KR20140043578A

KR20140043578A - The water-insoluble risedronate covered with amorphous surfactant and method for preparing the same

Info

Publication number: KR20140043578A
Application number: KR1020120106092A
Authority: KR
Inventors: 권돈선; 유우영
Original assignee: 한국콜마주식회사
Priority date: 2012-09-24
Filing date: 2012-09-24
Publication date: 2014-04-10

Abstract

The present invention relates to a barrier-free riserronate (Risedronate) and a method for producing the same. The barrier-free risedronate according to an embodiment of the present invention comprises 100 parts by weight of risedronate 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 risedronate. In addition, the surfactant is in the form of a bonded (amorphous) surrounding the outside of the risedronate in the form of an emulsion, dissolved in water, the riseronate attached to the surfactant has an average diameter of 0.5 To 30 μm, and the average range of sizes is within ± 200% of the diameter.

Description

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

The present invention relates to a barrier-free riserronate (Risedronate) and a method for producing the same. More specifically, the present invention relates to a barrier-free risedronate and a method for producing the poorly soluble risedronate, which does not contain a solubilizer, and has excellent emulsion stability.

Risedroate sodium (1-hydroxy-2- [3-pyridinyl] ethylidene bisphosphonic acid monosodium salt) is a bisphosphonate preparation widely used for the prevention and treatment of osteoporosis. FDA approved the drug in 1998 for the treatment of induced osteoporosis. The molecular formula is C7H11NO7P2 (molecular weight: 283.112), and the chemical structure is as follows.

The therapeutic dose is 5 mg per day, effective from 6 months of treatment, less digestive tract obstruction, and femoral fracture prevention. According to Vertellil efficacy with risedronate therapy (VERT) in North America, after 3 years of risedronate 5 mg, lumbar spine bone density increased by 5.4%, femoral neck bone density increased by 1.6%, new spinal fractures occurred by 41%, and non-vertebral fractures. Incidence was reduced by 39%. [Shin DH. Gain and Seal of Bisphosphonate Formulations. J Korean Acad Fam Med. 2006; 27 (11): Suppl. November. 355-360 .; Dunn CJ, Goa KL. Risedronate: a review of its pharmacological properties and clinical use in resorptive bone disease. Drugs 2001; 61 (5): 685-712 .; Mortensen L, Charles P, Bekker PJ, et al. Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of

follow-up. J Clin Endocrinol Metab. 1998; 83 (2): 396-402].

Clinical studies report that risedronate has a very low bioavailability (<1%), and the absorption rate is reported to be drastically reduced by food intake. Maintain an empty stomach 30 minutes before breakfast and take at least 2 hours before or after eating and drinking to increase your absorption. Also, take a sufficient amount (180-240 mL) of water to prevent oropharyngeal irritation, and sit or stand upright for at least 30 minutes to 1 hour to prevent the risk of developing esophagitis and esophageal ulcers. [Bekker P, Licata A, Harris S. Risedronate dose response in prevention of early postmenopausal bone loss. J Bone Miner Res. 1996; 11 (3): S347; Singer FR, Clemens TL, Eusebio RA, et al. Risedronate, a highly effective oral agent in the treatment of patients with severe Pagets disease. J Clin Endocrinol Metab. 1998; 83 (6): 1906-1910; Delmas PD, Balena R, Confravreux E. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study. J Clin Oncol 1997; 15 (3): 955-962; Reid D, Cohen S, Pack S, et al. Risedronate reduces the incidence of vertebral fractures in patients on chronic corticosteroid therapy. Arthritis Rheum. 1998; 41 (1): S136].

