KR20150000112A - Method for Increasing the Stabilization of Pre-Emulsion - Google Patents

Abstract

In the present invention, provided is a method for stabilizing a pre-emulsion using an inline mixer, comprising the steps of supplying an insoluble organic compound, a solvent which dissolves the insoluble organic compound and a surfactant to an inline mixer; and manufacturing a pre-emulsion by mixing the insoluble organic compound, the solvent which dissolves the insoluble organic compound and the surfactant in the inline mixer, wherein the pre-emulsion is used for drugs, food products and cosmetic products and includes a mixture of 0.00001-10 parts by weight of the insoluble organic compound and 10-0.00001 parts by weight of the surfactant. In addition, the pre-emulsion whose particle size is 0.2-10 micrometers forms emulsion via hydration. In the present invention, the manufactured pre-emulsion does not use cremophor, which is a solubilizing agent and causes side effects to a human body, thereby reducing side effects to the human body.

Description

Method for Increasing Stability of Pre-emulsion [

The present invention relates to a method for increasing the stability of a pre-emulsion to a poorly soluble organic compound, and more particularly, to a method for enhancing the stability of a pre-emulsion which greatly improves homogeneity by using an in-line mixer .

A great deal of research has been conducted on the technology for solubilising poorly soluble organic compounds over the last several decades. Here, the poorly soluble organic compound is called a hydrophobic organic compound whose solubility in water is generally as low as not more than 0.5 mg / L. Unless otherwise specified, the present invention defines the main components used in medicines and foods among the poorly soluble organic compounds, generally referred to as poorly soluble organic compounds, and is defined in detail in Table 1.

Generally, a poorly soluble organic compound can exhibit a pharmacological action only in a dissolved state, and solubilization of the drug is closely related to the drug efficacy.

Therefore, the insoluble drug becomes absolutely necessary for the solubilization step.

If an insoluble drug is taken orally, it is not dispersed as a single molecule in the gastrointestinal tract and is not absorbed at all because it exists as a large aggregate.

In addition, if it is used as an eye drop or an injection, a poorly soluble organic compound is crystallized and a blood vessel is clogged to cause a blood clot, resulting in a great risk of life. Soluble organic compounds used in eye drops and injections are the most essential conditions.

The solubilization of a poorly soluble organic compound means a process in which a poorly soluble compound is efficiently enclosed in a carrier and made into a colloidal state or a state in which it is enclosed in fine particles without being precipitated in an aqueous solution. To date, the most commonly used solubilizing agent for solubilization is surfactants.

Surfactants are amphoteric compounds in which lipophilic groups and hydrophilic groups are present together in the molecule. Surfactants are classified into cationic surfactants, negative ion surfactants and amphoteric surfactants.

Examples of the cationic surfactant include high-grade halides, saccharide ammonium salts and alkylpyridinium salts, and anionic surfactants include soaps and alkylbenzenesulfonic acid salts, and amphoteric surfactants include phospholipids and the like.

When the surfactant is put into water, the hydrophobic hydrocarbon chains themselves gather in the water because of the hydrophobicity, and the hydrophilic groups meet in the shape of spheres to meet the water. The poorly soluble organic compound forms a micelle which is mainly distributed in the hydrophobic hydrocarbon chain. The micelles thus formed are arranged according to the type of solubilizing agent, such as a spherical shape, a long cylinder-shaped one-side implementation, and a circular disk-shaped circular shape.

The micelles thus formed can be formed variously according to the temperature, the concentration of the self-association, the structure of the solubilizing agent, and the like.

Solubilizing agents, on the other hand, can be divided into water-soluble and water-insoluble.

Examples of the water-soluble usable agent include propylene glycol type, glycerin, polyethylene glycol (PEG) type, poloxamer type, polysorbate type, cyclodextrin type, phospholipid type such as lecithin, Examples of zero oil include castor oil, olive oil and soybean oil, and examples of the acid include oleic acid and soybean fatty acid.

In the present invention, particularly, a method for stably solubilizing a poorly soluble organic compound using phospholipid, particularly lecithin, which is an amphoteric solubilizing agent and a water soluble solubilizer has been studied for a long time.

Although the present invention has been mainly studied as a representative solubilizer for low toxicity lecithin, it is not limited to a specific solubilizing agent.

It is an object of the present invention to provide a novel process for producing a highly homogeneous, stable phase-stable emulsion on oil-in-water (o / w) using a poorly soluble organic compound and a solubilizing agent.

Generally, an emulsion is a liquid-liquid dispersion system in which two liquids which are not mixed with each other are dispersed in another liquid in the form of small droplets with a constant ratio, that is, in a state in which one or more liquid phases, , Which generally have various size distributions ranging from tens of nanometers to tens of micrometers.

The emulsions are classified in various physico-chemical aspects. In this patent, generally, Table 1 below is applied.

S.No Property Microemulsion Emulsion One Appearance Transparent (or translucent) Cloudy 2 Optical Isotropy Isotopic Anisotropic 3 Interfacial tension Ultra low High 4 Microstructure Dynamic (interface is continuously and spontaneously fluctuating) Static 5 Droplet size 20-200 nm > 500 nm 6 Stability Thermodynamically stable, long shelf-life Thermodynamically unstable (kinetically stable), will eventually phase separate 7 Phases Monophasic Biphasic 8 Preparation Facile preparation, relatively lower cost for commercial production Require a large input of energy, higher cost 9 Viscosity Low viscosity with Newtonian behavior Higher viscosity

It is called micro-emulsion when the droplet average diameter is 20-200 nm and it is called emulsion when the average particle diameter of the dispersed phase is 500 nm or more.

In general, the reason for producing a weakly soluble organic compound as an emulsion in medicine and food is to increase the water absorption rate by watering a poorly soluble organic compound.

When the emulsion is prepared from the emulsion, the content of the poorly soluble organic compounds trapped in the particles is dramatically increased, so that the amount of the poorly soluble organic compounds absorbed in the human body can be remarkably increased.

However, such emulsions are generally thermodynamically unstable and change to thermodynamically stable states such as flocculation, sedimentation, creaming, Ostwald ripening, and coalescence, In the end, it may have a property to be separated.

Conventionally, in order to solve the above-mentioned problem, the size of the emulsion particle is manufactured in the region of the microemulsion rather than the region of the emulsion. However, reducing the emulsion particle size could improve the stability of the emulsion in terms of kinetic, such as inter-particle Brownian motion, but ultimately the homogeneity between the particles is low, resulting in van der Waals attraction The emulsion is recrystallized and a poorly soluble organic compound is precipitated. Thus, it is very difficult to solve a pending problem of manufacturing a stabilized emulsion.

When the size of the emulsion particle is reduced to the microemulsion region, the stability of the emulsion can be relatively improved, and the cell permeability of the emulsion particle can be dramatically increased. However, when the size of the emulsion particle is small, the above-described merits are merely obtained. The content of the poorly soluble organic compound trapped in the surfactant or the emulsifier is significantly lower than that of the emulsion, and in order to realize the desired effect, There is a problem that a positive emulsion must be applied or taken.

Therefore, except for the case where the size of the emulsion particle is reduced to nano size and precise targeting is required due to an enhanced permeability and retention (EPR) effect or the like, an insoluble organic compound, which is captured by a surfactant or an emulsifier, It may be desirable to use particles in the emulsion region that can dramatically increase the content of the compound.

Therefore, in the case of the emulsion, the emulsion particles are prevented from being separated by various routes such as coagulation, sedimentation, creaming, particle growth and adhesion, and in the case of the microemulsion, recrystallized by the interfacial van der Waals attractive force, And ultimately the emulsion stability is dramatically increased.

Korean Patent No. 648515 relating to a method of stabilizing an emulsion has disclosed that a polymer solution prepared by dissolving and dispersing a bisphosphonate in an aqueous solution containing a water-soluble polymer and a hydrophilic surfactant is dispersed in a primary organic solvent containing a biodegradable polymer and a hydrophobic surfactant in an amount of 2 Treating a bone related disease comprising a bisphosphonate-containing polymer microparticle prepared by adding a primary emulsion solution (W / O) to a polymer solution prepared by adding a secondary organic solvent and dispersing the primary emulsion solution in an external continuous phase, or The present invention relates to an injection agent having a sustained-release effect.

Korean Patent No. 709015 also describes an invention relating to a polymer microparticle capable of continuous drug release and a manufacturing method thereof.

In US Pat. No. 5,616,330, taxol used as an anticancer agent and egg yolk lecithin using phospholipid was disclosed as an O / W emulsion injection, which is known to have a very low toxicity as compared with a formulation using a crèmeo solubilizer that has been developed previously have. In particular, US Pat. No. 5,616,330 is similar to the process of the present invention, but characterized in that it is homogenized using an ultra high speed mixer.

In addition, many patents and papers have been published which attempt to commercialize a poorly soluble compound as an emulsion or a microemulsion using a solubilizing agent as a medicine or a food.

The common point of many previous inventions and known papers in the process of manufacturing the emulsion is that the technique of making and homogenizing the liquid droplets under the condition that the droplet size can be controlled at a constant level is very important and the stability difference of the emulsion is determined thereby It is known.

