KR20140043577A - The water-insoluble isoflavone covered with amorphous surfactant and method for preparing the same - Google Patents

Abstract

The present invention relates to a barrier-free isoflavone and a method for producing the same. The barrier-free isoflavone according to an embodiment of the present invention is to include 100 parts by weight of isoflavones and 10 to 200 parts by weight of a surfactant having two or more alkyl chains attached to the hydrophilic portion with respect to the isoflavones. , The surfactant is in the form of a bonded (amorphous) surrounding the outer of the isoflavones are dissolved in water in an emulsified type, the isoflavones attached to the surfactant has an average diameter of 0.5 to 30㎛, The average range of sizes is within ± 200% of the diameter.

Description

Blessed cotton isoflavone and its manufacturing method {THE WATER-INSOLUBLE ISOFLAVONE COVERED WITH AMORPHOUS SURFACTANT AND METHOD FOR PREPARING THE SAME}

The present invention relates to a barrier-free isoflavone and a method for producing the same. More specifically, the present invention relates to a barrier-free isoflavone having a very excellent emulsification stability without containing a solubilizing agent for isoflavone which is a poorly water-soluble substance, and a method for manufacturing the same.

Isoflavones and their derivatives (Fig. 1, hereinafter referred to as isoflavones) are a kind of phytohormones that play a role similar to the female hormone estrogen (Fig. 2). It is known to reduce the incidence of breast or female cancer by preventing various syndromes and suppressing estrogen exposure as much as possible.

The isoflavone is contained in a large amount of soybeans that we can easily ingest, about 300mg of soybean 100g, 12 known isomers are mainly in the form of isoflavone glycoside, isoisolate in soybean Flavones are mostly genistein, daidzein and glycidin, and are known to contribute the most to the anticancer potential of soy.

              Figure 1. Isoflavones Figure 2. Estrogen

Since isoflavones are poorly soluble in water, it is generally difficult to emulsify the oil-in-water type. In addition, even if an oil-in-water emulsion is obtained, there is a problem that crystallization of isoflavones occurs in a short time. Therefore, the isoflavone is difficult to formulate, there is a problem that the stability and absorption is also poor.

Specifically, in the prior art for providing in the form of a hydrate of the isoflavone or to increase the solubility, the prior patent document 1 describes a soybean-derived isoflavone derivative or a method for producing the aglycone that precipitates and removes impurities. However, the soybean-derived α-glucosyl isoflavone derivatives are subjected to the enzymatic reaction on the alkali side containing isoflavones and soybean impurities other than the derivatives. In addition, there is a problem that decomposition reactions are liable to occur.

Prior Patent Document 2 describes a method for producing soluble isoflavones containing starch and a solubilizing agent. However, the manufacturing method includes a solubilizer, and a restriction on the use thereof occurs, and a low degree of stabilization causes a problem that crystallization progresses and the state of oil-in-water emulsification cannot be maintained.

Therefore, in order to solve the above problems, the emulsion stability of the isoflavones emulsified by the surfactant and the like should be minimized to minimize the amount of isoflavones precipitated in the digestive tract, and the amount of the drug entrapped in the surfactant and the like is dramatically increased. Even if a small amount of medicine to be administered should be able to exhibit sufficient pharmacological effect.

JP 10-2000-327691 A KR 10-2001-0006678 A

It is an object of the present invention to provide a barrier-free isoflavone containing isoflavone and a surfactant as a poorly soluble substance, and further to provide anhydrous barrier-free isoflavone which produces the barrier-free isoflavone when dissolved in water.

Another object of the present invention is to provide a method for preparing the barrier-free isoflavones and the anhydrous barrier-free isoflavones.

In order to achieve the above object, the barrier-free isoflavone according to an embodiment of the present invention has a surfactant having 100 parts by weight of isoflavones and at least two alkyl chains attached to the hydrophilic portion with respect to the isoflavones. To 200 parts by weight, wherein the surfactant is an amorphous form (amorphous) surrounding the outside of the isoflavones are bonded in the form of an emulsion, dissolved in water, the isoflavones attached to the surfactant has an average diameter It is 0.5-30 micrometers, and the average range of size is within ± 200% of a diameter basis.

The barrier-free isoflavone may further include a fatty acid between the surfactant and the isoflavone.

The fatty acid may be included in 10 to 1000 parts by weight based on the isoflavones.

The fatty acid may be selected from the group comprising caprylic acid , caprylic acid , stearic acid, palmitic acid, myristic acid, lauryl acid and oleic acid.

The surfactant may be selected from the group containing egg yolk lecithin, soy lecithin and hydrogenated lecithin.

The surfactant may be one containing 70% by weight or more of phosphatidylcholine (PC).

The anhydrous barrier-free isoflavones according to another embodiment of the present invention is to produce the barrier-free isoflavones when dissolved in water.

The anhydrous barrier-free isoflavone may further include an organic solvent having a polarity as a mixed adjuvant.

The organic solvent having the polarity may be two or more -0H groups.

The polar organic solvent may be selected from the group containing glycerin, 1,3 butylene glycol, propylene glycol, dipropylene glycol, ethylene glycol and polyethylene glycol.

According to another embodiment of the present invention, a method for preparing anhydrous non-interfacial isoflavones includes (a) mixing a surfactant having two or more alkyl chains attached to a hydrophilic portion and a polar organic solvent having two or more -OH groups. ; (b) raising the temperature of the mixture of step (a) to raise the fluidity of the mixture; (c) injecting isoflavone as a poorly soluble substance into the mixture of step (b); (d) performing phase mixing of the mixture into which isoflavone is added in step (c) using a mixer including a mixing blade structure having the concept of phase mixing; And (e) solidifying the phase mixed mixture of step (d).

The number of each blade of the unit blades constituting the mixed blade structure may be 20 or less.

The number of unit blades constituting the mixed blade structure may be 1 to 50.

A method for preparing a barrier-free isoflavone according to another embodiment of the present invention includes the step of adding water to the anhydrous barrier-free isoflavone prepared by the method for preparing the anhydrous barrier-free isoflavone.

Hereinafter, the present invention will be described in more detail.

Conventionally, it is not without the concept of using a surfactant to dissolve a poorly dissolved material in the form of liposomes or emulsions. However, the stability of the composition was excellent in the case of the conventional method of solubilizing poorly soluble substance in the form of liposomes, but there is a problem that the content of the poorly soluble substance that can be dissolved is very small. A large amount, poor emulsification stability, or toxicity of a substance used as a solubilizer (such as cremophore) has caused serious adverse effects on the human body. Therefore, in order to overcome the above-mentioned problem that the content of the dissolvable poorly soluble substance and the point of emulsification stability and adverse effects on the human body is required a new type of material that has not been conventionally.

Since the new material is a new concept material that does not exist in the prior art, a definition of a new term that may include all the properties of the new material is necessary. Therefore, the barrier-free isoflavone according to the embodiment of the present invention refers to the novel type of material, and the barrier-free isoflavone used in the present specification means that it belongs to the concept of the barrier-free isoflavone including the following characteristics. .

(a) First, the surfactant used should be at least two alkyl bodies attached to the hydrophilic portion of the surfactant. This is an important technical feature in that the liposomes of the prior art are required to be as standardized as possible, unlike the standardized ones.

