KR20140043562A

KR20140043562A - The water-insoluble latanoprost covered with amorphous surfactant and method for preparing the same

Info

Publication number: KR20140043562A
Application number: KR1020120105992A
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 an amorphous latanoprost covered with a surfactant and a preparation method thereof. The amorphous latanoprost covered with a surfactant according to an embodiment in the present invention comprises: 100 parts by weight of latanoprost; and 10-200 parts by weight of a surfactant with respect to the weight of the latanoprost, wherein the surfactant has two or more alkyl chains adhering to a hydrophilic part thereof. The surfactant adheres to the latanoprost while surrounding the outside of the latanoprost in an amorphous form, so that the latanoprost is dissolved in an emulsion type in water. The latanoprost to which the surfactant adheres has an average diameter of 0.5-30 micrometers, and the average range size of the latanoprost is ±200% with respect to the diameter of the latanoprost. [Reference numerals] (AA) Units blades constituting a mixed blade structure; (BB) Each blade of the units blades constituting a mixed blade structure

Description

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

The present invention relates to a latanoprost, and a process for producing the same. More specifically, the present invention relates to a latinopropetic latanoprost having a very excellent emulsification stability without including a solubilizing agent for latanoprost, which is a poorly soluble substance, and a manufacturing method thereof.

Glaucoma is a disease that causes damage to the optic nerve, which transmits light received by the eye to the brain. It is a progressive disease that cannot be cured after diagnosis and is a progressive disease that needs to be treated and observed for life. As the optic nerve is damaged, the field of vision gradually narrows, causing a loss of vision, and worsening of vision.

Intraocular pressure is the main cause of glaucoma, and intraocular pressure is known to be the most important cause of optic nerve damage (Lee and Higginbotham (2005) Am. J. Health-Syst. Pharm. 62, 691-699). In general, the average intraocular pressure is 14-16 mmHg and between 10 and 21 mmHg is generally considered normal. 22 mmHg on hand

If abnormal, you can suspect glaucoma. Glaucoma can be divided into Primary Open-Angle Glaucoma, Ocular Hypertension, Normal Tension Glaucoma, Secondary Glaucoma, and Congenital Glaucoma. The number of patients with glaucoma worldwide is estimated at 66 million, and the number of patients is gradually increasing.

The treatment of glaucoma focuses on reducing the increased intraocular pressure in a pharmacological or surgical way. Glaucoma treatment drugs include beta-blockers, carbonic anhydrase inhibitors, selective sympathetic agents, parasympathetic nerve contracts, and prostaglandin derivatives, among which prostaglandin derivatives have been spotlighted as primary therapeutic agents due to their strong intraocular pressure-lowering effects and fewer side effects. Prostaglandins reduce intraocular pressure by increasing the outflow of aqueous fluid from the eye. Prostaglandin derivatives have similar efficacy as natural prostaglandins, but have been developed to be free of side effects of natural prostaglandins that cause severe irritation and vasodilation in the conjunctiva and are currently being used for treatment. 6,429,226, 5,510,383, 5,688,819, 6,403,649). Unlike conventional drugs, prostaglandin-based drugs are administered once a day, resulting in higher patient compliance, higher intraocular pressure reduction effects, and fewer systemic side effects than conventional drugs.

The present invention relates to an improved formulation comprising latanoprost for topical treatment of ocular hypertension and glaucoma.

The latanoprost is chemical name isopropyl- (Z) -7 [(1R, 2R, 3R, 5S) 3,5-dihydroxy-2-[(3R) -3-hydroxy- of general formula (1) 5-phenylpentyl] cyclopentyl]

It is a prostaglandin-type glaucoma therapeutic agent represented by -5-heptanoate.

[Chemical Formula 1]

Ratanoprost is a selective FP (Prostaglandin F) receptor agonist, which lowers intraocular pressure by promoting the outflow of waterproofing (Japanese Patent No. 2721414). The route of administration of latanoprost is an ophthalmic administration, and commercial eye drops containing 0.005% latanoprost (trade name: Chisaratan Eye Drops) are commercially available.