Thus, in a situation in which a new technique for homogenizing in the production of a more stable emulsion is required, the researchers involved in the present invention have found, through a great deal of time and effort, a new homogenization preparation method , Thereby inventing a technique for producing more stable emulsions or microemulsions.

 The disclosures of the cited patents and patents are hereby incorporated by reference herein in their entirety, and the contents of the present invention may be more clearly described.

The present inventors have found that when preparing an emulsion in which many poorly soluble organic compounds used in medicines and foods are prepared, it is possible to make the emulsified organic compound soluble in water by the recrystallization precipitation action by the van der Waals attractive force between the emulsion particles The emulsion stability is remarkably lowered, and a lot of studies have been conducted to solve this problem.

As a result, it is possible to produce a pre-emulsion using a homogenizer (hereinafter referred to as an in-line mixer) containing a concept of re-mixture after putting a surfactant, a poorly soluble organic compound and the like used in conventional emulsion production, It has been found that when the emulsion is dispersed in water, the homogeneity between the emulsion particles is greatly improved and the stability of the emulsion is remarkably improved, thereby completing the present invention.

Accordingly, an object of the present invention is to provide a pre-emulsion stabilization method using an in-line mixer.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

The present invention provides a method for homogenizing a more stable emulsion for insoluble organic compounds.

The present inventors have found that when preparing an emulsion in which many poorly soluble organic compounds used in medicines and foods are prepared, it is possible to make the emulsified organic compound soluble in water by the recrystallization precipitation action by the van der Waals attractive force between the emulsion particles The emulsion stability is remarkably lowered, and a lot of researches have been conducted to solve the conventional emulsion research.

As a result, it is possible to produce a pre-emulsion using a homogenizer (hereinafter referred to as an in-line mixer) containing a concept of re-mixture after putting a surfactant, a poorly soluble organic compound and the like used in conventional emulsion production, It was confirmed that when the emulsion was dispersed in water, the homogeneity between the emulsion particles was greatly improved and the stability of the emulsion was remarkably improved.

According to one aspect of the present invention, the present invention provides a method for producing a water-soluble organic compound, comprising the steps of supplying a poorly soluble organic compound, a solvent capable of dissolving the poorly soluble organic compound, and a surfactant to an inline mixer, Mixing a solvent capable of dissolving the soluble organic compound and a surfactant with the inline mixer to prepare a pre-emulsion, wherein the pre-emulsion is used for medicines, foods and cosmetics , The insoluble organic compound and the surfactant are mixed at a weight ratio of 0.00001: 10 to 10: 0.00001, the particle size of the pre-emulsion is 0.2-10.0 탆, and the pre-emulsion is hydrated to form an emulsion. To provide a pre-emulsion stabilization method.

As used herein, the term " pre-emulsion stabilization " may mean a state in which the high temperature stability, low temperature stability and gravity or centrifugal stability of the pre-emulsion are increased.

As used herein, the term "pre-emulsion" may refer to a solid, liquid or a mixture thereof that forms an emulsion when dispersed in a solvent comprising water.

The term 'macro-emulsion' as used herein may mean an emulsion having an average particle size of the emulsion of 0.5 nm or more.

The term "micro-emulsion" as used herein may mean an emulsion in which the average particle size of the emulsion is less than 0.5 nm.

Meanwhile, the term 'emulsion' in the present specification may mean a state in which one of two liquids which do not melt each other is dispersed in a small particle state on the other side.

The emulsion may be the emulsion or microemulsion.

The term " dissolving, hydrating, hydrating or dissolving " as used herein refers to conventional dissolution, emulsification, liposomal and KR Patent Application No. 10-2012-0027176 (entitled " ) And KR Patent Application No. 10-2012-0027177, entitled Abrasive Interphase Material Containing a Fatty Acid Having a Linear Alkyl Chain.

The emulsion stabilization method according to an embodiment of the present invention includes a supply step of supplying a poorly soluble organic compound, a solvent capable of dissolving the poorly soluble organic compound, and a surfactant to an inline mixer.

The 'poorly soluble organic compound' can be understood to mean that the solubility in water is 0.5 mg / L or less. The 'poorly soluble' means that the pharmacologically active agent is dissolved in an aqueous solution (eg, water, physiological saline, Strose solution or the like).

The above " poorly soluble " will be described in more detail based on the meaning of the solubility. As shown below. USP / NF generally expresses solubility as the volume of solvent required to dissolve 1 gram of drug at a specific temperature (eg, 1 g aspirin in 300 ml H2O, 5 ml ethanol at 25 ° C). In other references, solubility can be described using more subjective terms, such as those given in Table 2, set forth in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., Latest edition.

Technical term Part of solvent required per solute solute Very High Availability <1 High availability 1 to 10 Availability 10 to 30 Insufficient Availability 30 to 100 Low availability 100 to 1000 Very low availability 1000 to 10,000 Substantially insoluble or insoluble > 10,000

Therefore, the term "insoluble" of the present invention means that the lower four solubility categories of Table 1, i.e., "insufficient availability", "low availability", " Quot; substantially insoluble or insoluble "as used herein.

The poorly soluble organic compound may include a pharmaceutically active agent, a diagnostic agent, a nutritional agent, and the like.