(b) Second, the diameter of the poorly soluble substance to which the surfactant is attached is 0.5 to 30 µm, preferably 1 to 10 µm, and more preferably 1.5 to 5 µm. Compared to the liposome having a diameter of 45 to 200 nm in the prior art, it has a size of several tens to hundreds of times. As a result, the amount of the isoflavone is greatly increased as the size of the poorly soluble substance surrounded by the surfactant increases. It is analyzed that it can be increased.

(c) Third, the poorly soluble substances to which the surfactant is attached have a very high homogeneity in size. The poorly soluble material to which the surfactant is attached has an average size of -200% to + 200% based on the total diameter. Preferably it is -30%-+ 30%, More preferably, it is -10%-+ 10%. This is an important factor in delaying recrystallization. The higher the homogeneity, the greater the effect of delaying recrystallization.

(d) Fourth, unlike the liposomes, the poorly soluble substance to which the surfactant is attached should not be standardized as much as possible. The amorphous state of the poorly soluble substance to which the surfactant is attached contributes significantly to the rate of recrystallization. As the degree of amorphousness increases, the rate of recrystallization may be delayed. In this case, however, there may be no complete amorphous form. In this sense, the term "amorphous" is used when describing the material of the present invention within the specification in that it is not intended to be a complete amorphous, but is oriented in an amorphous form.

(e) Fifth, the poorly soluble substance to which the surfactant is attached is directed to an emulsification type as a form dissolved in water.

Thus, in the case where the poorly soluble substance is isoflavone, the isoflavones exhibiting the above five characteristics may be used as a barrier-free isoflavone (shortened word of isoflavone covered with a surfactant on the outside of an oil-soluble water-soluble amorphous form). define.

In addition, a barrier-free isoflavone defines a solid isoflavone such as a solid isoflavone which becomes a barrier-free isoflavone when placed in water.

As used herein, the term " hydrated, dissolved or dissolved " may include conventional dissolution, emulsification, liposomal forms and non-interfacial material states as used herein. In a narrow sense, it can be different from the general dissolution of a barrier-free material. However, in the present specification, when using poorly soluble substances in foods or pharmaceuticals, it means that the recrystallization is extremely delayed in the macroscopic aspect (the concept of melting according to the present specification is used unless otherwise described separately). The above case is used as a comprehensive meaning.

As used herein, the term " poorly soluble " may mean that the pharmacologically active agent is not dissolved in an aqueous solution (e.g., water, physiological saline, injectable dextrose solution, etc.). 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 1, set forth in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., Latest edition.

Technical term 1 volume  Volume of solvent required per 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 poorly soluble in the present invention, when water is used as a solvent, belongs to the four solubility categories in the lower table of Table 1, namely, insufficient solubility, low solubility, very low solubility and pharmacological activity belonging to virtually insoluble or insoluble. It may include a formulation.