The pharmacokinetic parameters for dosed risedronate 30 mg to healthy Westerners were reported abroad with Cmax 5.1 ± 4.8 ng / mL, AUC 21.3 ± 19.1 ng / mL · h, and Tmax 0.81 ± 0.32 h [Fogelman I , Smith L, Mazess R, et al. Absorption of oral diphosphonate in normal subjects. Clin Endocrinol. 1986; 24 (1): 57-62; Mitchell DY, Eusebio RA, Dunlap LE, et al. Risedronate Gastrointestinal Absorption is independent of site and Rate of Administration. Pharm Res. 1998; 15 (2): 228-232; Mitchell DY, Heise MA, Pallone KA, et al. The effect of dosing regimen on the pharmacokinetics of risedronate. Br J Clin Pharmacol. 1999; 48 (4): 536-542; Lin J. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996; 18 (2): 75-85; Mitchell DY, Eusebio RA, Dunlap LE. Bioavailability administration of immediate-release and delayed-release risedronate formulations upon oral administration to healthy male subjects in fasted and fed state. Pharm Res 1996; 13: S-609], assays for risedronate in plasma include ELISA analysis and derivatization using diazomethane reagent. Mitchell DY, Eusebio RA, Sacco-Gibson NA, et al. Doseproportional pharmacokinetics of risedronate on singledose oral administration to healthy volunteers. J Clin Pharmacol. 2000; 40 (3): 258-265; Zhu LS, Lapko VN, Lee JW, et al. A general approach for the quantitative analysis of bisphosphonates in human serum and urine by high-performance liquid chromatography / tandem mass spectrometry. Rapid Commun Mass Spectrom. 2006; 20 (3): 421-426; Mitchell DY, Eusebio RA, Pallone KA, et al. Single dose 27 Necciari J, Kiefer G, Maillard D. Pharmacokinetics of linearity of risedronate following oral administration of 2.5, (4-chlorophenyl) thiomethylene bisphosphonic acid after 5, or 30 mg to healthy volunteers. Pharm Res 1997; 14: S-609.

Compound risedronates are disclosed in U.S. Patent Nos. 5,583,122 to Benetic et al., Published on Dec. 10, 1996, and Procter & Gamble, and US Conference, Bisphosphonates; The present status and future prospects are described in detail in London, UK, Royal Society of Physicians May 21-22, 1990, edited by IBC Technical Service, both of which are incorporated herein by reference.

The term risedronate active ingredient includes risedronate, risedronate name, and risedronate ester or mixtures thereof. Pharmaceutically acceptable non-toxic salts or esters of risedronate may be used as risedronate active ingredient in the new oral formulations of the present invention. Salts of risedronate may be acid addition salts, in particular hydrochloride, but pharmaceutically acceptable, non-toxic organic or inorganic acid salts may be used. In addition, salts comprising alkali metal salts (K, Na) and alkaline earth metals (Ca, Mg) formed by phosphonic acid groups can be used, with Ca and Na salts being preferred, but not limited to these.

Specifically, other esters of risedronate suitable for use herein as active ingredients include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, descin, lauryl, myri steel, including cetyl and stearyl, but are not limited to only those straight or branched chain C ₁ _- C ₁₈ Alkyl esters; Vinyl, including alkyl, undecyl enyl linoleate and alkylenyl, but are not limited to only those straight or branched chain C ₂ _- C ₁₈ Alkenyl esters; Include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, but are not limited to only these C ₃ _- C ₈ Cycloalkyl esters; Aryl esters including but not limited to phenyl, toluyl, xylyl and naphthyl; Alicyclic esters including but not limited to menthyl; And aralkyl esters including but not limited to benzyl and phenethyl.

Osteoporosis is a metabolic disease that affects 20 million people in the United States. More than 40% of white women and 13% of men have osteoporosis-related fractures. Osteoporosis is associated with an increase in bone tablets as bone density decreases. The National Osteoporosis Association estimates 13.8 billion for the treatment of fractures. In addition, in-hospital mortality due to pelvic fracture due to osteoporosis ranges from 4.0% to 11.5%.

