KR19990001565A - Eutectic Mixture of Antifungal Agents and Organic Acids and Pharmaceutical Formulations Containing the Same - Google Patents

Abstract

The present invention provides a eutectic mixture prepared by eutecting azole antifungal agent and organic acid to increase solubility and dissolution rate, and pharmaceutical preparation containing the same as an active ingredient.

Description

Eutectic Mixture of Antifungal Agents and Organic Acids and Pharmaceutical Formulations Containing the Same

1 is a graph showing the dissolution test results of the melt and azole of the present invention.

The present invention relates to a pharmaceutical composition of itraconazole, which is one of the antifungal agents having low solubility in aqueous solution, and to a method for producing a formulation suitable for oral administration by increasing solubility and dissolution rate.

Since azole antifungal agents, such as itraconazole, are difficult to dissolve in water, they are difficult to develop into pharmaceutically effective formulations. Therefore, it is possible to form a complex using cyclodextrin and its derivatives (WO 85/02767, US4,764,604), and to develop a bead formulation using a water-soluble polymer and a drug (WO 94/05263). Several attempts have been made to increase utilization.

Itraconazole has a molecular formula of C ₃₅ H ₃₀ C ₁₂ N ₈ O ₄ and has a molecular weight of 705.64. Pale yellow powder, difficult to dissolve in water (1 μg / ml or less), slightly soluble in alcohol (300 μg / ml), and soluble in methylene chloride (239 mg / ml). A weakly basic (pKa = 3.7) drug that is almost ionized at low pH, such as gastric juice, and is fat-soluble. It is also known pharmacologically (US4, 267, 179) which exhibits antifungal activity in a wide range of areas when applied orally, by injection or topically.

Solid drugs must be dissolved before they can be absorbed by epithelial cells. However, in the case of poorly water-soluble drugs, dissolution from the solid preparation is slow and dissolution is acted as a rate step during the absorption process. In this case, the rate of dissolution directly affects the expression time, intensity and duration of the drug. The reason is that the blood concentration is a function of absorption rate and disappearance rate, so when the dissolution rate is small, the absorption rate is also small, so that even if the total absorption is the same, the time to reach the effective blood concentration is long, and the maximum blood concentration is low and the effective blood concentration is The holding time changes. Therefore, it is necessary to attempt to increase the dissolution rate for such poorly soluble drugs. In this attempt, in the pharmaceutical domain, the solubility of the drug is generally varied by particle size, polymorphs, amorphous forms, solid solutions and eutectic mixtures, inclusion compounds, solvates and other concomitant drugs, and additives.

The present inventors completed the present invention by discovering surprising facts that azoles such as itraconazole form eutectic mixtures with organic acids, and the eutectic mixtures have not only high solubility but also increased dissolution rate.

Therefore, the wood base of the present invention is to provide a co-mixture of itraconazole and organic acids with increased solubility and increased dissolution rate.

Another object of the present invention is to provide a pharmaceutical formulation containing an eutectic mixture of itraconazole and organic acids having increased solubility and dissolution rate as an active ingredient.

Organic acids that can be used in the present invention are organic acids such as citric acid, tartaric acid, ascorbic acid, lactic acid, malic acid, and succinic acid.

The eutectic ratio of the azole compound and organic acids is 1.0: 0.1 to 1.0: 3.0 (W / W), preferably 1.0: 0.5 to 1.0: 2.0 (W / W). Most preferably, it is eutectic at a ratio of about 1: 1.

Physical changes in eutectic mixtures of organic acids and drugs can be identified by differential thermal analysis (DSC).

The methods for preparing eutectic mixtures of organic acids and drugs include melting and dissolving.

First, the melting method is a method in which the two drugs are homogeneously mixed, heated and dissolved, and then stored in the refrigerator to obtain recrystallization to obtain a eutectic mixture.

In the method for preparing a eutectic mixture by dissolution, two drugs are dissolved in an organic solvent to evaporate the solvent to form a eutectic mixture. As an organic solvent system, an antifungal agent, itraconazole, and a mixed solvent capable of appropriately dissolving an organic acid are used. The mixed solvent must contain methylene chloride which dissolves itraconazole well and an alcohol which can dissolve the organic acid well to dissolve the organic acid. The methylene chloride / ethanol ratio of the mixed solvent was able to dissolve the drug in the range of about 70/30 (W / W), preferably a mixed solvent at a ratio of about 60/40 (W / W). The amount of solids in this mixed solvent, i.

