KR20140043253A

KR20140043253A - The water-insoluble decursin covered with amorphous surfactant and method for preparing the same

Info

Publication number: KR20140043253A
Application number: KR1020120105991A
Authority: KR
Inventors: 권돈선; 유우영
Original assignee: 한국콜마주식회사
Priority date: 2012-09-24
Filing date: 2012-09-24
Publication date: 2014-04-09

Abstract

The present invention relates to a barrier-free decursin and a preparation method thereof. The barrier-free deckerin according to an embodiment of the present invention comprises 100 parts by weight of decursin 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 decusin. The surfactant is in the form of an amorphous (amorphous) surrounds the outer surface of the surfactant is dissolved in water in an emulsified type, the surfactant is attached to the deckerine has an average diameter of 0.5 to 30㎛, the average size The range is within ± 200% of the diameter.

Description

Blessed surface deckerine and its manufacturing method {THE WATER-INSOLUBLE DECURSIN COVERED WITH AMORPHOUS SURFACTANT AND METHOD FOR PREPARING THE SAME}

The present invention relates to a barrier-free decursin and a preparation method thereof. More specifically, the present invention relates to a deck-free surface deckercein having a very excellent emulsification stability without containing a solubilizing agent in the decosin, which is a poorly water-soluble substance, and a manufacturing method thereof.

Normal cells undergo proliferation after proliferation, and cancer cells are composed of immature cells that only proliferate infinitely without differentiation. Recently, cancer cell therapy has been widely used in leukemia as a method of inducing cancer cells into normal cells or similar cells using endothelial proliferation cells. Unlike the anticancer drugs based on existing cytotoxicity, it is encouraging in that it can reduce the toxic side effects of serious anticancer drugs by trying a new route of treatment, and induce cancer cell differentiation in patients whose administration of the conventional anticancer drugs was limited due to the high side effects. The development of new anticancer drugs with functions is required.

Angelica is a perennial herb belonging to the Buttercup family, Angelica gigas NAKAI is used in Korea, Angelica sinensis DIELS is used in China, and Angelica acutiloba KITAGAWA is used in Japan.

Angelica gigas NaKai has a blood-forming function (補血作用) that produces blood when blood is scarce. The roots of Chinese donkeys and Koreans donkeys have excellent blood-reducing effects, and the roots of true donkeys have better blood-sucking action (activ 血作用) that allows blood to circulate more smoothly, and have stronger anti-cancer effects and lower blood pressure. Pharmacologically, Angelica stimulates coronary blood flow and stimulates red blood cell production. Since ancient times, it has been widely used in blood and chewing drugs for gynecological diseases such as sedation, analgesic, anemia and dysmenorrhea and hypothermia, and coumarin-based compounds such as decusin, decosinol, and umbelifrone In recent years, antimutagenic activity, liver detoxification activity, neuroprotective activity and the like have been reported (Kang et al., J Nat Prod 68, 56-59, 2005).

Accordingly, decursin, decursinol angelate, decurcinol, or a mixture thereof (hereinafter referred to as decusin), which is a major component of Angelica gigas Nakai, is called. Many studies have been conducted on the pharmacological action of the pharmacological agent.

However, since the decusin is not dissolved in water, it should be extracted with a solvent, alcohol or a mixture thereof, and when the extract with the alcohol or the solvent is used, the intestinal absorption is low due to oral administration. There is a problem that the amount absorbed into the inside is insignificant.