Paget's disease is less than osteoporosis, but it's about 3% of US citizens 55 and older. Unlike osteoporosis, which lowers bone density, Paget's disease is a disease in which bone density increases due to bone parts and bone malformations. Paget's disease sometimes causes fractures, but fracture pain is common. Rarely, sarcoma symptoms are seen.

A major issue with these two diseases is the pathological part of the function of osteoclasts related to bone resorption. In osteoporosis, osteoclast function is hyperactive (age related or due to gluco-corticoids) or uncontrolled.

Paget's disease, on the other hand, is characterized by increased or vigorous osteoclasts. In summary, Paget's disease is 20 times higher than normal. Therapies for these two metabolic bone diseases are related to osteoclasts. Groups of drugs related to the regeneration and function of osteoclasts are calcitonin, estrogen, selective receptor agonists (raloxifene), bisphosphonates (alendronate, ethidronate, pmitronate, resetronate, tiludronate, etc.). All of these drugs are powerful drugs for the prevention and treatment of osteoclasts.

It is known that oral dosage forms of bisphosphonates do not absorb well in the gastrointestinal (GI) tract (less than 1% of oral dosage forms). Ezra et al., Adv. Drug Del. Rev. 42: 175-95 (2000). Several approaches have been proposed for increased absorption of oral bisphosphonates throughout the GI tract. This approach involves modifying the permeation properties of the intestinal mucosa (eg, using absorption enhancers), or altering the physical or chemical properties of the bisphosphonate compound itself (eg, via prodrugs).

Although the use of absorption enhancers such as ethylenediaminetetraacetic acid (EDTA) to increase intestinal permeability at high doses has been proposed as a means of increasing the absorption of oral bisphosphonates, the applicability of EDTA as a medicament in drug therapy in humans is due to EDTA for mucosal integrity. In view of its influence, it was considered impossible. Ezra et al., Adv. Drug Del. Rev. 42: 185 (2000). Others concluded that the large amount of EDTA needed to result in increased GI uptake excludes drugs as candidates for use in oral bisphosphonate therapy. Janner et al., Calcif. Tissue Int. 49: 280-83 (1991).

The primary absorption site of bisphosphonates is the small intestine, and bisphosphonates such as risedronate are similarly absorbed throughout the small intestine regardless of where it is delivered. Michell et al., Pharm Res., Vol. 15, No. 2: 228-232 (1998). Thus, targeted delivery to the small intestine of bisphosphonates alone does not increase the absorptivity or efficacy of bisphosphonates. However, others have attempted to increase the absorption of bisphosphonates by increasing the permeability only of their merits through the delivery of microparticles of chelating agents and bisphosphonates to the reported absorption sites (BR2001-006601).

Bisphosphonates, such as risedronate, have been approved by a number of management agencies to be effective in the treatment of various bone parhology. However, the interaction between bisphosphonates and food and minerals (especially cationics such as calcium, magnesium, aluminum, and iron-containing foods or supplements) allows less bisphosphonates to be absorbed. See, eg, Mitchell et.al., Br. J. Clin. Pharmacol. 48: 536-542 (1999) demonstrated that administration of risedronate within 30 minutes of a meal reduced the amount absorbed by 50% compared to administration on an empty stomach. To reduce the effects of these foods, the label of the oral bisponate product instructs the patient to take the medicine at least 30 minutes before the first food of the day, or at least 60 minutes before ibandronate, Instruct them to take calcium supplements at the time of day or on days when they are not taking oral dosage forms of bisphosphonates. Such dosing instructions may seem complicated and uncomfortable to the patient, which may make the patient less compliant.

The need to develop oral dosage forms of bisphosphonates that can be taken with or without food or beverage (ie, pharmaceutically effective absorption regardless of food or beverage intake) and do not cause upper gastrointestinal irritation, depending on the patient's preference. This continues to exist.

