Antifungal composition for oral administration comprising itraconazole and its preparation

 

The composition includes the obtained melt mixture of Itraconazole and phosphoric acid, pharmaceutically acceptable carrier and a surfactant. The mass ratio of Itraconazole and phosphoric acid in the obtained melt mixture is 1:0.1 to 1:10. The composition provides enhanced solubility of Itraconazole in an aqueous solution of the obtained melt mixture in comparison with solid Itraconazole, with the consequent increase the bioavailability of Itraconazole in vivo. 2 S. and 2 C.p. f-crystals, 1 Il., table 1.

Field of invention the Present invention relates to compositions of Itraconazole for oral administration, having improved bioavailability of Itraconazole, and to a method for producing such a composition.

Background of the invention Itraconazole, representing a compound triazole, as you know, has excellent antifungal activity. However, the oral bioavailability of the input Itraconazole is very low, because it has a very low solubility in water, less than 1 μg/ml, and remains ionized in the gastric juice due to its pKa value, equal to 3.7. In addition, it is known that the degree of bioavailability of the oral input Itraconazole wide>In international PCT publication WO 85/02767 and U.S. patent 4764604 disclosed a method of increasing the solubility of Itraconazole by applying compounds of Itraconazole, comprising cyclodextrin. However, the disadvantages of this method are that the increasing increasing the solubility of Itraconazole is only marginal and requires various complicated preparative procedures.

In a recently published international patent application PCT WO 94/05263 discovered the drug in the form of beads with a coating, where the core is made of pharmaceutically inert or neutral sucrose, dextrin, starch, etc. , cover with a mixture of Itraconazole and hydrophilic polymer, and then the obtained granules are again applied polymeric coating, for example, from polyethylene glycol. Such a drug in the form of beads coated with commercially available from Janssen Pharmaceutica (Beerse, Belgium) under the brand name Sporanoxin the form of capsules. However, the way to obtain this drug is very complicated due to the fact that the beads with an average size of only 600-700 microns tend to agglomerate in the manufacturing process.

In international PCT publication WO 97/44014 disclosed solid dispersion itracona the extrusion in the melt at temperatures in the range from 245 to 265oC. Such solid dispersion described as having improved bioavailability of Itraconazole, do not depend on chosen food, and it is commercially available from Janssen Pharmaceutica (Beerse, Belgium) under the brand name Sporanoxin the form of tablets. However, the method of obtaining a solid dispersion is complicated by the fact that there are difficulties of control of various process variables, and the bioavailability of Itraconazole in vivo, achieved with such variance, still remains low.

Therefore, there is a need to develop oral compositions of Itraconazole with improved bioavailability in vivo.

Summary of the invention the present invention therefore is the provision of improved compositions for oral administration comprising Itraconazole.

Another purpose of this invention is the provision of a method of obtaining the specified composition for oral administration.

In accordance with one aspect of the present invention provides an antifungal composition for oral administration comprising the obtained melt mixture of Itraconazole and phosphoric acid, pharmaceutically acceptable carrier and a surface-act the part II of the invention will be apparent from the following description of the invention with reference to the accompanying drawing, which demonstrates the bioavailability of the drug Itraconazole according to the invention and commercially available drug Itraconazole.

Detailed description of the invention Throughout this description, the solid is obtained by the implementation stages of fusion of Itraconazole with phosphoric acid with the formation of the melt and cooling of the melt will be obtained melt mixture of Itraconazole and phosphoric acid. This mixture has a melting temperature that is much lower than the melting temperature of Itraconazole, and solubility of Itraconazole from such a mixture in aqueous solution is significantly increased in comparison with solid Itraconazole, with the consequent increase the bioavailability of Itraconazole in vivo.

The weight ratio of Itraconazole and phosphoric acid in the obtained melt mixture of the present invention is in the range from 1:0.1 to 1:10, preferably from 1:0.5 to 1:5.

The composition according to the invention, comprising the obtained melt mixture of Itraconazole and phosphoric acid, may contain a pharmaceutically acceptable carrier, such as lactose, dextrin, starch, microcrystalline cellulose, gidroksipropilmetilzelluloza, hydroxypropylcellulose, hydroxyethylene the magnesium, aluminum hydroxide, aluminum silicate, metasilicate aluminum-magnesium bentonite and their mixture.