Like most prostaglandin analogs, latanoprost, travoprost, bimatoprost, unoprostone isopropyl, tafluprost and 8-isoprostaglandin E2 are almost insoluble in water. It is therefore important to provide an ophthalmic delivery means for delivering hydrophobic drugs.

The term ophthalmic means an emulsion that is administered to the eye and provides a pharmacological effect and is preferably applied topically. A problem that may arise with prostaglandins, particularly latanoprost, in ophthalmic preparations for treating glaucoma is the lower concentration in the formulation over time. U.S. Patents 011,062, 5,688,819, 5,849,792, and 4,599,353 disclose the use of several prostaglandin analogs to treat glaucoma and ocular hypertension. US Pat. No. 849,792 discloses the use of nonionic surfactants (polyethoxylated castor oil) to improve the chemical stability of prostaglandins. However, the proposed method for improving the stability of prostaglandins is not completely satisfactory. Moreover, the use of BAK or other quaternary ammonium as a preservative for prostaglandins in ophthalmic preparations has been shown to prolong BAK and / or other quaternary ammonium as described by C. Debbasch et al. In Investigative Ophthalmology & Visual Science, March 2001, Vol42 No3. It has been pointed out as a problem in that there is considerable toxicity in use.

By minimizing the use of the solvent by using a surfactant, the above-mentioned problems can be solved, and the size of the eye drops can also be drastically increased by making the size of the particles finer.

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

It is another object of the present invention to provide a method for preparing the non-facing surface latanoprost and the anhydrous non-facing latanoprost.

In order to achieve the above object, the latanoprost barrier-free interface according to an embodiment of the present invention is 100 parts by weight of latanoprost and an interface having two or more alkyl chains attached to the hydrophilic portion with respect to the latanoprost. It includes 10 to 200 parts by weight of the active agent, the surfactant is surrounded by an amorphous (amorphous) surrounding the outer surface of the latanoprost (Amorphous) is dissolved in water in an emulsified type, the la which is attached to the surfactant Thanofrost has an average diameter of 0.5 to 30㎛, the average range of the size is within ± 200% of the diameter.

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

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

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

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

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

According to another embodiment of the present invention, when the anhydrous unbounded surface latanoprost is dissolved in water, it produces a bloated surface-latanoprost.

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

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

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

According to another embodiment of the present invention, a method for preparing anhydrous non-facing surface latanoprost is (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 latanoprost as a poorly soluble material to the mixture of step (b); (d) mixing the phase into which the latanoprost of step (c) is mixed using a mixer comprising a mixing blade structure having the concept of phase mixing; And (e) solidifying the phase mixed mixture of step (d).

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

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

A method for preparing a latanopropanol-free latanoprost according to another embodiment of the present invention includes the step of adding water to the anhydrous-free zonal latanoprost prepared by the method for preparing the anhydrous-free-faceted latanoprost.

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 latanoprost according to an embodiment of the present invention refers to the novel type of material, and the barrier-free latanoprost used herein means to belong to the concept of the 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. 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, and as a result, the amount of latanoprost melted 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, in the case where the poorly soluble substance is latanoprost, the latanoprost, which shows the above five characteristics, of latanoprost (coated interface) in which the outer surface of the ethanol-type water-soluble amorphous of the emulsion type is covered (surfactant interface) Shortened).

In addition, anhydrous-free surface latanofrost defines a solid latanofrost, such as solid latanoprost, which becomes a wrought-free surface latanofrost 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).

