KR100455216B1 - Composition for oral administration of poorly soluble antifungal agent and process for the preparation thereof - Google Patents

Abstract

The present invention relates to a composition for oral administration of poorly soluble antifungal agents with increased bioavailability and a method for preparing the same. More specifically, the composition of the present invention comprising a poorly soluble antifungal agent, phosphoric acid, surfactant and oil is a high viscosity microemulsion preconcentrate, in which a poorly soluble antifungal agent is homogeneously dissolved in a mixture of an aqueous solution of phosphoric acid and a dissolution aid and then interfacial to the solution. It is prepared by adding the active agent and oil to obtain a microemulsion preconcentrate and then removing the dissolution aid.

Description

COMPOSITION FOR ORAL ADMINISTRATION OF POORLY SOLUBLE ANTIFUNGAL AGENT AND PROCESS FOR THE PREPARATION THEREOF}

The present invention relates to a composition for oral administration of poorly soluble antifungal agents with increased bioavailability and a method for preparing the same.

Itraconazole is poorly soluble in spite of its excellent antifungal activity, and thus has poor bioavailability when administered orally. In fact, itraconazole has a solubility in water of less than 1 μg / ml and a pKa value of 3.7, which ionizes and dissolves only at very low pH. In addition, the bioavailability (absorption or blood concentration) of orally administered itraconazole is known to be largely affected by the individual and greatly influenced by the ingested food.

Thus, attempts have been made to use clathrate compounds of itraconazole and cyclodextrin as an attempt to increase the solubility of itraconazole in water to increase bioavailability (WO 85/002767 and U.S. Patent No. 4,764,604). This method is not preferable because it hardly improves the solubility of itraconazole in water, and also requires a complicated step in the formation of inclusions in actual production processes.

Recently, it has been commercially developed by Janssen, a three-layered bead coated with itraconazole and a hydrophilic polymer on a core consisting of pharmaceutically inert or neutral sugar, dextrin, starch, etc., and then coated with a polymer such as polyethylene glycol. (International Publication No. 94/05263, product name; Sporanox capsule). However, this method uses a small core with a diameter of 600 to 700 ㎛, which causes difficulties in the production process such as agglomeration during coating process. There is a big disadvantage.

On the other hand, the bioavailability of itraconazole is increased and is hardly affected by food, which has been a problem of conventional commercial formulations, and a water-soluble polymer mixture such as itraconazole and hydroxypropyl methylcellulose is prepared according to a melt-extrusion method. Although solid dispersions have been developed in which melted itraconazole is dispersed in an unmelted water-soluble polymer by heating to 245 to 265 ° C. (International Publication No. 97/44014, product name; Sporanox tablet, Janssen), The melt-extrusion process has to be performed at a high temperature of 245 to 265 ° C., and the molten extraconazole must be dispersed very uniformly in the polymer. It is difficult to obtain a reproducible product because it can affect absorption. There is a point. Moreover, the specific effect on the increase in absorption rate has not been confirmed yet.

In addition, the Sporanox solution marketed by Janssen has the advantage of high absorption even when taken before meals, but it is required to take a large amount (10mg / ml) due to the low concentration of itraconazole in the preparation. There is a pharmaceutical disadvantage of producing an immediate precipitate and its indication is also limited to fungal infections of the esophagus.

Recently, International Publication No. 98/55148 discloses that high-viscosity compositions containing poorly soluble drugs, cyclodextrins, water-soluble acids, and water-soluble organic polymers exhibit high dissolution rates and are not affected by foods due to improved absorption even when taken at fasting. It is. However, this composition is difficult to take due to the high excipient dose, it is difficult to fill the composition into capsules, etc. due to the high viscosity, there is also a problem in formulating. In addition, the composition exhibits a low dissolution rate of less than 1% under alkaline conditions of pH 6.8 or higher, such as intestinal fluids, and thus has a low bioavailability.

The present inventors have found that the microemulsion preconcentrate composition comprising poorly soluble antifungal agent, phosphoric acid, cosurfactant, surfactant, and oil improves bioavailability by completely dissolving poorly soluble antifungal agent and filed with patent application No. 2000-83717. There is a bar. This composition had an improved emulsion stability than the conventional formulation under alkaline conditions of pH 6.8 or more, but there was a disadvantage that the dissolution rate was low enough.

Accordingly, the present inventors earnestly studied to develop a formulation having high dissolution rate even under alkaline conditions of pH 6.8 or higher and thus improving bioavailability.

Accordingly, it is an object of the present invention to provide a composition for oral administration of poorly soluble antifungal agents with increased bioavailability.