Antifungal composition for oral administration according to the present invention may optionally include a surfactant which promotes wetting of the obtained melt mixture of Itraconazole and phosphoric acid in the aquatic environment. Examples of surfactants include: (1) polyoxyethylene picolylamine natural or hydrogenated vegetable oils such as polyoxyethylene picolylamine natural or gidrirovannoe castor oil (Cremophor, BASF), (2) esters of polyoxyethylene-sorbitane fatty acid, where the fatty acid is a mono - or triluminous, palmitic, stearic or oleic acid (Tween, ICI), (3) esters of polyoxyethylene and fatty acids, such as esters of polyoxyethylene and stearic acid (Myrj, ICI), (4) block copolymers of polyoxyethylene-polyoxypropylene (Poloxamer, BASF),
(5) dioctylsulfosuccinate sodium or sodium lauryl sulfate,
(6) phospholipids,
(7) esters propylenglycol alisateur, propilenglikolstearat, propilenglikolstearat, complex fluids propylene glycol and Caprylic-capric acid (Miglyol840,ls),
(8) the products of the transesterification of triglycerides of natural oils and polyalkylene polyhydric alcohols (Labrafil, M, Gattefosse),
(9) mono-, di - or mono/diglycerides, such as mono - and diglycerides Caprylic/capric acid (Imwitor,ls) and
(10) esters sorbitan and fatty acids, such as monolauroyl, monopalmitate and monetarily esters sorbitan (Span, ICI).

Of the above surfactants in the present invention it is preferable to use polyoxyethylene picolylamine natural or hydrogenated vegetable oils, esters of polyoxyethylene-sorbitan fatty acid and a block copolymer of polyoxyethylene-polyoxypropylene.

In addition, in accordance with the following aspect of the present invention, provided is a method of obtaining the composition according to the invention, comprising (a) smeshivaemosti the molten mixture, (C) adding to the resulting mixture pharmaceutically acceptable carrier and a surfactant, (d) cooling the resulting mixture to obtain a solid substance, and (e) grinding the obtained solid substance into powder.

Alternatively, the composition according to the invention can be obtained by using an organic solvent, for example, ethanol, methylene chloride and chloroform. Specifically, Itraconazole is mixed with phosphoric acid and the resulting mixture is added a small amount of an organic solvent to obtain a solution. Then add pharmaceutically acceptable carrier and a surfactant and the resulting solution is heated to evaporate the solvent, and then cooled to obtain a solid substance, which is then crushed into powder.

The pharmaceutical composition according to the invention can be presented in the form of various pharmaceutical preparations such as powder, granules, tablets, drug coated and the liquid preparation using the normal procedure. For example, the hard capsules can be obtained by adding to pharmaceutical compositions lubricants and other pharmaceutical additives, processing the mixture in powder or granules and fill it with the powder or granules is tabletirovanija mixture; liquid drug by dissolving the pharmaceutical composition in water and the drug coating by applying a solution of the pharmaceutical composition in the form of a coating on the particles in the form of sugar balls, such as Nonpareil(Edward Mendell Co., UK).

As described above, the composition according to the invention, comprising the obtained melt mixture of Itraconazole and phosphoric acid, provides remarkably high bioavailability of Itraconazole in vivo. Furthermore, the method according to the invention receiving antifungal composition according to the invention, including Itraconazole, has advantages over methods of the prior art, which is that at a lower process temperature get higher performance.

The following examples are intended to further illustrate the present invention without limiting its scope.

The following percentages used to determine the solids content in the solid mixtures, liquid substance in the liquid and solids in the liquid, are given in the Mac calculation./wt., about./about. and wt./about., accordingly, unless otherwise indicated.

Example 1: preparation of solid capsules
Solid kapalama acid 85% - 150
Poloxamer407 - 30
CremophorRH40 - 10
The hypromellose - 20
Hydrotalcite - 70
Silicon dioxide - 20
Itraconazole and phosphoric acid are mixed and the mixture is heated to 160oWith obtaining the molten mixture. The mixture is allowed to cool and at this time, add other ingredients, with the exception of silicon dioxide. Then the mixture is cooled to room temperature, obtaining obtained by melt solids. This solid substance is mixed with silica, crushed into powder and fill them hard gelatin capsules.