The poorly soluble substance 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, naproxen sodium, buprenorphine hydrochloride, propoxyphen hydrochloride, propoxyphene naphsylate, meperidine hydrochloride, hydro Morfon Hydrochloride, Morphine Sulfate, Oxycodone Hydrochloride, Codeine Phosphate, Dihydrocodeine Bitartrate, Pentazosin Hydrochloride, Hydrocodone Bitartrate, Levorpanol Tartrate, Diflunisal, Trollamine Salicylate, Nalbuphine Hydrochloride, mephenamic acid, butorpanol tartrate, choline salicylate, butalbital, phenyltoloxamine citrate, diphenhydramine citrate, metotrimeprazine, cinnamedrine hydrochloride, meprobamate and the like); Anesthetics such as cyclopropane, enflurane, halotan, isoflurane, methoxyflurane, nitrous oxide, propofol and the like; Anti-asthmatic agents (eg, Azelastine, Ketotifen, Traxanox, etc.); Antibiotics (eg neomycin, streptomycin, chloramphenicol, cephalosporin, ampicillin, penicillin, tetracycline, etc.); Antidepressants such as neophorp, oxipherin, toxin 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 (e.g., propanolol, propaphenone, oxyprenolol, nifedipine, reserpine, trimetaphan campylate, phenoxybenzamine hydrochloride, pargiline hydrochloride, deserpidine, dia Side, guanethidine monosulfate, minoxidil, rescinnamin, sodium nitroprusside, lauwalpia serpentina, alseroxylon, phentolamine mesylate, reserpin, and the like); Anti-inflammatory agents such as (non-steroidal) indomethacin, naproxen, ibuprofen, ramipenazone, pyroxicam, (steroidal) cortisone, dexamethasone, fluazacorte, hydrocortisone, prednisolone, prednisone, etc .; Anti-neoplastic agents (e.g. adriamycin, cyclophosphamide, actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU) , Methyl-CCNU, cisplatin, etoposide, interferon, camptothecin and derivatives thereof, penesterin, taxanes and derivatives thereof (e.g. paclitaxel and derivatives thereof, docetaxel and derivatives thereof), vinblastine, vincristine , Tamoxifen, capulsulfan, etc.); Anti-anxiety agents (e.g. lorazepam, buspirone hydrochloride, prazepam, chlordiazepoxide hydrochloride, oxazepam, chlorazate dipotassium, diazepam, hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, draw Ferridol, halazepam, chlormezanone, dantrolene and the like); Immunosuppressants (e.g., cyclosporine, azathioprine, mizoribine, FK506 (tacrolimus), etc.); Antimigraine agents such as ergotamine tartrate, propanolol hydrochloride, isomeptene mucate, dichloralfenazone, etc.); Sedatives / sleeping agents (e.g. barbiturates (e.g. pentobarbital, pentobarbital sodium, secobarbital sodium, etc.), benzodiazapine (e.g. flulazepam hydrochloride, triazolam, tomazepam, midazolam hydrochloride etc); Antianginal agents (e.g. beta-adrenergic blockers, calcium channel blockers (e.g. nifedipine, diltiazem hydrochloride, etc.); nitrates (e.g. nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, ery Trityl tetranitrate, etc.); Antipsychotics (e.g., haloperidol, roxapsin succinate, roxaphine hydrochloride, thiolidazine, thiolidazine hydrochloride, thiotixene, flufenazine hydrochloride, flufenazine decanoate, flufenazine deanthate, Trifluoroperazine hydrochloride, chlorpromazine hydrochloride, perphenazine, lithium citrate, prochlorperazine and the like); Antimanic agents such as lithium carbonate and the like; Antiarrhythmic agents (e.g., brethlium tosylate, esmolol hydrochloride, verapamil hydrochloride, amiodarone, encainide hydrochloride, digoxin, digitoxin, mexyltine hydrochloride, disopyramid phosphate, procanamide hydrochloride, quinidine sulfate , Quinidine gluconate, quinidine polygalacturonate, flkanide acetate, tocainide hydrochloride, lidocaine hydrochloride, and the like); Anti-arthritis agents (e.g. phenylbutazone, sullindac, penicillamine, salsalate, pyroxicam, azathioprine, indomethacin, meclofenamate sodium, gold sodium thiomaleate, ketoprofen, oranopine , Orothioglucose, tolmethin sodium, etc.); Antigout agents (eg colchicine, allopurinol, etc.); Anticoagulants (eg, heparin, heparin sodium, warfarin, etc.); Thrombolytics (eg urokinase, streptokinase, altoplase, etc.); Antifibrinolytic agents (eg aminocaproic acid, etc.); Hemoheologic agents (eg, pentoxifylline, etc.); Antiplatelet agents (eg, aspirin, empyrin, ascriptin, etc.); Anticonvulsants (e.g. valproic acid, divalproate sodium, phenytoin, phenytoin sodium, clonazepam, pyrimidone, phenovabitol, phenovabitol sodium, carbamazepine, amovabitol sodium, metsuccimid, meta Slopes, mepobarbital, mefenitoin, fenximide, paramethadione, etotoin, phenacemid, secobabitol sodium, chlorazate dipotassium, trimetadione and the like); Anti-Pakison agents (eg, ethoximide, etc.); Antihistamines / antipruritic agents such as hydroxyzin hydrochloride, diphenhydramine hydrochloride, chlorpheniramine maleate, bromfeniramine maleate, ciproheptadine hydrochloride, terfenadine, clemastine fumarate, triprolidine hydro Chloride, carbinoxamine maleate, diphenylpyraline hydrochloride, phenanthamine tartrate, azatadine maleate, tripelenamine hydrochloride, dexchlorpheniramine maleate, metdylazine hydrochloride, trimprazine tartrate, etc.) ; Agents useful for modulating calcium (eg, calcitonin, parathyroid hormone, etc.); Antibacterial agents such as amikacin sulfate, aztreonam, chloramphenicol, chloramphenicol palmitate, chloramphenicol sodium succinate, ciprofloxacin hydrochloride, clindamycin hydrochloride, clindamycin palmitate, clindamycin phosphate, metronidazole, metronidazole hydrochloride, gentamisulfate , Lincomycin hydrochloride, tobramycin sulfate, vancomycin hydrochloride, polymyxin B sulfate, colistimitate sodium, colistin sulfate, etc.); Antiviral agents (eg interferon gamma, zidobudine, amantadine hydrochloride, ribavirin, acyclovir, etc.); Antimicrobial agents (e.g. cephalosporins (e.g. cefazoline sodium, cepradine, cefachlor, cefapirine sodium, ceftioxime sodium, cephaperazone sodium, cetethetan disodium, ceputoxime azotyl, cefotaxime sodium, Sephadroxyl Monohydrate, Ceftazidime, Cephalexin, Cephalotin Sodium, Cephalexin Hydrochloride Monohydrate, Sephamandol Naphate, Sepoxycitin Sodium, Cenisidide Sodium, Celanide, Ceftriaxone Sodium, Ceftazine Dim, cephadoxyl, cepradine, cefuroxime sodium, etc., penicillin (e.g., ampicillin, amoxicillin, penicillin G benzatin, cyclolaline, ampicillin sodium, penicillin G potassium, penicillin V potassium, piperacillin sodium, oxa Sodium Silin, Bacampicillin Hydrochloride, Soxacillin Sodium, Ticarcillin Disodium, Azlocillin Sodium, Carbenicillin Indanyl Nat , Penicillin G potassium, penicillin G procaine, methicillin sodium, naphcillin sodium, etc., erythromycin (e.g., erythromycin ethyl succinate, erythromycin, erythromycin estoleate, erythromycin lactobionate, erythromycin cy Acrylates, erythromycin ethyl succinate, etc.), tetracyclines (eg, tetracycline hydrochloride, doxycycline hydrate, minocycline hydrochloride, etc.); Anti-infectives (eg, GM-CSF, etc.); Bronchodilators (e.g., sympathomimetic) (e.g., epinephrine hydrochloride, metaproterenol sulfate, terbutaline sulfate, isotarin, isotarin mesylate, isotarin hydrochloride, albuterol sulfate, Albuterol, bitolterol, mesylate isoproterenol hydrochloride, terbutaline sulfate, epinephrine bitartrate, metaproterenol sulfate, epinephrine, epinephrine bitartrate, etc., anticholinergic agents (e.g., ipratropium bromide Xanthine (e.g. aminophylline, diphylline, metaproterenol sulfate, aminophylline, etc.), mast cell stabilizers (e.g. sodium chromoline), inhaled corticosteroids (e.g. fluolisolid) Beclomethasone dipropionate, beclomethasone dipropionate monohydrate, etc.), salbutamol, beckle Metason dipropionate (BDP), ifpratropium bromide, budesonide, ketotifen, salmetholol, xinapoate, terbutaline sulfate, triamcinolone, theophylline, nedocromil sodium, metaproterenol sulfate, Albuterol, flunisolid, etc.); Hormones (e.g. androgens (e.g. danazol, testosterone cypionate, fluoxymesterone, ethyltoosterone, testosterone enaniate, methyltestosterone, fluoxymesterone, testosterone cypionate, etc.), estrogen (e.g. Diols, estrophytates, conjugated estrogens, etc.), progestins (e.g. methoxyprogesterone acetate, noethynedrone acetate, etc.), corticosteroids (e.g. triamcinolone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, predense Methylprednisolone acetate suspension, triamcinolone acetonide, methylprednisolone, prednisolone sodium phosphate methylprednisolone sodium succinate, hydrocortisone sodium succinate, methyl prednisolone sodium succinate Nitrate, triamcinolone hexacatonide, hydrocortisone, hydrocortisone cypionate, prednisolone, fluorocortisone acetate, paramethasone acetate, prednisolone tebulate, prednisolone acetate, prednisolone sodium phosphate, hydrocortisone sodium succinate, etc.), thyroid hormones (examples) Levothyroxine sodium, etc.); Hypoglycemic agents (eg, human insulin, purified bovine insulin, purified porcine insulin, glyburide, chlorpropamide, glipizide, tolbutamide, tolazamide, etc.); Hemostatic agents (eg, clofibrate, dextrothyroxine sodium, probucol, lovastatin, niacin, etc.); Proteins (eg, DNases, alginases, superoxide dismutases, lipases, etc.); Nucleic acids (eg, sense or anti-sense nucleic acids, such as those encoding any therapeutically useful protein, including any protein described herein); Agents useful for hematopoietic stimulation (eg, erythropoietin, etc.); Antiulcer / antireflux agents (eg, famotidine, cimetidine, ranitidine hydrochloride, etc.); Anti-emetic / anti-emetic agents (eg meclazine hydrochloride, nabilone, prochlorperazine, dimenhydrinate, promethazine hydrochloride, thiethylperazine, 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 poorly soluble substances as pharmacologically active agents may include compounds listed in "Therapeutic Category and Biological Activity Index" of The Merck Index (12th Ed'n, 1996).

The barrier-free isoflavone according to an embodiment of the present invention is to include 100 parts by weight of isoflavones and 10 to 200 parts by weight of a surfactant having two or more alkyl chains attached to the hydrophilic portion with respect to the isoflavones. , The surfactant is in the form of a bonded (amorphous) surrounding the outer of the isoflavones are dissolved in water in an emulsified type, the isoflavones attached to the surfactant has an average diameter of 0.5 to 30㎛, The average range of sizes is within ± 200% of the diameter.

