The antifungal composition with enhanced bioavailability

 

The invention relates to a pharmaceutical composition comprising: 1) an antifungal agent, which is (-)-(2R-CIS-)-4-[4-[4-[4-[[5-(2,4-differenl)tetrahydro-5-(1H-1,2,4-triazole-1-ylmethyl)furan-3-yl] methoxy] phenyl] -1-piperazinil] phenyl] -2,4-dihydro-2-[(S)-hydroxypropyl]-3H-1,2,4-triazole-3-one, 2) at least one nonionic surfactant and (3) a diluent. The composition gives antifungal compounds with low water solubility, increased bioavailability in mammals, including humans. 2 C. and 17 C.p. f-crystals, 16 PL.

The present invention relates to compositions for increased or improved bioavailability of the new triazolopyridine compounds with antifungal properties.

In the international application 95/17407 published 29.06.95, reported on a new class of antifungal compounds containing the remains of tetrahydrofuran and triazole. It is shown that one of the specific compounds, (2R-CIS)-4-[4-[4-[4-[[5-(2,4-differenl)tetrahydro-5-(1H-1,2,4-triazole-1-ylmethyl)furan-3-yl] methoxy]phenyl]-1-piperazinil]phenyl]-2,4-dihydro-2-[(S)-1-ethyl-2 (S)-hydroxypropyl]-3H-1,2,4-triazole-3-one, in aqueous slurries reveals a high antifungal activity against whom rendered, what non-aqueous formulations, such as powders or granules, have reduced the antifungal activity and/or bioavailability, apparently, due to the extremely low solubility of this compound in water. It is desirable to create a pharmaceutical composition with enhanced or improved antifungal activity and/or bioavailability of this compound.

Summary of the invention the Present invention is directed to the creation of a pharmaceutical composition comprising: 1) an antifungal agent of the formula2) at least one nonionic surfactant and (3) a diluent.

The pharmaceutical composition optionally may also contain well-known experts inert fillers, such as 4) dezintegriruetsja substances, 5) binder 6) lubricating substances, substances that give the composition fluidity, and/or dyes. The pharmaceutical composition can also be transformed into any suitable dosage form, such as capsules (or solid or semi-solid fill, or liquid filled), pills, powders and gels for oral administration.

In another embodiment, its implementation of the present invention is directed to the creation of pharmaceutical preparations which, one nonionic surfactant; about 12-60 wt.% the diluent is microcrystalline cellulose; about 4-10 weight. % disintegrator, which is croscarmellose (PA+form);
about 3-6 weight. % binder, which is polyvinylpyrrolidone;
about 0.3 to 1.5 wt.% the lubricant, which is magnesium stearate, and
if necessary, about 3-8 wt.% lauryl sodium.

Unexpected and surprising was the fact that the introduction of non-ionic surface-active substance in the pharmaceutical composition including, in particular, an antifungal compound, may increase the bioavailability of antifungal compounds having in the other conditions of extremely low solubility in water.

It is also shown that the introduction of non-ionic surface-active substance in the pharmaceutical composition including, in particular, an antifungal compound, may increase the bioavailability of antifungal compounds in aqueous suspensions. These results are indeed surprising and unexpected, because in well-known publications, such as Peter G. Welling. "Pharmacokinetics, processes and mathematics", the American edition, 7 (1986), reported that the solutions and suspensions generally provide better bioavailability than capsules or tablets. In the publication J. G. Naim. "Remingtonhouse pharmaceutical science", vol. 18, 1990, ed. Mack Publishing Co., Chapter 83, pages 1519, it is also reported that, since the drugs are absorbed in a dissolved state, it is considered that the absorption rate of oral dosage forms decreases in the following series: water solution>water-suspension>capsule or tablet.

The advantage of the present invention is that it is able to provide an antifungal compound in the pharmaceutical composition, which can be easily converted into a non-aqueous or dry dosage forms such as capsules, tablets or powders with a high antifungal activity and/or bioavailability.

Detailed description of embodiments of the invention
In the international application 95/17407 published 29.06.95 year, reported the antifungal compounds of the formula

where R1means a linear or branched alkyl group with 3-8 carbon atoms in the alkyl part is substituted by one or two hydroxy groups,
their simple and complex etherape, the examples 24 and 32 of the international application 95/17407 is possessing antifungal activity of (-)-(2R-CIS)-4-[4-[4-[4-[[5-(2,4-differenl)tetrahydro-5-(1H-1,2,4-triazole-1-ylmethyl)furan-3-yl] methoxy] phenyl]-1-piperazinil] phenyl] -2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxypropyl] -3H-1,2,4-triazole-3-one, hereinafter referred to as an antifungal compound; gross formula C37H42F2N8About4molecular weight 700.8, so pl. 164-165oC []25D-293o(C 1.0, chloroform), the structure is described below formula

Microparticles antifungal compounds may be obtained or at the last stage of its receipt, or after the usual procedure of crystallization using known methods micromilieu.

