KR100834148B1 - Pharmaceutical formulations for itraconazole - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising itraconazole as an active ingredient, and more particularly, to a pharmaceutical composition comprising an itraconazole, a polylactic acid derivative, and an amphiphilic block copolymer. The polylactic acid derivative may be a metal ion bonded to the carboxylic acid terminal and the amphiphilic block copolymer forms micelles or nanoparticles in the aqueous solution.

Itraconazole, Polylactic Acid, Amphiphilic Block Copolymer

Description

Pharmaceutical formulations for itraconazole}

Itraconazole or (±) -cis-4- [4- [4- [4-[[2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazole-1) -Ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- (1-methylpropyl) -3H- 1,2,4-triazol-3one is one of many broad antifungal compounds and poorly water soluble. Other poorly water soluble azole compounds include oxyconazole, biponazole, isoconazole, isoconazole nitrate, terconazole, clotrimazole, nitrate econazol, ketoconazole, myconazole, myconazole nitrate, and serrate nitrate Taconazole, itraconazole, and saperconazole. The molecular formula of this itraconazole is C ₃₅ H ₃₀ C1 ₂ N ₈ O ₄ and has a molecular weight of 705.64. Appearance is white to pale yellow powder, practically insoluble in water (1 μg / ml or less), slightly soluble in alcohol (300 μg / ml), and well soluble in methylene chloride (239 mg / ml). It is a weakly basic compound with a pKa value of 3.7 and is almost completely ionized under strong acid conditions such as gastric juice. Pharmacologically, it is known to exhibit antifungal activity in a wide range of areas, as oral, non-oral and topical preparations. The effective blood concentration of itraconazole is 0.25-0.5 mcg / mL (The Annals of Pharmacotherapy. 2001, June, Vol 35).

The development of potent pharmaceutical formulations of azoles, such as itraconazole, is severely limited by the fact that azoles are almost insoluble in water. Itraconazole is difficult to prepare the drug in formulations because of its pH dependence and very low solubility.

In general, in the case of poorly soluble drugs, since the dissolution from the solid preparation is slow and the dissolution acts as a rate step in the absorption process, the dissolution rate has a direct influence on the expression time, strength and duration of the drug. Therefore, the formulation of poorly soluble drugs requires an attempt to increase the dissolution rate of the drug.

Pharmaceutical methods for increasing the solubility and dissolution rate of poorly soluble compounds include drug particle size reduction, polymorphism, amorphous, mixed grinding, solid dispersion, clathrate, solvate, protein binding, and interaction with additives. And the like are known. However, although many of the aforementioned pharmaceutical methods are known, it is not easy to increase the dissolution rate in consideration of the properties of specific drugs. In particular, in the formulation process for increasing the dissolution rate of poorly soluble drugs, many pharmaceutical factors, including ease of preparation, must also be considered. In order to increase the solubility of itraconazole in water, a method of forming a complex using cyclodextrin or a derivative thereof has been attempted (International Patent Publication No. 85-002767). International Patent Publication No. 93-015719 discloses the preparation of external liposome preparations containing itraconazole using phospholipids and solvent systems. International Patent Publication No. 96-039835 also attempts to add itraconazole to a volatile organic acid solvent having a low molecular weight such as acetic acid and formic acid.

However, the manufacturing methods are not valued as a commodity because of the disadvantages of poor solubility of itraconazole, improvement of oral incompatibility, and difficulty in manufacturing method.

On the other hand, International Patent Publication No. 94-005263 discloses a drug coating layer containing a hydrophilic polymer, hydroxypropyl methylcellulose and a drug, on a very small sugar sphere of about 25 to 30 mesh, so that the solubility and bioavailability of the drug. An oral bead-type drug with an increased content is disclosed. Janssen Pharmaceutica NV has been developed and marketed as a capsule formulation called Spranox®, but this is a patented capsule formulation of Janssen. Sporanox® has to go through a cumbersome manufacturing process, such as requiring a seal coating on the drug coating layer to prevent sticking between drug beads, which is bothersome and creates an undesirable effect of the accompanying decrease in solubility and bioavailability. There are disadvantages. In addition, the effect of food on the disintegration of drugs in the GI tract is relatively large. In addition, International Patent Publication No. 97-044014 discloses the preparation of a solid dispersion of itraconazole and a water-soluble polymer using a melt-extrusion method at a temperature of 245 to 265 ° C.

The solid dispersion is characterized by increasing the bioavailability of the drug and little influenced by food, but because the manufacturing process is performed at a higher temperature, it may not only affect the stability of the drug but also make the extrudate easy to manufacture. There is a disadvantage.

Accordingly, there is a trend of increasing the need for itraconazole formulations that have been secured while solving these problems, making the manufacturing process easier and improving the solubility of itraconazole to increase bioavailability.

Korean Patent Laid-Open Publication No. 1999-51527 discloses a technique for melting and grinding water-soluble sugars together with itraconazole to reduce the particle size of itraconazole and to change crystallinity to increase solubility and dissolution rate.

In Korean Patent Laid-Open No. 1999-62448, i) dissolving 1 part by weight of itraconazole and 0.5 to 5.0 parts by weight of a hydrophilic polymer with a solvent, ii) spray drying the mixture, and iii) preparing an oral solid dispersion. It describes a method for preparing the itraconazole oral preparation having improved bioavailability by forming the prepared solid dispersion. This patent document discloses the formation of a solid dispersion in which spherical amorphous particles having a small particle distribution of 1 to 5 탆 are formed and brought into intimate contact with a hydrophilic carrier to increase solubility and initial dissolution rate.