Example 2: preparation of solid capsules
Hard capsules produced by the procedure of Example 1 using the following ingredients:
- Quantity (mg/capsule)
Itraconazole - 100
Phosphoric acid 85% - 100
Poloxamer407 - 30
Tween80 - 10
The hypromellose - 20
Hydrotalcite - 70
Silicon dioxide - 20
Example 3: preparation of solid capsules
Hard capsules produced by the procedure of Example 1 using the following ingredients:
407 - 30
CremophorRH40 - 10
Hydrotalcite - 100
Silicon dioxide - 20
Example 4: preparation of solid capsules
Hard capsules produced by the procedure of Example 1 using the following ingredients:
- Quantity (mg/capsule)
Itraconazole - 100
Phosphoric acid 85% - 150
Tween80 - 20
CremophorRH40 - 10
Hydrotalcite - 70
Silicon dioxide - 20
Example 5: preparation of solid capsules
Hard capsules produced by the procedure of Example 1 using the following ingredients:
- Quantity (mg/capsule)
Itraconazole - 100
Phosphoric acid 85% - 50
Poloxamer407 - 40
CremophorRH40 - 20
Hydrotalcite - 70
Silicon dioxide - 20
Example 6: preparation of solid capsules
Hard capsules produced by the procedure of Example 1 using the following ingredients:
- Quantity (mg/capsule)
Itraconazole - 100
Phosphoric acid 85% - 150
Poloxamer407 - 30
CremophorR is Fe capsules get using the following ingredients:
- Quantity (mg/capsule)
Itraconazole - 100
Phosphoric acid 85% - 100
Ethanol - 500
Poloxamer407 - 100
CremophorRH40 - 50
Polyethylene glycol (PEG) 20000 - 200
Itraconazole and phosphoric acid are mixed and added to the mixture ethanol to obtain a solution. Add other ingredients and the resulting solution was heated to 100oFor evaporation of ethanol and then cooled to room temperature to obtain a solid substance. The solid is crushed into powder and fill them hard gelatin capsules.

Example 8: Preparation of hard capsules containing beads coated
Hard capsule containing beads coated, receive, using the following ingredients:
- Quantity (mg/capsule)
Itraconazole - 100
Phosphoric acid 85% - 200
Ethanol - 500
Poloxamer407 - 100
Polyethylene glycol (PEG) 20000 - 100
CremophorRH40 - 20
Sugar balls - 400
A mixture containing other ingredients, in addition to ethanol produced in accordance with the procedure of Example 7 with the use of the and then cover the remaining part of PEG 20000. Thus obtained beads coated fill hard gelatin capsules.

Comparative example: preparation of solid capsules
Hard capsules is obtained using the procedure of Example 1, except that they did not use phosphoric acid, and use the following ingredients:
- Quantity (mg/capsule)
Itraconazole - 100
Poloxamer407 - 30
CremophorRH40 - 10
The hypromellose - 20
Hydrotalcite - 70
Silicon dioxide - 20
The test example 1: Test solubility
Determined the dissolution rate of Itraconazole for preparations according to the invention listed in Examples 1-3; preparation of a Comparative Example; capsules Sporanox; and Sporanox tablets(Janssen Korea), in accordance with the method of testing the solubility II (method of mixing using a paddle device), as described in Chapter "General test methods Pharmacopoeia Korea, under the conditions listed below:
The test apparatus: Erweka DT80 (Erweka, Germany).

Solutions for test: 900 ml Hcl 0.1 N..

The temperature of the solutions for Analytical method: liquid chromatography
- column: Cosmosil C18 (150 mm4.6 mm; Nacalai tesque, Japan),
- mobile phase:acetonitrile/phosphate buffer (pH 7.0)=60:40,
- flow rate: 1.2 ml/min,
detector: ultraviolet of 255 nm,
- injected volume: 10 ám.

The amount of dissolved Itraconazole presented as the cumulative number of Itraconazole, lirovannomu for 45 min, and the results are shown in the table.