In general, solubility in water and permeability through the intestinal membrane have a significant effect on the absorption rate during oral administration of drugs (CA Lipinski, F. Lombardo, BW Dominy, P. Feeney, Experimental and computational approaches to estimate solubility and permeability in drug delivery and development setting, Adv.Drug Deliv. Rev. 46, 3-26, 2001)

Drugs with high solubility and high permeability have high absorption in the intestinal tract. However, low solubility and high permeability result in a decrease in particle size of the drug due to low absorption in the intestinal tract of the drug (AB Straughn, MC Meyer, G. Raghow, K. Rotenberg, Bioavailability of microsize and ultramicrosize griseofulvin products in man) , J. Pharmacokinet.Biopharm. 8, 347-362, 1980), the use of lipids or surfactants (SA Charman, WN Charman, MC Rogge, TD Wilson, FJ Dutko, CW Pouton, Self-emulsifying drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound, Pharm.Res. 9, 87-93, 1992), or the use of solid dispersions, including amorphous (C. Liu, J. Wu, B. Shi, Y. Zhang, T. Gao , Y. Pei, Enhancing the bioavailability of cyclosporin a using solid dispersion containing polyoxyethylene 40 stearate, Drug Dev. Ind. Pharm. 32, 115-123, 2006). Of the drug by increasing It is possible to increase the yield.

Conversely, drugs with high solubility but low intestinal permeability are also to be overcome. Such drugs are generally listed in various ways to increase intestinal permeability. Method of inducing chemical reaction with fatty acids to impart fat solubility (T. Fujita, T. Fujita, K. Morikawa, H. Tanaka, O. Iemura, A. Yamamoto, S. Muranishi, Improvement of intestinal absorption of human calcitonin by chemical modification with fatty acids: synergistic effects of acylation and absorption enhancers, Int. J. Pharm. 134, 47-57, 1996), increasing drug absorption through H ⁺ / peptide cotransporter, one of the enteric active inlet transporters. Peptidyl derivatives (I. Tamai, T. Nakanishi, H. Nakahara, Y. Sai, V. Ganapathy, FH Leibach, A. Tsuji, Improvement of L-dopa absorption by dipeptidyl derivation, activating peptide transporter PepT1, J. Pharm Sci. 87, 1542-1546, 1998; HK Han, DM Oh, GL Amidon, Cellular uptake mechanism of amino acid ester prodrugs in Caco-2 / hPEPT1 cells overexpressing a human peptide transporter, Pharm.Res. 15, 1382-1386. , 1998), conjugation with specific peptides that can penetrate cell membranes (S. Futaki, Arginine-rich peptides: potential for intracelluar delivery of macromolecules and the mystery of the translocation mechanism, Int. J. Pharm. 245, 1-7, 2002), use of absorption enhancers (VHL Lee, Protease inhibitors and penetration enhancers as approaches to modify peptide absorption, J. Control. Release 13, 213-223, 1990), the use of additives that inhibit the intestinal active drug transporter such as p-glycoprotein (Q. Shen, Y. Lin, T. Handa, M. Doi, M. Sugie, K Wakayama, N. Okada, T. Fujita, A. Yamamoto, Modulation of intestinal pglycoprotein function by polyethylene glycols and their derivatives by in vitro transport and in situ absorption studies, Int. J. Pharm. 313, 49-56, 2006). , M. Saffran, GS Kumar, C. Davariar, JC Burnham, F. Williams, DC Neckers, A new approach to the oral administration of insulin and other peptide drugs, Science 233, 1081-1084, 1986 And mucosal drug delivery (S. Sakuma, M. Hayashi, M. Akashi, Design of nanoparticles composed of graft copolymers for oral peptide delivery, Adv. Drug Deliv.Res. 47, 21-37, 2001). As a result, the absorption rate of the drug can be increased.

In the prior art, Patent Document 1 (KR 10-2004-0080854 A) relates to a method for extracting decosin and decosinol angelate, and the method of extracting decosin and decosinol angelate from Angelica gigas Although disclosed, even when the extract is used, the intestinal absorption rate is very low because the decusin is not dissolved in water.

Therefore, in order to solve the above problems, the emulsification stability of the decosin emulsified by the surfactant should be minimized to minimize the amount of decosin precipitated from the digestive tract, and the amount of the drug trapped in the surfactant will be drastically increased. Even if the drug is to be administered should be able to exhibit a sufficient pharmacological effect.