Korean Patent Laid-Open Publication No. 1999-1564 describes a method of increasing the solubility and dissolution rate by using spray drying to reduce the particle size of the poorly soluble drug itraconazole and to change the crystallinity. Here, the particle size of itraconazole is in the range of about 0.5 to 10 μm and the average particle size is about 3.7 μm, indicating that the particle diameter is reduced by 7 times compared to the itraconazole raw material and the solubility is increased by 62 times. However, this technique has the disadvantage that the solubility depends on the spray rate. If the spraying speed is too slow, the solvent evaporates too fast, causing a lot of drug loss. If the spraying speed is fast, the solvent size is entangled with each other before the solvent evaporates, so that the particle size distribution can be largely dependent on the manufacturing conditions. There is a problem in that it has a non-uniform particle distribution at each production time and thus the dissolution rate is also not uniform.

It has been recognized that by increasing the solubility of itraconazole, it would be advantageous to develop itraconazole formulations having both high stability and high bioavailability and easy preparation methods thereof.

The present invention provides a pharmaceutical composition containing itraconazole as an active ingredient. More particularly, the present invention relates to pharmaceutical compositions containing itraconazole as an active ingredient. The composition comprises itraconazole, and a polylactic acid derivative having one or more carboxylic acid end groups. One embodiment of the invention includes itraconazole, polylactic acid derivatives having one or more carboxylic acid end groups, and amphiphilic block copolymers. Another embodiment of the present invention is a polymer micelle or nanoparticle in an aqueous solution including itraconazole, a polylactic acid derivative having at least one of the above carboxylic acid end groups having a divalent or trivalent metal ion attached to a carboxylic acid end, and an amphiphilic block copolymer. Forming particles.

The present invention provides pharmaceutical compositions with improved solubility and stability compared to conventional itraconazole formulations. The present invention also provides a pharmaceutical composition containing itraconazole as an active ingredient, which effectively increases the solubility and stability of itraconazole in body fluids or aqueous solutions.

Prior to the disclosure of the polymer compositions of the present invention and methods of use and preparation thereof, it is to be understood that the present invention is not limited to particular forms, process steps, materials disclosed herein, and that such forms, process steps, and materials may vary. You have to understand. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is limited only by the appended claims and their equivalents.

In the specification and the appended claims, it should be noted that the singular forms "a" or "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a polymer containing “one end group” includes references to two or more such groups, and reference to “one hydrophobic drug” refers to two or more such drugs. Include references to Furthermore, referring to one amphiphilic block copolymer, it is understood that the composition of each of the A and B blocks, the respective ratios of each block, and the weight or number average molecular weight of each block and / or the total block polymeric composition are in accordance with the present invention. As long as it is within the defined range, a mixture of block copolymers is included.

In describing and claiming the present invention, the following terms will be used in accordance with the definitions set out below.

The term "biodegradable" or "biodegradable" as used herein refers to the conversion of a substance into a less complex intermediate or final product by dissolution hydrolysis or by the action of a biologically formed entity that may be the product of an enzyme or other organism. It is defined as.

As used herein, the term "biocompatibility" refers to a substance or intermediate of substance formed by dissolution hydrolysis or by the action of a biologically formed entity that may be a product of an enzyme or other organism and does not cause adverse effects on the living body. Or final product.

As used herein, “administration” and similar terms means delivering the composition to an individual to be treated so that the composition can be systemically circulated. Preferably, the compositions of the invention are administered by subcutaneous, intramuscular, transdermal, oral, mucosal, intravenous, or intraperitoneal routes. Injectable materials for such uses may be prepared in conventional forms, as solid solutions or suspensions, or as solids suitable for preparation as solutions or suspensions in liquids or as emulsions prior to injection. Suitable excipients that can be used for administration include, for example, water, saline, dextrose, glycerol, ethanol and the like; And optionally small amounts of auxiliary substances such as wetting or emulsifying agents, buffers and the like. For oral administration, it can be formulated in a variety of forms, such as solutions, tablets, capsules, and the like.

In the following, exemplary embodiments are shown and specific terminology will be used in the present invention to disclose the same. In addition, it goes without saying that the scope of the present invention is not limited by the above. Modifications and additional modifications of the invention exemplified herein, and further applications of the principles of the invention as exemplified herein, should be considered by those skilled in the art to be within the scope of the invention in connection with this description. do.

The pharmaceutical composition of the present invention comprises itraconazole and a polylactic acid derivative having one or more carboxylic acid end groups. Preferably the pharmaceutical composition of the present invention comprises itraconazole, a polylactic acid derivative having at least one carboxylic acid end group and an amphiphilic block copolymer. More preferably, the pharmaceutical composition of the present invention comprises itraconazole, a polylactic acid derivative having at least one of the above carboxylic acid end groups having a divalent or trivalent metal ion bonded to the carboxylic acid end, and an amphiphilic block copolymer. Therefore, the present invention can improve the solubility of poorly soluble itraconazole by forming polymer micelles or nanoparticles in an aqueous solution, and thus can be encapsulated in a large amount. The pharmaceutical composition allows the itraconazole to be present in the form of fine particles in an aqueous solution, so that stability can be used as an intravenous injection, and the blood concentration can be maintained for a long time.