Examples of pharmaceutically active agents include analgesics / antipyretics such as aspirin, acetaminophen, ibuprofen, sodium naproxen, buprenorphine hydrochloride, propoxyphene hydrochloride, propoxyphenaphthylate, meperidine hydrochloride, Morpholine hydrochloride, morphine sulfate, oxycodone hydrochloride, codeine phosphate, dihydrocodeain bitartrate, pentachosine hydrochloride, hydrocodone bitartrate, levorphanol tartrate, dipulose, trollamine salicylate, nalbuphine Hydrochloride, mefenamic acid, butorphanol tartrate, choline salicylate, butalbital, phenyltoloxamine citrate, diphenhydramine citrate, methotrimeprazine, cinnamoldine hydrochloride, meflobamate, etc.); Anesthetics such as cyclopropane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, propol, and the like; Anti-asthmatics (e.g., Azelastine, Ketotifen, Traxanox, etc.); Antibiotics such as neomycin, streptomycin, chloramphenicol, cephalosporin, ampicillin, penicillin, tetracycline, etc .; Antidepressants such as neophorp, oxypertin, oxepin hydrochloride, amoxapine, trazodone hydrochloride, amitriptyline hydrochloride, mafrotiline hydrochloride, phenelzine sulfate, desipramine hydrochloride, nortryptyline hydro- But are not limited to, chloride, tranylcyclopropamine sulfate, fluoxetine hydrochloride, toxepine hydrochloride, imipramine hydrochloride, imipramine pamoate, nortriptyline, amitriptyline hydrochloride, isocarboxaldehyde, Chloride, trimipramine maleate, protriptyline hydrochloride, etc.); Antidiabetic agents (eg, biguanides, hormones, sulfonylurea derivatives, etc.); Antifungal agents such as Griseofulvin, Keloconazole, Amphotericin B, Nystatin, Candididin, etc .; Antihypertensive agents such as propranolol, propaphenone, oxyprenolol, nifedipine, reserpine, trimapan camsylate, phenoxybenzamine hydrochloride, pargyline hydrochloride, Side, guanethidine monosulfate, minoxidil, rescinamin, sodium nitroproxide, rauwapiacypentina, alkoxycellone, phentolamine mesylate, reserpine, etc.); Anti-inflammatory agents such as (non-steroidal) indomethacin, naproxen, ibuprofen, lamifenazone, piroxycam, (steroidal) cortisone, dexamethasone, fluazacort, hydrocortisone, prednisolone, prednisone etc.); But are not limited to, antineoplastic agents such as adriamycin, cyclophosphamide, actinomycin, bleomycin, doanorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, , Methyl-CCNU, cisplatin, etoposide, interferon, camptothecin and derivatives thereof, phenesterin, taxanes and derivatives thereof (e.g., paclitaxel and derivatives thereof, docetaxel and derivatives thereof), vinblastine, , Tamoxifen, polypsulfan, etc.); Anxiolytics such as lorazepam, buspirone hydrochloride, plazepam, chlordia vaccinated hydrochloride, oxazepam, chlorazepate dipotassium, diazepam, hydroxyzin pamoate, hydroxyzine hydrochloride, alprazolam, Peridol, halazepam, chlormezanone, dantrolene, etc.); Immunosuppressants (e.g., cyclosporine, azathioprine, mizoribine, FK506 (tacrolimus), etc.); Anti-migraine agents (e.g., ergotamine tartrate, propanolol hydrochloride, isomepentenemukate, dichloralphenazone, and the like); (Such as benzodiazepines, such as benzodiazepines, such as fluazepam hydrochloride, triazolam, tomazepam, midazolam hydrochloride, etc); For example, anti-angina agents such as beta-adrenergic blockers, calcium channel blockers such as nifedipine, dithiazem hydrochloride and the like; nitrates such as nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, Trityl tetranitrate, etc.), etc.); It is also possible to use antipsychotic agents such as haloperidol, rossaffin succinate, rossaffin hydrochloride, thioridazine, thioridazine hydrochloride, thiothicene, fluphenazine hydrochloride, fluphenazine decanoate, fluphenazine enanthate, Triflouroperazine hydrochloride, chlorpromazine hydrochloride, perphenazine, lithium citrate, prochlorperazine, etc.); Antimanic agents such as lithium carbonate and the like; The use of antiarrhythmic agents such as Bretylium Tosylate, Esolol Hydrochloride, Verapamil Hydrochloride, Amiodarone, Enchainide Hydrochloride, Digoxin, Digitoxin, Mexyletin Hydrochloride, Dysopyrimidophosphate, Procainamide Hydrochloride, Quinidine Sulfate , Quinidine gluconate, quinidine polygalacturonate, flecainide acetate, toconeide hydrochloride, lidocaine hydrochloride, etc.); An anti-arthritic agent such as phenylbutazone, sulindac, penicillamine, salsarate, piroxycam, azathioprine, indomethacin, sodium meclofenamate, gold sodium thiomaleate, ketoprofen, oranopin , Aurothioglucose, tolmetin sodium, and the like); Antigout agents (e.g., colchicine, alophorinol, etc.); Anticoagulants (such as heparin, sodium heparin, warfarin, etc.); Thrombolytic agents (eg, urokinase, streptokinase, altoplast, etc.); Anti-fibrinolytic agents such as aminocaproic acid; Hemorheologic agents (such as pentoxyfilin); Antiplatelet agents (e.g., aspirin, ampicillin, aprilatin, etc.); Anticonvulsants such as valproic acid, divalproate sodium, phenytoin, sodium phenytoin, clonazepam, pyrimidone, phenobarbitol, phenobarbitol sodium, carbamazepine, amobabtol sodium, Diphenylmethane, diphenylmethane, diphenylmethane, diphenylmethane, diphenylmethane, diphenylmethane, diphenylmethane, diphenylmethane, diphenylmethane, diphenylmethane, diphenylmethane, diphenylmethane, diphenylmethane; Antiparkinsonian agents (e.g., ethosuximide); Antihistamine / antiprotonic agents such as hydroxyzine hydrochloride, diphenhydramine hydrochloride, chlorpheniramine maleate, brompenilamine maleate, cyproheptadine hydrochloride, terfenadine, clemastine fumarate, triprolidine hydro Chloride, carbinoxamine maleate, diphenylpyraline hydrochloride, penicillamine tartrate, azatadine maleate, tripelenamine hydrochloride, dexchlorpenilamine maleate, metdilazin hydrochloride, trimprazine tartrate, etc.) ; Agents useful for calcium modulation (e.g., calcitonin, parathyroid hormone, etc.); (Eg, amikacin sulfate, aztreonam, chloramphenicol, chloramphenicol palmitate, chloramphenicol sodium succinate, ciprofloxacin hydrochloride, clindamycin hydrochloride, clindamycin palmitate, clindamycin phosphate, metronidazole, metronidazole hydrochloride, gentamicin sulfate , Lincomycin hydrochloride, tobramycin sulfate, vancomycin hydrochloride, polymyxin B sulfate, colistin sodium, colistin sulfate, etc.); Antiviral agents such as interferon gamma, zidovudine, amantadine hydrochloride, ribavirin, acyclovir, and the like; The use of an antimicrobial agent such as a cephalosporin such as cephazoline sodium, cephradine, cepharchlor, cephapirin sodium, ceftioxan sodium, cell ferazon sodium, celltetanedisodium, Cephadoxine sodium, cepanid, ceftriaxone sodium, ceftazidone sodium, cephalexin hydrochloride monohydrate, sephadoxaline sodium, cephadoxine sodium, Amoxicillin, penicillin G benzotin, ciclassin, ampicillin sodium, penicillin G potassium, penicillin V potassium, piperacillin sodium, oxalic acid, sodium cadmium, Sodium silicate, bacampicillin hydrochloride, sodium chlorophyllin sodium, tricarcillin disodium, azulocillin sodium, carbenicillin indanylnat Such as erythromycin ethylsuccinate, erythromycin, erythromycin esters, erythromycin lactobionate, erythromycin, erythromycin, erythromycin, erythromycin, Erythromycin ethyl succinate, etc.), tetracyclines (e.g., tetracycline hydrochloride, doxycycline hydrochloride, minocycline hydrochloride, etc.)); Anti-infectives such as GM-CSF; Bronchodilators (e.g., sympathomimetic agents such as epinephrine hydrochloride, metaproterenol sulfate, terbutaline sulfate, isoetharine, isoetharin mesylate, isoetharine hydrochloride, albuterol sulfate, (Eg, albuterol, bitolterol, mesylate isoproterenol hydrochloride, terbutaline sulfate, epinephrine bitartrate, metaproterenol sulfate, epinephrine, epinephrine bitartrate), anticholinergics (eg, ipratropium bromide Etc.), xanthines (e.g., aminophylline, dipyrine, metaproterenol sulfate and aminophylline), mast cell stabilizers (such as sodium cromolyn), inhaled corticosteroids (e.g., Bechromethasone dipropionate, beclomethasone dipropionate monohydrate, etc.), Salbutamol, Bee But are not limited to, chlomethasone dipropionate (BDP), ipratropium bromide, budesonide, kettifen, salmeterol, xanthate, terbutaline sulfate, triamcinolone, theophylline, nedocromil sodium, metaproterenol sulfate , Albuterol, flunisolid, etc.); Hormones such as androgens (such as danazol, testosterone cypionate, fluoxymasterone, ethyltosterosterone, testosterone enanate, methyltestosterone, fluoxymasterone, testosterone cypionate, etc.), estrogens Diethanolamine, dexamethasone sodium phosphate, dexamethasone acetate, dexamethasone acetate, dexamethasone acetate, dexamethasone acetate, dexamethasone acetate, dexamethasone acetate and the like), progestins (e.g., methoxyprogesterone acetate, norethindrone acetate and the like), corticosteroids (e.g., triamcinolone, betamethasone, betamethasone sodium phosphate, dexamethasone sodium phosphate, , Methylprednisolone acetate suspension, triamcinolone acetonide, methylprednisolone, prednisolone sodium phosphate methylprednisolone sodium succinate, hydrocortisone sodium succinate, methylprednisolone sodium salt Prednisolone Tetrahlate, Prednisolone Sodium Phosphate, Prednisolone Sodium Phosphate, Hydrocortisone Sodium Succinate, etc.), Thyroid Hormone (Thyroid Hormone), Thyroid Hormone (Hydroxycortisone Hormone, Hydrocortisone, Hydrocortisone Ciphenate, For example, levothyroxine sodium, etc.); Hypoglycemic agents such as human insulin, refined insulin, refined pork insulin, glyburide, chlorpropamide, glyphedide, tolbutamide, tolazamide, etc.); Hemolytic agents such as clofibrate, sodium dextrothoxine, probucol, lovastatin, niacin and the like; Proteins (such as DNase, Alginase, superoxide dismutase, lipase, etc.); Nucleic acid (e.g., a sense or anti-sense nucleic acid encoding any therapeutically useful protein comprising any of the proteins described herein); Agents useful in hematopoietic stimulation (e.g., erythropoietin and the like); Anti-ulcer / anti-reflux agents (eg, famotidine, cimetidine, ranitidine hydrochloride, etc.); Antiepileptic / antiepidemic agents (eg, methicillin hydrochloride, nevallone, prochlorperazine, dimenhydrinate, promethazine hydrochloride, thiethylferrazine, scopolamine, etc.); Fat-soluble vitamins (eg, vitamins A, D, E, K, etc.); As well as other drugs such as mitotan, bisadin, halitnitrosourea, antrocyclin, ellipticine, and the like.

Further examples of insoluble organic compounds as pharmacologically active agents may include the compounds listed in " Therapeutic Category and Biological Activity Index "of The Merck Index (12th Ed '

Latanoprost, Bimatoprost, Travoprost, Amphotericin B, Cyclosporin A, Taxol, Docetaxel and the like which are used in the following examples of the present invention are typical substances included in the poorly soluble drugs and have been conventionally used in liposome form or emulsified form. Furthermore, the development of stabilized emulsions is becoming more important because the routes of administration of these drugs are used as eye drops and injections.

The term &quot; surfactant &quot; used throughout this specification is a compound having a hydrophilic moiety and a hydrophobic moiety at the same time in a molecule. Surfactant molecules gather at a certain concentration to form a micelle structure. Micelles are formed when the concentration of the surfactant is above the critical micelle concentration and the temperature is above the critical micelle temperature (Kraft temperature). When the micelles are formed in water, the hydrophobic portion of the surfactant collects at the center to form nuclei and the hydrophilic portion forms an outer portion in contact with the water. Like oil, hydrophobic materials are located in the inner part of the micelle and stabilize and dissolve in water, which is called solubilization. Therefore, even if not mentioned otherwise, the surfactant can be understood as a concept including an emulsifier.

