KR20140043251A - The water-insoluble alendronate covered with amorphous surfactant and method for preparing the same - Google Patents

Abstract

The present invention relates to a barrier-free Alendronate (Aendronate) and a method for producing the same. The barrier-free Alendronate according to an embodiment of the present invention comprises 100 parts by weight of Alendronate 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 Alendronate, the interface The active agent surrounds the outer portion of the alendronate in an amorphous form and is bonded to it. It is dissolved in water in an emulsified type, and the alendronate with the surfactant has an average diameter of 0.5 to 30 μm and an average range of sizes. The diameter is within ± 200%.

Description

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

The present invention relates to a barrier-free Alendronate (Aendronate) and a method for producing the same. More specifically, the present invention relates to a wrought-free interface allenronate having a very excellent emulsification stability without containing a solubilizing agent, allenronate, which is a poorly water-soluble substance.

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.

Currently developed bisphosphonate drugs are so polar that they do not penetrate the biological lipid membrane, and have a strong affinity with polyvalent metal ions such as calcium to form an insoluble complex when combined with them in vivo to be absorbed through the cell membrane in the digestive tract Is known to be difficult (Br. J. Cancer 71, 67, 1995). In addition, since it is anionic in the small intestine at pH 6-8, it is difficult to absorb in the small intestine, so that most drugs have an absorption rate of less than 10%, and in particular, the absorption rate of sodium alindronate is reported to be less than 1% (Clin. Pharmacol. Therapeutics 58,288-209, 1995).

In addition, Alendronate causes local irritation to the gastrointestinal mucosa of the upper gastrointestinal tract, causing side effects such as esophagitis, esophageal ulcers, and esophageal erosion, so that sufficient water must be consumed to quickly pass the drug and reduce the possibility of esophageal irritation. (PC De Groen, New Eng. J. Med. 335, 1016-1021, 1996; DO Castell, New Eng. J. Med. 335, 1058-1059, 1996; UA Liberman, New Eng. J. Med. 335 , 1060-1070, 1996).

Therefore, many formulation studies have been conducted to encapsulate drugs in biodegradable polymers in order to protect such alendronate from the external environment and increase biofilm affinity.

In Korean Patent 648515, a polymer solution prepared by dissolving and dispersing bisphosphonate in an aqueous solution containing a water-soluble polymer and a hydrophilic surfactant is prepared by adding a secondary organic solvent to a primary organic solvent containing a biodegradable polymer and a hydrophobic surfactant. Added to the prepared polymer solution to prepare a primary emulsion solution (W / O), and comprising a bisphosphonate-containing polymer microspheres prepared by dispersing the primary emulsion solution in an external continuous phase, having a sustained effect for treating or preventing bone-related diseases Described are inventions relating to injectables. Korean Patent No. 709015 also describes an invention relating to a polymer microparticle capable of continuous drug release and a manufacturing method thereof.

In addition, Korean Patent No. 631873 contains alendronic acid or a salt thereof and contains an absorption increasing agent and an absorption increasing auxiliary agent together to increase the bioavailability of the active ingredient by synergistic interaction with each other, thereby improving the treatment of osteoporosis and The invention relates to an alendronic acid preparation with enhanced bioavailability that can be expected to have a prophylactic effect.

In addition, US Pat. Nos. 6350471, 6676965 and EP 1296657 introduce a method of water-insoluble polymer membranes and enteric skin as a way to resolve the effects of alendronate, which is a side effect of acidic esophagitis.

However, in the case of the technique introduced in the above-mentioned patent document, the emulsification stability of the alendronate is not sufficient, and when the alendronate is precipitated in the digestive tract, there is a problem that may cause side effects such as gastroenteritis, enterocolitis, and the like. Since the amount is very small, there is a problem of taking a large amount of drugs in order to have sufficient pharmacological effects.

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

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

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

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

In order to achieve the above object, the barrier-free Alendronate according to an embodiment of the present invention is 100 to 200 parts by weight of Alendronate (Alendronate) and 10 to 200 weight of the surfactant having two or more alkyl chains attached to the hydrophilic portion with respect to the Alendronate In addition, the surfactant is a form in which the outer surface of the Alendronate in an amorphous form (amorphous) is adhered to the adhesive type dissolved in water, the surfactant is attached to the Alendronate has an average diameter of 0.5 to 30㎛ The average range of sizes is within ± 200% of the diameter.