The present invention relates to a pharmaceutical composition comprising 0.1 to 30.0 wt% of itraconazole, 5.0 to 99.9 wt% of a polylactic acid derivative having a carboxylic acid end group, and 0.0 to 94.9 wt% of an amphiphilic block copolymer composed of a hydrophilic block and a hydrophobic block. . Preferably, the pharmaceutical composition comprises 0.1-20.0 wt% itraconazole, 20.0-99.9 wt% polylactic acid derivative, and 0.0-79.9 wt% amphipathic block copolymer.

That is, the present invention provides a pharmaceutical composition comprising 0.1 to 30.0 wt% of itraconazole and 70.0 to 99.9 wt% of a polylactic acid derivative having at least one carboxylic acid end group when the polylactic acid derivative is used alone. The present invention also provides a pharmaceutical composition comprising 0.1 to 30.0% by weight itraconazole, 5.0 to 99.8% by weight polylactic acid derivative having at least one carboxylic acid end group and 0.1 to 94.9% by weight amphipathic block copolymer. Preferably, the pharmaceutical composition comprises 0.1-20.0 wt% of itraconazole, 20.0-80.0 wt% of the polylactic acid derivative, and 5.0-79.9 wt% of the amphipathic block copolymer. More preferably, the pharmaceutical composition comprises 0.1-15.0 wt% itraconazole, 40.0-80.0 wt% polylactic acid derivative, and 5.0-59.9 wt% amphipathic block copolymer.

The present invention also provides 0.1 to 30.0% by weight of itraconazole, 5.0 to 99.8% by weight of polylactic acid derivatives having at least one of the above-mentioned carboxylic acid end groups in which a divalent or trivalent metal ion is bonded to the carboxylic acid end and 0.1 to 94.9% by weight of an amphiphilic block copolymer. It provides a pharmaceutical composition comprising a. Preferably the pharmaceutical composition is 0.1 to 20.0% by weight of itraconazole, 20.0 to 99.8% by weight of a polylactic acid derivative having at least one of the carboxylic acid end groups in which a divalent or trivalent metal ion is bonded to the carboxylic acid end and the amphipathic block copolymer 0.1 To 79.9 wt%. More preferably, the pharmaceutical composition is 0.1 to 20.0 wt% of itraconazole, 20.0 to 70.0 wt% of the polylactic acid derivative having at least one of the carboxylic acid end groups having a bivalent or trivalent metal ion bonded to the carboxylic acid end, and an amphiphilic block in the air. 10 to 79.9 weight percent of coalescing.

As the polylactic acid derivative suitable for forming the polymer micelles in the present invention, those having a number average molecular weight of 500 to 2,500 daltons can be used, and those having a number average molecular weight of 800 to 1,500 daltons are more preferable.

Specific examples of such polylactic acid derivatives include D, L-polylactic acid, D-polylactic acid, polymandelic acid, copolymers of D, L-lactic acid and glycolic acid, copolymers of D, L-lactic acid and mandelic acid. , Copolymers of D, L-lactic acid and caprolactone, copolymers of D, L-lactic acid and 1,4-dioxan-2-one, and decanoyl, lauroyl, and pamitoyl carbon atoms of 8 to 14 The thing which the carboxylic acid or the alkali metal salt of carboxylic acid couple | bonded with the polylactic acid terminal selected from the acyl-D, L-lactic acid etc. which substituted acyl of may be used. The alkali metal salt is selected from monovalent metal ions such as sodium, potassium or lithium.

As described above, the polylactic acid derivative to be used in the present invention has at least one carboxylic acid group or carboxylic acid alkali metal salt, so that the polylactic acid derivative may act as a hydrophilic group in an aqueous solution of pH 4 or higher to form a polymer micelle.

Even when the above-mentioned polylactic acid derivatives are used alone, a pharmaceutical composition containing itraconazole, which forms a polymer micelle in an aqueous solution at a pH of 4 or more, for example, can be prepared under specific conditions, When added, it is possible to form the polymer micelles regardless of the pH of the aqueous solution. Therefore, since the biodegradable polymer is generally hydrolyzed at pH 10 or more, the polymer mixture composition may be used in the range of pH 1 to 10, and considering that the polymers are biodegradable polymers, It is preferable to use.

The pharmaceutical composition comprising the itraconazole of the present invention as an active ingredient comprises 0.1 to 30.0% by weight of itraconazole, 5.0 to 99.8% by weight of a polylactic acid derivative having at least one carboxylic acid end group, and 0.1 to 94.9% by weight of an amphipathic block copolymer. If possible, the polymer micelles may be formed regardless of the pH of the aqueous solution.

Preferably, the pharmaceutical composition of the present invention comprises 0.1 to 20.0 wt% of itraconazole, 20 to 80 wt% of the polylactic acid derivative having at least one carboxylic acid end group, and 5 to 79.9 wt% of the amphipathic block copolymer.

As the amphiphilic block copolymer constituting the pharmaceutical composition of the present invention, a hydrophilic block (A) and a hydrophobic block (B) are bi-block copolymers connected in an A-B form, and are characterized by being nonionic. In addition, the amphiphilic block copolymer is a core-shell-type polymer micelle in which a hydrophobic block (B) forms a core and a hydrophilic block (A) forms a shell in an aqueous solution. To form. Although the composition ratio of the hydrophilic block and hydrophobic block in such an amphiphilic block copolymer is 2-8: 8-2 (w / w), Preferably, the composition ratio is 4-7: 6-3 (w / w) It is good.