The surfactant is preferably a surfactant or emulsifier having two or more hydrophobic alkyl chains, more preferably lecithin, hydrogenated lecithin, PEG-30 dipolyhydroxystearate, , Polyglyceryl-2 Dipolyhydroxystearate, Polyglyceryl-2 diisostearate, PEG-150 Pentaerythritol tetrastearate (PEG-150 Pentaerythrityl Tetrastearate) and polyglyceryl-2 triisostearate, and most preferably may be lecithin or hydrogenated lecithin.

Natural lecithin includes soy lecithin and egg yolk lecithin, all of which are referred to in the present invention as lecithin unless otherwise specified.

According to one embodiment of the present invention, the surfactant may be a natural surfactant or a synthetic surfactant.

Natural surfactants include at least one interface selected from the group comprising soy lecithin, egg yolk lecithin, hydrogenated lecithin (hydrogenated soy lecithin and hydrogenated egg lecithin), sphingosine, ganglioside and phytosphingosine But are not limited thereto.

Natural lecithin is a mixture of diglycerides of stearic acid, palmitic acid and oleic acid linked to a choline ester of phosphoric acid, commonly referred to as phosphatidylcholine, and can be obtained from a variety of sources such as eggs and soybeans. Soybean lecithin and egg yolk lecithin (including hydrogenated lecithin) have long been safe in biological systems, have both emulsifying and solubilizing properties, and tend to degrade faster than most synthetic surfactants in a more harmless way. Commercially available soybean lecithins include Centrophase and Centrolex products [Central Soya], Phospholipon [Phospholipid GmbH, Germany], Lipoid [Lipoid GmbH, Germany] and EPIKURON [Degussa].

Hydrogenated lecithin is a hydrogenated product in which double bonds held by natural lecithin are reduced, and can be included in the technical idea of the present invention.

According to the USP, lecithin is composed of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphotidylinositol, mixed with various substances such as triglycerides, fatty acids and carbohydrates in various amounts. Acetone-insoluble phospholipids.

Pharmaceutically, lecithin is primarily used as a dispersant, emulsifier and stabilizer, and is included in intramuscular and intravenous injections, parenteral nutritional formulations and topical products. Lecithin is also listed in the FDA Inactive Ingredients Guide for inhalants, IM and IV injections, oral capsules, suspensions and tablets, rectal preparations, topical preparations and vaginal preparations.

Synthetic surfactants include, but are not limited to, diacylglycerols, phosphatidic acids, phosphocholines, phosphoethanolamines, phosphoglycerols, phosphoserines, mixed straight chain phospholipids, lysophospholipids and pegylated phospholipids Specific examples of the diacylglycerols and the like include, but are not limited to, the following:

Diacylglycerol

Di-lauroyl-sn-glycerol (DLG)

Di-myristoyl-sn-glycerol (DMG)

1,2-dipalmitoyl-sn-glycerol (DPG)

1,2-distearoyl-sn-glycerol (DSG)

Force Partidansan

Di-myristoyl-sn-glycero-3-phosphatidic acid, sodium salt (DMPA, Na)

Sodium glycero-3-phosphatidic acid, sodium salt (DPPA, Na)

1,2-distearoyl-sn-glycero-3-phosphatidic acid, sodium salt (DSPA, Na)

Phosphocholine

Di-lauroyl-sn-glycero-3-phosphocholine (DLPC)

Di-myristoyl-sn-glycero-3-phosphocholine (DMPC)

1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)

1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)

Phosphoethanolamine

Di-lauroyl-sn-glycero-3-phosphoethanolamine (DLPE)

Di-myristoyl-sn-glycero-3-phosphoethanolamine (DMPE)

1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE)

1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)

Phosphoglycerol

Di-lauroyl-sn-glycero-3-phosphoglycerol, sodium salt (DLPG)

1,2-dimyristoyl-sn-glycero-3-phosphoglycerol, sodium salt (DMPG)

Glycero-3-phospho-sn-1-glycerol, ammonium salt (DMP-sn-1-G, NH4)

1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, sodium salt (DPPG, Na)

1,2-distearoyl-sn-glycero-3-phosphoglycerol, sodium salt (DSPG, Na)

1-glycerol, sodium salt (DSP-sn-1G, Na), 1,2-

Phosphoserine

Phosphol-3-phospho-L-serine, sodium salt (DPPS, Na)

Mixed chain phospholipids

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, sodium salt (POPG, Na)

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, ammonium salts (POPG, NH4)

Lysozyme

1-palmitoyl-2-litho-sn-glycero-3-phosphocholine (P-

1-stearoyl-2-litho-sn-glycero-3-phosphocholine (S-

Pegylated phospholipids

N- (carbonyl-methoxypolyethylene glycol 2000) -MPEG-2000-DPPE

Sodium 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, sodium salt

N- (carbonyl-methoxypolyethylene glycol 5000) -MPEG-5000-DSPE

1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt

N- (Carbonyl-methoxypolyethylene glycol 5000) -MPEG-5000-DPPE

Sodium 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, sodium salt

N- (carbonyl-methoxypolyethylene glycol 750) -MPEG-750-DSPE

1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt

N- (Carbonyl-methoxypolyethylene glycol 2000) -MPEG-2000-DSPE

1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt

Wherein the organic poorly soluble organic compound and the surfactant are mixed in a weight ratio of 0.00001: 10 to 10: 0.00001, and the solvent capable of dissolving the poorly soluble organic compound and the poorly soluble organic compound is 0.00001: 10 to 10: 0.00001 weight ratio and supplied to the inline mixer. A more stable pre-emulsion can be produced by the above-mentioned range.

Preferably, the poorly soluble organic compound and the surfactant are mixed at a weight ratio of 1: 1 to 1: 10000, and the solvent capable of dissolving the poorly soluble organic compound and the poorly soluble organic compound is mixed at a ratio of 1: 0.5 to 1: 100000 weight ratio and supplied to the inline mixer. In the above range, excessive use of the surfactant is prevented, and the stability of the pre-emulsion to the poorly soluble organic compound is high.

The average particle size of the pre-emulsion according to an embodiment of the present invention may be preferably 0.1-10.0 mu m, more preferably 0.1-10.0 mu m, and most preferably 0.5-4.0 mu m , The amount of the poorly soluble organic compound and the surfactant contained therein, the stirring time of the inline mixer, the stirring pressure, and the like, the average particle size of the pre-emulsion can be freely adjusted.

The pharmaceutically usable solvent capable of dissolving the poorly soluble organic compound may be selected from the group including polyols, natural oils, hydrocarbon oils, higher alcohols and ester oils. The solvent can be freely used if it is a solvent capable of dissolving the poorly soluble organic compound. However, considering the properties of the poorly soluble organic compound, the amount of the solvent used can be minimized and the emulsion safety can be maximized It is preferable to use a solvent.

The emulsion stabilization method according to an embodiment of the present invention includes a step of mixing the poorly soluble organic compound, a solvent capable of dissolving the poorly soluble organic compound, and a surfactant in the inline mixer after the supplying step to prepare a pre-emulsion Step &lt; / RTI &gt;

The 'in-line mixer' is used to significantly increase the homogeneity of the pre-emulsion. The 'in-line mixer' is a step in which the phase separation step, the rotational circulation step or the radial mixing step Or a device that can be brought into simultaneous action.

Conventionally, there has already existed a mixer or a homogenizing device having stirring ability or homogeneity such as the above-mentioned inline mixer such as a microfluidizer or a high-pressure homogenizer. However, the pre-emulsion and the emulsion of the present invention were produced only through the above-described inline mixer, and could not be produced by a stirrer or a homogenizer such as a microfluidizer or a high-pressure homogenizer as well as a general mixer.

When we think about the reason, generally, in the case of high pressure homogenizer or microfluidizer, it is a mechanism to crush and stir a specific substance by transmitting strong physical force to one or more places. However, when moving away from the site, the physical force to be transmitted is weakened, and basically, the site is forced to be less crushed than the site where the force is transmitted. Thus, although the particles can be finely pulverized and agitated, it can not be concluded that the homogeneity of the produced particles becomes constant or forms a stabilized emulsion.

However, in the case of the above-mentioned inline mixer, the added surfactant, poorly soluble organic compound, etc. are divided into 1/2 to 1/10 of the unit blades each time they pass through the unit blades included in the tube of the inline mixer, do.

In addition, as the process of passing through the unit blade is repeated a lot, the amount and ratio of the poorly soluble organic compound and the surfactant to be combined are quantified in proportion to the input amount and the input ratio of the poorly soluble organic compound and the surfactant, .

Although the proportion and / or the amount of the poorly soluble organic compound and the surfactant to be combined are not quantitative in the initial stirring step, the proportion and amount of the poorly soluble organic compound and the surfactant to be bound are quantified as the stirring progresses, When the surfactant and the poorly soluble organic compound quantitatively measured in terms of ratio and quantity are combined, the sizes of the surfactant and the poorly soluble organic compound are almost the same and the homogeneity of the resulting material is remarkably increased.

Therefore, the use of the inline mixer in the present invention is the most essential component.

The use of the inline mixer to produce a pre-emulsion or emulsion produced by the process of the present invention is an essential component, but does not limit the use of other stirrers or homogenizers in parallel with the use of the inline mixer.

According to one embodiment of the present invention, the pre-emulsion or emulsion prepared by the method of the present invention may be a pharmaceutical composition.

