MXPA06008477A - Method of preparing low-crystallinity oltipraz or amorphous oltipraz - Google Patents

Abstract

Provided is a method of preparing low-crystallinity oltipraz or amorphous oltipraz. The method includes:obtaining a mixed solution containing oltipraz and a water-soluble polymer or a water-insoluble polymer in a solvent, the solvent being an organic solvent or purified water;and solid-dispersing the oltipraz in the polymer. In the solid-dispersing, the mixed solution may be spray dried using a spray dryer or granulated using a fluid bed granulator.

Description

METHOD OF PREPARATION OF LOW CRYSTALLINE OLTIPRAZ OR OLTIPRAZ AMORFO FIELD OF THE INVENTION The present invention relates to a method for the preparation of oltipraz of low crystallinity or amorphous oltipraz, and more particularly, to a method of preparing oltipraz of low crystallinity or amorphous oltipraz to increase solubility and bioavailability of oltipraz, the which has a low solubility.

BACKGROUND OF THE INVENTION The liver is an organ with consistent enzymatic reactions and energy metabolism and plays a key role in the metabolism of xenobiotics and in the metabolism of endogenous substances. Among many chronic diseases that lead to death, liver disease such as hepatitis, cirrhosis, and liver cancer, and cardiovascular diseases are the most widespread. Accordingly, there is a need to develop therapeutic and prophylactic pharmaceutical compositions which can reduce the damage of liver tissue and are ultimately applied to treat the liver. Several substances, including various synthetic compounds and galenical preparations, show hepatoprotective functions Ref.: 174732 both in vitro and in vivo. Although it has been known that silymarin and betaine have protective effects of the liver as a result of the action mechanism of cytokine inhibition and an increase in the level of glutathione, a therapeutic effect could be difficult to expect due to its low effectiveness. Because unsuitable treatment agents against liver disease are currently available, the agents are used for clinical trials. Malotylate and its derivatives, the indication of which is the treatment of liver fibrosis, protect the liver from toxic chemicals and the possible mechanism of action includes the induction of phase II conjugation enzymes and the inhibition of cytochrome P450s. However, the compounds non-selectively inhibit cytochrome P450s and show only prophylactic effects. It is known that various derivatives of dithiolithione, which are naturally present in cruciferous vegetables and contain sulfur, have protective effects of the liver. Among them, oltipraz was used as a treatment agent for schistosomiasis in the early 1980s and was represented by the following formula (KR 2000-0010540): It has been reported that oltipraz has therapeutic and prophylactic effects on liver fibrosis and cirrhosis by inhibiting the generation of TGF-β (see, Korean Published Patent Publications Nos. 2001-91012 and 2003-67935). However, oltipraz is soluble in lipid and seldom soluble in water with a solubility in water of 1 [/ D or less and has high crystallinity. Accordingly, in order to increase an effective concentration of oltipraz in the blood to a level adequate to exhibit the effects, a relatively large amount of the drug must be administered orally. That is, its rate of dissolution in a digestive tract determines a rate of absorption in a body. Conventionally, oltipraz is formulated in a preparation, for example, tablets, powders, capsules, or suspensions. Specifically, the oltipraz is mixed with a predetermined amount of lactose, starch, or magnesium stalk, etc., and the mixture is granulated and compressed to form tablets. Alternatively, the resulting granules are filled into a capsule to form a hard capsule. A method for preparing a soft capsule is described in Korean Published Patent Publication No. 2003-67935. In this method, a suspension of sucrose, isomerized sugar, flavoring agent, etc., is mixed with polyethylene glycol 400, concentrated glycerin, purified water, etc., to prepare a soft capsule.

Although oltipraz preparations can be prepared in a simple manner using the above methods, the solubility and bioavailability of oltipraz can not be increased sufficiently.

DESCRIPTION OF THE INVENTION Technical Problem The present invention provides a method of preparing oltipraz that has a high solubility and bioavailability. According to one aspect of the present invention, there is provided a method for preparing low crystallinity oltipraz or amorphous oltipraz, comprising: obtaining a mixed solution containing oltipraz and a water soluble polymer or a water insoluble polymer in a solvent, the solvent is an organic solvent or purified water; and dispersing the oltipraz in the polymer in solid. According to another aspect of the present invention, there is provided a method for using the low crystallinity oltipraz or amorphous oltipraz in the preparation of a tablet or a capsule.