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

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

In order to achieve the above object, the barrier-free risedronate according to an embodiment of the present invention is an interface having 100 parts by weight of risedronate and two or more alkyl chains attached to the hydrophilic portion with respect to the risedronate. It includes 10 to 200 parts by weight of the active agent, the surfactant is surrounded by an amorphous form (amorphous) bonded to the outside of the risedronate is dissolved in water in an emulsified type, the surfactant is attached to the The drawonate has an average diameter of 0.5 to 30 µm and an average range of sizes within ± 200% of the diameter.

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

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

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).

Anhydrous barrier-free risedronate according to another embodiment of the present invention is to produce a barrier-free risedronate when dissolved in water.

The anhydrous barrierless risedronate may further include an organic solvent having polarity as a mixing aid.

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 barrierless risedronate 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. step; (b) raising the temperature of the mixture of step (a) to raise the fluidity of the mixture; (c) adding risedronate as a poorly soluble material to the mixture of step (b); (d) performing phase mixing of the mixture into which the risedronate 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 riserdronate includes adding water to an anhydrous barrier-free risedronate prepared by the method for preparing the anhydrous barrier-free risedronate.

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. Accordingly, the barrier-free risedronate according to an embodiment of the present invention refers to the novel type of material, and the barrier-free risedronate used in the present specification means that it belongs to the concept of a barrier-free material including the following properties. do.

(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. It has a size of several tens to hundreds of times as compared to liposomes having a diameter of 45 to 200 nm in the prior art, through which the amount of risedronate dissolved as the size of the poorly soluble substance surrounded by the surfactant increases. It is analyzed that it can be greatly increased.

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

(d) Fourth, unlike the liposomes, the poorly soluble substance to which the surfactant is attached should not be standardized as much as possible. The amorphous state of the poorly soluble substance to which the surfactant is attached contributes significantly to the rate of recrystallization. As the degree of amorphousness increases, the rate of recrystallization may be delayed. In this case, however, there may be no complete amorphous form. In this 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 water-soluble substance is risedronate, risedronate, which has the above five characteristics, is made of a barrier-free risedronate (the outer surface of the emulsion-soluble water-soluble amorphous (surfacing interface) risedronate). Shortened).

In addition, anhydrous barrierless risedronate defines a solid risedronate such as a solid risedronate which becomes a barrier-free risedronate 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 calcium regulation (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 risedronate according to an embodiment of the present invention comprises 100 parts by weight of risedronate 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 risedronate. In addition, the surfactant is in the form of a bonded (amorphous) surrounding the outside of the risedronate in the form of an emulsion, dissolved in water, the riseronate attached to the surfactant has an average diameter of 0.5 To 30 μm, and the average range of sizes is within ± 200% of the diameter.

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

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

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

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

Lecithin is acetone, consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphodidylinositol, according to USP, mixed with various substances such as triglycerides, fatty acids and carbohydrates A generic name describing complex mixtures of insoluble phospholipids. Pharmaceutically, lecithin is primarily used as a dispersant, emulsifier and stabilizer, and is included in intramuscular and intravenous injections, parenteral nutritional formulations and topical products. Lecithin is also listed in the FDA Inactive Ingredients Guide for inhalants, IM and IV injections, oral capsules, suspensions and tablets, rectal preparations, topical preparations and vaginal preparations.

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

Diacylglycerol

Di-lauroyl-sn-glycerol (DLG)

Di-myristoyl-sn-glycerol (DMG)