When using the technique of micromelia antifungal compound can be converted into particles of the desired size by conventional means, for example using a ball mill, or ultrasonic methods, or preferably using disk crushers, using the power of water, such as crusher company Plastomer products, Newton, PA, 18940. Use the same connection to the crusher.

About 99% microtrenching particles antifungal compounds in terms of size less than or equal to 100 μm, 95% less than or equal to 90 μm. Preferably, if 99% microtrenching particles less than or equal to 50 μm, of which 95% is less than or equal to 40 microns. More preferably, if 99% microtrenching particles less than or equal to 20 microns, of which 95% is less than or equal to 10 microns.

The antifungal compound used in the composition in amounts that effectively control the growth of the target fungus. Such amounts can vary from about 2 to about 85 wt.% from the total composition, more preferably from 5 to about 80 wt.%, most preferably from about 18 to about 50 wt.%. The number of staff in each of the dosage forms such as capsule, tablet, etc., may vary from about 10 mg to about 500 mg of antifungal compounds in dosage form, preferably from about 50 mg to about 200 mg, for Example, dosage form in the form of capsules may contain from about 50 mg to about 100 mg antifungal compounds. Similarly dosage form in the form of tablets may contain about 50 mg, about 100 mg or about 200 mg of the antifungal compounds.

Pharm is Yu, as capsules (or solid or semi-solid filling, or liquid filling), pills, powders or gels for oral administration.

For descriptions of pharmaceutical compositions according to the present invention, ingredients that can be used in the manufacture of dosage forms, and methods for assessing the bioactivity or bioavailability following terms are used.

Dosage form composition containing an antifungal compound, is introduced into the delivery system, i.e. tablet, capsule, oral gel, powder for systemic use, or suspension, in Association with inactive ingredients.

Capsule - special container or shell, made of methyl cellulose, polyvinyl alcohol, denatured gelatins or starch for holding or premises compositions containing the active antifungal compound. Capsules, hard shell usually made of gelatin mixtures with relatively high gelling ability, obtained from bones and pig skin. The capsule itself may contain small amounts of dyes, light absorbing agents, plasticizers and preservatives.

The tablet is pressed or fused solid dosage which can be manufactured by extrusion of mixtures or granules, obtained by wet granulation, dry granulation or compression.

Oral gel means dispersed in a hydrophilic semi-solid solution antifungal compound.

Powders for systemic use means a powder mixture containing an antifungal compound and the appropriate diluents which can be suspended in water or juices.

Surface-active agent means a compound which, due to presence of two localized areas, one of which is inherently hydrophilic and the other hydrophobic, can reduce the interphase tension between two immiscible phases.

Non-ionic surfactant means of surface-active substance in aqueous media has a negative charge and does not dissociate. Properties of non-ionic surfactants largely depend on the ratio of hydrophilic and hydrophobic groups in the molecule. The hydrophilic group include oxyethylene group (-och2CH2) and the hydroxy-group. By changing the number of hydrophobic groups in the molecule, such as fatty acid, get substances in the range from vysokolegirovannyh and water ne, such as macrogol. Between these two extreme types of compounds are those in which the ratio of hydrophilic and hydrophobic groups in a balanced manner, such as ethers and esters of macrogol and derivatives sorbitan. The corresponding non-ionic surfactants can be found in the manual MARTINDALE, the Extra Pharmacopoeia, edition 28, 1982, ed. Pharmaceuticl Press, London, UK, pages 370-379. Such nonionic surfactants include block copolymers of ethylene oxide and propylene oxide, glycol and glycerin esters of fatty acids and their derivatives, esters of polyoxyethylene and fatty acids (macrosolve esters), ethers of polyoxyethylene and fatty alcohols and their derivatives (macrosolve simple esters), polyvinyl alcohols and esters sorbitan. Preferred non-ionic surface-active agent is a block copolymer of ethylene oxide and propylene oxide.

Suitable block copolymers of ethylene oxide and propylene oxide have a common name Poloxamer and include polymers having the following chemical structure:

in which a represents a number varying from about 10 to Primula, varying from about 20 to about 60, more preferably from about 20 to about 56, and from about 20 to 27. The most preferred surface-active substance is a polymer, and in which means 80 and b means 27, is known as PluronicF68 (trade mark company BASF Corporation, mount olive, new Jersey, USA). Surfactant PluronicF68 is also known under the name of Poloxamer 188. This surface-active substance with a molecular weight of 8400 is solid at 20oAnd has a viscosity (Brookfield) 1000 CPS (at 77oC. Other suitable block copolymers of ethylene oxide and propylene oxide are PluronicF87, known as Poloxamer 237, in which as well as 64 and b is equal to 37, PluronicF127, known as Poloxamer 407, in which as well as 101 and b is equal to 56.