This mixed solvent is used to make a eutectic mixture of antifungal and organic acids. The production method includes a method using a spray dryer, a method using a C / F granulator, a method using a reduced pressure distillation, a method of blowing the solvent by heating.

It is important to control the spray rate in both a spray dryer and a C / F granulator. If the spraying rate is too slow, the solvent evaporates too quickly and there is a lot of drug loss. If the spraying rate is too fast, problems arise in formulation, such as entanglement with each other before the solvent evaporates. Therefore, the spraying rate is initially slow sprayed and sprayed more and more quickly.

As with the spray rate, the pressure of the atomizing air has a significant effect on the particle size of the eutectic mixture. If the air pressure is too small, the size of the particles to be sprayed will increase, causing agglomeration between the particles. If the air pressure is increased, the air particles will have an excellent effect on atomization. Therefore, the air pressure is adjusted to the maximum.

In the present invention, a binder, a disintegrating agent, a thickening agent, a lubricant, a stabilizer, a surfactant, a preservative, an electrolyte, a complex and a complex, or other active substances may be added to the formulation.

Eutectic mixtures of organic acids and itraconazole prepared in the present invention can be applied to various formulations. Formulations for oral administration using eutectic mixtures of organic acids and itraconazole include tablets, capsules, granules, and granules. In the case of tablets, it may be formulated as a formulation containing 50 mg or 100 mg of itraconazole per tablet. In the case of a capsule, it can also be formulated as a formulation containing an amount equivalent to 50 mg or 100 mg as itraconazole per capsule.

The present invention is explained in more detail by the following examples.

Example 1 (melting method)

Itra Conazole 10g

10 g citric acid

Accurately weigh the prescribed medication, place it in a glass container, adjust the temperature of the thermostat to 160 ± 5 degrees, melt itraconazole and citric acid, and cool it in a refrigerator to obtain crystals.

Example 2. (Dissolution Method, C / F Granulator)

Itra Conazole 30g

30 g citric acid

Lactose 60g

Lactose in the prescribed medication is placed in the C / F scoop. In addition, itraconazole and citrate, weighed exactly, were dissolved in 1000 ml of methylene chloride: ethanol (60:40) mixed solvent, and a eutectic mixture was prepared using a C / F granulator. The C / F granulator can be prepared at eutectic mixtures when the inlet air temperature is 60 ± 5 degrees and the outlet air temperature is 50 ± 5, and the fan rotation speed is 200 rpm. The spraying rate is initially slow sprayed and then slowly increased to give sufficient drying time of the solvent during operation.

Example 3. (Solution method, vacuum distillation method)

Itra Conazole 10g

10 g citric acid

20 g lactose

It is precisely weighed itraconazole and citric acid in the drug of the prescription, dissolve in 400 ml of methylene chloride: ethanol (60: 40) mixed solvent, disperse lactose in a mixed solvent of two drugs and using a reduced pressure distillation to prepare a eutectic mixture of itraconazole and citric acid Manufacture. When the pressure distillation conditions are manufactured by making it into a vacuum degree of 65 mmHg and the temperature of 40 degreeC, a eutectic mixture can be obtained. The distillation is operated under reduced pressure for a sufficient time so that there is no residual solvent.

Example 4. Formulation of Tablets

Prescription (in 1 tablet)

Itraconazole and citric acid mixture (melting method) 200 mg

(100 mg as itraconazole)

Lactose 229mg

Calcium Carboxymethyl Cellulose 250mg

Magnesium Stearate 1mg

Hydroxypropylmethylcellulose 20mg

The eutectic mixture prepared by the melting method of itraconazole and citric acid in the above manufacturing prescription to uniform particle size using a No. 60 body, homogeneously mixed with lactose, potassium carboxymethyl cellulose, hydroxypropyl methyl cellulose and roller by dry granulation method After preparing granules using a compactor (Roller Compactor), the magnesium stearate is mixed with a lubricant as a lubricant and then compressed into tablets.