The hydrophilic A block is a water-soluble polymer, specifically, polyalkylene glycol, polyethylene glycol, polyethylene-co-propylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, monomethoxypolyalkylene glycol and Although monoacetoxy polyethyleneglycol is used, it is more preferable to use monomethoxypolyalkylene glycol. The hydrophilic block described above uses a number average molecular weight of 1,000 to 10,000 Daltons, preferably 1,000 to 5,000 Daltons.

The hydrophobic B block is insoluble in water, has excellent biocompatibility, and is a biodegradable polymer, specifically, polylactide, polyglycolide, polydioxan-2-one, polycaprolactone, polylactic-co-glycolide, Polylactic-co-caprolactone, polylactic-co-dioxane2-one, polyD-lactic acid, polyL-lactic acid, polyDL-lactic acid, and the like are selected from among polyD-lactic acid, polyL-lactic acid or poly More preferably, DL-lactic acid is used. The hydroxy end groups of the hydrophobic B blocks described above may be substituted with fatty acid groups such as butyric acid, propionic acid, acetic acid, stearic acid and palmitic acid. The hydrophobic block described above uses a number average molecular weight of 1,000 to 10,000 Daltons, and preferably 1,500 to 5,000 Daltons.

As can be seen in Figure 1, the polylactic acid derivative is first reacted with itraconazole to form a polymer-drug complex and encapsulated in a hydrophobic core of micelles or nanoparticles composed of the amphiphilic block copolymer of the present invention. A polylactic acid derivative having at least one carboxylic acid end group is sandwiched between the amphiphilic block copolymers. The polymer-drug complex stabilizes itraconazole and does not precipitate in aqueous solution. The stability of the hydrophobic core consisting of the hydrophobic B block of the drug complex and the amphiphilic block copolymer increases due to the interaction between the drug and the polylactic acid derivative. In order to minimize the amount of the polymer used and to stabilize the polymer-drug complex, it is preferable that all polylactic acid derivatives which form micelles without forming a complex with the drug are ionic. Given the sufficient dissolution of pKa (pKa 3.8) of the polylactic acid derivatives and the complex, the entire composition is preferably in the range of pH 4-7, more preferably in the range of pH 4-6. According to the invention, itraconazole is generally not soluble with amphiphilic block copolymers known to dissolve poorly water soluble drugs, but can be dissolved with polylactic acid derivatives alone or with amphiphilic block copolymers. . When only polylactic acid derivative is used, the composition of this invention becomes like this. Preferably it is pH 4-7, More preferably, it exists in the range of pH 5-6.

The particle size of the micelle of the present invention can be adjusted in size depending on the molecular weight of the polymer used and the composition ratio of the polylactic acid derivative and the amphiphilic block copolymer, the particle size can be adjusted in the range of 10 to 200 nm, preferably Below, polymer micelles having a range of 10 to 100 nm can be formed.

Further, the pharmaceutical composition is 0.1 to 30.0% by weight of itraconazole, 5.0 to 99.8% by weight of polylactic acid derivative having a divalent or trivalent metal ion at the carboxylic acid end, an amphiphilic block copolymer composed of a hydrophilic block and a hydrophobic block 0.1 To 94.9% by weight of the pharmaceutical composition.

More preferably, the pharmaceutical composition comprises 0.1 to 20.0 wt% of itraconazole, 20.0 to 70 wt% of the polylactic acid derivative having 0.5 to 4.0 equivalents of the divalent or trivalent metal ion to the carboxylic acid end group equivalent and the amphipathic block. It is the case containing 10-79.9 weight% of copolymers.

The polylactic acid derivative and the amphiphilic block copolymer are the same as described above. In particular, a divalent or trivalent metal ion is bonded to the carboxylic acid terminal of the polylactic acid derivative. The metal ion is a divalent or trivalent metal ion corresponding to 0.5 to 4.0 equivalents to the carboxylic acid terminal group equivalent of the polylactic acid. Specifically, calcium (Ca ^{2 +} ), magnesium (Mg ^{2 +} ), barium (Ba ^{2 +} ), manganese (Mn ²⁺ ), nickel (Ni ^{2 +} ), copper (Cu ^{2 +} ), zinc (Zn ^{2 +),} chromium (Cr ^{+ 3),} iron (Fe ^{+ 3),} and aluminum (Al ³⁺⁾ may be used one selected from among, preferably, the calcium (Ca ^{+ 2).}

The metal ion is added to the mixed polymer composition of the amphiphilic block copolymer and polylactic acid in the form of sulfate, carbonate, hydrochloride, phosphate, or hydroxylate, preferably calcium chloride (CaCl ₂ ), magnesium chloride (MgCl). ₂ ), zinc chloride (ZnCl ₂ ), aluminum chloride (AlCl ₃ ), iron chloride (FeCl ₃ ), calcium carbonate (CaCO ₃ ), magnesium carbonate (MgCO ₃ ), calcium phosphate (Ca ₃ (PO ₄ ) ₂ ), phosphoric acid Magnesium (Mg ₃ (PO ₄ ) ₂ ), Aluminum Phosphate (AlPO ₄ ), Magnesium Sulfate (MgSO ₄ ), Calcium Hydroxide (Ca (OH) ₂ ), Magnesium Hydroxide (Mg (OH) ₂ ), Aluminum Hydroxide (Al (OH) ) ₃ ) or zinc hydroxide (Zn (OH) ₂ ) can be used.