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

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

Force Partidansan

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

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

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

Phosphocholine

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

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

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

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

Phosphoethanolamine

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

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

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

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

Phosphoglycerol

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

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

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

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

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

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

Phosphoserine

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

Mixed chain phospholipids

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

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

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

Lysozyme

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

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

Pegylated Phospholipids

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

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

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

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

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

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

N- (carbonyl-methoxypolyethyleneglycol 750) -MPEG-750-DSPE

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

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

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

Anhydrous undressed risedronate 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 riseronate (Risedronate). In the case of a conventional liposome, 500 to 1000 parts by weight of a surfactant is used to dissolve 100 parts by weight of risedronate, but in the case of the barrier-free risedronate according to the present invention, the risedronate is watered by using a surfactant in the above range. It can be dissolved in the relatively has the advantage that the content of the surfactant can be significantly reduced. In addition, when more than 200 parts by weight of a surfactant having two or more alkyl chains attached to the hydrophilic part is used in excess, the content ratio of risedronate is lowered compared to the amount of the surfactant, so the efficiency may be significantly reduced. And, if it is included in less than 10 parts by weight it is difficult to contact while completely surrounding the riseronate amorphous, so that 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 dissolving the surfactant in water while amorphous surrounding the outside of the risedronate can be significantly increased.

In the anhydrous barrierless risedronate according to an embodiment of the present invention, the diameter of the barrier-free risedronate to which the surfactant is attached is 0.5 to 30 μm. When the diameter of the barrier-free risedronate exceeds 30 μm, internal crystallization may be increased in the vicinity of hydrophobic groups, and thus the sustaining effect of the emulsified state may be reduced. Can be.

The diameter of the barrier-free risedronate is very important in terms of functional dissolving the poorly soluble risedronate. That is, the diameter of the barrier-free risedronate is an indicator of the size of the barrier-free risedronate because it is an important factor in determining the amount of risedronate that the hydrophobic group of the surfactant can bear. In the case of liposomes, it is unknown whether risedronate is completely dissolved in the vicinity of the hydrophobic group, but since the barrier-free risedronate is much larger than the liposome, at least the riser inside the barrier-free risedronate Dronate may be partially crystallized internally. However, since the surface of the risedronate is surrounded by the amorphous form of the surfactant and the form, the barrier-free risedronate is emulsified in water, and its size is so small (although it is very large compared to liposomes). Even if it is not completely 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 risedronate is 1 to 10 ㎛, more preferably 1.5 to 5 ㎛. According to the above range, the stability of the barrier-free risedronate can be maintained to have a stable emulsified state.

Anhydrous undressed risedronate 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 risedronate 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 undressed risedronate may have an average range of sizes from -30% to + 30% based on the diameter, more preferably -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 untreated risedronate 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 risedronate particles is offset by the repulsive force due to the zeta potential of the barrier-free risedronate particles, thereby delaying 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 risedronate particles is so high that the particles are almost the same size, the repulsive force due to the interparticle zeta potential and the attraction force due to van der Waals are almost the same. If the repulsive forces are approximately equal, it is possible to counteract the recrystallization of the barrier-free risedronate particles because each attractive force and repulsive force cancel (or even if the repulsive force is superior to the attractive force).

As described above, in order to significantly increase the homogeneity of the barrier-free risedronate, 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 risedronate of the present invention can be prepared only through the phase mixing mixer, but also through a very powerful stirrer or homogenizer such as the microfluidizer, the high pressure homogenizer, as well as a general mixer. none.

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, 1/2 to 1 / quantitatively each time the mixture containing the surfactant and risedronate introduced passes through the unit blade included in the tube of the liquid mixing mixture. Divided into 10 and stirred. In addition, as the unit blade passes through the process repeatedly, the content and ratio of the surfactant and risedronate to be bound may be quantified while being proportional to the dose and the loading ratio of risedronate and the surfactant to be initially added.

Although the content or ratio of the surfactant and risedronate in the initial stirring step is not quantitative, the ratio and amount of risedronate and surfactant bound as the stirring process proceeds may be quantified. As a result, when the surfactant and risedronate quantified in terms of 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 found the first case of risedronate in a barrier-free state, and derived the concept thereof, and the invention of the substance is protected by the substance itself, and the scope of rights of the present invention cannot be limited. The scope of the right is not limited to that according to the above mixing mixer.