Another object of the present invention is to provide a method for preparing the composition.

Figure 1 shows the bioavailability of the itraconazole formulations according to one aspect of the present invention in comparison with commercially available control formulations (Sporanox ^R capsules, Sporanox ^R solutions).

In accordance with the above object, the present invention provides a microemulsion preconcentrate composition comprising a poorly soluble antifungal agent, phosphoric acid, surfactant and oil.

According to the above another object, in the present invention, (a) homogeneously dissolving a poorly water-soluble antifungal agent in a mixed solution of an aqueous solution of phosphoric acid and a dissolution aid, (b) adding a surfactant and oil to the solution, and then (c) dissolving aid It provides a method of preparing the composition, comprising the step of removing.

Hereinafter, the components used to prepare the composition of the present invention will be described in detail.

(1) Active Ingredient

In the present invention, all of the poorly soluble antifungal agents may be used as the active ingredient, for example, arylamine-based, imidazole-based, triazole-based antifungal agents and the like, and especially triazole-based antifungal agent itraconazole is preferable.

(2) solubilizer

Phosphoric acid is preferable as the solubilizer used for dissolving itraconazole in the present invention, and an aqueous 85% phosphoric acid solution is preferable, and in some cases, a more diluted aqueous solution of phosphoric acid may be used.

(3) dissolution aids

The dissolution aid used in the preparation of the composition in the present invention is not included in the final composition because it is removed during the manufacturing process, but it does not only assist the dissolution of the antifungal agent by phosphoric acid, but also reduces the amount of phosphoric acid, thereby reducing the amount of phosphoric acid solution in which the antifungal agent is dissolved. The viscosity is lowered to facilitate the preparation of the compositions of the present invention. As the dissolution aid, an organic solvent which is easy to volatilize at a temperature of less than about 100 ° C. may be used, and even if it remains in the final composition, it is preferable that it can be orally ingested because it is harmless to the human body. Representative examples thereof include alcohols such as ethanol, propanol, isopropyl alcohol, and ethanol is particularly preferable.

(4) surfactant

In the present invention, any of the pharmaceutically acceptable surfactants capable of forming a stable microemulsion by stably emulsifying oil components and hydrophilic components such as phosphoric acid and a dissolution aid in water can be used. Is as follows.

① Reaction products of natural or hydrogenated vegetable oils with ethylene glycol:

Polyoxyethylene glycolated natural or hydrogenated vegetable oils are, for example, polyoxyethylene glycolated natural or hydrogenated castor oils (trade names: Cremophor ^R (BASF), HCO ^R (Nikkol)).

② polyoxyethylene-sorbitan-fatty acid esters:

Examples are esters of mono, trilauryl, palmityl, stearyl, oleyl (trade names: Tween ^R , ICI).

③ polyoxyethylene stearic acid esters:

For example polyoxyethylene stearic acid ester (trade name Myrj).

④ polyoxyethylene-polyoxypropylene block copolymer (product name: Poloxamer, Pluronic or Lutrol)

⑤ sodium dioctylsulfosuccinate or sodium lauryl sulfate

⑥ Phospholipids

Propylene glycol mono-fatty acid esters or propylene glycol di-fatty acid esters:

Examples include propylene glycol dicaprylate, propylene glycol monocaprylate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol monolaurate and propylene glycol ricinorate, among which propylene glycol monolaurate. Rate is preferred.

⑧ Trans-esterification reaction products of natural vegetable oil triglycerides and polyalkylene polyols (trade name: Labrafil M)

⑨ mono-, di- or mono / di-glycerides:

Examples are caprylic / capric acid mono- and diglycerides (trade name Imwitor).

⑩ sorbitan fatty acid ester:

Examples are sorbitan monolauryl, sorbitan monopalmityl and sorbitan monostearyl (trade name: Span).

⑪ sterols and derivatives thereof:

For example cholesterol, phytosterol and cytosterol.

Among them, polyoxyethylene products of hydrogenated vegetable oils, polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene sorbitan fatty acid esters and the like are preferable.

(5) oil components

The oil component used in the present invention can be used as long as it is a pharmaceutically acceptable oil that is well mixed with the surfactant and can be stably emulsified in water to form a stable microemulsion, and representative examples thereof are as follows.

① Fatty acid triglycerides:

Preferably it is a coconut oil (fractionatedcoconut oil) marketed under the product name Miglyol as a medium chain fatty acid triglyceride.

② mono-, di- and mono / di-glycerides:

Preferred are mono- and diglycerides of oleic acid.