The surfactant having two or more alkyl chains attached to the hydrophilic portion may be a natural surfactant or a synthetic surfactant.

The natural surfactant includes at least one selected from the group consisting of soybean lecithin, egg lecithin, hydrogenated lecithin (hydrogenated soybean lecithin and hydrogenated egg lecithin), sphingosine, ganglioside and phytosphingosine It may include a surfactant, but is not limited thereto.

The natural lecithin is a mixture of diglycerides of stearic acid, palmitic acid and oleic acid linked to choline esters of phosphoric acid, commonly referred to as phosphatidylcholine, and can be obtained from various sources such as eggs and soybeans. Soybean lecithin and egg 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].

The hydrogenated lecithin is a product of controlled hydrogenation of lecithin, and may be included in the technical idea of the present invention.

Lecithin is acetone, consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphodidylinositol, according to USP, mixed with various substances such as triglycerides, fatty acids and carbohydrates A generic name describing complex mixtures of 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.

The synthetic surfactants include diacylglycerols, phosphatidic acids, phosphocholines, phosphoethanolamines, phosphoglyceryls, phosphoserines, mixed chain phospholipids, lysophospholipids and pegylated phospholipids. It may include, and examples of the specific diacylglycerols and the like are as follows, but is not limited thereto.

Diacylglycerol

Di-lauroyl-sn-glycerol (DLG)

Di-myristoyl-sn-glycerol (DMG)

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

1,2-dstearoyl-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-lyso-sn-glycero-3-phosphocholine (P-lyso-PC)

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-methoxypolyethyleneglycol 750) -MPEG-750-DSPE

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

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

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

In the anhydrous, isoflavone-free isoflavone according to an embodiment of the present invention is a surfactant having two or more alkyl chains attached to the hydrophilic portion is contained in 10 to 200 parts by weight based on 100 parts by weight of isoflavone. In the case of a conventional liposome, 500 to 1000 parts by weight of a surfactant is used to dissolve 100 parts by weight of isoflavone. However, in the case of the barrier-free isoflavone according to the present invention, the isoflavone is dissolved in water by using a surfactant in the above range. It has the advantage that the content of the surfactant can be significantly reduced. In addition, in the case where the surfactant having two or more alkyl chains attached to the hydrophilic part is contained in an amount of more than 200 parts by weight, excessively excessive use may result in a decrease in the isoflavone content ratio compared to the amount of the surfactant. , When it is included in less than 10 parts by weight is difficult to contact while completely surrounding the isoflavones in an amorphous form, the efficiency of dissolving in water as an emulsified type may be reduced.

In addition, preferably, the surfactant having two or more alkyl chains attached to the hydrophilic portion may be included in 20 to 80 parts by weight, more preferably 40 to 60 parts by weight. According to the above range, while the surfactant is amorphous surrounding the isoflavones in an amorphous form, the efficiency of dissolving in water can be significantly increased.

In the anhydrous, isoflavone-free isoflavone according to an embodiment of the present invention is a diameter of the barrier-free isoflavone attached to the surfactant is 0.5 to 30 ㎛. If the diameter of the barrier-free isoflavones exceeds 30 μm, the internal crystallization may increase in the vicinity of the hydrophobic group, and thus the sustaining effect of the emulsified state may be lowered. have.

The diameter of the barrier-free isoflavones is very important in terms of functional dissolution of poorly soluble isoflavones. That is, the diameter of the barrier-free isoflavone is an indicator of the size of the barrier-free isoflavone because it is an important factor in determining the amount of isoflavones that the hydrophobic group of the surfactant can bear. In the case of liposomes, it is unknown whether the isoflavones are completely dissolved near the hydrophobic groups, but the isoflavones of the barrier-free interface are much larger than the liposomes. The part may be crystallized internally. However, since the surface of the isoflavone is amorphous and surrounds the surface of the isoflavone, the barrier-free isoflavone is dissolved in water as an emulsified type, and its size is very small (although it is very large compared to liposomes). Even if it is not dissolved, the premise is that it is not harmful to the human body (animal body when used in an animal) as long as the emulsion type is maintained.

On the other hand, preferably the diameter of the barrier-free isoflavone is 1 to 10 ㎛, more preferably 1.5 to 5 ㎛. In the above range, the stability of the barrier-free isoflavone may be the highest, thereby maintaining a stable emulsification state.

Anhydrous unsoluble isoflavones according to an embodiment of the present invention is that the average range of the size is -200% to + 200% based on the diameter. This can be said that the homogeneity is very high. According to the above range, the recrystallization of the barrier-free isoflavone may be significantly delayed to increase its stability, and if it is outside the above range, such stability may be lowered.

In addition, preferably, the anhydrous isoflavone is an average range of size may be -30% to + 30% based on the diameter, more preferably -10% to + 10%. According to the above range, since recrystallization is further delayed, there is an advantage in that the stability of the anhydrous isoflavone is very high.

The precise mechanism of whether the recrystallization is delayed when the homogeneity is high is not yet fully understood. However, Van der Waals attraction between the barrier-free isoflavone particles is offset by the repulsive force due to the zeta potential of the barrier-free isoflavone particles.

More specifically, according to Stern's double-layer theory, negatively charged particles on the surface of the particles attract opposite charges in the water, that is, positive charges, because the negatively charged particles attempt to be electrically neutralized. To achieve. This layer is called a fixed layer (Stern layer). The outer layer is called the diffused layer (Guoy layer). The outer layer is the diffusion layer (Guoy layer). As the particles move, the ions outside the diffusion layer stay without migration, and the surface of the ion layer moving with the particles is called the shear surface. There is a potential on the particle surface, the fixed layer, and the diffusion layer, and since the potential of the particle surface can not be measured directly, it can be indirectly detected by measuring the potential at the front surface surrounding the particle when the particle moves. The potential is called the zeta potential. The dislocation is greatest at the particle surface and decreases away from the particle. When two particles with the same charge approach each other, they are pushed against each other by electrostatic repulsive force, which reduces the van der Waals attractive force acting between the particles to keep the particles stable.

In summary, if the homogeneity of the barrier-free isoflavone particles is significantly high and the sizes of the particles are almost the same, the repulsive force due to inter-particle zeta potential and the attraction force due to van der Waals are almost the same. If this is almost the same, each attraction force and repulsive force are canceled (or it can be assumed that the repulsive force is superior to the attraction force). The recrystallization of the barrier-free isoflavone particles can be delayed as much as possible.

As described above, in order to significantly increase the homogeneity of the barrier-free isoflavones, an inline mixer including a mixing blade structure having a concept of liquid phase mixing may be used.

The meaning of the liquid phase mixing is 10 at regular intervals as shown in FIG. 5 so that the liquid passing through it can be cut in the form of 2 ⁿ , 3 ⁿ , 4 ⁿ and 5 ⁿ or the like, or the mixture can be finely homogenized. The following blades, preferably four or less blades repeatedly change direction and pass through the ducts arranged inside in a fixed manner, so that the solution is conceptually cut every time through each unit of the blade. Say mix.