When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the formulation and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans in various routes such as oral or parenteral routes such as oral, rectal or intravenous, muscular, subcutaneous, intra-uterine, Can be administered by injection. Preferably, it is applied by transdermal administration during parenteral administration, more preferably by topical application by application.

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The dose of the pharmaceutical composition of the present invention can be administered in an amount of 0.1-100 mg / kg on an adult basis once or several times a day in the case of an oral formulation, and in the case of an external preparation, It is preferable to apply it once to 5 times a day in an amount of 3.0 ml and continue for 1 month or longer. However, the dosage is not intended to limit the scope of the present invention.

The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in any form suitable for pharmaceutical preparations including oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations such as ointments and creams, suppositories and sterile injectable solutions, , Dispersants, or stabilizers.

According to one embodiment of the present invention, the pre-emulsion or emulsion prepared by the method of the present invention may be a food composition.

When the composition of the present invention is prepared with a food composition, it includes not only the active ingredient, but also ingredients normally added during the manufacture of the food, including, for example, proteins, carbohydrates, fats, nutrients, flavoring agents and flavoring agents . Examples of the above-mentioned carbohydrates are monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavorings such as tau martin and stevia extract (e.g., rebaudioside A and glycyrrhizin) and synthetic flavorings (saccharine, aspartame, etc.) can be used as flavorings.

For example, when the food composition of the present invention is prepared as a drink, it may further contain citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, mulberry extract, jujube extract, licorice extract, have.

According to another aspect of the present invention, there is provided an emulsifying apparatus comprising: an emulsification tank containing a mixture of a poorly soluble organic compound, a solvent capable of dissolving the poorly soluble compound, and a surfactant; A circulation pipe connecting the lower side and the upper side of the emulsification tank; A pump installed in the circulation pipe; An inline mixer installed in the circulation pipe and through which the mixture passes and is emulsified by operation of the pump; And a discharge pipe connected to the lower side of the emulsion tank or the circulation pipe.

 Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.

FIG. 9 is a flow diagram of an emulsifying apparatus according to an embodiment of the present invention.

9, the emulsifying apparatus 1 according to the embodiment of the present invention includes an inline mixer 10, an emulsification tank 20, an inflow pipe 30, circulation pipes 40 and 50, a circulation valve 41 A pump 60, a discharge pipe 70, a discharge valve 71, and a mixer 80. [

A mixture C to be emulsified is accommodated in the emulsion tank 20. An inflow pipe 30 is connected to the upper side of the emulsifying tank 20 so that the mixture C or the like as described above can be introduced into the emulsifying tank 20.

Circulation pipes 40 and 50 are connected to the lower side and the upper side of the emulsification tank 20. The circulation pipes 40 and 50 are provided with an inline mixer 10, a circulation valve 41 and a pump 60.

The circulation valve 41 is provided in the circulation pipe 40 connected to the lower side of the emulsification tank 20 so that the mixture C flows or does not flow through the circulation pipe 40 when the circulation valve 41 is opened or closed .

The mixer 80 may be installed below the emulsifying tank 20 as shown. The mixer 80 can be used in a case where the degree of homogenization of the mixture C introduced into the emulsion tank 20 through the inlet pipe 30 is extremely low, that is, when a relatively large solid or liquid particle exists in the mixture C, Can be reduced.

The discharge pipe 70 is connected to the lower side of the emulsifying tank 20 and the discharge pipe 70 is provided with a discharge valve 71. When the discharge valve 71 is opened after the completion of the emulsification for the mixture C, the emulsified mixture C can be discharged to the outside of the emulsion tank 20 through the discharge pipe 70.

When the circulation valve 41 is opened and the pump 60 is operated, the mixture C is circulated through the circulation pipe 40 connecting the lower side of the emulsification tank 20 and one side of the inline mixer 10 to the inline mixer 10 ). The mixture C having passed through the inline mixer 10 flows into the emulsion tank 20 through the circulation pipe 50 connecting the upper side of the emulsion tank 20 and the other side of the inline mixer 20.

The inline mixer 10 reduces the particle size of the material contained in the passing mixture C, while at the same time allowing the size of the reduced particles to be uniform. To this end, the in-line mixer 10 may include flow division, rotational circulation, and radial mixing, etc., in the flow of the mixture C while the mixture C passes through the inline mixer 10 .

The emulsifying apparatus 1 having the above-described connection relationship is operated as follows.

First, the mixture C to be emulsified is introduced into the emulsion tank 20 through the inlet pipe 30, and then the mixer 80 is operated as necessary to increase the mixing ratio of the mixture C, C to be reduced in size.

Thereafter, when the circulation valve 41 is opened and the pump 60 is operated, the mixture C passes through the circulation pipe 40 through the inline mixer 10 and then flows into the emulsion tank 20 through the circulation pipe 50 Circulated. Thus, the mixture C is repeatedly passed through the inline mixer 10 to increase the degree of emulsification.

If it is determined that the mixture C has been sufficiently emulsified, the operation of the pump 60 is stopped and the circulation valve 41 is shut off. Then, the discharge valve 71 is opened to emulsify the mixture C through the discharge pipe 70 To be discharged.

Thus, the mixture C can be emulsified by the emulsification apparatus 1 to have a very high homogeneity.

The inline mixer 10 may have a channel resistance of a certain level or more in order to sufficiently generate the surface division, the redirection, and the blending in the flow of the mixture C in the inline mixer 10. [

Therefore, the pump 60 should be able to apply a sufficient discharge pressure to the mixture C flowing into the inline mixer 10 through the circulation pipe 40 and prevent backflow. A plunger pump or a gear pump may be used as the pump 60 for this purpose. The plunger pump and gear pump are well known and will not be described further.

Fig. 10 is a partial cross-sectional view of the inline mixer shown in Fig. 9, and Fig. 11 is a perspective view for explaining the structure of the blade shown in Fig. 10 and 11 together.

10, the blades 11 and the pressure-resistant pipe 12 are included in the inline mixer (10 in Fig. 9).

The pressure-resistant tube 12 is a hollow tube manufactured to withstand a high pressure, and both ends are coupled to a circulation tube (40, 50 in Fig. 1) as shown in Fig. At this time, the inline mixer 10 may be detachably coupled to the circulation pipe (40, 50 in FIG. 9) in order to replace the inline mixer 10 for reasons such as aging of the inline mixer 10 .

The blade (11) is disposed in the pressure-resistant pipe (12).

The blade 11 includes a plurality of unit blades 11a arranged in a row in the pressure vessel 12 as shown in the figure and the unitary blade 11a includes a first element 110 and a second element 120 .

11, the first element 110 includes a first element body 111 and the first element body 111 has a front edge 112, a rear edge 113, and a pair of side edges 114).

Here, the front and rear are based on the direction in which the mixture C flows into the inline mixer (10 in Fig. 9). The direction in which the mixture C flows is referred to as forward, and the mixture C flows The direction of going is called rear.

The first element body 111 has a rectangular member having four sides of a front edge 112, a rear edge 113 and a pair of opposite side edges 114 facing each other on a pair of opposite sides, (A) with a first center line (not shown) connecting the center points of the front and rear edges 113, 112 and the rear edge 113 as the central axis.

In other words, the first element body 111 has a unidirectional twisted shape indicated by A in the drawing as it goes from the front edge 112 toward the rear edge 113 in the figure.

Here, the side edge 114 is formed so as to be in contact with the inner peripheral surface of the pressure-resistant tube 12 when the first element body 111 is disposed in the pressure- Therefore, the first element body 111 forms a flow path in the pressure-resistant tube 12 having a spiral shape in the A direction with respect to the flow direction of the mixture C.

The second element 120 includes a second element body 121 and the second element body 121 includes a forward edge 122, a rear edge 123 and a pair of side edges 124.

The second element body 121 has a pair of opposite sides, that is, a front edge 122, a rear edge 123, and a rectangular member having four sides of a pair of side edges 124, And a second center line (not shown) connecting the center points of the rear edge 123 and the rear edge 123 as a center axis.

In other words, the second element body 121 has a unidirectional twisted shape indicated by B in the drawing as it goes from the front edge 122 toward the rear edge 123 in the figure.

Here, the side edge 124 is formed so as to be in contact with the inner peripheral surface of the pressure-resistant tube 12 when the second element body 121 is disposed in the pressure- Therefore, the second element body 121 forms a flow path in the pressure-resistant tube 12 having a helical shape in the direction B with respect to the flow direction of the mixture C.

Meanwhile, the first element 110 and the second element 120 may be coupled to each other.

The first element 110 and the second element 120 are configured such that a first centerline (not shown) of the first element 110 and a second centerline (not shown) of the second element 120 are shown And the rear edge 113 of the first element body 111 and the front edge 122 of the second element body 121 are in contact with each other, Lt; / RTI &gt;

At this time, the rear edge 113 and the front edge 122 are disposed to intersect with each other. In other words, the rear edge 113 and the front edge 122 are arranged to form an angle rather than being arranged side by side.

The angle formed by the front edges 112 and 122 and the rear edges 113 and 123, that is, the degree of twist of the rear edges 113 and 123 with respect to the front edges 112 and 122, respectively, can be arbitrarily selected.