③ ester compounds of fatty acids and monovalent alkanols:

As ester compound of C8-C20 fatty acid and C3-C3 monovalent alkanol, there is an isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, etc., for example.

④ Natural vegetable oils or animal oils:

For example, corn oil, olive oil, soybean oil, fish oil.

⑤ Hydrocarbons:

Examples include squalene, squalane and the like.

⑥ Tocopherols:

For example, tocopherol or tocopherol acetate, tocopherol succinate, polyethylene glycol-1000-tocopherol succinate (TPGS), and the like.

Propylene glycol fatty acid ester

For example, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monolaurate and the like.

Among them, tocopherols, ester compounds of fatty acids and monovalent alkanols, or propylene glycol fatty acid esters are particularly preferable.

The composition of the present invention comprises (a) homogeneously dissolving the poorly soluble antifungal agent in a mixture of an aqueous solution of phosphoric acid and a dissolution aid, (b) adding a surfactant and oil to the solution, and then (c) removing the dissolution aid. Can be prepared. In step (c), the dissolution aid may be removed in a conventional manner, for example, by heating at normal pressure or under reduced pressure to volatilize the dissolution aid, preferably about 40 to 100 ° C., more preferably about 40 It heats to the temperature of about 80 degreeC. In the manufacturing process, the active ingredient, phosphoric acid, dissolution aid, surfactant and oil component may be used in a ratio of 1: 0.5 to 15: 0.5 to 20: 0.5 to 15: 0.5 to 15 based on the weight, preferably It is the ratio of 1: 1: 1: 10: 1-15: 1-1: 10: 1-10. In addition, the final composition obtained by removing the dissolution aid comprises the active ingredient, phosphoric acid, surfactant and oil components in a ratio of 1: 0.5 to 15: 0.5 to 15: 0.5 to 15 by weight, preferably 1 : 1 to 10: 1 to 10: 1 to 10.

The composition thus obtained is a microemulsion preconcentrate having a high viscosity and containing a poorly soluble antifungal agent in a completely dissolved state, which forms very stable microemulsion particles when administered orally. In particular, the composition has a significant increase in bioavailability by releasing antifungal agents with high dissolution rate while maintaining stable microemulsion particles even under alkaline conditions above pH 6.8, such as in intestinal fluids, and has the advantage of little difference in absorption rate by food. Therefore, the composition of the present invention can be formulated into soft capsules, hard capsules according to conventional methods.

In addition, the composition of the present invention may further include a pharmaceutically acceptable additive such as antioxidants in addition to the above components.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.

Example 1 Preparation of Hard Capsule

Component Content (mg / Formulation)

Itraconazole 50

85% aqueous phosphoric acid 200

(Ethanol) (300)

Polyoxyethylene-50-Hydrogenated Castor Oil (HCO-50) 80

Cremophor EL 80

Poloxamer 124NF 64

Twin 20 64

dl-α-tocopherol 96

Propylene Glycol Monocaprylate 32

An aqueous solution of phosphoric acid and ethanol were added to the pharmacologically active ingredient, itraconazole, and dissolved homogeneously. Then, the remaining components were added and dissolved in turn, and the mixture was warmed and concentrated at 55 ° C. for 4 hours to obtain a microemulsion preconcentrate. The preconcentrate was filled into hard capsules according to the method for preparing hard capsules in the Korean Pharmacopoeia General Formulation to prepare hard capsules.

Example 2: Preparation of Soft Capsule

Component Content (mg / Formulation)

Itraconazole 50

85% aqueous phosphoric acid 200

(Ethanol) (300)

Polyoxyethylene-50-Hydrogenated Castor Oil (HCO-50) 80

Cremophor EL 80

Poloxamer 124NF 64

Twin 20 64

dl-α-tocopherol 96

Propylene Glycol Monocaprylate 32

Using the above components in the same manner as in Example 1 to obtain a microemulsion pre-concentrate, a soft capsule was prepared according to the manufacturing method of the soft capsule term of the Korean Pharmaceutical Formulation.

Example 3: Preparation of Hard Capsule

Component Content (mg / Formulation)

Itraconazole 50

85% aqueous phosphoric acid 200

(Ethanol) (300)

Polyoxyethylene-50-hydrogenated castor oil (HCO-50) 160

Poloxamer 124NF 64

Twin 20 64

dl-α-tocopherol 96

Propylene Glycol Monocaprylate 32

Using the above ingredients in the same manner as in Example 1 to prepare a hard capsules.