In the present invention, a mixer capable of such phase mixing is defined as a mixer for phase mixing. The liquid phase mixing mixer is meant to include a structure capable of the liquid phase mixing in any part of the mixer, and it is not limited to all pipelines having a liquid phase mixing structure.

In the prior art, there is a mixer or homogenizer having a stronger stirring or homogeneous capability than the liquid mixing mixer such as a microfluidizer or a high-pressure homogenizer. Surprisingly, however, the barrier-free isoflavones of the present invention can be prepared only through the mixing mixture mixer, and can not be manufactured through general mixers as well as very powerful agitators or homogenizers such as the microfluidizer and the high pressure homogenizer. .

Specifically, a powerful stirrer or homogenizer such as a high pressure homogenizer or a microfluidizer is a mechanism for crushing and stirring a specific material by transmitting a strong physical force to one or more places. Therefore, the site where the physical force is transmitted may be strongly pulverized and agitated, but when it is moved away from the site, the physical force transmitted is weakened, which is inevitably less pulverized than the site where the physical force is transmitted. Accordingly, since the size of the ground particles is different depending on the stirring position, the average size of the stirred particles may be finely ground and agitated, but the homogeneity of the resulting particles may be reduced.

However, in the case of using the liquid phase mixing mixer, the mixture containing the surfactant and isoflavone to be introduced is quantitatively 1/2 to 1/10 each time it passes the unit blade included in the tube of the liquid mixing mixture. Divided into agitation process. In addition, as the unit blade passes through the process, the content and ratio of the surfactant and isoflavone to be bound may be quantified while being proportional to the dose and the input ratio of the isoflavone and the surfactant to be initially added.

In the initial stirring step, even if the content or ratio of the surfactant and isoflavone is not quantitative, the proportion and amount of the isoflavone and the surfactant to be combined may be quantified as the stirring process proceeds. As a result, when the surfactant and isoflavone quantified in terms of proportion and quantity are bound as described above, the size of the surfactant and the isoflavone are bound to be almost the same.

Therefore, the use of the liquid mixing mixer can be said to be one of the most essential components in the present invention. However, the present inventors first discovered isoflavones in a non-interfacial state and derived a concept thereof, and the invention of the substance is protected by the substance itself, and the scope of the right cannot be limited to the manufacturing room. The range is not limited to that according to the above-described mixing mixer.

That is, even in the case of not using the liquid mixing mixer, the homogeneity is substantially sufficient that a homogenizer or stirrer capable of more easily preparing the barrier-free isoflavones pursued by the present invention may exist. do. For example, many homogenizers or stirrers of various types that can amplify the homogeneity can be considered in addition to the phase mixing mixer, and by using a mixer or homogenizer having the strong stirring ability or homogeneous capacity, and using a membrane filter or the like. A method of ensuring the homogeneity can be considered. Therefore, the barrier-free isoflavones prepared according to the above method other than the mixing mixture mixer are also considered to be within the scope of the present invention.

The barrier-free isoflavone may further include a fatty acid between the surfactant and the isoflavone.

When the fatty acid is further included, the fatty acid is intertwined irregularly with the alkyl chain of the surfactant attached to the isoflavone, thereby preventing the surfactant from being formalized. Therefore, the isoflavones have an effect of significantly lowering the probability of recrystallization by combining with each other.

In addition, since the fatty acid can dissolve the isoflavones well in the molten state, when the isoflavone is added in the state where the fatty acid is mixed with the surfactant, the degree of dispersion and homogeneity of the isoflavone may be increased.

The fatty acid may be included in 10 to 1000 parts by weight based on the isoflavones. When the fatty acid exceeds 1000 parts by weight, the dispersion and homogeneity improvement effect according to the amount of the fatty acid is no longer improved. When the fatty acid is included below 10 parts by weight, the recombination of isoflavones is prevented, the dispersion degree is improved, and the homogeneity is improved. Can be lowered.

In addition, preferably the fatty acid may be included in 10 to 500 parts by weight, and more preferably 20 to 100 parts by weight. Although not limited to the above range, the dispersion and homogeneity of the isoflavone can be the highest when the above range.

The fatty acid may be selected from the group comprising caprylic acid , caprylic acid , stearic acid, palmitic acid, myristic acid, lauryl acid and oleic acid. In the case of using the fatty acid, there is an advantage in that recombination prevention, dispersion degree improvement and homogeneity degree improvement of isoflavones are higher.

The surfactant may be lecithin, and the lecithin may be one selected from the group comprising egg yolk lecithin, soy lecithin, and hydrogenated lecithin. However, the present invention is not limited thereto.

In the case of using the lecithin, the adhesive is emulsified while surrounding the isoflavone, so that it can be dissolved in water as an emulsifying type. The egg yolk lecithin, soybean lecithin and hydrogenated lecithin have the advantage of preventing recombination of the isoflavones and improving dispersion.

In addition, the surfactant may be a PC (Phosphatidylcholine) is contained in more than 70% by weight. However, the present invention is not limited thereto, and when the PC content is included in an amount of 70 wt% or more, the recombination of the isoflavones may be excellent and the dispersion may be improved.

The anhydrous barrier-free isoflavones according to another embodiment of the present invention is to produce the barrier-free isoflavones when dissolved in water.

The anhydrous barrier-free isoflavone is intended to be provided in the form of an oral dosage form, and the anhydrous barrier-free isoflavone is dissolved in water and the surfactant is isoflavone dispersed in a mixture containing the surfactant and isoflavone. The emulsified type is formed in the form of being bonded while surrounding the outer portion of the flavone in an amorphous form, and is dispersed in water as a form of the emulsified type to produce the barrier-free material.

The anhydrous barrier-free isoflavone may further include an organic solvent having a polarity as a mixed adjuvant.

Since the mixed adjuvant is often a solid isoflavone and a surfactant, the liquid phase mixture should be in a solution state in order to perform liquid phase mixing. For this purpose, the mixture adjuvant plays a role of making a mixture having an appropriate viscosity. It is responsible for preventing the burning of isoflavones and surfactants.

The mixed adjuvant is not excluded from being included in the barrier-free isoflavone, but when the anhydrous barrier-free isoflavone is prepared, the mixed adjuvant may include the first isoflavone and the surfactant in a fluidized bed process. It may be included in a barrier-free isoflavone. In particular, the fluidized bed process may be desirable to add a polar organic solvent to the initial isoflavones and the surfactant to make a more stable fluidized bed.

The organic solvent having the polarity may include a -0H group and two or more -0H groups. Unlike the barrier-free isoflavone, the anhydrous barrier-free isoflavone contains an organic solvent having a polarity such as -OH. In general, the organic solvent is mostly dissolved in water when the anhydrous barrier-free isoflavones are dissolved in water, so that most of the organic solvents do not adhere to the barrier-free isoflavones. When the —OH group of the organic solvent becomes two or more, the solubility in water may be increased, and the anhydrous barrier-free isoflavone may form the barrier-free isoflavone.

In addition, preferably, the organic solvent may be selected from the group containing glycerin, 1,3 butylene glycol, propylene glycol, dipropylene glycol, ethanol, ethylene glycol and polyethylene glycol. However, the present invention is not limited thereto.