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

The fatty acid may be included in an amount of 10 to 1000 parts by weight based on the alendronate.

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, the anhydrous barrier-free alendronate is to produce the barrier-free alendronate when dissolved in water.

The anhydrous barrier-free alendronate may further include an organic solvent having 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-facing interface alendronate 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 alendronate as a poorly soluble material to the mixture of step (b); (d) mixing the phases of the mixture of the alendronate 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 allenronate may include adding water to the barrier-free interface allenronate prepared by the method for preparing the anhydrous barrier-free allenronate.

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 alendronate according to an embodiment of the present invention refers to the novel type of material, and the barrier-free allenronate used in the present specification means that it belongs 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 alendronate 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 an alendronate, an aldondronate showing the above five characteristics is defined as a barrier-free alendronate (an abbreviation of an aldronate of an emulsion-soluble water-soluble amorphous outside (coated interface)).

In addition, anhydrous barrier-free alendronate defines a solid allendronate such as a solid allendronate that becomes a barrier-free alendronate 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, 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 Edn, 1996).

The barrier-free Alendronate according to an embodiment of the present invention comprises 100 parts by weight of Alendronate 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 Alendronate. The active agent surrounds the outer portion of the alendronate in an amorphous form and is bonded to it. It is dissolved in water in an emulsified type, and the alendronate with the surfactant has an average diameter of 0.5 to 30 μm and an average range of sizes. The diameter is within ± 200%.

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

In the anhydrous and unbroken allenronate according to an embodiment of the present invention, the surfactant having two or more alkyl chains attached to the hydrophilic portion is included in an amount of 10 to 200 parts by weight based on 100 parts by weight of the allendronate. In the case of conventional liposomes, 500 to 1000 parts by weight of a surfactant is used to dissolve 100 parts by weight of alendronate. However, in the case of the barrier-free alendronate according to the present invention, the alandronate 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 portion is contained in an amount of more than 200 parts by weight, excessively excessive use may result in a decrease in the content ratio of the alendronate relative to the amount of the surfactant, which may significantly reduce the efficiency. When it is included in less than 10 parts by weight it is difficult to contact while completely surrounding the alendronate in amorphous form, so that 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, the efficiency of dissolving the water in the surfactant while amorphous surrounding the outer portion of the alendronate can be significantly increased.

The anhydrous, unbroken allenronate according to one embodiment of the present invention has a diameter of 0.5 to 30 μm of the non-alloyed allenronate to which the surfactant is attached. When the diameter of the barrier-free alendronate exceeds 30 μm, internal crystallization may be increased in the vicinity of the hydrophobic group, and thus the sustaining effect of the emulsified state may be lowered.

The diameter of the barrier-free Alendronate is very important in terms of functional dissolving the poorly soluble Alendronate. That is, the diameter of the barrier-free allenronate is an indicator of the size of the barrier-free allenronate because it is an important factor in determining the amount of the allenronate that the hydrophobic group of the surfactant can bear. It is unknown whether liposomes are completely dissolved in the hydrophobic group.However, in the case of barrier-free alendronate, its size is much larger than liposomes. It may be crystallized. However, since the surface of the allendronate is amorphous and surrounds the surfactant, the barrier-free allenronate is an emulsified type, which is dissolved in water, and its size is so small that it is completely dissolved in liposomes. Even if it is not, 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 Alendronate is 1 to 10 ㎛, more preferably 1.5 to 5 ㎛. According to the above range, the stability of the barrier-free Alendronate is the highest, so that a stable emulsified state can be maintained.

In the anhydrous and unbroken allenronate according to an embodiment of the present invention, the average range of sizes 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 alendronate may be significantly delayed, and thus its stability may be increased, and if it is outside the above range, such stability may be lowered.

In addition, preferably, the anhydrous anhydrous alendronate may have an average range of sizes ranging from -30% to + 30% based on the diameter, and more preferably, from -10% to + 10%. According to the above range, since the recrystallization is further delayed, there is an advantage in that the stability of the anhydrous anhydrous aldronate is very high.

The precise mechanism of whether the recrystallization is delayed when the homogeneity is high is not yet fully understood. However, it is assumed that the van der Waals attraction between the barrier-free allendronate particles is canceled by the repulsive force due to the zeta potential of the barrier-free allendronate 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, the homogeneity of the barrier-free Alendronate particles is so high that if the particles are about the same size, the repulsive force due to inter-particle zeta potential and the attraction force due to van der Waals are almost the same. If substantially the same, each attraction and repulsive force will be offset (or even better if the repulsive force is greater than that). The recrystallization of the barrier-free allenronate particles can be delayed as much as possible.