Example 4 Preparation of Hard Capsule

Component Content (mg / Formulation)

Itraconazole 50

85% aqueous phosphoric acid 200

(Ethanol) (300)

Polyoxyethylene-50-hydrogenated castor oil (HCO-50) 160

Poloxamer 124NF 124

dl-α-tocopherol 96

Propylene Glycol Monocaprylate 32

Using the above ingredients in the same manner as in Example 1 to prepare a hard capsules.

Example 5: Preparation of Hard Capsule

Component Content (mg / Formulation)

Itraconazole 50

85% aqueous phosphoric acid 200

(Ethanol) (300)

Polyoxyethylene-50-hydrogenated castor oil (HCO-50) 160

Poloxamer 124NF 124

dl-α-tocopherol 140

Using the above ingredients in the same manner as in Example 1 to prepare a hard capsules.

Example 6: Preparation of Hard Capsule

Component Content (mg / Formulation)

Itraconazole 50

85% aqueous phosphoric acid 200

(Ethanol) (300)

Cremophor EL 160

Twin 20 124

dl-α-tocopherol 120

Using the above ingredients in the same manner as in Example 1 to prepare a hard capsule.

Example 7: Preparation of Hard Capsule

Component Content (mg / Formulation)

Itraconazole 50

85% aqueous phosphoric acid 200

(Ethanol) (300)

Cremophor EL 160

Twin 20 124

Propylene Glycol Monocaprylate 120

Using the above ingredients in the same manner as in Example 1 to prepare a hard capsules.

Example 8: Preparation of Hard Capsule

Component Content (mg / Formulation)

Itraconazole 100

85% aqueous phosphoric acid 200

(Ethanol) (300)

Cremophor EL 200

Twin 20 160

Propylene Glycol Dicaprylate 30

dl-α-tocopherol 130

Using the above ingredients in the same manner as in Example 1 to prepare a hard capsules.

Comparative Example: Preparation of Hard Capsule

Component Content (mg / Formulation)

Itraconazole 50

85% aqueous phosphoric acid 200

Ethanol 300

Polyoxyethylene-50-Hydrogenated Castor Oil (HCO-50) 80

Cremophor EL 80

Poloxamer 124NF 64

Twin 20 64

dl-α-tocopherol 96

Propylene Glycol Monocaprylate 32

Phosphoric acid aqueous solution and ethanol were added to the pharmacologically active ingredient itraconazole and homogeneously dissolved, and then the remaining components were added and dissolved to obtain a microemulsion preconcentrate. Since this preconcentrate was prepared without a separate ethanol removal process, it contains ethanol as it is, and this ethanol acts as a co-surfactant to assist the surfactant when the preconcentrate is emulsified in contact with an aqueous solution. The preconcentrate was filled into hard capsules according to the method for preparing hard capsules in the Korean Pharmacopoeia General Formulation to prepare hard capsules.

Test Example 1: Comparative Dissolution Test

The preparations prepared in Example 1 and Comparative Example, and commercially available itraconazole dermal granules (Sporanox capsules, Jansensa), melted tablets (Sporanox tablets, Jansensa) and solution formulations (Sporanox solution, Jansensa) as control agents The test was carried out according to the second dissolution test method (paddle method), and after 45 minutes, the eluate was taken, filtered using a 1 μm membrane filter, and the elution amount was determined according to the following analysis method.

Dissolution Test Equipment: Erweka DT 80

Eluent: pH 1.2 artificial gastric fluid 900 ml and pH 6.8 phosphate buffer

Eluent Temperature: 37 ± 0.5 ℃

Rotational Speed: 100 ± 4 rpm

Assay: Liquid Chromatography

Column-Cosmosil C ₁₈ (150 mm × 4.6 mm)

Mobile phase-acetonitrile: pH 7.0 phosphate buffer (60:40)

Injection volume-10 μl

Flow rate-1.2 ml / min

Detector-UV 255 nm

The results are shown in Tables 1 and 2 below.

Dissolution rate in pH 1.2 artificial gastric juice Specimen Example 1 Comparative example Sporanox capsule Spornox Tablets Sporanox Liquid Dissolution rate (45 minutes) 99% 97% 50% 92% 98%

Dissolution Rate in pH 6.8 Phosphate Buffer Specimen Example 1 Comparative example Sporanox capsule Spornox Tablets Sporanox Liquid Dissolution rate (45 minutes) 95% 70% 0.6% 0.5% 5.5%

As shown in Tables 1 and 2, the microemulsion preconcentrate of the present invention forms stable microemulsion particles not only in 0.1 N hydrochloric acid but also in phosphate buffer of pH 6.8, and there is no change such as precipitation of the active ingredient according to the pH change. The dissolution rate in the phosphate buffer of 6.8 was significantly higher than that of the comparative and control formulations.