As can be seen in Figure 2, when the divalent or trivalent metal ions are substituted with the monovalent metal cation of the polylactic acid carboxylic acid terminal group, the stability of the polymer micelle or nanoparticles is further improved.

In addition, the equivalent amount of the divalent or trivalent metal ions is added in an amount of 0.5 to 4.0 equivalents to the equivalent of the carboxylic acid end groups of the polylactic acid derivative. Preferably, the metal ions are added to the equivalent of the carboxylic acid end groups of the polylactic acid derivative. It is preferable to use 0.5-2.0 equivalent with respect to it. The rate of release of itraconazole contained in the polymer micelles or nanoparticles can be controlled by controlling the equivalent of the divalent or trivalent metal ions. That is, when divalent or trivalent metal ions are contained in an amount of less than 0.5 equivalents to the equivalent of the carboxylic acid end groups of the polylactic acid derivatives, the number of divalent or trivalent metal ions bonded to the carboxylic acid end groups of the polylactic acid derivatives is less. When the release rate is increased and is included in an amount exceeding 4.0 equivalents, the number of divalent or trivalent metal ions reacting with the carboxylic acid end groups of the polylactic acid derivative is increased, thereby delaying the release rate of itraconazole. Thus, a small amount of metal ions may be used to increase the release rate of the drug, and a large amount of metal ions may be used to delay the release rate of the drug.

Further, the present invention includes a method for preparing the pharmaceutical composition. After dissolving a proportion of itraconazole and polylactic acid derivative or itraconazole, polylactic acid derivative and amphiphilic block copolymer in an organic solvent, the organic solvent is evaporated and the obtained mixture is added to an aqueous solution to prepare a polymer micelle containing itraconazole.

In this case, the polymer micelles or nanoparticles fixed with divalent or trivalent metal ions may be prepared by fixing the carboxylic acid end groups of the polylactic acid derivative by adding divalent or trivalent metal ions to the polymer micelles.

A proportion of itraconazole and the polylactic acid derivative or the itraconazole, polylactic acid derivative and the amphiphilic block copolymer are one or more of the group consisting of acetone, ethanol, methanol, ethyl acetate, acetonitrile, methylene chloride, chloroform, acetic acid and dioxane Dissolve in mixed solvent. The solvent is volatilized to produce a homogeneous mixture containing itraconazole. An aqueous solution having a pH of 4 to 8 is added to the mixture to prepare an itraconazole-containing mixed polymer micelle at 0 to 60 ° C. The itraconazole-containing polymer micelle aqueous solution may be prepared as a polymer micelle in a solid form by freeze drying.

In addition, an aqueous solution containing 0.001 to 2 M of divalent or trivalent metal ions was added to the mixed aqueous micelle solution, stirred slowly at room temperature for 0.1 to 1 hour, and then lyophilized to form a divalent or trivalent metal in solid form. It is made of polymer micelles or nanoparticles immobilized with ions. The composition in solid form may be diluted or reconstituted with an aqueous solution such as water for injection, saline or 5% dextrose solution.

The composition of the present invention further comprises pharmaceutically acceptable excipients such as stabilizers, pigments, preservatives.

The size of the particles in the aqueous solution of the present invention is formed in the range of 10 to 200 nm, especially when formed in the range of 10 to 100 nm is more preferable when used in the intravenous and oral dosage form because the particles are fine.

In the present invention, itraconazole may be contained in the core portion of the polymer micelle or nanoparticle and be administered orally or parenterally to a human body or an animal. In particular, the polymer micelles or nanoparticles immobilized by the use of divalent or trivalent metal ions remain in the blood for a long time when administered to the body, thereby increasing the pharmacological effect of itraconazole and significantly reducing the frequency of administration. There is an effect.

The composition of the present invention can be used to treat fungal diseases such as blastomycosis, histoplasmosis, aspergillosis, and onychomycosis. The dosage of itraconazole may vary depending on the type of disease, severity, age, weight, sex and condition of the patient, but can generally be from 50-100 mg itraconazole / day to 800-1000 mg itraconazole / day.

The pharmaceutical composition of the present invention may be administered orally by vascular, muscle, subcutaneous, intraperitoneal, nasal, nasal, rectal, eye, or lung routes, orally or in the form of tablets or capsules, or aqueous solutions.

Amphiphilic block copolymers and polylactic acid derivatives used in the present invention are prepared according to the methods disclosed in WO 03/033592, the disclosure of which is incorporated herein by reference in its entirety.

Additional features and advantages of the invention will be apparent from the following detailed description, which together with the accompanying drawings illustrate the features of the invention by way of example.

These and other features of the invention will be described in the following disclosure in conjunction with the accompanying drawings:

1 shows a model diagram of micelles in which itraconazole is encapsulated in a polylactic acid derivative having a carboxylic acid end group sandwiched between a hydrophobic core and an amphiphilic block copolymer of a core-shell carrier composed of an amphiphilic block copolymer under an aqueous environment.

FIG. 2 shows a model diagram of polymer micelles in which itraconazole is immobilized with Ca ⁺⁺ enclosed in the hydrophobic core of micelles.

Figure 3 is a graph showing the change in concentration of itraconazole with time in the blood upon administration of the composition solubilized using the nanoparticle composition prepared according to Example 9 of the present invention and the cyclodextrin prepared according to Comparative Example 2.

Figure 4 is a graph showing the concentration change of itraconazole with time in the blood oral administration of the micelle composition prepared according to Example 2 of the present invention and the composition solubilized using the cyclodextrin prepared according to Comparative Example 2.