According to one embodiment of the present invention, the latanoprost is 10 to 200 parts by weight of a surfactant having two or more alkyl chains attached to 100 parts by weight of latanoprost and a hydrophilic portion with respect to the latanoprost. To be included, the surfactant is in the form of a bonded (amorphous) surrounding the outside of the latanoprost in the form of an emulsion, dissolved in water, the latanoprost with 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-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-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-methoxypolyethylene glycol 750) -MPEG-750-DSPE

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

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

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

Anhydrous, unmanned latanoprost according to an embodiment of the present invention is to include 10 to 200 parts by weight of the surfactant having two or more alkyl chains attached to the hydrophilic portion relative to 100 parts by weight of latanoprost. 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 latanoprost. However, in the case of the barrier-free latanoprost according to the present invention, the latanoprost 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, in the case where the surfactant having two or more alkyl chains attached to the hydrophilic part is included in an amount of more than 200 parts by weight, excessive use of the surfactant may lower the ratio of latanoprost compared to the amount of the surfactant, which may significantly reduce the efficiency. And, when included in less than 10 parts by weight it is difficult to contact while completely surrounding the latanoprost 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. In the case of the above range, the efficiency of dissolving the surfactant in water while amorphous surrounding the outside of the latanoprost can be significantly increased.

The anhydrous latanoprost according to an embodiment of the present invention has a diameter of 0.5 to 30 μm of the latanoprost to which the surfactant is attached. When the diameter of the barrier-free latanoprost exceeds 30 μm, internal crystallization may increase in the vicinity of the hydrophobic group, and thus the sustaining effect of the emulsified state may be lowered. Can be.

The diameter of the barrier-free latanoprost is very important in terms of the ability to dissolve the soluble latanoprost. That is, the diameter of the barrier-free latanoprost is an indicator of the size of the barrier-free latanoprost because it is an important factor in determining the amount of latanoprost that the hydrophobic group of the surfactant can bear. In the case of liposomes, it can be said that latanoprost is completely dissolved in the vicinity of hydrophobic groups, but since the latanoprost of the barrier-free interface is much larger than the liposomes, at least in the individual barrier-free latanoprost. Thanofrost may be partially crystallized internally. However, since the surfactant surrounds the latanoprost in an amorphous form and is in the form, the ethanol-free surface latanoprost 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 latanoprost may be 1 to 10 ㎛, more preferably 1.5 to 5 ㎛. According to the above range, the stability of the barrier-free latanoprost can be maintained at the highest stability level.

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

In addition, preferably the anhydrous unmanned latanoprost may have an average range of sizes ranging from -30% to + 30% based on 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 latanoprost is very high.

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

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

In summary, if the homogeneity of the barrier-free latanoprost particles is significantly high and the sizes of the particles are about the same, 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, each attractive force and repulsive force are canceled (or it can be assumed that the repulsive force is superior to the attractive force). The recrystallization of the barrier-free latanoprost particles can be delayed as much as possible.

As described above, in order to significantly increase the homogeneity of the barrier-free latanoprost, an inline mixer including a mixing blade structure having the 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 latanoprost of the present invention can be prepared only through the mixing mixer for phase compensation, 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, the mixture containing the surfactant and the latanoprost injected is quantitatively 1/2 to 1 / every time it passes 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 the ratio of the surfactant and the latanoprost to bind can be quantified while being proportional to the dosage and the input ratio of the latanoprost and the surfactant to be initially introduced.

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

Therefore, the use of the liquid mixing mixer can be said to be one of the most essential components in the present invention. However, the present inventors first discovered a latanoprost in a non-interface state and derived a concept thereof, and the invention of the substance is protected by the substance itself, and the scope of 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 mixing mixer, the homogeneity is substantially sufficient that a homogenizer or stirrer capable of more easily producing a rinse-free interface latanoprost pursued 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, it is also considered that the bleeding-free latanoprost prepared according to the above-described method other than the mixing mixture mixer falls within the scope of the present invention.

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

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

The fatty acid may be included in 10 to 1000 parts by weight based on the latanoprost. When the fatty acid is more than 1000 parts by weight, the dispersion and homogeneity improvement effect according to the amount of the fatty acid is no longer improved. When the fatty acid is included in less than 10 parts by weight, it is possible to prevent recombination of latanoprost, to improve dispersion and homogeneity. 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 the latanoprost may 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 that the degree of prevention of recombination of latanoprost, improvement of dispersion degree, and improvement of homogeneity are higher.