As described above, in order to significantly increase the homogeneity of the barrier-free alendronate, an inline mixer including a mixing blade structure having a concept of 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 alendronate of the present invention is produced only through the phase mixing mixer, and cannot be prepared through a general mixer, as well as a very powerful stirrer or homogenizer such as the microfluidizer or 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 the alendronate 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. The process is divided and stirred. In addition, as the unit blade passes through the process repeatedly, the content and the ratio of the surfactant and the alendronate to be bound may be quantified while being proportional to the dose and the addition ratio of the alendronate and the surfactant to be initially added.

Although the content or ratio of the surfactant and the alendronate is not quantitative in the initial stirring step, the proportion and amount of the alendronate and the surfactant to be bound may be quantified as the stirring process proceeds. As a result, when the surfactant and the alendronate quantified in terms of proportion 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 found alendronate in a non-face-to-face 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 method thereof. Is not limited to that according to the liquid mixing mixer.

That is, even if it is not the method of using the phase mixing mixer, the homogeneity is substantially there is a possibility that a homogenizer or stirrer capable of more easily preparing the barrier-free alendronate sought by the present invention may appear. . 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, it is also considered that the non-compensating interface blender prepared in accordance with the other method other than the mixing mixture mixer also falls within the scope of the present invention.

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

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

In addition, since the fatty acid can dissolve the alendronate well in a molten state, when the alendronate is added in a state in which the fatty acid is mixed with a surfactant, the dispersion and homogeneity of the alendronate may be increased.

The fatty acid may be included in an amount of 10 to 1000 parts by weight based on the alendronate. 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 prevention of the alendronate is improved, the dispersion degree is improved, and the homogeneity is 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 alendronate may 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, it is advantageous to prevent recombination of the alendronate, to improve the degree of dispersion, and to improve the homogeneity.

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 emulsified type by being emulsified by enclosing the allenronate. The egg yolk lecithin, soybean lecithin and hydrogenated lecithin have an advantage of preventing recombination of the allandronate and improving dispersibility.

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. However, when the PC content is included in an amount of 70% by weight or more, it may be excellent in preventing recombination of the alendronate and improving dispersion degree with high purity.

According to another embodiment of the present invention, the anhydrous barrier-free alendronate generates the barrier-free alendronate when dissolved in water.

The anhydrous barrier-free alendronate is intended to be provided in the form of an oral dosage form, and the anhydrous barrier-free alendronate is dissolved in water, and the surfactant is dispersed in water while the surfactant disperses in the water and the surfactant forms the outline of the allandronate. 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.

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

Since the admixture additive is often a solid alendronate and a surfactant, the liquid phase mixture should be in a solution state in order to make the phase mixing, for this purpose it serves to create a mixture of the appropriate viscosity, and also when the temperature rises And surfactant to prevent burning.

The mixed adjuvant is not excluded from the inclusion in the barrier-free alendronate, but when preparing the anhydrous barrier-free alendronate, the mixed adjuvant may include a fluidized bed process of the first allendronate and the surfactant. Can be included. In particular, the fluidized bed process may be desirable to add a polar organic solvent to the first allendronate 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. The anhydrous barrier-free alendronate contains an organic solvent having a polarity such as -OH, unlike the barrier-free alendronate. In general, the organic solvent is mostly dissolved in water when the anhydrous barrier-free alendronate is dissolved in water to maintain a state in which most of the organic solvent is not attached to the barrier-free interface. When the —OH group of the organic solvent is two or more, the solubility in water may be increased, and the anhydrous barrier-free alendronate may form the barrier-free alendronate.

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 alendronate can be improved in solubility in water to form an excellent barrier-free alendronate.

According to another embodiment of the present invention, a method for preparing anhydrous non-facing interface alendronate 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 alendronate as a poorly soluble material to the mixture of step (b); (d) mixing the phases of the mixture of the alendronate 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 the amount of the alendronate 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 phase mixing mixer increases, which may cause the device to be damaged. Because. 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 further quantify the ratio and amount of the alendronate and the surfactant 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 phase mixing mixer to prepare the barrier-free Alendronate 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 alendronate are the same as those of the barrier-free allendronate described above, the description thereof is omitted in order to prevent the present invention from becoming too complicated.