The present inventors have recognized the above problems and tried to solve the above problem, when the decosin and the surfactant as a poorly soluble material when agitation using a reparation mixture mixer does not use a solubilizer causing serious side effects to the human body Even if it was found that a very large amount of a poorly soluble material that can be dissolved while producing a new state of the material having excellent emulsion stability was completed the present invention.

SUMMARY OF THE INVENTION An object of the present invention is to provide a barrier-free deckerin comprising a deckerine and a surfactant as a poorly water-soluble substance, and further provide an anhydrous barrier-free deckerine that produces the barrier-free deckerin when dissolved in water.

It is another object of the present invention to provide a method for preparing the barrier-free deckercin and the anhydrous barrier-free deckerine.

In order to achieve the above object, the barrier-free deckerin according to an embodiment of the present invention 10 to 100 parts by weight of decursin (Decursin) and 10 to 10 or more surfactant having an alkyl chain attached to the hydrophilic portion with respect to the decusin It is included in 200 parts by weight, the surfactant is surrounded by an amorphous (amorphous) of the outer form of the adhesive form (Amorphous) is dissolved in water in the emulsification type, the surfactant is attached to the deckerine has an average diameter of 0.5 to 30 μm, and the average range of sizes is within ± 200% of the diameter.

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

The fatty acid may be included in 10 to 1000 parts by weight with respect to the decusin.

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).

According to another embodiment of the present invention, when the anhydrous barrier-free deckerine is dissolved in water, the barrier-free deckerin is produced.

The anhydrous barrier-free deckerine may further comprise 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-detergent interface deckerine includes the steps of: (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 deckersin as a poorly soluble substance into the mixture of step (b); (d) performing phase mixing of the mixture into which the decusin 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.

According to another embodiment of the present invention, a method for preparing a barrier-free interface deckerine includes adding water to an anhydrous barrier-free deckerine prepared by the method for preparing the anhydrous barrier-free interface deckerine.

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 deckerine according to an embodiment of the present invention refers to the novel type of material, and the barrier-free deckerine used herein means to belong to the concept of the barrier-free material including the following properties.

(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, thereby greatly increasing the amount of melting of the decusin as the size of the poorly soluble substance surrounded by the surfactant increases. It can be analyzed.

(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 regard, the material of the present invention may not be called completely amorphous, but the term amorphous is used in describing the material of the present invention in that it is oriented in the 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.

Therefore, when the poorly soluble substance is deckerin, the deckerin showing the above five characteristics is defined as a barrier-free deckerine (shortened word of deckerine covered with a surfactant on the outside of an emulsion-soluble water-soluble amorphous form).

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

The term solubilizing, dissolving or dissolving herein may include conventional dissolution, emulsification, liposome forms, and the no- north interphase state 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 (eg, 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 Remingtons 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, deckerin channel blockers (e.g. nifedipine, diltiazem hydrochloride, etc.); nitrates (e.g. nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, Erytrityl 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 controlling decosin (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 Edn, 1996).

The barrier-free deckerin according to an embodiment of the present invention comprises 100 parts by weight of Decursin 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 decusin. The surfactant is in the form of an amorphous (amorphous) surrounds the outer surface of the surfactant is dissolved in water in an emulsified type, the surfactant is attached to the deckerine has an average diameter of 0.5 to 30㎛, the average size The range 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-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-dstearoyl-sn-glycero-3-phosphoethanolamine, sodium salt

Anhydrous undeckersin according to an embodiment of the present invention is that the surfactant having two or more alkyl chains attached to the hydrophilic portion is included in 10 to 200 parts by weight based on 100 parts by weight of decursin (Decursin). In the case of conventional liposomes, 500 to 1000 parts by weight of a surfactant is used to dissolve 100 parts by weight of deckerin. However, in the case of the barrier-free deckerin according to the present invention, the deckerin can be dissolved in water by using a surfactant in the above range. As a result, the content of the surfactant can be greatly reduced. In addition, in the case where the surfactant having two or more alkyl chains attached to the hydrophilic part is included in an amount of more than 200 parts by weight, excessively excessive use may result in a significant decrease in efficiency due to a decrease in the content of deckerin compared to the amount of the surfactant. When it is included in less than 10 parts by weight it is difficult to contact while completely surrounding the deckerin in an amorphous form, the efficiency of dissolving in water in the emulsion 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, the efficiency of the surfactant dissolved in water while amorphous surrounding the outside of the deckerin can be significantly increased.