In other words, even if it is not the method of using the liquid phase mixing mixer, the homogeneity is substantially sufficient that a homogenizer or stirrer capable of more easily preparing the barrier-free risedronate sought by the present invention may emerge. exist. 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 risedronate prepared according to the above method other than the liquid 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 risedronate, thereby preventing the surfactant from being formalized. Therefore, there is an effect of significantly lowering the probability of recrystallization by combining the risedronate.

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

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

In addition, preferably the fatty acid may be included in 10 to 500 parts by weight, and more preferably 20 to 100 parts by weight. Although not limited to the above range, the dispersion and homogeneity of risedronate can be the highest by 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 the recombination of risedronate is prevented, the degree of dispersion is improved, and the degree of homogeneity is 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 emulsification type by being bonded and emulsified surrounding the risedronate. The egg yolk lecithin, soybean lecithin and hydrogenated lecithin have the advantage of preventing the recombination of risedronate and improving the 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 and dispersion of the risedronate as high purity.

Anhydrous barrier-free risedronate according to another embodiment of the present invention is to produce the barrier-free risedronate when dissolved in water.

The anhydrous barrier-free risedronate is intended to be provided in the form of an oral dosage form, and the anhydrous barrier-free risedronate is dissolved in water when the mixture containing the surfactant and risedronate is dispersed in water and the surfactant Is to form an emulsion type in the form of being bonded while surrounding the outside of the riseronate in an amorphous form, and is dispersed in water in the form of the emulsion type to produce the barrier-free material.

Since the mixed adjuvant is often a riserate and a surfactant is solid, the liquid phase mixture should be in a solution state in order to perform liquid phase mixing. For this purpose, the mixture adjuvant serves to make a mixture having an appropriate viscosity. It serves to prevent burning of the risedronate and the surfactant.

The mixed adjuvant is not to be included in the barrier-free risedronate, but when preparing the anhydrous barrier-free risedronate may include the initial risedronate and the surfactant in the fluidized bed process, the mixing aid May be included in the anhydrous barrier-free risedronate. In particular, the fluidized bed process may be desirable to add a polar organic solvent to the initial risedronate 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 risedronate, the anhydrous barrier-free risedronate contains an organic solvent having a polarity such as -OH. In general, the organic solvent is mostly dissolved in water when the anhydrous barrier-free risedronate dissolved in water to maintain a state that is not mostly attached to the barrier-free risedronate. When the —OH group of the organic solvent is two or more, the solubility in water may be higher, and the anhydrous barrier-free risedronate may form the barrier-free risedronate.

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 barrierless risedronate can be improved in solubility in water, thereby making it possible to form an excellent barrierless risedronate.

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 risedronate and 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 break. 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, in the above range, the ratio and amount of risedronate and the surfactant can be more quantified while maintaining the internal pressure of the liquid mixing mixer.

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

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

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

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 risedronate 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 risedronate are the same as those of the barrier-free risedronate described above, and thus the description thereof is omitted in order to prevent the present invention from being overly complicated.

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

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans in various routes such as oral or parenteral routes such as oral, rectal or intravenous, muscular, subcutaneous, intra-uterine, Can be administered by injection.

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

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

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

Accordingly, the barrier-free risedronate of the present invention does not use any solubilizer, such as cremofo, which can cause fatal side effects in the human body, thereby minimizing side effects caused in the human body. In addition, when the above-mentioned barrier-free risedronate is administered to the human body, the AUC (curve area under blood concentration) can be dramatically increased compared to the conventional method, thereby significantly improving the pharmacological effect compared to conventional risedronate preparations. You can. Furthermore, the barrier-free risedronate 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 risedronate precipitation.