With reference now to the exemplary embodiments illustrated, the above will be described using the terms used in the present invention. It is of course not intended to limit the scope of the invention by the above.

The following examples will enable those skilled in the art to more clearly understand the practice of the present invention. Although the present invention has been described in connection with certain preferred embodiments thereof, it is of course not intended that the following limit the scope of the present invention. Other aspects of the invention will be apparent to those skilled in the art.

Example  1-2 itraconazole and Polylactic acid  Having derivatives Micelle  Produce

Next, after dissolving itraconazole and polylactic acid derivative in 2 mL of methylene chloride, the methylene chloride was completely dissolved, and purified water was added thereto to completely dissolve it, and sodium hydrogencarbonate was added to pH 4.0 to 7.0. After filtration using a filter having a pore size of 200 nm and freeze-drying, a polymer micelle composition containing powdery itraconazole was prepared.

Example  3-8 itraconazole, Polylactic acid  Derivatives and Amity Block copolymer  Preparation of Having Michel

Next, the itraconazole, polylactic acid derivative, and amphiphilic block copolymer were completely dissolved by adding 2 mL of methylene chloride, and then the methylene chloride was removed, and purified water was added thereto to completely dissolve the carbonic acid to pH 4.0 to 7.0. After adding sodium hydrogen, the mixture was filtered using a filter having a pore size of 200 nm, and then freeze-dried to prepare a polymer micelle composition containing powdery itraconazole.

Comparative example  One

Next, the amount of itraconazole and the amphiphilic block copolymer was completely dissolved by adding 2 mL of methylene chloride, and then the solvent was completely removed, completely dissolved by adding purified water, and sodium hydrogencarbonate was added to pH 4.0 to 7.0. Filtration was carried out using a filter having a pore size of 200 nm and then lyophilized to prepare a polymer micelle composition containing itraconazole in powder form.

division Furtherance(%) Itraconazole Polylactic acid derivative ^{1 )} Amphiphilic block copolymer ^{2 )} Example 1 15.0 85.0 - Example 2 5.0 95.0 - Example 3 15.0 65.5 19.5 Example 4 15.0 47.5 37.5 Example 5 15.0 42.5 42.5 Example 6 15.0 25.0 60.0 Example 7 5.0 47.5 47.5 Example 8 8.0 50.0 42.0 Comparative Example 1 15.0 - 85.0 1) D, L-PLA-COONa, number average molecular weight (Mn) 1,150 Daltons 2) monomethoxy polyethylene glycol-polylactide, number average molecular weight 2,000-1,766 Daltons

Example  9 to 11: metal With ionic salt Fixed  Nano Particle  Produce

Step 1 : After dissolving the itraconazole, polylactic acid derivative and amphiphilic block copolymer mixture in the amounts shown in the following Table 2 by adding 2 mL of methylene chloride, the methylene chloride was removed and dissolved in purified water, thereby preparing a mixed micelle aqueous solution.

Step 2 : 0.1 M anhydrous calcium chloride aqueous solution was added to the mixed micelle aqueous solution prepared in Step 1, stirred at room temperature for 20 minutes, sodium bicarbonate was added to pH 4.0-7.0, and filtered using a filter having a pore size of 200 nm. After freeze-drying to prepare a polymer nanoparticle composition containing powder itraconazole.

division Usage (% by weight) Itraconazole Polylactic acid derivative ¹⁾ Amphiphilic block copolymer ²⁾ Metal ions ^{3 )} Example 9 4.9 46.4 46.4 2.3 Example 10 14.9 24.7 59.3 1.1 Example 11 14.7 46.4 36.7 2.2 1) D, L-PLA-COONa, number average molecular weight 1,150 Dalton 2) monomethoxy polyethylene glycol-polylactide, number average molecular weight 2.000-1,766 dalton 3) calcium chloride

Comparative example  2

100 mg of itraconazole and 4 g of hydroxypropyl-β-cyclodextrin are dissolved in ethanol and methylene chloride solution, and an organic solvent is evaporated to prepare a homogeneous mixture. To this, purified water is added, and then 250 mg of propylene glycol is added and hydrochloric acid 38 Μl was added and then filtered using a filter with a pore size of 200 nm to prepare an itraconazole composition solubilized in cyclodextrin.

Experimental Example  1: Itraconazole encapsulation efficiency and particle size measurement

The polymer mixed micelles or nanoparticle compositions of Examples 1 to 11 and Comparative Example 1 were measured according to the HPLC conditions specified in the following Table 3 to determine the content of itraconazole, and the weight of the itraconazole contained in the sample was converted to the electrophoretic light scattering photometer. The particle size was measured by dynamic light scattering (DLS). Itraconazole encapsulation efficiency was calculated by the following equation, the results are shown in Table 4.