When the organic solvent is used, a more stable fluidized bed process may be achieved, and the anhydrous barrier-free isoflavone may be improved in solubility in water to form an excellent barrier-free isoflavone.

According to another embodiment of the present invention, a method for preparing anhydrous non-interfacial isoflavones includes (a) mixing a surfactant having two or more alkyl chains attached to a hydrophilic portion and a polar organic solvent having two or more -OH groups. ; (b) raising the temperature of the mixture of step (a) to raise the fluidity of the mixture; (c) injecting isoflavone as a poorly soluble substance into the mixture of step (b); (d) performing phase mixing of the mixture into which isoflavone is added in step (c) using a mixer including a mixing blade structure having the concept of phase mixing; And (e) solidifying the phase mixed mixture of step (d).

According to an embodiment of the present invention, the number of each blade of the unit blades constituting the mixed blade structure may be 20 or less.

This has the advantage that the ratio and amount of the isoflavones and surfactants are more quantified as the number of blades of the unit blades forming the mixed blade structure increases, but the internal pressure of the liquid mixing mixer increases, which may cause damage to the device. Because there is. That is, when the number of the blades of the unit blades constituting the mixed blade structure exceeds 20, there may be a problem that the internal pressure of the phase mixing mixture is excessively increased.

In addition, preferably the number of each blade of the unit blades constituting the mixed blade structure may be 10 or less, more preferably 1 to 4. Therefore, according to the above range, the ratio and amount of the isoflavone and the surfactant can be more quantified while maintaining the internal pressure of the liquid mixing mixer.

According to one embodiment of the present invention, the number of unit blades constituting the mixed blade structure may be 1 to 50.

When the number of unit blades constituting the mixing blade structure exceeds 50, the internal pressure of the mixing mixture for mixing may increase, and if there is less than one, the mixing of phases may not be achieved.

Preferably it may be 2 to 30, more preferably may be 4 to 15. According to the above range can stir the material quantitatively while increasing the stability of the liquid phase mixing mixer, it can increase the homogeneity of the material produced.

Meanwhile, the term 'unit blades forming the mixed blade structure' and the 'each blade of the unit blades forming the mixed blade structure' may be understood through FIG. 1.

When using the phase mixing mixer, the flow rate and the stirring time passing through the phase mixing mixer may be different for each phase mixing mixer used. However, the five conditions that must be in order to become the barrier-free material have been defined, and it will be necessary to repeat compensation mixing as necessary until the object becomes such.

On the other hand, using the liquid phase mixing mixer to prepare the barrier-free isoflavones of the present invention can be an important component. However, it is not limited to use another stirrer in parallel with the use of the phase mixing mixer.

In the present invention, since the matters related to the manufacturing method of the anhydrous barrier-free isoflavone are the same as those of the barrier-free isoflavone described above, the description thereof is omitted in order to prevent the present invention from becoming too complicated.

A method for preparing a barrier-free isoflavone according to another embodiment of the present invention includes the step of adding water to the anhydrous barrier-free isoflavone prepared by the method for preparing the anhydrous barrier-free isoflavone.

The barrier-free isoflavones and anhydrous barrier-free isoflavones according to the present invention may be prepared as pharmaceutical compositions.

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.

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 dosage of the pharmaceutical composition of the present invention may be administered once or several times a day in an oral dosage form of 0.1 to 100 mg / kg on an adult basis. It is recommended to apply 1 to 5 times a day in an amount of 3.0 ml to continue for 1 month or more. 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.

The barrier-free isoflavone of the present invention has the advantage of increasing the content of isoflavones that can be dissolved by several tens to hundreds of times compared to the conventional method of solubilizing isoflavones in liposome form or emulsion form.

Accordingly, the barrier-free isoflavones of the present invention can minimize the side effects caused by the human body by not using any solubilizer such as cremofo which may cause fatal side effects. In addition, when administered to the human body without barrier surface isoflavones can significantly increase the AUC (surface area under blood concentration) compared to the conventional method, it can significantly improve the pharmacological effect compared to conventional isoflavones have. In addition, isoflavones without barrier surface have excellent emulsification stability, so that precipitation in the digestive organs such as the esophagus, stomach, duodenum, large intestine and small intestine rarely occurs, thereby minimizing side effects due to isoflavone precipitation.

In addition, the method for producing a barrier-free isoflavone of the present invention enables the production of the barrier-free isoflavone. In addition, according to the anhydrous barrier-free isoflavone of the present invention and its manufacturing method, the barrier-free isoflavone may be utilized.

1 is a view showing an embodiment of each blade of the unit blade constituting the mixed blade structure and the unit blade constituting the mixed blade structure.
2 is a diagram showing an embodiment of a conventional liposome.
Figure 2 is a diagram showing another embodiment of the existing liposomes.
Figure 3 is a diagram showing another embodiment of the existing liposomes.
4 is a diagram conceptually illustrating the emulsified form of one barrier-free material in water according to an embodiment of the present invention.
5 is a diagram of an embodiment of an inline mixer including a mixing blade structure having the concept of reparation mixing.
Figure 6 is a schematic diagram of the manufacturing process of the barrier-free isoflavones according to an embodiment of the present invention.
7 is a DSC graph of isoflavone sodium and a barrier-free isoflavone prepared by the method of Example 17 as a control.
FIG. 8 is a DSC graph of isoflavone sodium and a barrier-free isoflavone prepared by the method of Example 18 as a control. FIG.
FIG. 9 is a SEM photograph of isoflavone sodium and a barrier-free isoflavone prepared by the method of Example 3 of the present invention as a control. In the photograph, 1000 and 7000 represent the SEM magnification.
Figure 10 is a graph showing the degree of solubility of the barrier-free isoflavones according to an embodiment of the present invention.

Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily carry out the present invention. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

In addition, throughout this specification,% used to indicate the concentration of a particular substance is (weight / weight)% solids / solid, (weight / volume)%, and unless otherwise stated, and Liquid / liquid is (volume / volume)%.

[ Manufacturing example  1-1: Free-standing interface  Preparation of Isoflavones]

Dispersing isoflavone and dipropylene glycol which are relatively stable at high temperature in the first open tank with the composition of Table 2, and stirring glyceryl stearate and stearic acid, which require premixing with lecithin and lecithin, which are susceptible to high temperature in the second open tank. After mixing, the material of Example 1 was prepared by stirring and mixing the solution of the first open tank and the second open tank with a homomixer, and mixing the solution of the first open tank and the second open tank with a microfluidizer. The material of Example 2 was prepared, and the material of Example 3 was prepared by stirring and mixing a solution of the first open tank and the second open tank with an in-line mixer.

ingredient Example 1
(weight%) Example 2
(weight%) Example 3
(weight%) Isoflavones lecithin Stearic acid Dipropylene glycol Glyceryl stearate Whether to manufacture free-standing interface materials Manufacturing × Manufacturing × Manufacturing ○

Referring to Table 2 above, in the case of Example 1 and Example 2, the barrier-free isoflavone was not prepared, but in the case of Example 3, the barrier-free isoflavone of the present invention was prepared.