Technical Solution In one embodiment of the present invention, there is provided a method for preparing low crystallinity oltipraz or amorphous oltipraz, comprising: obtaining a mixed solution containing oltipraz and a water soluble polymer or a water insoluble polymer in a solvent, the solvent is an organic solvent or purified water; and dispersing the oltipraz in the polymer in solid. In the solid dispersion, the mixed solution can be spray dried using a spray or granulated drier using a fluidized bed granulator. The mixed solution may further comprise an absorption enhancer. The absorption enhancer may include at least one compound selected from the group consisting of ascorbic acid, citric acid, xylitol, and polyethylene glycol or its derivative. The organic solvent used in the preparation of the mixed solution can be methylene chloride, acetone, chloroform, acetonitrile, methanol, or ethanol, and preferably methylene chloride. The water-soluble polymer can include at least one polymer selected from the group consisting of polyvinylpyrrolidone or its derivative, a copolymer of polyvinylpyrrolidone-vinyl acetate, alginic acid, alginate or its derivative, -cyclodextrin or its derivative, β-cyclodextrin or its derivative, β-cyclodextrin or its derivative, polyoxyethylene-polyoxypropylene copolymer, polyethylene glycol or its derivative, polyvinyl alcohol, xanthan gum, gum arabic, or a combination thereof. The polyvinyl pyrrolidone can have a molecular weight of 2,500-3,000,000. The polyvinylpyrrolidone-vinyl acetate copolymer can have a molecular weight of 30,000-50,000. The alginate derivative can be an ethylene or propylene derivative of sodium alginate and has a molecular weight of 20,000-200,000. The β-cyclodextrin derivative can be a propylene derivative of β-cyclodextrin or a methylated derivative of β-cyclodextrin. The polyoxyethylene-polyoxypropylene copolymer may have an oxyethylene content of 45-75%. The polyethylene glycol or its derivative can have a molecular weight of 200-90,000. The polyethylene glycol derivative may be an esterified polyethylene glycol derivative. The water-insoluble polymer can include at least one selected from the group consisting of cellulose or its derivative, polymethacrylate, and polyalkyl acrylate. The cellulose derivative may be cellulose acetate, cellulose acetate phthalate, hydroxypropylene methylcellulose, hydroxypropylene methylcellulose phthalate, ethylcellulose, methylcellulose, or hydroxypropylene cellulose. The cellulose derivative can be hydroxypropylene methylcellulose having a viscosity of 5-50 cps. In the mixed solution, the concentration of the water-soluble polymer or water-insoluble polymer can be 5-90 parts by weight based on 100 parts by weight of oltipraz. If the concentration of the soluble polymer "in water or water insoluble polymer is less than 5 parts by weight, the amorphous or low crystallinity oltipraz can not be obtained.If the concentration of the water-soluble polymer or water-insoluble polymer is greater than 90 parts by weight, a dissolution speed and bioavailability of oltipraz is decreased, when the mixed solution also comprises the absorption enhancer, the concentration of the water-soluble polymer or water-insoluble polymer in the mixed solution can be 5-90 parts by weight and the concentration of the absorption enhancer in the mixed solution can be 5-90 parts by weight, respectively, based on in 100 parts by weight oltipraz. Preferably, the concentration of the water-soluble polymer or water-insoluble polymer is 45 parts by weight and the concentration of the absorption enhancer is 10 parts by weight, respectively, based on 100 parts by weight of oltipraz. If the concentration of the absorption improver is greater than 90 parts by weight, it may take a long time to spray dry the mixed solution due to an increase in a total amount of solvent. The vitreous transition temperature is measured in the above concentration ranges, when it is shown that the components are intimately mixed in the above concentration ranges. The low crystallinity oltipraz or amorphous oltipraz prepared using the above method can be used alone or formulated in a tablet or capsule. A method of dispersion in oltipraz solid in a polymer according to an embodiment of the present invention will now be described in more detail. According to a method for preparing low crystallinity oltipraz or amorphous oltipraz in one embodiment of the present invention, the bioavailability of oltipraz, an agent for the treatment of cirrhosis, can be increased. In this method, oltipraz, which is a crystalline or rarely soluble pharmaceutical preparation, a water soluble polymer or a water insoluble polymer, and optionally, an absorption enhancer, are dissolved in an organic solvent or purified water, and then, the oltipraz is dispersed in solid in the polymer. The solid dispersion method of oltipraz includes a method in which the mixed solution is spray dried using a spray dryer and a method in which the mixed solution is granulated using a fluidized bed grader. The solid dispersion method of oltipraz will now be described in more detail. The first process: oltipraz seldom soluble dissolves in an organic solvent or purified water. The organic solvent can be a volatile solvent, such as methylene chloride, acetone, chloroform, acetonitrile, methanol, or ethanol. The organic solvent is preferably methylene chloride, since oltipraz has a solubility of 7.6 mg / m in methylene chloride and methylene chloride is less explosive than acetone, although oltipraz can be very easily dissolved in a liquid polymer of oil phase, such as polyethylene glycol or polypropylene glycol, and an oily solvent, such as N, N-dimethylformamide and N-methylpyrrolidone, these solvents have a very low volatility, and consequently, spray drying can not be easily performed. That is, it is advantageous that the organic solvent can easily dissolve the oltipraz and be highly volatile. The solubilities of oltipraz in various organic solvents and oil phase liquid polymers are listed in Table 1.