In addition, the method for producing a barrier-free risedronate of the present invention enables the production of the barrier-free risedronate. In addition, according to the anhydrous barrier-free risedronate of the present invention and a method for producing the same, the barrier-free risedronate 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 risedronate according to an embodiment of the present invention.
FIG. 7 is a DSC graph of risedronate sodium and the barrier-free risedronate prepared by the method of Example 17 as a control. FIG.
FIG. 8 is a DSC graph of risedronate sodium and the barrier-free risedronate prepared by the method of Example 18 as a control. FIG.
9 is a SEM photograph of risedronate sodium and the barrier-free risedronate 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 degree of solubility of the barrier-free risedronate 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 Risedronate Produce]

Glyceryl stearate and stearic acid are dispersed in a relatively stable risedronate and dipropylene glycol at a high temperature in the first open tank in the composition of Table 2, and the pre-mixing with lecithin, lecithin vulnerable to high temperature in the second open tank After stirring and 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 the solution of the first open tank and the second open tank was stirred with a microfluidizer. The material of Example 2 was prepared by mixing, and the material of Example 3 was prepared by stirring and mixing the 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%) Risedronate 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 risedronate was not prepared, but in Example 3, the barrier-free risedronate of the present invention was prepared.

[ Manufacturing example 1-2: Does not contain fatty acids Free-standing interface Risedronate 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 risedronate 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%) Risedronate 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 Risedronate Produce]

Glyceryl stearate and stearic acid in the first open tank to disperse relatively stable risedronate and dipropylene glycol in the first open tank, and a high temperature-vulnerable surfactant, pre-mixing with surfactant 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 inline mixer to prepare a barrier-free risedronate. 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 risedronate was prepared, but in Example 7, a barrier-free risedronate was not prepared. PEG-150 Stearate as a surfactant is a surfactant having only one alkyl chain attached to the hydrophilic portion, so it is considered that the barrier-free risedronate of the present invention was not prepared.

ingredient Example 7
(weight%) Example 8
(weight%) Example 9
(weight%) Example 10
(weight%) Example 11
(weight%) Risedronate 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 Risedronate 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. A barrier-free risedronate was prepared in the same manner as in the stirring method using the in-line mixer in Example 1-1, and the specific composition thereof is shown in Table 5 below. In Example 12, Example 13, and Example 14, the barrier-free risedronate could be prepared, but in Example 10 and Example 11, the barrier-free risedronate could not be prepared.

ingredient Example 12
(weight%) Example 13
(weight%) Example 14
(weight%) Example 15
(weight%) Example 16
(weight%) Risedronate 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 Risedronate 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. A barrier-free risedronate was prepared in the same manner as the method of stirring using a single inline mixer, and the specific composition thereof is shown in Table 6 below. In Examples 17 to 19, the barrier-free risedronate could be prepared, but Examples 17 and 18 showed the most stable solubilization state.

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

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

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

Experimental Example 1-1: Identification of amorphous state

The amorphous barrier Riddronate 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 risedronate itself, and it can be seen that the arrangement is very regular as shown. Even though it is not dispersed in water by the ordered risedronate crystals, it is in a state where recrystallization occurs even if it is dispersed by physical force for 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 risedronate 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 barrier-free risedronate in water phase can be roughly determined by measuring the potential difference using Zeta-Potential Analyzer. There is a limit to this. Therefore, the size and homogeneity of emulsified particles according to aging changes were confirmed directly by using a microscope, and its stability was confirmed. In Table 7 and the particle photographs of FIGS. 12 to 27, recrystallization of risedronate is not observed according to changes over time, and the particle size also shows a constant distribution of _______ to ________ μm. You can see that it does not appear.

Generally, when the particle size is different according to aging, the particles are coalesced and agglomerated due to the difference of the repulsive force and the attraction force of each other. When such coalescence and aggregation accelerate, the particle size becomes very large while affecting the stability. However, when looking at the particle picture of Figures 11 to 26, it can be seen that the particle size according to the change over time is uniform, showing a very stable form.