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

In the case of using the lecithin, it is possible to dissolve in water as an emulsified type by being emulsified while surrounding the latanoprost. The yolk lecithin, soy lecithin and hydrogenated lecithin have the advantage of preventing the recombination of the latanoprost, improving the dispersion degree.

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 the recombination of the latanoprost and improving the dispersion degree as high purity.

According to another embodiment of the present invention, when the anhydrous unbounded surface latanoprost is dissolved in water, the unprotected interfaced latanoprost is produced.

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

Since the mixing aid is often a solid latanoprost and a surfactant, the liquid phase mixture should be in a solution state for liquid phase mixing. For this purpose, the mixing aid serves to make a mixture having an appropriate viscosity, and at a temperature increase. The latanoprost and the surfactant serves to prevent burning.

The mixed adjuvant is not excluded from the inclusion in the barrier-free latanoprost, but the mixed adjuvant because the initial latanoprost and the surfactant may include a fluidized bed process when preparing the anhydrous uncensored latanoprost. May be included in the anhydrous barrier-free latanoprost. In particular, the fluidized bed process may be desirable to add a polar organic solvent to the initial latanoprost and the surfactant to make a more stable fluidized bed.

The organic solvent having the polarity may include a -0H group and two or more -0H groups. Unlike the barrier-free latanoprost, the anhydrous barrier-free latanoprost contains an organic solvent having a polarity such as -OH. In addition, the organic solvent is usually dissolved in water when the anhydrous barrier-free latanoprost is dissolved in water and maintains most of the organic solvent is not attached to the latanoprost. When the —OH group of the organic solvent becomes two or more, the solubility in water may be higher, and the anhydrous unbounded surface latanoprost may form the undocked surface latanoprost.

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 latanoprost increases the solubility in water to form an excellent barrier-free latanoprost.

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

This has the advantage that the ratio and amount of the latanoprost and the surfactant are more quantified as the number of blades of the unit blades forming 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, the ratio and amount of the latanoprost and the surfactant can be more quantified while maintaining the internal pressure of the liquid mixing mixer according to the above range.

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 in order to prepare the latanoprost 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 latanoprost are the same as the barrier-free latanoprost described above, the description thereof is omitted in order to prevent the present invention from being overly complicated.

The barrier-free latanoprost and the barrier-free latanoprost 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.

In comparison with the method of solubilizing latanoprost in a liposome form or an emulsified form, the bloated latanoprost of the present invention has an advantage of increasing the content of latanoprost that can be dissolved by several tens to hundreds of times.

Accordingly, the bloated surface latanoprost of the present invention can minimize the side effects caused by the human body by not using a solubilizer such as cremofo, which has the potential to cause fatal side effects. In addition, in the case of administering the above-mentioned latanoprost 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 the conventional latanoprost preparation. You can. In addition, the latanoprost without bloating has excellent emulsification stability, so that almost no precipitation occurs in the digestive organs such as the esophagus, stomach, duodenum, large intestine, and small intestine, thereby minimizing side effects due to latanoprost precipitation.

In addition, the method for producing a blunt surface latanoprost of the present invention makes it possible to produce the bloated surface latanoprost. In addition, according to the anhydrous unbounded surface latanoprost of the present invention and a method for producing the same, it is possible to utilize the non-destructive surfaced latanoprost.