Anhydrous, undecided deckerine according to an embodiment of the present invention has a diameter of 0.5 to 30 μm of the barrier-free deckerine to which the surfactant is attached. When the diameter of the barrier-free deckerin exceeds 30 μm, internal crystallization may increase in the vicinity of hydrophobic groups, thereby decreasing the sustaining effect of the emulsified state, and when less than 0.5 μm, the stability of the inner barrier-free deckerin may be reduced.

The diameter of the barrier-free deckerin is very important in terms of functional dissolving poorly soluble decusin. In other words, the diameter of the barrier-free deckerin is an indicator of the size of the barrier-free deckerin because it is an important factor in determining the amount of deckerin that the hydrophobic group of the surfactant can bear. It is unknown whether liposomes are completely dissolved in the hydrophobic group, but since the decosin of the barrier-free interface is much larger than the liposomes, the deckerin at least in the individual barrier-free decosin is at least partially internally. It may be crystallized. However, since the surfactant surrounds the decosin outside in an amorphous form, the uncoated surface decosin is in an emulsified type and dissolved in water, 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 deckersin is 1 to 10 ㎛, more preferably 1.5 to 5 ㎛. By the above range can be maintained in the stable emulsification state the highest degree of stabilization of the barrier-free deckersin.

Anhydrous decaffeinated 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, recrystallization of the barrier-free deckerine may be remarkably delayed to increase its stability, and if it is outside the above range, such stability may be degraded.

In addition, preferably, the anhydrous undeckersin may have a mean size range of -30% to + 30%, more preferably -10% to + 10% of the diameter. According to the above range, since recrystallization is further slowed, there is an advantage in that the stability of the anhydrous decosin is very high.

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

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 deckercin particles is so high that the particles are almost the same size, the repulsive force due to inter-particle zeta potential and the attraction force due to van der Waals can be said to be 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). As a result, recrystallization of the barrier-free deckercin particles can be delayed as much as possible.

As described above, in order to significantly increase the homogeneity of the barrier-free deckercin, an inline mixer including a mixing blade structure having a concept of reparation 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 deckerine of the present invention can be prepared only through the reparation mixing mixer, not through a general mixer, as well as a very powerful stirrer or homogenizer such as the microfluidizer, 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 deckerine to be introduced is quantitatively 1/2 to 1/10 each time it passes the unit blade included in the internal liquid mixing mixer tube. The process is divided and stirred. In addition, as the unit blade passes through the process repeatedly, the content and ratio of the surfactant and deckerin to be bound may be quantified while being proportional to the dosage and the ratio of the decosin and the surfactant to be initially introduced.

Although the content or ratio of the surfactant and deckerin is not quantitative in the initial stirring step, the proportion and amount of the decosin and surfactant to be bound may be quantified as the stirring process proceeds. As a result, when the surfactant and the decansin quantified in the ratio and quantity as described above are bound to be almost the same, it is judged that the homogeneity of the resulting material is significantly increased.

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 a decosin in a non-interface state and derived a concept thereof, and the invention of the substance is protected by the substance itself, and the scope of the present invention cannot be limited to the manufacturing room. Is not limited to that according to the liquid mixing mixer.

In other words, even if it is not the method of using the liquid mixing mixer, there is a sufficient possibility that a homogenizer or stirrer can be produced that can more easily produce the barrier-free deckerine pursued by the present invention. . 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 deckerce prepared according to the above method other than the above mixing mixer is also considered to be within the scope of the present invention.

When the fatty acid is further included, the fatty acid is irregularly entangled with the alkyl chain of the surfactant attached to the decusin, thereby preventing the surfactant from being formalized. Therefore, there is an effect of significantly lowering the probability of recrystallization by combining the deckerins.