Table 1 - The second process: a water-soluble polymer or a water-insoluble polymer, alone or in conjunction with an absorption enhancer, is dissolved in an organic solvent or purified water. The water soluble polymer can include at least one compound selected from the group consisting of polyvinylpyrrolidone or its derivative, polyvinylpyrrolidone-vinyl acetate copolymer, alginic acid, alginate or its derivative, an a-cyclodextrin or its derivative, β-cyclodextrin or its derivative, β-cyclodextrin or its derivative, polyoxyethylene-polyoxypropylene copolymer, polyethylene glycol or its derivative, polyvinyl alcohol, xanthan gum, and gum arabic. Preferably, the water soluble polymer is polyvinylpyrrolidone having a molecular weight of 40,000-50,000 and a polyvinylpyrrolidone-vinyl acetate copolymer having a molecular weight of 30,000-50,000. The water-insoluble polymer may include, but is not limited to, at least one compound selected from the group consisting of "cellulose or its derivative, polymethacrylate, and polyalkyl acrylate.The cellulose derivative may include, - but not be limited a, cellulose acetate, cellulose acetate phthalate, hydroxypropylene methylcellulose, hydroxypropylene methylcellulose phthalate, ethylcellulose, methylcellulose, or hydroxypropylene cellulose The cellulose derivative may be hydroxypropylene methylcellulose having a viscosity of 5-50 cps. of cellulose is greater than 50 cps, spray drying can not be carried out easily, and consequently, the desired spray-dried product can not be obtained.The polymethacrylate and polyalkyl acrylate can be used, as a combination of at least two components, for example, a combination of polymethacrylate and polymethyl methacrylate in a ratio of 1: 1, or a combination of and polyethylene acrylate, polymethyl methacrylate, and polytrimethylammonioethyl methacrylate chloride in a ratio of 1: 2: 0.1 or 1: 2: 0.2. The solvent which can dissolve the water soluble polymer or water insoluble polymer can include at least one solvent selected from the group consisting of ethanol, methanol, methylene chloride, acetonitrile, acetone, isopropyl alcohol, and chloroform. As the purified water, purified, non-ionized water is used. When the water-soluble polymer or water-insoluble polymer is dissolved in the organic solvent, the absorption enhancer can also be added to the organic solvent. The absorption enhancer has a high tendency to form a complex with the main drug substance via a hydrogen bond, and therefore allows the formation of an amorphous state of the pharmaceutical substance and increases the absorption of the pharmaceutical substance in the digestive organ. The absorption enhancer may be an organic acid. The organic acid may include at least one compound selected from the group consisting of ascorbic acid, citric acid, xylitol, and polyethylene glycol. Preferably, the organic acid is citric acid. The oltipraz solution and the polymer solution are produced separately in the first process and the second process, respectively. Alternatively, the oltipraz and the water soluble polymer or water insoluble polymer, or the oltipraz, the water soluble polymer or water insoluble polymer, and the absorption enhancer can be dissolved simultaneously in a solvent to obtain a mixed solution. - The third process: the oltipraz solution is mixed with the aqueous solution of the polymer to obtain a mixed solution. When the oltipraz solution is mixed with the aqueous solution of the polymer, its mixing ratio can be such that the concentration of the polymer in the mixed solution is 10-90 parts by weight based on 100 parts by weight of oltipraz. Preferably, the mixing ratio of the oltipraz solution and the aqueous solution of the polymer is 3: 7. When the absorption enhancer is added in addition, its mixing ratio may be such that the concentration of the polymer in the mixed solution is 5-90 parts by weight and the concentration of the absorption improver is 5-90 parts by weight, respectively, based on 100 parts by weight of oltipraz . Preferably, the mixing ratio of oltipraz, the polymer, and the absorption enhancer is 100: 45: 10. - The fourth process: a spray-dried product or granules are obtained using the mixed solution containing the oltipraz and the polymer. The mixed solution is stirred in a mechanical mixer for 30-60 minutes, and then, spray dried using a spray dryer to obtain a spray-dried product having fine particles. First, the well-stirred mixed solution can be spray dried using the spray dryer at an inlet temperature of 60-100 ° C and an outlet temperature of 40-80 ° C. An input speed of the mixed solution is 300-1500 D / hr and can be selected considering a drying state of the spray dried product and the exit temperature. Preferably, the inlet temperature is 80-85 ° C, the outlet temperature is 60-65 ° C, and the inlet velocity of the mixed solution is 720 G / hr. Alternatively, the mixed solution can be granulated using a fluidized bed granulator. The predetermined amounts of microcrystalline cellulose and hard anhydrous silicic acid were completely mixed in the fluidized bed granulator while preheated to an inlet temperature of 60-100 ° C and an outlet temperature of 40-80 ° C, and then, the well-stirred mixed solution containing the oltipraz and the polymer was allowed to flow in the fluidized bed granulator at an inlet speed of 300-1500 D / hr. While in drying, the oltipraz and the polymer are adsorbed on the microcrystalline cellulose and the hard anhydrous silicic acid to obtain the granules. Preferably, the inlet temperature is 80-85 ° C, the outlet temperature is 60-65 ° C, and the inlet speed of the mixed solution is 720 0 / hr. The polysorbate or its derivative, or sodium lauryl sulfate can also be added to the mixed solution to increase the solubility of oltipraz. The amount of polysorbate or its derivative, or sodium lauryl sulfate can not be more than 2.5% by weight in the granules. A mixing ratio of a mixture of the oltipraz and the polymer to the microcrystalline cellulose can be 1: 1- 1: 3. A mixing ratio of the oltipraz mixture and the polymer to the hard anhydrous silicic acid can be 1: 0.1-1: 1. Preferably, a mixing ratio of the mixture, the microcrystalline cellulose, and the hard anhydrous silicic acid is 1: 2: 0.5. The spray-dried product or granules produced using the above method can be used alone or formulated in a tablet or capsule.