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 latano-frost rust-free interface according to an embodiment of the present invention.
FIG. 7 is a DSC graph of latanoprost sodium as a control and a barrier-free latanoprost prepared by the method of Example 17.
FIG. 8 is a DSC graph of latanoprost sodium as a control and a barrier-free latanoprost prepared by the method of Example 18.
FIG. 9 is a SEM photograph of latanoprost sodium as a control and a barrier-free latanoprost prepared by the method of Example 3 of the present invention. FIG. In the photograph, 1000 and 7000 represent the SEM magnification.
10 is a graph showing the degree of solubility of the latanoprost barrier-free in accordance with 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 Latano Frost Produce]

Glyceryl stearate and stearic acid are dispersed in the first open tank with relatively stable latanoprost and dipropylene glycol in the composition of Table 2, and require pre-mixing with lecithin, lecithin, which is susceptible to high temperatures 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%) Ratanofrost 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, but without the latanoproast of the barrier-free interface, in the case of Example 3 was prepared latanoprost of the present invention.

[ Manufacturing example 1-2: Does not contain fatty acids Free-standing interface Latano Frost 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 bloated surface latanoprost 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%) Ratanofrost 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 Latano Frost Produce]

Glyceryl stearate and stearic acid, which are dispersed in a relatively stable high temperature latanoprost and dipropylene glycol in the first open tank in the composition of Table 4, and require pre-mixing with a surfactant, a surfactant susceptible to high temperature in the second open tank After stirring and mixing, the solution of the first open tank and the second open tank was stirred and mixed with an in-line mixer to prepare a barrier-free latanoprost. 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, but without the lattice latanoprost was prepared, but in Example 7, the latanoprost was not prepared. PEG-150 Stearate as a surfactant is a surfactant having only one alkyl chain attached to the hydrophilic moiety.

ingredient Example 7
(weight%) Example 8
(weight%) Example 9
(weight%) Example 10
(weight%) Example 11
(weight%) Ratanofrost 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 Latano Frost 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 in the stirring method using an in-line mixer in Example 1-1 to prepare a latano-free frost surface, the specific composition is shown in Table 5. In Example 12, Example 13, and Example 14, it was possible to prepare a barrier-free latanoprost, but in Example 10 and Example 11, it was not possible to produce a barrier-free latanoprost.

ingredient Example 12
(weight%) Example 13
(weight%) Example 14
(weight%) Example 15
(weight%) Example 16
(weight%) Ratanofrost 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 Latano Frost 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. In the same manner as the stirring method using a single in-line mixer was prepared latanoprost free surface, the specific composition is shown in Table 6. In the case of Examples 17 to 19, it was possible to prepare the latanoprost without barriers, but the examples of Example 17 and Example 18 showed the most stable solubilization state.

ingredient Example 17
(weight%) Example 18
(weight%) Example 19
(weight%) Ratanofrost 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 Latano Frost Produce]

The buffalo latanoprost prepared by the method of Preparation Example 1 was solidified and finely powdered to prepare anhydrous buffalo latanoprost.

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

Experimental Example 1-1: Identification of amorphous state

The amorphous state of the barrier-free latanoprost prepared by the method of Example 3 was confirmed using an electron scanning microscope (SEM). Photographing was performed at 7000 times and 1000 times magnification, and specific results are shown in FIG. 10. The blue photo of Fig. 10 shows the latanoprost itself, but 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 latanoprost 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. Due to the amorphous form of latanoprost and the irregular arrangement of crystals, it is very easy to disperse water and maintain the disperse state for a long time (more than 3 years at room temperature).

Experimental Example 1-2: Evaluation of homogeneity and dispersibility

Dispersibility, homogeneity, and particle size of the water-free interface of latanoprost can be roughly determined by measuring the potential difference using a Zeta-Potential Analyzer, but this method confirms the presence or absence of recrystallization in the colloid system. 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. Table 7 and the particle photographs of FIGS. 12 to 27 show that the recrystallization of latanoprost according to the change over time is not observed, 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

Fix the latanoprost content to 30% by weight, and adjust the content of the surfactant and the solvent to prepare the bloated surface latanoprost of Examples 17 to 19 with the composition shown in Table 6, each composition sample 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 using a 100 ml measuring cylinder to obtain a degree of water solubility (called latanoprost). ) 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 by freeze-drying and powdering the finished latanoprost. Disperse the water-free interface latanoprost 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 latanoprost prepared by the methods of Examples 17 and 18. As a control, raw material latanoprost sodium was used.