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

The fatty acid may be included in 10 to 1000 parts by weight with respect to the decusin. 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 in less than 10 parts by weight, the recombination prevention, the dispersion degree and the homogeneity improvement effect of the decusin are improved. Can be degraded.

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 decusin 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 decosin recombination prevention, dispersion degree improvement and homogeneity degree improvement 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, it is possible to dissolve in water as an emulsifying type by being emulsified while surrounding the deckerin. The egg yolk lecithin, soy lecithin and hydrogenated lecithin have the advantage of preventing the recombination of the decusin, and the effect of 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, it may be excellent in preventing the recombination of the decusin and improving the dispersion degree with high purity.

The anhydrous barrier-free deckerin is intended to be provided in the form of an oral dosage form, and the anhydrous barrier-free deckerin is dissolved in water when the mixture containing the surfactant and the deckerin is dispersed in water, and the surfactant disperses the outline of the deckerin. It forms an emulsion type in the form of being bonded while being surrounded in an amorphous form, and is dispersed in water as the form of the emulsion type to produce the barrier-free material.

Since the mixing aid is often a solid deckersin and surfactant to be in the liquid phase mixture to be phased mixing for this purpose to put a liquid substance to play a role of making a mixture of the appropriate viscosity, and also at the elevated temperature the decker It is responsible for preventing burning of the scene and surfactant.

The mixed adjuvant is not excluded from being included in the barrier-free deckerin, but when preparing the anhydrous de-bleached decosin, the mixed adjuvant may include a fluidized bed process of the initial deckerin and the surfactant. It may be included in the interfacial deckin. In particular, the fluidized bed process may be desirable to add a polar organic solvent to the initial deckercin and the surfactant to 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 deckerin, the anhydrous barrier-free deckerin contains an organic solvent having a polarity such as -OH. In addition, the organic solvent is usually dissolved in water when the anhydrous barrier-free deckerin is dissolved in water to maintain a state that most do not adhere to the barrier-free deckerin. When the —OH group of the organic solvent is two or more, the solubility in water may increase, and the anhydrous barrier-free deckerin may form the barrier-free deckerin.

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 can be achieved, and the anhydrous barrier-free deckerin increases the solubility in water to form an excellent barrier-free deckerin.

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 deckercin and the surfactant are more quantified as the number of blades of the unit blades constituting 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 it is possible to quantify the ratio and the amount of the deckercin and the surfactant more 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.

On the other hand, the terminology herein in the unit blade constituting the mixed blade structure and each blade of the unit blade constituting the mixed blade structure can be understood through FIG.

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 deckerine 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, the matters related to the manufacturing method of the anhydrous barrier-free deckerin are the same as those of the barrier-free deckerin described above, and thus the description thereof is omitted in order to prevent the present invention from being excessively complicated.

The barrier-free deckerin and the anhydrous-free deckerin according to the present invention may be prepared as a pharmaceutical composition.

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 decusin of the present invention has the advantage of increasing the content of decosin that can be dissolved by several tens to several hundred times as compared with the method of solubilizing the decosin in the form of liposome or emulsion.

Accordingly, the barrier-free deckacin of the present invention can minimize the side effects caused by the human body by not using a solubilizer such as cremofo, which has the potential to cause fatal side effects. In addition, when the above-mentioned surface-free decosin is administered to the human body, the AUC (curve area under blood concentration) can be dramatically increased as compared to the conventional method, and the pharmacological effect can be remarkably improved as compared with the conventional decosin preparation. . In addition, the mucosal decosin has excellent emulsification stability, so that almost no precipitation occurs in the digestive organs such as the esophagus, the stomach, the duodenum, the large intestine, and the small intestine, thereby minimizing the side effects due to the deposition of the decusin.