[ Manufacturing example  1-2: Does not contain fatty acids Free-standing interface  Preparation of Isoflavones ]

The inline mixer of Preparation Example 1-1 was used, except that it did not contain fatty acids and purified water (Example 4), dipropylene glycol (Example 5) and ethanol (Example 6) were used as the adjuvant. To prepare a barrier-free isoflavone in the same manner as the method of stirring, the specific composition is shown in Table 3.

ingredient Example 4
(weight%) Example 5
(weight%) Example 6
(weight%) Isoflavones lecithin Purified water Dipropylene glycol ethanol Whether to manufacture free-standing interface materials Manufacturing ○ Manufacturing ○ Manufacturing ○

 [ Manufacturing example  1-3: Depending on the type of surfactant Free-standing interface  Preparation of Isoflavones]

Dispersion of isoflavones and dipropylene glycol, which are relatively stable at high temperatures in the first open tank with the composition of Table 4, and glyceryl stearate and stearic acid, which require premixing with surfactants, surfactants, which are susceptible to high temperatures in the second open tank. After stirring and mixing, the solution of the first open tank and the second open tank was stirred and mixed with an in-line mixer to prepare a barrier-free isoflavone. The material of Example 7 was prepared using PEG-150 Stearate as the surfactant, the material of Example 8 was prepared using Surfactant 2 as the surfactant, and the Example 9 was prepared using Surfactant 3 as the surfactant. The material was prepared, and the material of Example 10 was prepared using Surfactant 4 as surfactant, and the material of Example 11 was prepared using Surfactant 5 as surfactant. In Examples 8 to 11, a barrier-free isoflavone was prepared, but in Example 7, a barrier-free isoflavone was not prepared. PEG-150 Stearate as a surfactant is a surfactant having only one alkyl chain attached to the hydrophilic portion, so it is considered that the barrier-free isoflavone of the present invention was not prepared.

ingredient Example 7
(weight%) Example 8
(weight%) Example 9
(weight%) Example 10
(weight%) Example 11
(weight%) Isoflavones PEG-150 Stearate Other Surfactants 2 Other Surfactants 3 Other Surfactants 4 Other Surfactants 5 Dipropylene glycol Glyceryl stearate Stearic acid Whether to manufacture free-standing interface materials Manufacturing × Manufacturing ○ Manufacturing ○ Manufacturing ○ Manufacturing ○

 [ Manufacturing example  1-4: By fatty acid type Free-standing interface  Preparation of Isoflavones]

The preparation was carried out except that lauric acid (Example 12), mystic acid (Example 13), palmitic acid (Example 14), stearic acid (Example 15) and behenic acid (Example 16) were used as fatty acids. A barrier-free isoflavone was prepared in the same manner as in the stirring method using the in-line mixer in Example 1-1, and the specific composition thereof is shown in Table 5 below. In Example 12, Example 13, and Example 14, a barrier-free isoflavone could be prepared, but in Example 10 and Example 11, a barrier-free isoflavone could not be prepared.

ingredient Example 12
(weight%) Example 13
(weight%) Example 14
(weight%) Example 15
(weight%) Example 16
(weight%) Isoflavones lecithin Dipropylene glycol Glyceryl stearate Lauric acid (C12) Myristic acid (C14) Palmitic acid (C16) Stearic acid (C18) Behenic acid (C22) Whether to manufacture free-standing interface materials Manufacturing ○ Manufacturing ○ Manufacturing ○ Manufacturing ○ Manufacturing ○

 [ Manufacturing example  1-5: lecithin PC  Depending on the content Free-standing interface  Preparation of Isoflavones ]

Preparation Example 1- except that 75 wt% lecithin (Example 17), PC 80 wt% lecithin (Example 18), and 50 wt% lecithin PC (Example 19) were used as the surfactant. A barrier-free isoflavone was prepared in the same manner as the method of stirring using a single inline mixer, and the specific composition thereof is shown in Table 6 below. In Examples 17 to 19, all of the barrier-free isoflavones could be prepared, but Examples 17 and 18 showed the most stable solubilization state.

ingredient Example 17
(weight%) Example 18
(weight%) Example 19
(weight%) Isoflavones Lecithin (PC 75w%) Lecithin (PC 80w%) Lecithin (PC 50w%) Dipropylene glycol Glyceryl stearate Stearic acid Whether to manufacture free-standing interface materials Manufacturing ○ Manufacturing ○ Manufacturing ○

[ Manufacturing example  2 : Free-flowing interface  Preparation of Isoflavones]

The barrier-free isoflavone prepared by the method of Preparation Example 1 was solidified and finely powdered to prepare anhydrous barrier-free isoflavone.

[ Experimental Example  One : Free-standing interface  Property Evaluation of Isoflavones]

Experimental Example  1-1: Identification of amorphous state

The amorphous surface isoflavone prepared by the method of Example 3 was confirmed using an electron scanning microscope (SEM). Photographing was performed at 7000 times and 1000 times magnification, and specific results are shown in FIG. 10. The picture shown in blue letters in FIG. 10 is isoflavone itself, and it can be seen that the arrangement is very regular as shown. Even though it is not dispersed in water by the regular arrangement of isoflavone crystals, it is in a state where recrystallization occurs even if it is dispersed by physical force in a moment. However, when the photograph of the result of Example 3 is shown in a red color photograph taken by a scanning electron microscope, it is confirmed that the amorphous crystals are irregularly dispersed. Due to the amorphous form of the isoflavones and the irregular arrangement of crystals, it is very easy to disperse the water and maintain the disperse state for a long time (more than 3 years at room temperature).

Experimental Example  1-2: Evaluation of homogeneity and dispersibility

Dispersibility, homogeneity, and particle size of the water-free interface isoflavones can be roughly determined by measuring the potential difference using a Zeta-Potential Analyzer.However, this method is not sufficient to confirm the recrystallization in the colloid system. There is a limit. Therefore, the size and homogeneity of emulsified particles according to aging changes were confirmed directly by using a microscope, and its stability was confirmed. Table 7 and the particle photographs of FIGS. 12 to 27 show no recrystallization of isoflavones with changes over time, and the particle size also shows a constant distribution of _______ to ________ μm. You can see that it does not.

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, when looking at the particle picture of Figures 11 to 26, it can be seen that the particle size according to the change over time is uniform, showing a very stable form.

Manufacturing method Particle size (쨉 m) After 1 day After 7 days After 1 month 2 months later Three months later 4 months later Example 3 Example 4 Example 5 Example 6 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19

Experimental Example  1-3: Degree of acceptance  evaluation

The isoflavone content was fixed to 30% by weight, and the content of the surfactant and the solvent was adjusted to prepare the barrier-free isoflavones of Examples 17 to 19 using the compositions shown in Table 6 above, and 10% by weight of each composition sample. In a round flask containing 90% by weight purified water, sealed, dispersed at 70 ° C. for 30 minutes using a magnetic stirrer, and then evaluated for solubility (swelling degree of isoflavone) using a 100 ml measuring cylinder. It was.

The results are shown in Table 8 and FIG. 11. As a result of the evaluation, it was found that the degree of solubility was different according to the phospholipid (PC) content of lecithin. However, in the case of 75% and 80% of phospholipids, the difference in solubility was not large even after repeated experiments. Therefore, if the content of phospholipids of lecithin is 75% or more, it can be easily applied to the product. Could.