According to another embodiment of the present invention, a method for preparing a barrier-free interface allenronate may include adding water to the barrier-free interface allenronate prepared by the method for preparing the anhydrous barrier-free allenronate.

The barrier-free alendronate and the barrier-free alendronate according to the present invention may be prepared in 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 alendronate of the present invention has the advantage of increasing the content of the altenronate that can be dissolved by several tens to several hundred times as compared with the conventional method of solubilizing the alendronate in the form of liposomes or emulsions.

Accordingly, the barrier-free alendronate of the present invention does not use any solubilizer, such as cremofo, which may cause fatal side effects to the human body, thereby minimizing side effects caused to the human body. In addition, when the above-mentioned barrier-free alendronate is administered to a 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 alendronate preparation. Furthermore, the abalone interface alendronate has excellent emulsification stability, so that precipitation hardly occurs in the digestive organs such as the esophagus, the stomach, the duodenum, the large intestine, and the small intestine, thereby minimizing side effects due to the precipitation of the alendronate.

In addition, the method for preparing the barrier-free alendronate of the present invention enables the production of the barrier-free alendronate. In addition, according to the anhydrous barrier-free alendronate of the present invention and a method for manufacturing the same, the barrier-free interface allenronate 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 Alendronate according to an embodiment of the present invention.
FIG. 7 is a DSC graph of Alendronate Sodium and the barrier-free Alendronate prepared by the method of Example 17 as a control. FIG.
8 is a DSC graph of Alendronate Sodium and the barrier-free Alendronate prepared by the method of Example 18 as a control.
9 is a SEM photograph of Alendronate Sodium and the barrier-free Alendronate prepared by the method of Example 3 of the present invention as a control. In the photograph, 1000 and 7000 represent the SEM magnification.
10 is a graph showing the water solubility of the barrier-free Alendronate 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 Of alendronate  Produce]

The composition of Table 2 disperses relatively stable alendronate and dipropylene glycol at high temperatures in the first open tank, and stir-mixes glyceryl stearate and stearic acid, which require premixing with lecithin, lecithin, which are susceptible to high temperatures in the second open tank. Then, 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 the solution of the first open tank and the second open tank was stirred and mixed 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%) Alendronate 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 Alendronate was not prepared, but in Example 3, the barrier-free Alendronate of the present invention was prepared.

[ Manufacturing example  1-2: Does not contain fatty acids Free-standing interface Of alendronate  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 Alendronate in the same manner as the stirring method, the specific composition is shown in Table 3.

ingredient Example 4
(weight%) Example 5
(weight%) Example 6
(weight%) Alendronate 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 Of alendronate  Produce]

The composition of Table 4 disperses relatively stable alandronate and dipropylene glycol at high temperature in the first open tank, and stirred glyceryl stearate and stearic acid, which need to be premixed with surfactant, which is susceptible to high temperature in the second open tank. After 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 blend of alandronate. 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 alendronate was prepared, but in Example 7, a barrier-free alendronate was not produced. 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 alendronate of the present invention was not prepared.

ingredient Example 7
(weight%) Example 8
(weight%) Example 9
(weight%) Example 10
(weight%) Example 11
(weight%) Alendronate 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 Of alendronate  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 Alendronate, the specific composition is shown in Table 5. In Example 12, Example 13, and Example 14, it was possible to prepare the barrier-free alendronate, but in Example 10 and Example 11, it was not possible to prepare the barrier-free alendronate.

ingredient Example 12
(weight%) Example 13
(weight%) Example 14
(weight%) Example 15
(weight%) Example 16
(weight%) Alendronate 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 Of alendronate  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 Alendronate 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, all of the barrier-free alendronate could be prepared, but Examples 17 and 18 showed the most stable solubilization state.

ingredient Example 17
(weight%) Example 18
(weight%) Example 19
(weight%) Alendronate 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 Of alendronate  Produce]