Advantageous Effects As described above, according to the present invention, oltipraz of low crystallinity or amorphous oltipraz can be prepared, thereby increasing the solubility and bioavailability of oltipraz, which has a low solubility.

BRIEF DESCRIPTION OF THE FIGURES The foregoing and other features and advantages of the present invention will be more apparent by describing in detail exemplary embodiments thereof with reference to the. annexed figures in which: Figure 1 is a plot of time versus dissolution concentration for tablets prepared in Comparative Example 1, Example 10, and Example 11; Figure 2 is a time plot against concentrations of oltipraz in blood plasma for rats to which a spray-dried product prepared in Example 1, a spray-dried product prepared in Example 2, and a micronized powder prepared in the Comparative Example 1 were respectively administered orally; Figure 3A is a photo of the scanning electron microscope (SEM) of oltipraz powders as a raw material; Figure 3B is a SEM photo of powdered oltipraz using an air jet impact mill; Figure 3C is a SEM photo of polyvinylpyrrolidone (molecular weight: 40,000); Figure 3D is a SEM photo of a polyvinylpyrrolidone-vinyl acetate copolymer; Figure 3E is a SEM photo of a spray dried product prepared in Example 1; Figure 3F is a SEM photo of a spray dried product prepared in Example 2; Figure 3G is a SEM photo of a spray dried product prepared in Example 5; Figure 3H is a SEM photo of a spray dried product prepared in Example 3; Figure 31 is a SEM photo of granules prepared in Example 6; Figure 3J is a SEM photo of granules prepared in Example 9; Figure 3K is a SEM photo of a mixture of oltipraz and polyvinylpyrrolidone-vinyl acetate copolymer in a ratio of 3: 7; Figure 4A is a graph illustrating the crystallinity of each oltipraz as a raw material, polyvinylpyrrolidone (molecular weight: 40,000), and microcrystalline cellulose, measured using an X-ray diffraction; and Figure 4B is a graph illustrating the crystallinity of each spray-dried product prepared in Example 1, the spray-dried product prepared in Example 5, the granules prepared in Example 6, and the granules prepared in Example 7 , measured using an X-ray diffractor.