Example 5. Formulation of Tablets

Prescription (during one tablet)

Eutectic Mixture of Itraconazole and Citric Acid and Lactose Mixture 400mg

(100 mg as itraconazole)

Calcium Carboxymethyl Cellulose 279mg

Magnesium Stearate 1mg

Hydroxypropylmethylcellulose 20mg

In the preparation, the particle composition was made constant by using No. 60 mixture of itraconazole and citric acid (Example 3) which improved the solubility and dissolution rate of itraconazole as a poorly soluble drug, and calcium carboxymethyl cellulose and hydroxypropyl methyl cellulose. After mixing homogeneously with dry granulation method to prepare granules by using a roller compactor (Roller Compactor) and then mix the magnesium stearate with a lubricant to make a tablet.

Experimental Example 1. Solubility Measurement

The solubility of the itraconazole and itraconazole raw materials prepared in Example 1 without the addition of the eutectic mixture of citric acid and citric acid and citric acid was measured, respectively. Solubility was measured by adding an excess of itraconazole to pH 1.2 artificial gastric liquid, stirring at 37 ° C. for 2 hours, filtering the liquid through a 0.45 μm filter, and then analyzing the filtrate by high performance liquid chromatography.

The results are shown in Table 1.

TABLE 1 Solubility results (37 ° C., 2 hours, pH 1.2)

From the experimental results, it can be seen that the solubility of the itraconazole prepared by the melting method is 40 times higher than that of the itraconazole raw material, and the eutectic mixture of the itraconazole and citric acid prepared by the melting method is increased by 54 times. Therefore, it is possible to increase the solubility by forming a eutectic mixture with citric acid and itraconazole.

Experimental Example 2. Dissolution Test

Example 5 formulated as a tablet using a mixture of itraconazole and acid prepared in Example 3 (dissolution, distillation under reduced pressure) and the same method as in Example 3, but the preparation of itraconazole and raw materials prepared without addition of citric acid The dissolution test was carried out using a tablet prepared by adding an excipient as in Example 5 using the itraconazole raw material which was not pretreated.

The dissolution test was performed using the Korean Pharmacopoeia, General Test Method, and Method 2 (Fiddle Method). The eluate was pH 1.2 artificial gastric fluid and maintained at 37 degrees for 5 hours, 10, 30, and 60 hours. 5 ml of the sample was collected at 120 minutes, filtered through a 0.45 μm filter, and the filtrate was analyzed using liquid chromatography.

The results are shown in FIG.

The experimental results show that the dissolution rate and the solubility increase when the dissolution method (pressure distillation method) is used, compared to the itraconazole raw material, and the dissolution rate and dissolution rate are the highest in the eutectic mixture of itraconazole and citric acid.

As demonstrated in the above examples and experimental examples, the present invention forms a eutectic mixture of itraconazole and citric acid to increase the solubility of itraconazole as well as to increase the dissolution rate. Therefore, it can be used to provide a manufacturing method that can contribute to the development of a formulation suitable for oral administration.

Claims (6)

A eutectic mixture prepared by eutecting azole antifungal agents and organic acids to increase solubility and dissolution rate. A process for the preparation of eutectic mixtures prepared by eutecting azole antifungal agents and organic acids to increase solubility and dissolution rate. The eutectic mixture with an increased solubility and dissolution rate obtained by eutectic by using an organic acid selected from citraic acid, tartaric acid, lactic acid, ascorbic acid, malic acid and succinic acid as an antifungal agent of azoles according to claim 1. The eutectic mixture according to claim 1 or 2, wherein the ratio of the azole antibacterial agent and the organic acid is 1.0: 0.1 to 1.0: 3.0 (w / w). It contains a eutectic mixture with an increased solubility and dissolution rate prepared by eutecting azole antifungal agent and organic acid as an active ingredient, and it is a conventional pharmaceutically acceptable binder, disintegrant, lubricant, thickener, stabilizer, interface. A pharmaceutical formulation containing one or more excipients selected from active agents, preservatives, electrolytes, complexes and complexes, and formulated in conventional pharmaceutically acceptable formulations. The pharmaceutical preparation according to claim 4, wherein the pharmaceutical preparation is a tablet, capsule, granule or fine granule.