Estimated Usage% = [(Itraconazole Usage) / (Itraconazole Usage + Polymer Usage + Metal Ion Salt Usage)] x 100

Actual fill amount (%) = (itraconazole weight / sample weight) x 100

Encapsulation Efficiency (%) = (Itraconazole Encapsulation / Itraconazole Consumption) x 100

division Condition Eluent 54% Acetonitrile / 46% Water / 0.05% Diethylamine column C18, inner diameter 4 mm, length 25 cm (bydak, USA) Detection wavelength 258 nm Flow rate 0.8 ml / min Temperature Room temperature Injection volume 80 μl Retention time  18 minutes

division Itraconazole Estimated Usage (%) Itraconazole actual loading (%) Itraconazole Encapsulation Efficiency (%) Particle Size (nm) Example 1 15.0 12.5 83.3 100 Example 2 5.0 4.6 92.0 80 Example 3 15.0 13.6 90.1 100 Example 4 15.0 14.5 96.7 36 Example 5 15.0 14.2 94.7 34 Example 6 15.0 14.5 96.7 27 Example 7 5.0 4.7 94.0 25 Example 8 8.0 7.4 92.5 28 Example 9 4.9 4.5 91.8 20 Example 10 15.0 14.5 96.7 32 Example 11 14.7 14.1 95.9 28 Comparative Example 1 15.0 0.5 3.3 -

As shown in Table 4, compared with the composition solubilized only with the amphiphilic block copolymer (Comparative Example 1), the composition of the present invention has a sealing efficiency of 80% or more, and the solubility of itraconazole in Examples 1 to 11 is 10 mg / It was more than mL, wherein the size of the particles in the aqueous solution is fine particles of less than 100 nm it can be seen that it is also suitable for intravenous formulation.

Experimental Example  2: stability experiment

The composition of Examples 2, 7 and 9 was filtered with a filter having a pore size of 200 nm to dilute with purified water to prepare an itraconazole concentration of 3.3 mg / mL, and then change the content of itraconazole while incubating at 25 ° C. It was measured by HPLC at the time intervals given under the conditions of Table 3. The results are shown in Table 5 below.

Residual Itraconazole Content (%) = (Storage Huytraconazole Content) / (Itraconazole Content at Start) x 100

division Itraconazole Content (%) Example 2 Example 7 Example 9 Time (hours) 0 100.0 100.0 100.0 2 98.0 99.2 99.6 24 93.0 95.2 97.6

As shown in Table 5, the amount of itraconazole in the aqueous solution of the present invention is maintained at 90% or more for 24 hours, and the polylactic acid derivative having a carboxylic acid terminal group and the parent relative to the micelle composition (Example 2) using polylactic acid derivative alone It can be seen that the stability is further increased in the case of mixed micelle compositions using the block copolymers (Examples 7 and 9). In particular, when methoxy polyethylene glycol-polylactide and calcium ions were added as the amphiphilic block copolymer (Example 9), the stability of the polymer nanoparticle composition was further increased.

Experimental Example  3: by intravenous administration Bioavailability  exam

Male Sprague-Dawley rats weighing 230-250 g were used for experiments after two weeks of adaptation, and the samples prepared according to Example 9 or Comparative Example 2 were used as samples.

A tube was inserted into the femoral artery and femoral vein of the male rat, and the prepared sample was injected into the femoral vein at a dose of 10 mg / kg of itraconazole for 15 seconds. After injection, 0.3 ml of whole blood was taken at 1, 5, 15, 30, 60, 120, 180, and 300 minutes from the femoral artery and centrifuged.

Place 100 μl of plasma into a glass tube with a lid and dissolve the ketoconazole in athenitrile as an internal standard. Then, 50 μl of 0.1 M-carbonate buffer solution prepared with 0.1 μg equivalent and pH 10 and a mixture of heptane / isoamyl alcohol (90/10). After 7 ml of the solution was stirred vigorously for 10 seconds and gently shaken for 10 minutes, the supernatant was centrifuged at 1200 rpm for 10 minutes to completely evaporate the solvent at 40 ° C., and 125 μl of HPLC mobile phase was added thereto. Analysis was carried out by HPLC according to the conditions of Table 3, and the results are shown in FIG.

As shown in Fig. 3, when the ninth example of the present invention was administered intravenously, the effective blood concentration was always exceeded. In addition, it can be seen that the composition of Example 9 of the present invention has a higher blood concentration than the composition of Comparative Example 2 in which itraconazole is solubilized using hydroxypropyl-beta-cyclodextrin.

Experimental Example  4: by oral administration Bioavailability  exam

The same mice as in Experiment 3 were used for experiments after 2 weeks of purchase, and the samples prepared according to Example 2 or Comparative Example 2 of the present invention were used.

The composition was administered orally to two groups of rats fasted 24 hours at a dose of itraconazole 10 mg / kg.

30 minutes, 60 minutes, 120 minutes, 180 minutes, and 300 minutes after administration, blood was collected into the tail vein and analyzed according to the method described in Experimental Example 3, and the results are shown in FIG. 4.

As shown in FIG. 4, when the composition of Example 2 of the present invention was administered orally, effective blood concentration was achieved after 30 minutes, and the composition of Example 2 was itraconazole using hydroxypropyl-beta-cyclodextrin. It can be seen that the bioavailability is higher than the composition of Comparative Example 2 solubilized.

As described above, the pharmaceutical composition comprising the itraconazole of the present invention as an active ingredient can improve the solubility of the poorly soluble itraconazole by forming polymer micelles or nanoparticles in an aqueous solution, and thus can be encapsulated in large quantities, and form fine particles in the aqueous solution. In addition to being present as well as stability, it can be used as an intravenous injection. In addition, it is possible to maintain the blood concentration of itraconazole for a long time by improving the stability as described above, thereby increasing not only the pharmacological effect of itraconazole but also significantly reducing the frequency of administration.

It is to be understood that the foregoing embodiments merely illustrate the application of the principles of the present invention. Numerous variations and alternative embodiments may be derived without departing from the spirit and scope of the invention, and the appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been shown in the drawings and is particularly fully described in detail in connection with what is presently considered to be the most practical and preferred embodiment (s) of the invention, to those skilled in the art, numerous modifications are possible. It will be apparent that the invention can be carried out as indicated in the claims without departing from the principles and concepts.