Classification Example 17 Example 18 Example 19 Thickness (cm)

Experimental Example  1-4: Moisture content measurement

Moisture content was measured to determine whether the ease of use as a pharmaceutical raw material could be improved by freeze-drying and powdering the finished isoflavone. Disperse the barrier-free isoflavones of Examples 4, 5, and 6 of Preparation Example 1-2 in water at a concentration of 10%, and then centrifuge at 10000 rpm for 15 minutes to obtain a clear supernatant to quantify the moisture. The moisture content was measured as shown in Table 9 below. Through the above experiments, it has been found that the solvent such as dipropylene glycol and ethanol easily exits from the water and plays a role as a mixing aid for mixing and mixing the poorly soluble materials.

ingredient Example 4 Example 5 Example 6 10% aqueous solution Water content

Experimental Example  1-5: DSC  Measure

DSC graphs were analyzed to determine the phase transition temperatures of the barrier-free isoflavones prepared by the methods of Examples 17 and 18. As a control, isoflavone sodium as a raw material was used.

The DSC graph of the control interface and the barrier-free isoflavones prepared by the method of Example 17 is shown in FIG. 8, and the DSC graph of the barrier-free isoflavones prepared by the control and Example 18 is shown in FIG. 9. As shown in Figure 8, in the case of the control (a), isoflavone isoflavone prepared by the method of Example 17 of the present invention, while the temperature of the phase transition to the liquid phase isoflavone sodium crystalline at room temperature is ________ ℃ In the case of (b), the temperature of the phase transition into the liquid phase was ________ ° C. , which showed that a significant difference in the phase transition temperature occurred. As shown in FIG. 8, in the case of the control group (a), the temperature at which the isoflavone sodium, which is the crystalline form at room temperature, is phase-transferred into the liquid phase is ________ ° C. , and the barrier-free isoflavone prepared by the method of Example 18 of the present invention. In the case of (b), the temperature of the phase transition into the liquid phase was ________ ° C. , which showed that a significant difference in the phase transition temperature occurred.

[ Experimental Example  2 : Free-standing interface  Evaluation of Efficacy of Isoflavones]

Experimental Example  2-1: in vitro  Test

Cell permeability experiments using monolayer epithelial cells using CaCo-2 cells were performed to analyze the relative permeability coefficient (Papp) relative to the conventional formulation and to compare it with bioavailability. At this time, metoprolol was used as a positive control drug, atenolol was used as a negative control drug, and a control drug (F) isoflavone sodium (F) and a main ingredient were used. . Experimental results As shown in Table 10, the barrier-free isoflavones according to the present invention showed superior drug permeation efficacy compared to the reference drug.

Formulations P _app (± SD) × 10 ⁶ (cm / s) ^a Enhancement factor (%) ^b Isoflavone sodium Foasmax Example 3 Example 8 Example 9 Example 10 Example 11

^a All measurements are expressed as mean ± SD (n = 3)

^? Significantly different in comparison to parent Isoflavone sodium (ρ <0.05).

^{‥ Significantly different in comparison to parent Isoflavone} sodium (ρ <0.01).

^b Enhancement factor (%)-[P _app (formulation) / P _app (control) * 100] -100

Experimental Example  2-2: Dissolution test evaluation

Elution test described in the 15th revised Japanese Pharmacopoeia using isoflavones prepared in Example 3 and isoflavones prepared by the method of Example 1 (cannot produce non-interfacial materials, control) (temperature: 37 ° C, test solution) : Elution test No. 2 solution, test method: paddle method, rotation speed: 50 rpm). Table 11 shows the dissolution rate after 5 minutes, 15 minutes, and 30 minutes after the start of the experiment.

As a result of the test, the barrier-free isoflavones prepared by the method of Example 3 were found to have a dissolution rate of ________% or more at 30 minutes after the start of the dissolution test, and exhibit high dissolution properties significantly exceeding the solubility of the drug. On the other hand, the isoflavone of Example 1, in which no barrier-free material was prepared, showed a low dissolution rate of ________%.

Example Dissolution rate (%) 5 minutes after the test 15 minutes after the test 30 minutes after the test Example 1 Example 3 Example 4 Example 5 Example 6 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, Of the right.

Claims (14)

100 parts by weight of isoflavones and
10 to 200 parts by weight of a surfactant having two or more alkyl chains attached to the hydrophilic part with respect to the isoflavone,
The surfactant is a form that is bonded to surround the isoflavones in an amorphous form (amorphous), dissolved in water in an emulsion type,
The isoflavone is attached to the surfactant has an average diameter of 0.5 to 30㎛, the average range of the size is within ± 200% of the diameter
Uncut interface isoflavones.
The method according to claim 1,
The barrier-free isoflavone further comprises a fatty acid between the surfactant and the isoflavone
Uncut interface isoflavones.
3. The method of claim 2,
The fatty acid is included in 10 to 1000 parts by weight based on the isoflavone
Uncut interface isoflavones.
3. The method of claim 2,
The fatty acid is selected from the group comprising caprylic acid , caprylic acid , stearic acid, palmitic acid, myristic acid, lauryl acid and oleic acid
Uncut interface isoflavones.
The method according to claim 1,
The surfactant is selected from the group comprising egg yolk lecithin, soy lecithin and hydrogenated lecithin
Uncut interface isoflavones.
The method according to claim 1,
The surfactant is that the PC (Phosphatidylcholine) is contained in more than 70% by weight
Uncut interface isoflavones.
When dissolved in water,
Anhydrous barrier-free isoflavone which produces the barrier-free isoflavone of any one of Claims 1-6.
8. The method of claim 7,
Wherein the anhydrous barrier-free isoflavones further comprises an organic solvent having a polarity as a mixed adjuvant
Anhydrous, uncompounded isoflavones.
9. The method of claim 8,
The organic solvent having the polar is that -0H group is two or more
Anhydrous, uncompounded isoflavones.
9. The method of claim 8,
The polar organic solvent is selected from the group consisting of glycerin, 1,3 butylene glycol, propylene glycol, dipropylene glycol, ethylene glycol and polyethylene glycol
Anhydrous, uncompounded isoflavones.
(a) mixing a surfactant having two or more alkyl chains attached to a hydrophilic moiety and a polar organic solvent having two or more OH groups;
(b) raising the temperature of the mixture of step (a) to raise the fluidity of the mixture;
(c) injecting isoflavone as a poorly soluble substance into the mixture of step (b);
(d) performing phase mixing of the mixture into which isoflavone is added in step (c) using a mixer including a mixing blade structure having the concept of phase mixing; And
(e) solidifying the phase mixed mixture of step (d)
Method for producing an anhydrous, non-compound interface isoflavone comprising a.
12. The method of claim 11,
The number of each blade of the unit blades constituting the mixed blade structure is 20 or less
Process for the production of anhydrous non-sealing interface isoflavones.
12. The method of claim 11,
The number of unit blades constituting the mixed blade structure is 5 to 30
Process for the production of anhydrous non-sealing interface isoflavones.
Claim 1 to 13 comprising the step of adding water to the anhydrous barrier-free isoflavones prepared by the method of any one of claims
Process for producing isoflavones without barrier.

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