or a mixture thereof. The method according to any one of the items 1 to 9 of the invention, wherein the step of the emulsion contains a stabilizer, a solubilizer, a cosolvent, a gold, a osmotic agent, One or more of an antioxidant or a preservative. Ut. The method of claim 1, wherein the antioxidant is from a water/complex oxygenating agent or an oil-soluble antioxidant, and the water-soluble antioxidant is dissolved in an aqueous phase. The antioxidant is dissolved in the oil phase, and the water-soluble antioxidant is selected from the group consisting of sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, ascorbic acid, sodium ascorbate, L-cysteine or a mixture thereof. The soluble antioxidants are selected from "tocopherol, alpha-tocopherol tocopherol, alpha-tocopherol saponin 95060 25 201223560, tert-butyl-(tetra)- or di-tert-butyl-p-type. 12.2 = range 1st 〇 The method described in the item, wherein the metal chelate: 自: from ethylamine tetralithic acid, ethylenediaminetetraacetic acid disodium salt, ethylenediaminetetraacetic acid dicalcium salt or a mixture thereof. 13·If the application 鄕(4) 1G shot The branch, the osmotic pressure::: a method according to the first aspect of the glycerin, sorbitol, mannitol, glucose, sodium chloride or paste, wherein the stabilizer is self-, sodium oleate , cholesterol, bile acid, sodium cholate, deoxycholic acid, sodium deoxycholate or a mixture thereof. 15=^利_method as described in item 10 The preservative + sesame oil, propylene glycol, sorbitol, sorbic acid, formic acid, p-hydroxy dimethyl hydrazine g #5, methyl p-hydroxybenzoate, p-propyl benzoate, benzyl alcohol, benzene One or more of formic acid. The method described in claim 10, wherein the co-solvent, self-oleic acid (tetra), benzoic acid vinegar, benzyl alcohol, lactic acid, ethanol, 2-propanol, poly The method of any one of the above-mentioned items, wherein the drug is for the treatment of a human or animal body disease (IV) active ingredient. The method of any one of clauses 1 to 17, wherein the drug-loaded emulsion is a topical, oral or parenteral dosage form. The method of claim 18, wherein the drug-loaded Mfr pulse The method of any one of the invention, wherein the therapeutically effective amount of the drug is added to the blank, the method of any one of the inventions, wherein the therapeutically effective amount of the drug is added to the blank. In the emulsion, the food: the pH value is the oil-water partition coefficient of the drug. °. That is, 2L, as in the method of claim 1, wherein the drug is selected from the group consisting of an antineoplastic drug, a cardiovascular drug, an antiinfective drug, an antibacterial agent, an antiviral drug, Antiallergic, anti-inflammatory, endocrine, psychotropic antibiotics, immunosuppressive agents, vitamins or anesthetics. _ 22.^ The method described in any of the claims 1 to 17 The medicated emulsion is a venous, intradermal, subcutaneous, intramuscular, intra-articular or intra-abdominal administration. The method of any one of the first to seventh aspects of the invention, the drug-loaded emulsion Formulation for intravenous administration. The method described in Item 1, wherein the amount of the chemical is added to change the phase transition temperature of the emulsion or to perform high energy. 95060 27 201223560 IV. Designated representative map: There is no schema in this case (1) The representative representative figure of this case is: (). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: This case does not represent the chemical formula 2 95060