As you can see from the table, the preparations according to examples 1-3 demonstrate significantly higher levels of Itraconazole, which was dissolved in comparison with the products of the Comparative Example and capsules Sporanox. These results prove that the solubilization of Itraconazole in water is significantly increased with the use presented in this invention is obtained by melt mixture of Itraconazole and phosphoric acid.

In addition, despite the fact that the pill Sporanoxdemonstrate a high level of dissolved Itraconazole, comparable with the level of solubility of Examples 1-3, the method of producing preparations according to the invention is much simpler and has a higher performance compared with the method to obtain tablets Sporaranoxsignificantly lower in comparison with the composition of the present invention, as shown in test Example 2.

The test example 2: Test of absorption in vivo
For the investigation of bioavailability of Itraconazole contained in the preparations according to the present invention, testing of absorption in vivo was carried out in the following way.

Thirty rats Sprague-Dawly age 14-15 weeks, each weighing about 300 g were starved for 48 h, at the same time they received free access to water, and then they were divided into two groups of 10 rats each.

Two groups of rats orally administered the preparation of Example 1 of the present invention and tablets Sporanox, respectively, at the dose of 20 mg of Itraconazole/kg body weight in rats. Blood samples were taken directly from the hearts of rats before administration of the drug and after 2, 4, 6, 8 and 24 h after injection and was separated from serum.

To each serum sample volume of 500 ál was added 50 μl of internal standard solution (methanol solution containing 500 μg/ml of nitrate econazole) and 200 ál of 1M carbonate buffer (pH of 10.0). Added 7 ml of solvent for extraction (n-heptane:isoamyl alcohol=9:1) and poluchenno is an increase of 10 min, and the solvent evaporated in nitrogen atmosphere at a temperature of 50oC. To the obtained residue was added 200 μl of 0.05% aqueous solution of triethylamine and 65% aqueous acetonitrile and the resulting mixture was subjected to HPLC under the following conditions:
- column: Inertsil ODS2 (250 mm4.6 mm; 5 mm; GL science, Japan);
- mobile phase: 65% aqueous solution of acetonitrile containing 0.05% triethylamine;
detector: UV at 258 nm;
- flow rate: 1.2 ml/min;
- the amount of input: 100 μm.

The result, shown in the drawing, indicates that the bioavailability of Itraconazole observed for the preparation of the present invention, much higher in comparison with Sporanox tablets..

Although the invention has been described with reference to its specific embodiment, as described above, it is necessary to understand that the experts in this field can make various modifications and changes of the present invention, which are also included in the scope of the present invention as defined by the attached claims.


Claims

1. Antifungal composition for oral administration comprising the obtained melt mixture of itracon sawoe ratio of Itraconazole and phosphoric acid in the obtained melt mixture is 1: 0.1 to 1: 10.

2. Antifungal composition under item 1, in which the pharmaceutically acceptable carrier is selected from the group comprising lactose, dextrin, starch, microcrystalline cellulose, hypromellose, hydroxypropylcellulose, hydroxyethyl cellulose, ethylcellulose, methylcellulose, polyethylene glycol, silicon dioxide, hydrotalcite silicate of aluminum-magnesium, aluminum hydroxide, aluminum silicate, metasilicate aluminum-magnesium bentonite and their mixture.

3. Antifungal composition under item 1, in which the surfactant is selected from the group comprising polyoxyethylene picolylamine natural or hydrogenated vegetable oils, esters of polyoxyethylene-sorbitan-fatty acid esters of polyoxyethylene and fatty acids, block copolymers of polyoxyethylene-polyoxypropylene, dioctylsulfosuccinate sodium, sodium lauryl sulfate, phospholipids, esters of propylene glycol and mono - or digiray acid, the products of interesterification of triglycerides of natural oils and polyalkylene polyhydric alcohols, monoglycerides, diglycerides, mono/diglycerides, esters sorbitan and fatty acids.

4. The method of obtaining an antifungal composition p is x from 100 to 170oWith homogeneous molten mixture, (C) adding to the resulting mixture pharmaceutically acceptable carrier and a surfactant, (d) cooling the molten mixture to obtain a solid substance, (e) grinding the solids in the powder.

 

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