Claims (19)

delete Itraconazole 0.1-30.0 wt%, 5.0-99.8 weight percent of a polylactic acid derivative having at least one carboxylic acid end group, and A hydrophilic block selected from polyalkylene glycol, polyethylene glycol, polyethylene-co-propylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, monomethoxypolyalkylene glycol and monoacetoxypolyethylene glycol, and polylac Tide, polyglycolide, polydioxan-2-one, polycaprolactone, polylactic-co-glycolide, polylactic-co-caprolactone, polylactic-co-dioxan-2-one, polyD-lactic acid, poly 0.1 to 94.9% by weight of amphiphilic block copolymer consisting of hydrophobic blocks selected from L-lactic acid and polyDL-lactic acid It is a pharmaceutical composition comprising an itraconazole comprising an active ingredient, A composition for improving the solubility and stability of the itraconazole and forming polymer micelles or nanoparticles in an aqueous solution having a pH of 4-7. The method of claim 2, Pharmaceutical compositions to form micelles in aqueous solution. The method of claim 2, A pharmaceutical composition wherein the polylactic acid derivative has a number average molecular weight of 500 to 2,500 daltons. The method of claim 2, Polylactic acid derivatives include D, L-polylactic acid, D-polylactic acid, polymandelic acid, copolymers of D, L-lactic acid and glycolic acid, copolymers of D, L-lactic acid and mandelic acid, and D, L-lactic acid A copolymer of caprolactone, a copolymer of D, L-lactic acid and 1,4-dioxan-2-one, and an acyl-D, L-lactic acid substituted with acyl having 8 to 14 carbon atoms, , At least one carboxylic acid or an alkali metal salt ion of the carboxylic acid is covalently bonded to at least one terminal of the polylactic acid derivative. delete delete The method of claim 2, A pharmaceutical composition wherein the hydrophilic block and the hydrophobic block each have a number average molecular weight of 1,000 to 10,000 Daltons. The method of claim 2, A pharmaceutical composition wherein the composition ratio of the hydrophilic block and the hydrophobic block of the amphiphilic block copolymer is from 2 to 8: 8 to 2 (w / w). The method of claim 2, Pharmaceutical composition comprising 0.1-20.0 wt% of itraconazole, 20-80 wt% of polylactic acid derivative, and 5.0-79.9 wt% of amphiphilic block copolymer Itraconazole 0.1-30.0 wt%, 5.0-99.8% by weight of a polylactic acid derivative having at least one of the above carboxylic acid terminal groups in which a divalent or trivalent metal ion is bonded at the carboxy terminal, and A hydrophilic block selected from polyalkylene glycol, polyethylene glycol, polyethylene-co-propylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, monomethoxypolyalkylene glycol, and monoacetoxypolyethylene glycol, and polylac Tide, polyglycolide, polydioxan-2-one, polycaprolactone, polylactic-co-glycolide, polylactic-co-caprolactone, polylactic-co-dioxan-2-one, polyD-lactic acid, poly 0.1 to 94.9% by weight of amphiphilic block copolymer consisting of hydrophobic blocks selected from L-lactic acid and polyDL-lactic acid It is a pharmaceutical composition comprising an itraconazole comprising an active ingredient, A composition for improving the solubility and stability of the itraconazole and forming polymer micelles or nanoparticles in an aqueous solution having a pH of 4-7. The method of claim 11, Pharmaceutical compositions forming micelles or nanoparticles in aqueous solution. delete delete The method of claim 11, A pharmaceutical composition in which the hydrophilic block and the hydrophobic block each have a number average molecular weight of 1000 to 10,000 Daltons. The method of claim 11, A pharmaceutical composition wherein the composition ratio of the hydrophilic block and the hydrophobic block of the amphiphilic block copolymer is from 2 to 8: 8 to 2 (w / w). The method of claim 11, Divalent or trivalent metal ions Ca ^{2 +,} Mg ^{2 +,} Ba ^{2 +,} Mn ^{2 +,} Ni ^{2 +,} Cu ^{2 +,} Zn ^{2 +,} Cr ^3+, Fe ³⁺ and Al group consisting of ^{3 +} Pharmaceutical composition selected from. The method of claim 11, A pharmaceutical composition wherein the metal ion is used in the range of 0.5 to 4.0 equivalents relative to the carboxy end group equivalent of the polylactic acid derivative. The method of claim 11, Itraconazole 0.1-20.0 wt%, 20.0 to 70% by weight of a polylactic acid derivative having at least one of the carboxylic acid end groups to which 0.5 to 4.0 equivalents of divalent or trivalent metal ions are bonded, relative to the equivalent of carboxylic acid end groups; A hydrophilic block selected from polyalkylene glycol, polyethylene glycol, polyethylene-co-propylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, monomethoxypolyalkylene glycol and monoacetoxypolyethylene glycol, and polylac Tide, polyglycolide, polydioxan-2-one, polycaprolactone, polylactic-co-glycolide, polylactic-co-caprolactone, polylactic-co-dioxan-2-one, polyD-lactic acid, poly 10 to 79.9% by weight of an amphiphilic block copolymer consisting of a hydrophobic block selected from L-lactic acid and polyDL-lactic acid Pharmaceutical composition comprising a.

Images