The DSC graph of the control plane and the barrier-free latanoprost prepared by the method of Example 17 is shown in FIG. 8, and the DSC graph of the barrier-free latanoprost prepared by the method of the control and Example 18 is shown in FIG. 9. As shown in Figure 8, in the case of the control (a), latanoprost sodium crystalline form at room temperature phase transition to the liquid phase is ________ ℃ , the barrier-free surface prepared by the method of Example 17 of the present invention In the case of tanofrost (b) it was confirmed that the temperature of the phase transition to the liquid phase is ________ ℃ , a significant difference in the phase transition temperature. As shown in FIG. 8, in the case of the control group (a), the temperature at which the crystalline form of latanoprost sodium transitions to the liquid phase at room temperature is ________ ° C. , and the barrier-free surface prepared by the method of Example 18 of the present invention. In the case of tanofrost (b) it was confirmed that the temperature of the phase transition to the liquid phase is ________ ℃ , a significant difference in the phase transition temperature.

[ Experimental Example 2 : Free-standing interface Latano Frost 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 prepared by using the F (latanoprost sodium) preparation and the main ingredient raw material sold by D Company. It was. As a result of the experiment, as shown in Table 10, the barrier-free latanoprost according to the present invention showed superior drug penetration efficacy compared to the reference drug.

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

^{‥ Significantly different in comparison to parent Latanoprost} 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 latanoprost prepared in Example 3 and the latanoprost prepared in the method of Example 1 (non-produced non-interfacial materials, 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 latanoprost prepared by the method of Example 3 had a dissolution rate of ________% or more after 30 minutes from the start of the dissolution test, and showed high dissolution ability significantly exceeding the solubility of the drug. On the other hand, the latanoprost of Example 1, where 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 latanoprost and
It comprises 10 to 200 parts by weight of a surfactant having two or more alkyl chains attached to the hydrophilic portion relative to the latanoprost,
The surfactant is in the form of being bonded to surround the latanoprost amorphous (amorphous) in an emulsion type dissolved in water,
The latanoprost with the surfactant has an average diameter of 0.5 to 30㎛, the average range of the size is within ± 200% of the diameter
Rabano frost without barrier.

The method according to claim 1,
The barrier-free latanoprost will further include a fatty acid between the surfactant and the latanoprost.
Rabano frost without barrier.

3. The method of claim 2,
The fatty acid is included in 10 to 1000 parts by weight based on the latanoprost
Rabano frost without barrier.

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
Rabano frost without barrier.

The method according to claim 1,
The surfactant is selected from the group comprising egg yolk lecithin, soy lecithin and hydrogenated lecithin
Rabano frost without barrier.

The method according to claim 1,
The surfactant is that the PC (Phosphatidylcholine) is contained in more than 70% by weight
Rabano frost without barrier.

When dissolved in water,
Anhydrous barrier-free latanoprost which produces | generates the barrier-free latanoprost of any one of Claims 1-6.

8. The method of claim 7,
Wherein the anhydrous barrier-free latanoprost will further comprise an organic solvent having a polarity as a mixed adjuvant
Anhydrous, non-woven surface latanofrost.

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

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-woven surface latanofrost.

(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 latanoprost as a poorly soluble material to the mixture of step (b);
(d) mixing the mixture into which the latanoprost of step (c) is mixed using a mixer including a mixing blade structure having the concept of liquid phase mixing; And
(e) solidifying the phase mixed mixture of step (d)
Method for producing an anhydrous, uncensored surface latanoprost 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 undulating interface latanoprost.

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 undulating interface latanoprost.

Claim 1 to 13 comprising the step of adding water to the anhydrous unbounded surface latanoprost prepared by the method of any one of claims
Process for producing latanofrost without barrier.