In addition, the method for preparing the barrier-free deckerin of the present invention enables the preparation of the barrier-free deckerin. In addition, according to the anhydrous barrier-free deckerine and the manufacturing method of the present invention, the barrier-free deckerine can 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 decker scene according to an embodiment of the present invention.
FIG. 7 is a DSC graph of decosin sodium as a control and a barrier-free decosin prepared by the method of Example 17.
FIG. 8 is a DSC graph of decosin sodium as a control and a barrier-free decusin prepared by the method of Example 18.
FIG. 9 is a SEM photograph of deckusin sodium as a control and a barrier-free deckercin prepared by the method of Example 3 of the present invention. FIG. In the photograph, 1000 and 7000 represent the SEM magnification.
10 is a graph showing the degree of solubilization of the barrier-free deckercin 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 Decker Produce]

The composition of Table 2 disperses relatively stable decusin and dipropylene glycol at high temperature in the first open tank, and stirs 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%) Decker 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, no barrier-free deckerine was prepared, but in Example 3, the barrier-free deckerine of the present invention was prepared.

[ Manufacturing example 1-2: Does not contain fatty acids Free-standing interface Decker Produce ]

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 deckerine in the same manner as the stirring method, the specific composition is as shown in Table 3.

ingredient Example 4
(weight%) Example 5
(weight%) Example 6
(weight%) Decker 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 Decker Produce]

The composition of Table 4 disperses relatively stable decusin and dipropylene glycol at a high temperature in the first open tank, and glyceryl stearate and stearic acid, which need to be premixed with a surfactant that is susceptible to high temperature 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 deckercin. 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 Example 8 to Example 11, a barrier-free deckersin was prepared, but in Example 7, a barrier-free deckercin was not produced. PEG-150 Stearate as a surfactant is a surfactant having only one alkyl chain attached to a hydrophilic moiety.

ingredient Example 7
(weight%) Example 8
(weight%) Example 9
(weight%) Example 10
(weight%) Example 11
(weight%) Decker 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 Decker Produce]

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. In the same manner as the stirring method using an in-line mixer in Example 1-1 to prepare a barrier-free deckerine, the specific composition is shown in Table 5. In Example 12, Example 13, and Example 14, it was possible to prepare a barrier-free deckercin, but in Example 10 and Example 11 it was not possible to produce a barrier-free decker.

ingredient Example 12
(weight%) Example 13
(weight%) Example 14
(weight%) Example 15
(weight%) Example 16
(weight%) Decker 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 Decker Produce ]

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. To prepare a barrier-free deckerine in the same manner as the stirring method using a single inline mixer, the specific composition is shown in Table 6. In Examples 17 to 19, it was possible to produce a barrier-free deckercin, but Examples 17 and 18 showed the most stable solubilization state.

ingredient Example 17
(weight%) Example 18
(weight%) Example 19
(weight%) Decker 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 Decker Produce]

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

[ Experimental Example One : Free-standing interface Decker Property evaluation]

Experimental Example 1-1: Identification of amorphous state

The amorphous surface deckercin 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 blue photo of Fig. 10 shows that Decakin itself is a very regular arrangement as shown. Even though it is not dispersed in water by a regular array of Decusin 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. Decursin's amorphous form and irregular arrangement of crystals make it very easy to disperse and maintain dispersal for a long time (more than 3 years at room temperature).

Experimental Example 1-2: Evaluation of homogeneity and dispersibility

The dispersibility, homogeneity, and particle size of the surface-free deckersin phase can be roughly determined by measuring the potential difference using a Zeta-Potential Analyzer, but this method is limited to confirm the presence or absence of recrystallization in the colloid system. There is. 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 that no recrystallization of Decusin was observed with time-dependent change, and that the particle size also showed a constant distribution of _______ to ________ μm. You can see that.

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

Fixing the deckerin content to 30% by weight, by adjusting the content of the surfactant and the solvent to prepare the barrier-free deckerine of Examples 17 to 19 with the composition shown in Table 6, 10% by weight of each composition sample After sealing in a round flask containing 90% by weight purified water and sealing it for 30 minutes at 70 ° C. using a magnetic stirrer, the degree of solubility (degree of expansion) was evaluated using a 100 ml measuring cylinder.