DETAILED DESCRIPTION OF THE INVENTION In the following, the present invention will describe in more detail with reference to the following examples. However, these examples are given for the purpose of illustration and are not intended to limit the scope of the invention.

Example 1: Preparation of a spray-dried product (1) Thirty grams of oltipraz were dissolved in 1.8 1 of methylene chloride and 70 g of polyvinylpyrrolidone (molecular weight: 40,000) were dissolved in 200 ml of ethanol, and then the two solutions were mixed to obtain a mixed solution. Then, the mixed solution was sprayed using a spray dryer (Buch B250, Switzerland) at an inlet temperature of 80 ° C, an outlet temperature of 60 ° C, and an inlet speed of 720 D / hr to obtain approximately 30 g of the product dried by spraying, which has a weight ratio of oltipraz and polyvinylpyrrolidone of 3: 7.

Example 2: Preparation of a spray-dried product (2) A spray-dried product having a weight ratio of oltipraz and polyvinylpyrrolidone of 3: 7 was prepared in the same manner as in Example 1, except that a copolymer of Polyvinylpyrrolidone-vinyl acetate was used instead of polyvinylpyrrolidone.

Example 3: Preparation of the spray-dried product (3) Thirty grams of oltipraz were dissolved in 1.8 1 of methylene chloride and 70 g of hydroxypropylmethylcellulose were dissolved in 200 ml of acetone, and then, the two solutions were mixed for 30 minutes to obtain a mixed solution. Then, the mixed solution was sprayed using a spray dryer at an inlet temperature of 80 ° C, an outlet temperature of 60 ° C, and an inlet speed of 720 D / hr to obtain the spray-dried product, the which has a weight ratio of oltipraz and hydroxypropylmethylcellulose of 3: 7.

Example 4: Preparation of the spray-dried product (4) Thirty grams of oltipraz were dissolved in 1.8 1 of methylene chloride and 30 g of hydroxypropyl-β-cyclodextrin were dissolved in 500 ml of ethanol, and then, the two solutions were mixed for 30 minutes to obtain a mixed solution. Then, the mixed solution was sprayed using a spray dryer at an inlet temperature of 80 ° C, an outlet temperature of 60 ° C, and an inlet speed of 720 D / hr to obtain the spray-dried product, the which has a weight ratio of oltipraz and hydroxypropyl-β-cyclodextrin of 1: 1.

Example 5: Preparation of spray-dried product (5) Ten grams of oltipraz were dissolved in 1.8 1 of methylene chloride and, in a separate vessel, 30 g of polyvinylpyrrolidone (molecular weight: 40,000) and 60 g of α-cyclodextrin were added. They were dissolved in 1 liter of 50% ethanol, and then, the two solutions were mixed for 30 minutes in another vessel to obtain a mixed solution, then the mixed solution was sprayed using a spray drier at an inlet temperature of 50.degree. 80 ° C, an outlet temperature of 60 ° C, and an inlet speed of 720 G / hr to obtain the spray-dried product, which has a weight ratio of oltipraz, polyvinylpyrrolidone (molecular weight: 40,000), and ? -cyclodextrin of 1: 3: 6.