Experiments have shown that the mixing efficiency of the mixture C is high when the rear edges 113 and 123 are formed at 90 to 180 degrees with respect to the front edges 112 and 122, The angle at which the first element body 111 is twisted in the A direction and the angle at which the second element body 121 is twisted in the B direction can be 180 degrees.

The angle formed by the rear edge 113 and the front edge 122 when the first element 110 and the second element 120 are connected may also be arbitrarily selected. The first element 110 and the second element 120 may be arranged such that the rear edge 113 and the front edge 122 are connected to form a 90 degree or vertical shape.

In the present specification, 'parallelism' and 'vertical' do not mean mathematically 'parallelism' and 'verticalness' but 'parallelism' and 'verticalness' .

On the other hand, as described above, the blade 11 includes a plurality of unit blades 11a. Accordingly, the blade 11 has a structure in which the first element 110 and the second element 120 are alternately arranged in a line.

That is, the rear edge 123 of the second element 120 is connected to the front edge 112 of the first element 110 again. As a result of the experiment, in this case also, when the front edge 112 connected to the rear edge 123 is vertically formed and arranged to be connected, since the emulsification efficiency of the mixture C is the highest, the blade 11 has the first element The rear edge 113 of the second element 120 and the front edge 122 of the second element 120 and the front edge 112 of the first element 110 and the rear edge 123 of the second element 120 are both orthogonal Can be arranged continuously.

F shown by a dotted line in FIG. 10 represents a part of the flow of the mixture (C).

Here, F is surface division by F1 and F2 during the flow due to the arrangement structure of the first element 110 and the second element 120 as described above, and this surface division occurs along the longitudinal direction of the blade 11 The mixture C is continuously generated in the course of flowing in the direction indicated by the straight arrow.

Therefore, the mixture C is repeatedly mixed and separated in the course of passing through the inline mixer (10 of FIG. 9), so that the degree of homogenization of the mixture C, that is, the mixing state, is increased.

As described with reference to Fig. 11, since the direction A and the direction B are opposite to each other, the mixture C rotates in the direction A and the direction B in the course of flowing along the blade 11 I repeat. In other words, the mixture C repeats the one-directional rotation and the other-directional rotation about the axis parallel to the longitudinal direction of the blade 11 while passing through the inline mixer (10 in FIG. 9).

Therefore, the mixture (C) is redirected a number of times, and the mixture (C) is mixed due to inertia, so that the degree of emulsification of the mixture (C) becomes extremely high.

Therefore, the mixture C passes through the in-line mixer 10, and the components constituting the mixture C, for example, the above-mentioned organic poorly soluble substance, the solvent capable of dissolving the poorly soluble substance, and the surfactant are fine A very small particle shape having a uniform size is formed, and an emulsified state having high homogeneity and stability is obtained.

Fig. 12 shows an exploded perspective view showing another example of the inline mixer, and Fig. 13 shows a partial cross-sectional view of the inline mixer shown in Fig. 12 and 13 together.

The inline mixer 200 includes a blade 201 and a pressure-resistant pipe 202. The blade 201 includes a plurality of unit blades 201a arranged in a line. A pair of unit blades 201a disposed adjacent to each other will be referred to as a first element 210 and a second element 220 for convenience of explanation.

The first element 210 includes the first element body 211.

The first element body 211 is formed in a disk shape, and a spacing protrusion 212 protrudes from the center of one surface of the first element body 211. A through hole 213 is formed in a portion of the first element body 211 excluding a portion where the spacing protrusion 212 is formed. The number of the through holes 213 can be increased or decreased as needed. That is, at least one through hole 213 may be formed, and preferably a plurality of through holes 213 are formed. This is explained below again.

A lateral edge 214 is formed at an edge portion of the first element body 211. The side edge 214 is a portion contacting the inner circumferential surface of the pressure-resistant tube 202 when the first element body 211 is disposed in the pressure-resistant tube 202 and supporting the first element body 211 to be fixed.

The second element 220 includes a second element body 211 and the second element body 211 also has a spacing protrusion 222, a through hole 223 and a lateral edge 224, The through hole 212, the through hole 213, and the side edge 214 of the main body 211, respectively, so that overlapping descriptions will be omitted.

The third element 230 is disposed at the farthest rear side of the pressure-resistant pipe 202, and a plurality of elements (not shown) are disposed between the second element 220 and the third element 230. A plurality of elements not shown and the third element 230 also have the same structure as that of the first element 210, and therefore, illustration and description thereof are omitted for the sake of convenience.

The first to third elements 210, 220 and 230 and a plurality of unit blades 201a not shown are arranged in a line in the pressure-resistant pipe 202 as shown in Fig.

First, the first element body 211 and the second element body 221 are spaced apart from each other by the spacing protrusions 222, as shown in the arrangement of the first element 210 and the second element.

The through holes 213 formed in the first element body 211 and the through holes 223 formed in the second element body 221 are arranged to be shifted from each other with respect to the longitudinal direction of the blade 210. The virtual straight line connecting the center point of the through hole 213 and the center point of the through hole 223 is arranged so as not to be parallel to the center line CL of the blade 210. [

13, the through holes 213 formed in the first element body 211 and the through holes 223 formed in the second element body 221 are mutually shifted from each other so that the adjacent element bodies 211 and 221 Is arranged to be rotated by a predetermined angle about the centerline CL as a center axis, the mixture C passing through the inline mixer 200 is repeatedly mixed and separated.

That is, as indicated by F 'in FIG. 13, the mixture C that has passed through the through holes 213 is mixed with the vortex at intervals between the adjacent element bodies 211 and 221 formed by the spacing protrusions 222 , And passes through the through hole (223) disposed rearward again.

Here, the number, diameter, and arrangement of the through holes 213 and 223 can be changed as needed. As a result of the experiment, it was found that at least one pair of the through holes 213 and 223 were formed to have a high emulsifying effect, and the through holes 213 and 223 had diameters not overlapping each other when viewed from the center line direction of the blades 210 It was found that the emulsification effect becomes higher as they are disposed at positions which are not overlapped with each other at the same time.

As described above, in the flow F 'of the mixture C, surface division occurs while passing through the plurality of through holes 213 in the course of passing through the inline mixer 200, The second element body 221 disposed on the rear side is collided with the second element body 221, and again, a direction change and a surface division are caused while passing through the plurality of through holes 223.

Therefore, the inline mixer 200 can obtain the effect of emulsifying the mixture (C) by the structure and operation as described above.

Although only the first element 210 and the second element 220 included in the unit blade 201a have been described above, a plurality of elements (not shown) disposed behind the second element 220 may also be used 1 &lt; / RTI &gt;

Fig. 14 is an exploded perspective view showing another example of the inline mixer, and Fig. 15 is a view for explaining the operation of the inline mixer shown in Fig. 14 and 15 together.

The inline mixer 300 includes a blade 301 and a pressure-resistant pipe 302. The blade 301 includes a cylindrical blade body 310 having a diameter smaller than the inner diameter of the pressure-

A plurality of mixing protrusions 311 protrude from the outer circumferential surface of the blade main body 310. A plurality of mixing protrusions 311 protrude from the outer circumferential surface of the blade main body 310. The mixing protrusions 311 protrude forward, The first guide surface 313 and the second guide surface 314 are formed adjacent to each other so that the second guide surface 312 is formed.

A supporting surface 315 is formed at an end of the mixing protrusion 311 so that when the blade 301 is disposed in the hollow portion of the pressure-resistant pipe 302, And the blade main body 310 is in contact with and supports the blade main body 310.

15, the mixing protrusions 311 themselves are arranged in a rhombic lattice pattern on the outer circumferential surface of the blade main body 310, and the mixing protrusions 311 themselves include a front edge 312, Shape.

15, the flow of the mixture C is separated by the front edge 312 as the mixture C is moved along the longitudinal direction of the blade 301, and the flow of the mixture C is separated by the first guide surface 313 and the second guide surface 314 and is repeatedly mixed again in the space formed between the adjacent plurality of mixing projections 311. [

In this process, the mixture C introduced into one side of the inline mixer 300 is divided by the edges formed on the plurality of mixing protrusions 311, i.e., the front edge 312, and the first guide surface 313 and the 2 guide surface 314, and the vortex generated by colliding with the guide surfaces of other adjacent mixing projections causes directional switching and mixing.

Therefore, the inline mixer 200 can obtain the effect of emulsifying the mixture (C) by the structure and operation as described above.

While the present invention has been described with reference to the exemplary embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, Other embodiments may easily be suggested by adding, changing, deleting, adding, etc. elements within the scope of the present invention, but this is also within the scope of the present invention.

The features and advantages of the present invention are summarized as follows:

(a) The present invention provides a method for producing a water-soluble organic compound, which comprises the steps of supplying a poorly soluble organic compound, a solvent capable of dissolving the poorly soluble organic compound and a surfactant to an inline mixer, Mixing the solvent and the surfactant with the inline mixer to prepare a pre-emulsion, wherein the pre-emulsion is used for medicines, foods and cosmetics, and the poorly soluble organic Wherein the compound and the surfactant are mixed in a weight ratio of 0.00001: 10 to 10: 0.00001, the particle size of the pre-emulsion is 0.2-10.0 탆, and the pre-emulsion is hydrated to form an emulsion. .

