Antifungal pharmaceutical composition

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a ketoconazole-base antifungal pharmaceutical composition. The composition is prepared as a solid medicinal formulation. The composition comprises the following components, wt.-%: ketoconazole, 50.5-75.0; lactose, 1.0-12.0; starch, 5.0-25.0; polyvinylpyrrolidone, 2.0-12.0; stearic acid or calcium, magnesium or zinc stearate or mixture of indicated compounds, 0.2-1.2; aerosil and/or talc, 0.5-10.0. The novel antifungal composition comprises ketoconazole in the amount 50 wt.-%, not less, and it satisfies Pharmacopoeia requirements, stable in storage for 2 years, not less, and shows high therapeutic activity.

EFFECT: improved and valuable medicinal and pharmaceutical properties of composition.

3 cl, 2 tbl, 6 ex

 

The invention relates to the field of medicine and relates to pharmaceutical compositions on the basis of ketoconazole, which can be used to treat infections smooth skin, scalp, nails caused by dermatophytes and/or yeast-like fungi; infections of the gastrointestinal tract caused by yeast-like fungi; chronic vaginal candidiasis, systemic fungal infections, such as systemic candidiasis, paracoccidioidomycosis, histoplasmosis, coccidiomycosis, blastomycosis; as well as the prevention of fungal infections in patients with a decrease in the protective forces of an organism.

Fungal infections are one of the leading causes of disease worldwide, and their number continues to grow. The frequency of these infections is increasing due to a number of reasons, including greater use of antibiotics broad-spectrum antibiotics and other chemotherapeutic drugs, an increase in the frequency of invasive procedures plus the increasing number of patients with compromised immune systems.

Ketoconazole is a compound from the class imidazolylidene with direct fungicidal (anti-fungal action. Direct fungicidal effect of ketoconazole due to its highly specific suppressive effect on the enzyme, which catalyzes one of the early stages of si the importance of ergosterol cells of the fungus.

Ketoconazole has a broad antifungal spectrum, has fungicidal activity against dermatophytes, fungi, yeasts and certain dimorphic fungi and to date remains one of the most effective substances for the treatment of fungal infections.

For use in medical practice have been developed in different dosage forms of ketoconazole (RF patents №2120305, No. 2154464, U.S. patent No. 4661493, 5456851). However, when the drug is designed for oral ingestion, one of the most convenient for manufacture, storage and use is a solid dosage form, particularly a tablet.

Known pharmaceutical compositions on the basis of ketoconazole made in the form of tablets (RLS-encyclopedia of drugs, M: RLS-2000", 2000). However, the specific qualitative and quantitative composition of auxiliary ingredients are not listed.

In U.S. patent No. 6040307, 2000, described the closest to the claimed composition antifungal pharmaceutical composition is in the form of tablets. It contains as active substance one of the optical isomers of ketoconazole - (-) ketoconazole (20-40 wt.%), and as auxiliary ingredients: milk sugar 41,8-61,8%by weight, corn starch - 18,0-36,0 wt.% and magnesium stearate and 2.0 to 4.0 wt.%.

Known farmace the political composition unstable in time, because they will not be stored for a long time and has a shelf life of less than 1 year. The disadvantages of the known compositions include the low content of active substance in the dosage form (below 50 wt.%).

It is known that ketoconazole is quite unstable connection and easily undergoes decomposition in the manufacturing process of the medicinal product and during storage of the latter, which imposes additional difficulties in the development of new compositions of ketoconazole and selection of optimal qualitative and quantitative ratio of auxiliary substances.

The task of the invention is to create a stable antifungal composition that contains at least 50 wt.% ketoconazole and meets the requirements of Gosfarmakapei XI edition (GF XI), and when implementing the claimed invention achieves the following technical result in a new composition is stable during storage and has a shelf life of not less than 2 years.

According to the invention offers an antifungal pharmaceutical composition comprising as active ingredient ketoconazole, and as auxiliary substances, milk sugar, starch, polyvinylpyrrolidone, stearic acid or calcium stearate, magnesium or zinc or a mixture of these compounds, Aerosil and/or the hoist is in the following ratio of ingredients, wt.%:

Ketoconazole50,5-75,0,
Milk sugarof 1.0 to 12.0,
Starch5,0-25,0,
Polyvinylpyrrolidone2,0-12,0,
Stearic acid, or
calcium stearate, magnesium or
zinc, or a mixture of these compounds0,2-1,2,
Aerosil and/or talc0.5 to 10.0.

From stearates of calcium, magnesium or zinc, it is preferable to use magnesium stearate or calcium.

The claimed ratio of ingredients is best found experimentally. By selecting the stated qualitative and quantitative ratio of the ingredients was obtained antifungal composition on the basis of ketoconazole, stable during storage and has a shelf life of not less than 2 years. In the invention were able to increase the content of active substance in comparison with the prototype, which is in the new song more of 50.5 wt.%. The proposed arrangement satisfies the requirements of the global Fund XI (in appearance, dissolution, microbiological purity and other parameters). Study of pharmacological activity of a new composition showed the presence of the high antifungal activity.

Thus, in accordance with the invention claimed an antifungal composition contains at least 50 wt.% ketoconazole, satisfies the requirements of the global Fund XI, has a shelf life of not less than 2 years and a high therapeutic activity.

Used according to the invention, the starch may be potato and/or corn and/or rice and/or modified starch. As the latter is preferable to use sodium glycolaldehyde (commercial products - modified starch brand "Primogel" or brand "Explotab").