Example 6: preparation of granules (1) Thirty grams of oltipraz were dissolved in 1.8 1 of methylene chloride and 70 g of polyvinylpyrrolidone (molecular weight: 40,000) were dissolved in 200 ml of ethanol, and then, the two solutions were mixed to obtain get a mixed solution. Two hundred grams of microcrystalline cellulose (Avicel PHlOl) and 50 g of hard anhydrous silicic acid were completely mixed in a fluidized bed granulator (FREUND Spir-A-Flow, Japan) while being preheated to an inlet temperature of 60 ° C and an outlet temperature of 40 ° C. Next, the mixed solution was pulverized to absorb the oltipraz dissolved in the polyvinylpyrrolidone, in the microcrystalline cellulose (Avicel PHlOl) and the hard anhydrous silicic acid. Accordingly, dry granules were obtained from which the solvent was completely removed.

Example 7: preparation of granules (2) Thirty grams of oltipraz were dissolved in 1.8 1 of methylene chloride and 70 g of a copolymer of polyvinylpyrrolidone-vinyl acetate were dissolved in 200 ml of ethanol, and then, the two solutions were mixed to obtain a mixed solution. Two hundred grams of microcrystalline cellulose (Ávicel PHlOl) and 50 g of hard anhydrous silicic acid were completely mixed in a fluidized bed granulator while preheated to an inlet temperature of 60-100 ° C and an outlet temperature of 40-80 ° C. Next, the mixed solution was pulverized to adsorb the oltipraz dissolved in the polyvinylpyrrolidone-vinyl acetate copolymer, in the microcrystalline cellulose (Avicel PHlOl) and the hard anhydrous silicic acid. Accordingly, dry granules were obtained from which the solvent was completely removed.

Example 8: Preparation of a spray-dried product (6) Forty-five grams of oltipraz were dissolved in 2.7 1 of methylene chloride and 45 g of polyvinylpyrrolidone (molecular weight: 40,000) and 60 g of citric acid were added to 300 ml of ethanol and dissolved while ground using a high speed emulsifier. Then, the two solutions were mixed for 30 minutes to obtain a mixed solution. Then, the mixed solution was sprayed using a spray dryer at an inlet temperature of 80 ° C, an outlet temperature of 60 ° C, and an inlet speed of 720 D / hr to obtain the spray-dried product, the which has a weight ratio of oltipraz, polyvinylpyrrolidone and citric acid of 45:45:60.

Example 9: Preparation of a spray-dried product (7) Forty-five grams of oltipraz were dissolved in 2.7 1 of methylene chloride and 45 g of polyvinylpyrrolidone-vinyl acetate copolymer and 10 g of citric acid were added to 300 ml of ethanol and dissolved while ground using a high speed emulsifier. Then, the two solutions were mixed for 30 minutes to obtain a mixed solution. Then, the mixed solution was sprayed using a spray dryer at an inlet temperature of 80 ° C, an outlet temperature of 60 ° C, and an inlet velocity of 60 ° C. 720 D / hr to obtain the spray-dried product, which has a weight ratio of oltipraz, polyvinylpyrrolidone-vinyl acetate copolymer and citric acid of 45:45:10.

Example 10: Tablet preparation (1) Forty-eight point five parts by weight of microcrystalline cellulose for direct compression, 6.0 parts by weight of sodium gluconate, and 1.61 parts by weight of magnesium stearate were mixed with 100 parts by weight of the spray dried product containing oltipraz, prepared in Example 1. The resulting mixture was compressed to form tablets having a hardness of 10 Kp.

Example 11: Tablet preparation (2) Forty-eight point five parts by weight of microcrystalline cellulose for direct compression, 6.0 parts by weight of sodium gluconate, and 1.61 parts by weight of magnesium stearate were mixed with 100 parts by weight of the spray dried product containing oltipraz, prepared in Example 2. The resulting mixture was compressed to form tablets having a hardness of 10 Kp.

Example 12: Preparation of capsules (1) Thirty grams of microcrystalline cellulose and 3 g of magnesium stearate were mixed with 100 g of the spray-dried product containing oltipraz, prepared in Example 1. The resulting mixture was filled into capsules to obtain oltipraz capsules.

Example 13: Preparation of capsules (2) Five grams of magnesium stearate were mixed with 350 g of the oltipraz granules prepared in Example 6. The resulting mixture was filled into capsules to obtain oltipraz capsules. Comparative Example 1 Thirty grams of oltipraz was sprayed to particles with an average particle size of 5 D using an air jet impact mill (SANKI Jet-miller, Japan) and suspended in physiological saline.