(b) The pre-emulsion prepared by the method of the present invention can increase the content of the poorly soluble organic compound which can be dissolved by several tens to several hundreds times as compared with the method in which the poorly soluble compound is solubilized in the conventional liposome form or emulsified form .

(c) The pre-emulsion prepared by the method of the present invention has the advantage of minimizing adverse effects caused by the use of a solubilizing agent such as crèmepo, which has a possibility of causing fatal side effects on the human body.

(d) When the pre-emulsion prepared by the method of the present invention is administered to the human body, the AUC (area under the blood concentration curve) can be dramatically increased compared with the conventional method, and the pharmacological effect is remarkably improved There is an advantage to be improved.

(e) The pre-emulsion prepared by the method of the present invention is excellent in emulsion stability, and can be particularly useful for preparing eyedrops and injectable emulsion formulations directly exhibiting toxicity by a solubilizing agent, The phenomenon of precipitation of crystals of the poorly soluble organic compound in the organs hardly occurs, and there is a great advantage that the side effects can be minimized.

Fig. 1 shows SEM photographs of the ceramide as a control and the pre-emulsion prepared by the method of Example 1 of the present invention. In the photograph, 1000 and 7000 represent the SEM magnification.
Figs. 2 to 4 show the evaluation of the homogeneity (1 to 2 years) of the emulsion in which the pre-emulsion prepared by the method of Example 1 below is dispersed in water.
5 shows a photograph of latanoprost pre-emulsion particles prepared by the method of Example 5 and Comparative Example 5 using an electron microscope.
Fig. 6 shows a DSC graph of the ceramide as a control and the pre-emulsion prepared by the method of Example 1. Fig.
7 shows the thermal stability test results of a latanoprost formulation containing 0.005% latanoprost by hydrating the latanoprost pre-emulsion prepared by the method of Example 5 below.
Fig. 8 shows the thermal stability test results of the Xalatan preparation as a comparative agent.
FIG. 9 shows a flow diagram of an emulsifying apparatus according to an embodiment of the present invention.
Figure 10 shows a partial cross-sectional view of the inline mixer shown in Figure 9;
11 is a perspective view for explaining the structure of the blade shown in Fig.
12 shows an exploded perspective view showing another example of the inline mixer.
13 shows a partial cross-sectional view of the inline mixer shown in Fig.
14 shows an exploded perspective view showing another example of the inline mixer.
Fig. 15 shows a diagram for explaining the operation of the inline mixer shown in Fig. 14. Fig.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not to be construed as limiting the scope of the present invention. It will be self-evident.

Example

Throughout this specification, "%" used to denote the concentration of a particular substance is intended to include solids / solids (wt / wt), solid / liquid (wt / The liquid / liquid is (vol / vol)%.

Preparation Example 1: Preparation of pre-emulsion

Production Example 1-1: Selection of Solvent for Preparing Preemulsion

In order to find a solvent capable of adequately lyophilizing a poorly soluble drug, it is preferable to use polyols such as polyolglycerine, butyleneglycol, propylene glycol, dipropylene glycol, diethylene glycol, benzyl alcohol, ethanol, ethoxydiglycol , Polypropylene glycol and polyethylene glycol were used. As natural oils, sunflower oil, olive oil, corn oil and soybean oil were used. Hydrogenated polyisobutene was used as the hydrocarbon oil. Octyldodecane Nol was used, and isopropyl myristate and isostearic acid were used as the ester oil.

As a result of the experiment, ceramide 3 has been found to be effective in the treatment of diabetes, such as dipropylene glycol, urdodoxycholic acid (UDCA), cyclosporin A, Dercusin, Latanoprost, Travoprost, Bimatoprost, Ginsenoside Rg1, Valsartan, Tacrolimus and Paclitaxel may be formulated with propylene glycol, Docetaxel, Amphotericin B, and isoflavones Isoflavone is diethylene glycol, Itraconazole is benzyl alcohol, Meloxicam is ethoxydiglycol, Celecoxib is ethanol, Ibandronate is isostearic acid, It was confirmed that the acid was the most suitable solvent to dissolve the poorly soluble drug mentioned above.

Production Example 1-2: Preparation of pre-emulsion -

Ceramide 3 and dipropylene glycol which were relatively stable at a high temperature in a first open tank at room temperature (20 ± 5 ° C) shown in Table 3 were dispersed at 75 ° C for 10 minutes at 3000 rpm using a general mixer, , Glyceryl stearate and stearic acid, which require preliminary mixing with hydrogenated lecithin, were mixed at 3000 rpm for 10 minutes using a general mixer, and then the solutions of the first open tank and the second open tank were in-line After three passes through the mixer, the pre-emulsion of Example 1 was prepared by solidifying and finely pulverizing. The solutions of the first open tank and the second open tank were mixed with stirring using a general mixer at 3000 rpm for 10 minutes, and then solidified and finely pulverized to prepare a pre-emulsion of Comparative Example 1. [ The pre-emulsion prepared through the above-described high-temperature process pre-emulsion production method can form a very stable emulsion when dispersed in water using a general mixer in a solid state.

ingredient Example 1
(weight%) Comparative Example 1
(weight%) Ceramide 3 40 40 Hydrogenated lecithin (PC 80%) 20 20 Stearic acid 10 10 Dipropylene glycol 20 20 Glyceryl stearate 10 10

Production Example 1-3: Preparation of pre-emulsion - Low temperature process

The poorly soluble materials, solvents, and surfactants were mixed in a general mixer at 3000 rpm for 10 minutes with the composition shown in Table 4 below to prepare a mixture. The mixture was then passed through an inline mixer three times to prepare the preemulsions of Examples 2-6. The pre-emulsions of Comparative Examples 2 to 16 were prepared without using the inline mixer by further stirring the mixture at 3000 rpm for 10 minutes using a general mixer. The pre-emulsion prepared through the above-mentioned low temperature process pre-emulsion preparation method can form a very stable emulsion when dispersed in water using a general mixer in a liquid state.

Example Poorly soluble substance menstruum Surfactants Example 2 UDCA
6.25% Propylene glycol
88.75 & Lecithin (PC95%)
5% Example 3 Cyclosporine A
0.05% Propylene glycol
94.95% Lecithin (PC95%)
5% Example 4 Decasin
16.875% Propylene glycol
78.125% Lecithin (PC95%)
5% Example 5 Latano Frost
2% Propylene glycol
93% Lecithin (PC95%)
5% Example 6 Traboproth
0.004% Propylene glycol
94.996% Lecithin (PC95%)
5% Example 7 Doclex
4.268% Diethylene glycol
90.732% Lecithin (PC95%)
5% Example 8 Bimatofrost
0.003% Propylene glycol
94.997% Lecithin (PC95%)
5% Example 9 Amphotericin B
14.062 Diethylene glycol
80.938% Lecithin (PC95%)
5% Example 10 Itraconazole
25% Benzyl alcohol
70% Lecithin (PC95%)
5% Example 11 Isoflavone
16.875% Diethylene glycol
78.125% Lecithin (PC95%)
5% Example 12 Mexican kam
3.75% Ethoxydiglycoll
91.25% Lecithin (PC95%)
5% Example 13 Celecoxib
50% ethanol
49% Lecithin (PC95%)
One% Example 14 Ginsenoside Rg1
One% Propylene glycol
94% Lecithin (PC95%)
5% Example 15 Tacrolimus
1.25% Propylene glycol
93.75% Lecithin (PC95%)
5% Example 16 Paclitaxel
0.6% Propylene glycol
94.4% Lecithin (PC95%)
5%

Experimental Example 1: Evaluation of physical properties of pre-emulsion and emulsion

Experimental Example 1-1: Confirmation of pre-emulsion state

The irregular state of the pre-emulsion prepared by the method of Example 1 was confirmed by using an electron microscope (SEM). The photographs were taken at a magnification of 7000 times and 1000 times, and concrete results are shown in FIG. The picture shown in blue in Figure 1 is the ceramide itself, which shows that it is very regularly arranged as shown. By the ceramide crystals in the regular arrangement, they are not dispersed in water, and even if they are dispersed by physical force for a moment, they are in a state where recrystallization occurs immediately. However, it was confirmed that the amorphous crystals were irregularly dispersed in the photographs of the results of Example 1, which were obtained by photographing with a red color photographed by a scanning electron microscope. The irregular shape of the ceramides and irregular arrangement of the crystals make water dispersion very easy and maintain a water dispersed state for a long time (more than 3 years at room temperature).

Experimental Example 1-2: Evaluation of homogeneity and dispersibility

The method of measuring the dispersibility, homogeneity and particle size of the pre-emulsion prepared by the method of Example 1 can be roughly determined by measuring the potential difference using a Zeta-Potential Analyzer, There is a limit to the presence of recrystallization. Therefore, the size and homogeneity of emulsified particles according to aging changes were confirmed directly by using a microscope, and its stability was confirmed. In the particle photographs shown in the following Table 5 and Figs. 2 to 4, recrystallization of ceramides was not observed with time, and a uniform distribution of the particle size of 2.6-3.8 탆 was observed, indicating that aggregation by recrystallization did not occur I could confirm.