We offer an antifungal composition is in the form of solid dosage forms, preferably in tablet form.

Obtaining the claimed composition can be carried out generally in accordance with known techniques. For example, a mixture of ketoconazole with auxiliary substances, granulata, drying and pressing of the granules. Stearic acid or calcium stearate, magnesium or zinc or a mixture of these compounds, Aerosil and/or talc can be entered partially or completely immediately before the pressing of the granules. These methods obtain are not exhaustive, and may use other known mainly techniques, for example, the method of dry granulation or a combination of the above methods.

Pharmacokinetic study the claimed means were carried out in comparison with known drug - tablets "Nizoral" (active ingredient ketoconazole) on rabbits male breed chinchilla with body weight 3,0±0.2 kg after a single injection of drugs per os at a dose of 66 mg/kg of ketoconazole. It is found that the values of the main pharmacokinetic parameters (maximum concentration of active substance in blood serum, the time to reach this concentration, the average residence time of drug in the body, the half-life, measure of the rate of absorption) were significantly different between the degree of bioavailability for a new composition constituted of 105.2% compared to the reference drug. Further studies have been conducted on volunteers. The analysis obtained after administration of equivalent doses (per os 200 mg ketoconazole) of the new composition and the reference drug (tablets Nizoral" company Janssen pharmaceutica) data also revealed no differences in pharmacokinetic parameters of the two drugs and have shown that the processes of absorption, distribution and excretion of ketoconazole happen the same way. Thus, the results show that the inventive composition and the comparator drug is therapeutically equivalent.

In more detail, the present invention is illustrated by the following examples (see Tables 1, 2).

Example 1. Mix the sifted powders of ketoconazole (200,0 g; 6.5 wt.%), milk sugar (30,4 g; 9.5 wt.%) and dry potato starch (48,0 g; 15.0 wt.%) moisturize with a 15%aqueous solution of vinylpyrrolidone (polyvinylpyrrolidone - 5.0 wt.%), mix to a uniform distribution of moisture, granularit on the device for producing granules and dried. After dry granulating the resulting mass optivault a mixture of 4.1 g of Aerosil (2.0 wt.%), 7.6 g of talc (2.5 wt.%), of 2.05 g of magnesium stearate (1.0 wt.%). The mixture is compressed on a tablet machine. Get a white pill with an average weight of 0.32 g, the content of ketoconazole (HPLC method) - 0.20 g, the release of the active substance (test "dissolution", 0,1M HCl) - 100% after 45 min (GF XI - not less than 75%), impurities (TLC) - 0.3 wt.% by weight of the active substance. The obtained tablets meet the requirements of the global Fund XI and have a shelf life of more than 27 months.

Example 2 is carried out analogously to example 1 with the difference that as the starch used corn starch, Aerosil enter to wet granulation, part of the starch (4.5 wt.%) injected directly prior to pelletizing together with stearic acid and calcium stearate.

Example 3 perform similarly to example 1 with the difference that the Aerosil enter to wet granulation and as a salt of stearic acid used calcium stearate.

Example 4 perform similarly to example 1, however the one, as starch using a mixture of corn starch and modified starch brand Primogel (4:1) and the last injected directly prior to pelletizing.

Examples 5, 6 perform similarly to example 1. Obtained in examples 2-6 tablets ketoconazole comply with pharmacopoeial requirements and have a shelf life of over 2 years (table 2).

Table 1
IngredientsContent, wt.%
Examples
123456
Ketoconazole62,5a 50.575,062,562,562,5
Milk sugar9,5to 12.01,07,35,010,0
Starch15,023,85,025,014,019,0
Polyvinyl-pyrrolidone5,0to 12.08,02,07,57,0
Aerosil4,50,58,0-10,0-
is ALK 2,5-2,03,0-0,5
Stearic acid or calcium stearate, magnesium or zinc or a mixture of these compounds1,01,21,00,21,01,0
Only100,0100,0100,0100,0100,0100,0

Table 2
The quality indicatorsStandards of quality requirementsThe actual indicators
Example 1Example 2Example 3Example 4Example 5Example 6
The deviation in the weight of individual tablets from the average mass %±5,0+1,2; -2,5+3,8; -3,2+1,5; -1,4+1.2; -1,2+1,5; -2,6+2,6; -3,8
Raspadaemost, minNot more than 156107887
Dissolution,

%
Not less than 75 per 45 min100of 98.210099,6100 100
ImpuritiesOne impurity not more than 0,5%0,30,450,20,40,40,45
The amount of the impurities is not more than 1.0%0,30,650,40,60,70,45
Microbiological purityOn GF XI and ISMthe activity is tiedthe activity is tiedthe activity is tiedthe activity is tiedthe activity is tiedthe activity is tied

1. Antifungal pharmaceutical composition in the form of a solid dosage form comprising as active ingredient ketoconazole, and as auxiliary substances, milk sugar, starch, polyvinylpyrrolidone, stearic acid or calcium stearate, magnesium or zinc or a mixture of these compounds, Aerosil and/or talc in the following ratio of ingredients, wt.%:

Ketoconazole50,5-75,0
Milk sugarof 1.0 to 12.0
Starch5,0-25,0
Polyvinylpyrrolidoneof 2.0 to 12.0
Stearic acid or calcium stearate,
magnesium or zinc, or a mixture of the above
connections0,2-1,2
Aerosil and/or talc0.5 to 10.0

2. The pharmaceutical composition according to claim 1, characterized in that it is made in tablet form.

3. The pharmaceutical composition according to claim 2, characterized in that it contains as starch and potato starch.



 

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