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 free lyophilization and powdering of the finished surface-free surface decker can enhance the ease of use as a pharmaceutical ingredient. After dispersing the water-free interface deckerine of Examples 4, 5, and 6 of Preparation Example 1-2 in water at a concentration of 10%, centrifugation was performed at 10000 rpm for 15 minutes, and the clear supernatant was taken to quantify the water. The moisture content was measured as 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 temperature of the barrier-free deckercin prepared by the methods of Examples 17 and 18. As a control, raw material deckusin sodium was used.

The DSC graph of the barrier-free Deckerin prepared by the control and the method of Example 17 is shown in FIG. 8, and the DSC graph of the barrier-free Deckerin prepared by the method of the control and Example 18 is shown in FIG. 9. As shown in FIG. 8, in the case of the control group (a), the temperature at which phase-transferred sodium in the crystalline form of decosin is changed to the liquid phase is ________ ° C. , and the surface-free decosin prepared by the method of Example 17 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. As shown in FIG. 8, in the case of the control, (a), the temperature at which phase-transferred sodium in the crystalline form of decosin is changed to the liquid phase is ________ ° C. , so that the surface-free decosin 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 Decker Efficacy evaluation]

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) (deconsin sodium) sold by D was used as a main ingredient. . As a result of the experiment, it was found that the barrier-free deckacin according to the present invention showed superior drug permeation efficacy as compared to the reference drug.

Formulations P _app (± SD) × 10 ⁶ (cm / s) ^a Enhancement factor (%) ^b Decursin 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 Decursin sodium (ρ <0.05).

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

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

Experimental Example 2-2: Dissolution test evaluation

Elution test (temperature: 37 ° C., test solution) described in the 15th Amendment of Japan, using Deoksine prepared in Example 3 and Deckerin prepared by the method of Example 1 (non-manufactured non-surfactant, control). Elution test No. 2 solution, test method: paddle method, rotation speed: 50 rpm) was performed. 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, it was found that the barrier-free deckercein prepared by the method of Example 3 had a dissolution rate of ________% or more after 30 minutes from the start of the dissolution test, and showed high dissolution ability significantly exceeding the solubility of the drug. On the other hand, the deckerine 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

100 parts by weight of decursin and
It comprises 10 to 200 parts by weight of a surfactant having two or more alkyl chains attached to the hydrophilic portion relative to the decusin,
The surfactant is in the form of an amorphous (amorphous) surrounding the outside of the decusin is bonded in the form of an emulsion, dissolved in water,
The deckerine 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
Deckersin, a warrior.

The method according to claim 1,
The barrier-free deckerin is further comprising a fatty acid between the surfactant and the deckerin
Deckersin, a warrior.

3. The method of claim 2,
The fatty acid will be included in 10 to 1000 parts by weight relative to the decusin
Deckersin, a warrior.

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
Deckersin, a warrior.

The method according to claim 1,
The surfactant is selected from the group comprising egg yolk lecithin, soy lecithin and hydrogenated lecithin
Deckersin, a warrior.

The method according to claim 1,
The surfactant is that the PC (Phosphatidylcholine) is contained in more than 70% by weight
Deckersin, a warrior.

When dissolved in water,
Anhydrous barrier-free deckerin, which produces the barrier-free deckerin of any one of claims 1 to 6.

8. The method of claim 7,
Wherein the anhydrous barrier-free deckerine further comprises an organic solvent having a polarity as a mixed adjuvant
Anhydrous uncensored surface deckerine.

9. The method of claim 8,
The organic solvent having the polar is that -0H group is two or more
Anhydrous uncensored surface deckerine.

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 uncensored surface deckerine.

(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 deckersin as a poorly soluble substance into the mixture of step (b);
(d) performing phase mixing of the mixture into which the decusin 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 of producing anhydrous uncensored interface deckerine 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, unsealed interface deckerine.

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, unsealed interface deckerine.

Claim 1 to 13 comprising the step of adding water to the anhydrous barrier-free deckerine prepared by any one of the methods of claim
Process for preparing deucin-free cotton.