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

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

Experimental Example  1-1: Identification of amorphous state

The amorphous state of the barrier-free Alendronate 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 photo in blue letters in FIG. 10 is the Alendronate 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 the alendronate crystals, it is in a state where recrystallization occurs even if it is dispersed by a 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. The amorphous form of the alendronate and the irregular arrangement of crystals make it very easy to disperse and maintain the dispersion 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 of Alendronate can be roughly determined by measuring the potential difference using Zeta-Potential Analyzer, but this method is limited to confirm the presence or absence of recrystallization in 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 no recrystallization of the alendronate with time-dependent change, and the particle size also shows a uniform distribution of _______ to ________ μm, which does not show agglomeration due to recrystallization. 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 Alendronate content to 30% by weight, by adjusting the content of the surfactant and the solvent to prepare the barrier-free Alendronate 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 wt% purified water and sealing it for 30 minutes at 70 ° C. using a magnetic stirrer, the degree of solubility (swelling degree of the alendronate) 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 ease of use as a pharmaceutical raw material can be improved through lyophilization and powdering of the finished barrier-free alendronate. After dispersing the water-free interface Alendronate of Examples 4, 5 and 6 of Preparation Example 1-2 in water at 10% concentration, centrifuged at 10000 rpm for 15 minutes, and then taking a clear supernatant 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 Alendronate prepared by the methods of Examples 17 and 18. As a control, raw material Alendronate Sodium was used.

The DSC graph of the barrier-free alendronate prepared by the control and the method of Example 17 is shown in FIG. 8, and the DSC graph of the barrier-free alendronate 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 transition of the crystalline form of alendronate sodium into a liquid phase was ________ ° C. , the barrier-free allendronate prepared by the method of Example 17 of the present invention (b) ), The phase transition to the liquid phase is ________ ℃ bar, it was confirmed that a significant difference in the phase transition temperature occurs. As shown in FIG. 8, in the case of the control, (a), the temperature at which phase transition of the crystalline form of alendronate sodium into a liquid phase was ________ ° C. , and the barrier-free alendronate prepared by the method of Example 18 of the present invention (b). ), The phase transition to the liquid phase is ________ ℃ bar, it was confirmed that a significant difference in the phase transition temperature occurs.

[ Experimental Example  2 : Free-standing interface Of alendronate  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 the control drug was a F (alendronate sodium) formulation and a main ingredient material sold by D Company. As a result of the experiment, as shown in Table 10, the barrier-free alendronate 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 Alendronate 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 Alendronate sodium (ρ <0.05).

^{‥ Significantly different in comparison to parent Alendronate} 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: elution) described in the fifteenth revised Japanese Pharmacopoeia by using the non-surfactant alendronate prepared in Example 3 and the alendronate prepared by the method of Example 1 (the preparation of the non-surfactant-free material, control). Test 2nd liquid, a test method: a paddle method, rotation speed: 50 rpm) were 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 alendronate 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 properties significantly exceeding the solubility of the drug. On the other hand, in the case of the alendronate of Example 1 in which no barrier-free material was prepared, the dissolution rate was low as ________%.

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 Alendronate and
10 to 200 parts by weight of the surfactant having two or more alkyl chains attached to the hydrophilic portion with respect to the alendronate,
The surfactant is in the form of being bonded to surround the amorphous of the Alendronate amorphous (amorphous), dissolved in water as an emulsion type,
Alendronate 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
Faceless interface Alendronate. The method according to claim 1,
The barrier-free alendronate further comprises a fatty acid between the surfactant and the allendronate.
Faceless interface Alendronate. 3. The method of claim 2,
The fatty acid will be included in 10 to 1000 parts by weight based on the alendronate
Faceless interface Alendronate. 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
Faceless interface Alendronate. The method according to claim 1,
The surfactant is selected from the group comprising egg yolk lecithin, soy lecithin and hydrogenated lecithin
Faceless interface Alendronate. The method according to claim 1,
The surfactant is that the PC (Phosphatidylcholine) is contained in more than 70% by weight
Faceless interface Alendronate. When dissolved in water,
Anhydrous barrier-free alendronate which produces the barrier-free alendronate of any one of Claims 1-6. 8. The method of claim 7,
Wherein the anhydrous barrier-free Alendronate further comprises an organic solvent having a polarity as a mixed adjuvant
Anhydrous-free interface Alendronate. 9. The method of claim 8,
The organic solvent having the polar is that -0H group is two or more
Anhydrous-free interface Alendronate. 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-free interface Alendronate. (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 alendronate as a poorly soluble material to the mixture of step (b);
(d) mixing the phases of the mixture of the alendronate 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, unbroken interface Alendronate 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-facing interface Alendronate. 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-facing interface Alendronate. Claim 1 to 13 comprising the step of adding water to the anhydrous barrier-free Alendronate prepared by the method of any one of claims
Process for producing a sol-less dronate.

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