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

Experimental Example 1-3: Degree of acceptance evaluation

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

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 risedronate. Disperse the barrier-free risedronate of Examples 4, 5 and 6 of Preparation Example 1-2 in water at a concentration of 10%, and then centrifuge at 10000 rpm for 15 minutes to obtain a clear supernatant to quantify moisture. As a result, the moisture content was measured as shown in Table 9 below. Through the above experiments, it has been found that the solvent such as dipropylene glycol and ethanol easily exits from the water and plays a role as a mixing aid for mixing and mixing the poorly soluble materials.

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

Experimental Example 1-5: DSC Measure

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

The DSC graph of the barrier-free risedronate prepared by the control and the method of Example 17 is shown in FIG. 8, and the DSC graph of the barrier-free risedronate prepared by the control and the method of Example 18 is shown in FIG. 9. As shown in Figure 8, in the case of the control (a), the temperature of the phase transition of the crystal form riseronate sodium to the liquid phase at room temperature is ________ ℃ , a barrier-free Lise prepared by the method of Example 17 of the present invention In the case of the dronenate (b), the temperature of the phase transition to the liquid phase was ________ ℃ , it was confirmed that a significant difference in the phase transition temperature occurs. As shown in Figure 8, in the case of the control (a), the temperature of the phase transition of liquid crystals of risedronate sodium in the liquid phase at room temperature is ________ ℃ , a barrier-free rinse prepared by the method of Example 18 of the present invention In the case of the dronenate (b), the temperature of the phase transition to the liquid phase was ________ ℃ , it was confirmed that a significant difference in the phase transition temperature occurs.

[ Experimental Example 2 : Free-standing interface Risedronate 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 (risedronate sodium) preparation and a main ingredient material sold by D Company. It was. Experimental results As shown in Table 10, it was found that the barrier-free risedronate 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 Risedronate 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 Risedronate sodium (ρ <0.05).

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

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

Experimental Example 2-2: Dissolution test evaluation

The dissolution test described in the 15th revised Japanese Pharmacopoeia using the barrier-free risedronate prepared in Example 3 and the risedronate prepared by the method of Example 1 (the preparation of the barrier-free material, no control) (temperature: 37 ° C) , Test solution: dissolution test second solution, test method: paddle method, rotation speed: 50 rpm). Table 11 shows the dissolution rate after 5 minutes, 15 minutes, and 30 minutes after the start of the experiment.

As a result of the test, it was found that the barrier-free risedronate 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, the risedronate 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 risedronate and
It contains 10 to 200 parts by weight of a surfactant having two or more alkyl chains attached to the hydrophilic portion relative to the risedronate,
The surfactant is in the form of being bonded to surround the amorphous of the risedronate amorphous (amorphous) is dissolved in water as an emulsion type,
The risedronate 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
Blessed cotton risedronate.

The method according to claim 1,
Wherein the barrier-free risedronate further comprises a fatty acid between the surfactant and risedronate.
Blessed cotton risedronate.

3. The method of claim 2,
The fatty acid will be included in 10 to 1000 parts by weight based on the risedronate
Blessed cotton risedronate.

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
Blessed cotton risedronate.

The method according to claim 1,
The surfactant is selected from the group comprising egg yolk lecithin, soy lecithin and hydrogenated lecithin
Blessed cotton risedronate.

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

When dissolved in water,
To produce the barrier-free risedronate of any one of claims 1 to 6
Anhydrous non-facing surface risedronate.

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

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

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 non-facing surface risedronate.

(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) adding risedronate as a poorly soluble material to the mixture of step (b);
(d) performing phase mixing of the mixture into which the risedronate is added in step (c) using a mixer including a mixing blade structure having the concept of phase mixing; And
(e) solidifying the phase mixed mixture of step (d)
Method for producing an anhydrous barrier-free risedronate 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 risedronate.

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 risedronate.

Claim 1 to 13 comprising the step of adding water to the anhydrous barrier-free risedronate prepared by the method of any one of claims
Process for producing a barrier-free risedronate.