Test Example 2: Comparative Absorption Test

In order to investigate the bioavailability of the formulation of the present invention, the absorption test was carried out using the formulation of Example 1, which is a test formulation, and a commercial formulation, Sporanox capsule (Jansen Corporation) and Sporoxox solution (Jansen Corporation).

Sprague-Dawley male rats (300g body weight, 14-15 weeks old) were used as 10 animals per sample, and the rats were solid feed and water for normal rats which were constant for 4 days or more under the same conditions. Was fed to feed. Rats were fasted for more than 48 hours and used for testing, and water was allowed to drink freely during fasting.

Rats were administered with test or control formulations by pushing them with water using an oral device at an equivalent dose of 20 mg as itraconazole per kg of rat body weight. Blood was collected before and after 1, 2, 3, 4, 5, 7 and 24 hours after administration.

To 500 µl of plasma, 50 µl of internal standard solution (500 µg / ml methanol solution of Econitrate) and 200 µl of 1 M carbonate buffer (pH 10) were added and mixed, followed by extraction solvent (n-heptane: isoamyl alcohol = 9: 1). 7 ml was added and shaken. The solution was centrifuged at 3,000 rpm for 10 minutes, and 6 ml of the supernatant was evaporated and concentrated under a nitrogen gas stream at 50 캜. To the residue was dissolved by adding 200 µl of the mobile phase, followed by HPLC.

Column: Inertsil ODS2 (4.6 × 250 mm, 5 μm)

Mobile phase: 65% acetonitrile aqueous solution with 0.05% triethylamine (pH 7.0)

Injection volume: 100 μl

Flow rate: 1.2 ml / min

Detection: 258 nm

The results are shown in Table 3 and FIG.

Variable AUC (nghr / ml) C _max (ng / ml) T _max (hours) Control Formulation 1 (Sporanox Capsule) 3838.2 ± 1189.8 (31.0%) 388.8 ± 97.0 (24.9%) 2.8 ± 1.0 (35.7%) Control Agent 2 (Sporanox Liquid) 1170.3 ± 667.9 (57.1%) 232.3 ± 134.7 (58.0%) 2.2 ± 1.1 (50.0%) Example 1 5144.0 ± 526.9 (10.2%) 446.6 ± 43.3 (9.7%) 4.3 ± 1.2 (27.9%) AUC: The blood concentration curve up to 24 hours after the final sample was obtained by trapezoidal formula. C _max : The maximum blood concentration was used as the concentration at the time of direct peak concentration T _max : The highest blood concentration Time of day.

As shown in the AUC values of Table 3 and in Figure 1, the formulation of Example 1 showed about 4 times more bioavailability compared to the sporoxox capsules, the control, and about 1.4 times compared to the Spronox solution. In addition, the differences between individuals were much reduced when compared to CV (%). From these results, the microemulsion preconcentrate according to the present invention forms a very stable microemulsion particle when it is emulsified in contact with the body fluid and there is no change in emulsification such as precipitation of the active ingredient according to the pH change, so that the absorption rate in vivo is constant and improved. Able to know.

The composition of the present invention is a microemulsion preconcentrate containing a poorly soluble antifungal agent such as itraconazole in a completely dissolved state without including a separate co-surfactant, and when orally administered, forms a very stable microemulsion particle of the poorly soluble antifungal agent. Bioavailability is significantly increased and is not affected by pH, so the effect of food and individual absorption difference is significantly reduced.

Claims (7)

Triazole-based antifungal agent, phosphoric acid, surfactant and oil, oral administration microemulsion preconcentrate composition. The method of claim 1, The triazole-based antifungal agent, phosphoric acid, surfactant and oil are contained in a ratio of 1: 0.5 to 15: 0.5 to 15: 0.5 to 15 by weight. The method of claim 1, Wherein said triazole antifungal agent is itraconazole. The method of claim 1, Wherein said surfactant is a polyoxyethylene product, a polyoxyethylene-polyoxypropylene block copolymer or a polyoxyethylene sorbitan fatty acid ester of a hydrogenated vegetable oil. The method of claim 1, Wherein said oil is a tocopherol, a propylene glycol fatty acid ester or an ester compound of a fatty acid and a monovalent alkanol. (a) homogeneously dissolving the triazole antifungal agent in a mixture of an aqueous solution of phosphoric acid and a dissolution aid, (b) adding a surfactant and oil to the solution, and then (c) removing the dissolution aid from the mixture. , The method for producing the composition according to claim 1. The method of claim 6, The dissolution aid is alcohol.