Experimental Example 1: Evaluation of solubility and bioavailability To evaluate the solubility of each of the tablets prepared in Examples 10 and 11, a dissolution test was carried out. Also, to evaluate the bioavailability of each of the spray dryer products prepared in Examples 1 and 2, an animal test was performed.

A. Dissolution test The dissolution test was performed according to the Dissolution test (second method) among the General tests described in The Korean Pharmacopoeia. 900 ml of 3% sodium lauryl sulfate was used as a solution solution for a tablet prepared using the oltipraz prepared in Comparative Example 1, the tablet prepared in Example 10, and the tablet prepared in Example 11 and the solution was performed at 100 revolutions / minute for 120 minutes. The solution solution was taken at 0, 15, 30, 60, 90, 120 minutes after the start of the dissolution test and filtered, and then, each of the resulting filtrates was analyzed using high performance liquid chromatography (HPLC). ). Figure 1 is a plot of time versus dissolution concentrations for the tablets prepared in Comparative Example 1, Example 10, and Example 11. It was confirmed from Figure 1 that the tablets prepared in Examples 10 and 11 have a speed of dissolution and a quantity of solution markedly higher than the tablet prepared using the oltipraz prepared in Comparative Example 1.

B. Animal Testing Each spray-dried product prepared in Example 1, the spray-dried product prepared in Example 2, and the product prepared in Comparative Example 1 was orally administered to food-deprived rats weighing 180-230 g. a dose of 50 equ.mg/5 ml / kg. Then, a concentration of oltipraz in blood plasma was measured for 30 hours. The results are shown in Table 2 and Figure 2. Table 2 The spray-dried products prepared in Examples 1 and 2 have Cma? superior and Tmá? shorter than the micronized powder prepared in Comparative Example 1. In addition, they have AUC at least 1.5 times higher than the micronized powder prepared in Comparative Example 1. It was confirmed from the above results that oltipraz tablets prepared using a method of preparation according to the embodiments of the present invention have a remarkably superior bioavailability than the oltipraz prepared in Comparative Example 1.

Experimental Example 2: Scanning Electron Microscope (SEM) Photographs SEM photos were taken for oltipraz powders used as a raw material in the previous Examples (Figure 3A), the pulverized oltipraz using an air jet impact mill (a recovery speed of 2.5 kg / hr and nozzle pressure of 0.70 mPa) Figure 3B), polyvinylpyrrolidone (molecular weight 40,000) (Figure 3C), a copolymer of polyvinylpyrrolidone-vinyl acetate (Figure 3D), the product spray-dried prepared in Example 1 (Figure 3E), the spray-dried product prepared in Example 2 (Figure 3F), the spray-dried product prepared in Example 5 (Figure 3G), the spray-dried product prepared in Example 3 (Figure 3H), the granules prepared in Example 6 (Figure 31), the spray dried product prepared in Example 9 (Figure 3J), and a mixture of oltipraz and polyvinylpyrrole copolymer idona-vinyl acetate in a ratio of 3: 7 (Figure 3K). Forming a spray-dried product using oltipraz, which has a needle-like crystal structure, and polyvinylpyrrolidone or polyvinylpyrrolidone-vinyl acetate copolymer, which has a circular shape and is amorphous, the oltipraz similar to a needle does not it was observed, which shows that the oltipraz is an amorphous form. The spray-dried product has a clear difference in the oltipraz structure of the simple mixture of oltipraz and polyvinylpyrrolidone-vinyl acetate copolymer in a ratio of 3: 7 illustrated in Figure 3K.