Generally, when the particle size is different according to aging, the particles are coalesced and agglomerated due to the difference of the repulsive force and the attraction force of each other. When such coalescence and aggregation accelerate, the particle size becomes very large while affecting the stability. However, in the particle photographs of FIGS. 2 to 4, since the particle size according to the aging changes uniformly, it can be considered that it is in a very stable form.

Manufacturing method Particle size (쨉 m) After 1 day After 7 days After 1 month Three months later 1 year later Two years later Example 1 2.65-3.61 2.73-3.51 2.64-3.21 2.7-3.24 3.24-3.76 3.32-3.67

5 shows a photograph of the latanoprost emulsion (containing 0.005% of latanoprost) particles prepared by the method of Example 5 using an electron microscope, and the photograph on the right side of FIG. 5 shows a state in which the particles of latanoprost emulsion (containing 0.005% of latanoprost) were photographed using an optical microscope. It can be confirmed that the latanoprost emulsion particles prepared by the method of Example 5 are more homogeneous than the latanoprost emulsion particles prepared by the method of Comparative Example 5. [

On the other hand, the average particle size of the pre-emulsion particles of Examples 2 to 16 was measured using ELS equipment, and it was confirmed that each example exhibited an average particle size of 0.2-10.0 탆.

Experimental example 1-3: DSC measurement

The DSC graph was analyzed to determine the phase transition temperature of the pre-emulsion prepared by the method of Example 1 above. Ceramide, a raw material, was used as a control.

The DSC graph of the control and the pre-emulsion prepared by the method of Example 1 is shown in Fig. As shown in FIG. 5, in the case of the control (a), the temperature at which the ceramide, which is a crystalline form at room temperature, phase-transitions to the liquid phase is 97.70 ° C., whereas in the case of the pre-emulsion prepared by the method of Example 1 of the present invention, As the phase transition temperature was 52.08 ° C, it was confirmed that a significant difference in the phase transition temperature occurred.

Experimental Example 2: Measurement of long-term stability according to aging

EXPERIMENTAL EXAMPLE 2-1: Test for Storing a Thermostat

The preemulsions prepared by the methods of Comparative Examples 1 to 16 were stored in a thermostatic chamber at 4 ° C, 20 ° C, 38 ° C and 50 ° C for 1 to 90 days to confirm the long-term stability of preemulsion. As a result, it was confirmed that fine powder appeared on the water surface at the time when 15 days passed at 38 캜 and 50 캜. However, as shown in Table 6 below, the pre-emulsion prepared by the methods of Examples 1 to 16 was stable even after 90 days in a constant temperature bath at 4 캜, 20 캜, 38 캜 and 50 캜 .

1 day 2 days 5 days 7 days 15th 30 days 60 days 90 days Thermostat
keep 4 ℃ stability stability stability stability stability stability stability stability 25 ℃ stability stability stability stability stability stability stability stability 37 ℃ stability stability stability stability stability stability stability stability 50 ℃ stability stability stability stability stability stability stability stability

Experimental Example 2-2: Cycling test (4-50 DEG C)

The pre-emulsions prepared by the methods of Comparative Examples 1 to 16 were stored in a 4 ° C heat bath and a 50 ° C thermostat in a day-by-day basis to confirm the long-term stability of the pre-emulsion. As a result, it was confirmed that fine powder appeared on the surface from the time when 3 days passed. However, as shown in Table 7 below, the pre-emulsion prepared by the methods of Examples 1 to 16 was stable even after 14 days.

1 day 2 days 5 days 7 days 14 days 30 days 60 days 90 days Cycling test (4 ~ 50 ℃) stability stability stability stability stability - - -

EXPERIMENTAL EXAMPLE 2-3: Low Temperature (-10 ° C) Test

In order to confirm the long-term stability of the pre-emulsion prepared by the methods of Comparative Examples 1 to 16, a low-temperature test was conducted at -10 ° C. As a result, a fine powder appeared on the water surface at three days at -10 ° C . However, as shown in Table 8 below, the pre-emulsion prepared by the methods of Examples 1 to 16 was stable even after 7 days at -10 ° C.

1 day 2 days 5 days 7 days 15th 30 days 60 days 90 days Low temperature (-10 ℃) stability stability stability stability - - - -

Experimental Example 2-4: Phase Separation Test Using Centrifuge

The latanoprost pre-emulsion prepared by the method of Example 5 was hydrated to complete a latanoprost formulation containing 0.005% of latanoprost. Each of the prepared solutions was packed and sealed in a 1.5-mL tube, and the respective samples were prepared. Then, each sample was placed in a centrifuge, and it was confirmed whether or not phase separation was performed with respect to each RPM (8500, 9500, 10000 and 13000) according to time. As a comparative example, latanoprost free emulsion And a latanoprost formulation containing 0.005% of latanoprost was used. As shown in the following Table 9, the latanoprost formulation prepared by the method of Example 5 had no phase separation in each RPM, but the latanoprost formulation prepared by the method of Comparative Example 5 had 10 minutes at 9500 RPM Over time, phase separation was observed.

time 8,500 RPM 9,500 RPM 10,000 RPM 13,000 RPM Example 5 10 minutes stability stability stability stability 20 minutes stability stability stability stability 30 minutes stability stability stability stability Comparative Example 5 10 minutes stability stability Phase separation Phase separation 20 minutes stability Phase separation Phase separation Phase separation 30 minutes stability Phase separation Phase separation Phase separation

Experimental Example 2-5: Thermal stability test

4 ° C, 25 ° C, 40 ° C and 70 ° C were prepared, and the latanoprost pre-emulsion prepared by the method of Example 5 was hydrated to complete a latanoprost formulation containing 0.005% latanoprost. As a comparative example, Xalatan preparation, which contains 0.005% latanoprost and is distributed in the market, was purchased and used. Each of the latanoprost and Xalatan preparations was filled in a glass ampule in an amount of 2.5 mL each and sealed to prepare respective samples. Then, each sample was taken at each temperature for each period and subjected to a content analysis test using a high performance liquid chromatograph.

7 and 8, there was no significant difference between the latanofrost formulation of the present invention and the Xalatan preparation of the present invention at 4 ° C, 25 ° C and 40 ° C, In the case of preservation, it was confirmed that the latanofrost formulation of the present invention had a survival rate of 92% or more for 7 days and was remarkably stable as compared with the control drug.

1: Emulsification device 10: Inline mixer
11: blade 11a: unit blade
110: first element 111: first element body
112: front edge 113: rear edge
114: lateral edge 120: second element
121: second element body 122: front edge
123: rear edge 124: lateral edge
12: pressure-resistant pipe 20: emulsification tank
30: inlet pipe 40, 50: circulation pipe
41: circulation valve 60: pump
70: discharge pipe 71: discharge valve
80: mixer 200: inline mixer
201: blade 201a: unit blade
202 pressure-resistant pipe 210: first element
211: first element body 212:
213: through hole 214: lateral edge
220: second element 221: second element body
222: spacing projection 223: through hole
224: lateral edge 300: inline mixer
301: blade 302: pressure-resistant pipe
310: blade main body 311: mixing projection
312: front edge 313, 314:
315: Support surface

Claims (5)

A supply step of supplying a poorly soluble organic compound, a solvent capable of dissolving the poorly soluble organic compound and a surfactant to an inline mixer, and
And a mixing step of mixing a solvent capable of dissolving the poorly soluble organic compound, the poorly soluble organic compound and a surfactant with the inline mixer to prepare a pre-emulsion,
The pre-emulsion is used for medicines, foods and cosmetics,
The poorly soluble organic compound and the surfactant are mixed in a weight ratio of 0.00001: 10 to 10: 0.00001, the particle size of the pre-emulsion is 0.2-10.0 [mu]
Wherein the pre-emulsion is hydrated to form an emulsion
A pre - emulsion stabilization method using an inline mixer.
The method according to claim 1,
Wherein the solvent capable of dissolving the poorly soluble organic compound is selected from the group consisting of a polyol, a natural oil, a hydrocarbon oil, a higher alcohol and an ester oil.
The method according to claim 1,
The surfactant may be selected from the group consisting of lecithin, hydrogenated lecithin, PEG-30 Dipolyhydroxystearate, Polyglyceryl-2 Dipolyhydroxystearate, Polyglyceryl-2 diisostearate polyglyceryl-2 diisostearate, PEG-150 PEG-150 Pentaerythrityl Tetrastearate, and polyglyceryl-2 triisostearate. Wherein the pre-emulsion is stabilized by using an in-line mixer.
The method according to claim 1,
Wherein the mixing step comprises stirring and homogenizing the pre-emulsion particles while the step of dividing the surface and the step of rotational circulation or the step of radial mixing being performed sequentially or simultaneously.
The method according to claim 1,
Wherein the emulsion is a micro-emulsion or an emulsion. 2. The method of claim 1, wherein the emulsion is a micro-emulsion or an emulsion.

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