Experimental Example 3_j measurement of crystallinity using an X-ray diffractor To confirm a reduction in crystallinity, the oltipraz used as a raw material in the previous Examples, polyvinylpyrrolidone (molecular weight: 40,000), and microcrystalline cellulose (Figure 4A) and the spray-dried product prepared in Example 1, the spray-dried product prepared in Example 5, the granules prepared in Example 6, and the granules prepared in Example 7 (Figure 4B) were measured for its crystallinity using an X-ray diffractor (Rigaku D / MAX-IIIB). The results are shown in Figures 4A and 4B. The crystallinity of each of the components of the composition used in Examples 1-13 can be confirmed from Figure 4A. The oltipraz exhibits sharp peaks, which demonstrate that the oltipraz has high crystallinity. Polyvinylpyrrolidone, which was used in the spray-dried product of Example 1, exhibits broad peaks, which demonstrate that it is amorphous. Referring to Figure 4B, the spray-dried product prepared using polyvinylpyrrolidone (molecular weight: 40,000) in Example 1 is poorly crystallized and the spray dried product prepared in Example 5 is crystallized due to α-cyclodextrin. The granules prepared in Examples 6 and 7 are slightly crystallized due to the effect of microcrystalline cellulose. Although the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those of ordinary skill in the art that various changes in form and detail can be made therein without departing from the spirit and scope of the present invention. invention as defined by the following claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (18)

CLAIMS Having described the invention as above, the contents of the following claims are claimed as property:

1. Method for preparing low crystallinity oltipraz or amorphous oltipraz, characterized in that it comprises: obtaining a mixed solution containing oltipraz and a water soluble polymer or a water insoluble polymer in a solvent, the solvent is an organic solvent or purified water; and dispersing in oltipraz solids in the polymer.

2. Method according to claim 1, characterized in that in the solid dispersion, the mixed solution is spray dried using a spray dryer or granulated using a fluidized bed granulator.

Method according to claim 1, characterized in that the mixed solution further comprises an absorption enhancer.

Method according to claim 3, characterized in that the absorption enhancer includes at least one compound selected from the group consisting of ascorbic acid, citric acid, xylitol, and polyethylene glycol or its derivative.

Method according to claim 1, characterized in that the water-soluble polymer includes at least one polymer selected from the group consisting of polyvinylpyrrolidone or its derivative, a copolymer of polyvinylpyrrolidone-vinyl acetate, alginic acid, alginate or its derivative, α-cyclodextrin or its derivative, β-cyclodextrin or its derivative, β-cyclodextrin or its derivative, polyoxyethylene-polyoxypropylene copolymer, polyethylene glycol or its derivative, polyvinyl alcohol, xanthan gum, gum arabic, or a combination thereof ".

Method according to claim 5, characterized in that the polyvinylpyrrolidone has a molecular weight of 2,500-3,000,000 7.

Method according to claim 5, characterized in that the polyvinylpyrrolidone-vinyl acetate copolymer has a molecular weight of 30,000- 50,000 8.

Method according to claim 5, characterized in that the alginate derivative is a derivative of ethylene or propylene of sodium alginate and has a molecular weight of 20,000-200,000.

Method according to claim 5, characterized in that the β-cyclodextrin derivative is a propylene derivative of β-cyclodextrin or a methylated derivative of β-cyclodextrin.

10. Method according to claim 5, characterized in that the polyoxyethylene-polyoxypropylene copolymer has an oxyethylene content of 45-75%.

Method according to claim 5, characterized in that the polyethylene glycol or its derivative has a molecular weight of 200-90,000.

Method according to claim 11, characterized in that the polyethylene glycol derivative is an esterified polyethylene glycol derivative.

13. Method according to claim 1, characterized in that the water-insoluble polymer includes at least one selected from the group consisting of cellulose or its derivative, polymethacrylate, and polyalkyl acrylate.

14. Method according to claim 13, characterized in that the cellulose derivative is cellulose acetate, cellulose acetate phthalate, hydroxypropylene methylcellulose, hydroxypropylene methylcellulose phthalate, ethylcellulose, methylcellulose, or hydroxypropylene cellulose.

15. Method according to claim 13, characterized in that the cellulose derivative is hydroxypropylene methylcellulose having a viscosity of 5-50 cps.

Method according to claim 1, characterized in that the concentration of the water-soluble polymer or water-insoluble polymer in the mixed solution is 10-90 parts by weight based on 100 parts by weight of oltipraz.

Method according to claim 3, characterized in that the concentration of the water-soluble polymer or water-insoluble polymer in the mixed solution is 5-90 parts by weight and the concentration of the absorption enhancer in the mixed solution is 5-90. parts by weight, respectively, based on 100 parts by weight of oltipraz.

18. Method for using the low crystallinity oltipraz or amorphous oltipraz according to claim 1, characterized in that it is used in the preparation of a tablet or a capsule.