Suitable glycol and glycerin esters of fatty acids and their derivatives include monohalogenated and similar water-soluble derivatives.

Suitable esters of polyoxyethylene and gidrogenizirovannogo castor oil.

Suitable ethers of polyoxyethylene and fatty alcohols and their derivatives (macrosolve ethers) include Cetomacrogol 1000, Lauromacrogol (some simple laurynovich esters of microhollow with different chain length), for example, Laureth 4, Laureth 9 and Lauromacrogol 400.

Suitable esters of sorbitan (esters of one or more hydroxyl groups of sorbitan with fatty acids such as stearic, palmitic, oleic or lauric acid) include, for example, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, Polysorbate 80, Polysorbate 85, Sorbitan-monolaurate, Sorbitan-monooleate, Sorbitan-monopalmitate, Sorbitan-monostearate, Sorbitan-sesquioleate, Sorbitan-trioleate, Sorbitan-tristearate.

The amount of nonionic surfactant may vary from about 5 to about 50 wt.% of the total composition, preferably from about 5 to about 25 wt.%.

If necessary, the composition may also contain anionic surfactant such as sodium lauryl sulfate, the amount of which may vary from about 1 to about 10 wt.% of the total composition, preferably from about 3 to about 8 wt.%.

Thinner means and include sugar, such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, beans, rice and potatoes; cellulose, such as microcrystalline cellulose. The amount of diluent in the composition can vary from about 10 to about 90 wt.% of the total composition, preferably from about 25 to about 75 wt.%, more preferably from about 30 to about 60 wt.%, even more preferably from about 12 to about 60 wt.%.

Disintegrator means substances that are added to the composition to facilitate splitting it into parts (grinding) and release of drugs. Suitable disintegrators include starch; "soluble in cold water" modified starches such as carboximetilkrahmal (Na+-form); natural and synthetic resins and gums, such as locust beans, karaya, guar, tragakant and agar; cellulose derivatives such as methylcellulose and carboxymethylcellulose (Na+-form); microcrystalline cellulose and branched (cross-linked) microcrystalline cellulose, such as croscarmellose (Na+-form); alginates such as alginic acid and sodium alginate; clays such as bentonites, and effervescent mixtures. The amount of the cage is about 10 wt.%.

Binder materials shall mean substances which bind or "glue" powders and contribute to the cohesion of the resulting granules, being thus "adhesive" upon receipt of the dosage form. The binder increases the strength of coupling present in the diluent or filler. Suitable binders include sugars such as sucrose; starches derived from wheat, beans, rice and potatoes; natural resins such as gum Arabic, gelatin and tragakant; derivatives obtained from seaweed such as alginic acid, sodium alginate and ammonium alginate-calcium; cellulose derivatives such as methylcellulose, carboxymethylcellulose (Na+-form), and hypromellose; polyvinylpyrrolidone; inorganic salts, such as silicate of magnesium-aluminum. The amount of binder in the composition can vary from about 2 to about 20 wt.% from the total composition, more preferably from about 3 to about 10 wt.%, even more preferably from about 3 to about 6 wt.%.

Lubricating substance means a substance which when added to a formulation allows the release of tablets, granules, etc. out of the mold or matrix after presonality with metals, such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high-melting waxes and water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, glycols and DL-leucine. Lubricants usually add at the very last stage before pressing, because they must be on the surface of the granules and in the space between them and the parts of the tablet press. The amount of lubricant in the composition can vary from about 0.2 to about 5 wt.% from the total composition, preferably from about 0.5 to about 2 wt.%, more preferably from about 0.3 to about 1.5 wt.%.

Substances that give the composition fluidity, are substances that prevent caking and improve flowability of the mixture during granulation so that the granulate was homogeneous. Suitable substances for making the composition of turnover include silicon dioxide and talc. The amount of these substances in the composition can vary from about 0.1 to about 5 wt.% from the total composition, preferably from about 0.5 to about 2 wt.%.

The colors are fillers that provide a coloring composition or dosage form. Such fillers may is luminia. The amount of dye can vary from about 0.1 to about 1%.

Bioavailability means the rate and extent of penetration into the systemic circulation of the active ingredient or therapeutic component introduced dosage forms in comparison with a standard or control.

Values Formaxrefer to the maximum concentrations of antifungal compounds ("peak"), defined in the serum of the blood plasma.

The values of AUC (0-72 h) refers to the area under the curve of concentration of antifungal compounds in plasma/serum from time to time during the designated period.

Well-known, conventional methods for the manufacture of tablets. They include dry methods such as direct pressing and compressing the granulate produced by compression or wet methods, or other special procedures.

The compositions according to the present invention can be obtained by blending or granulation antifungal compounds with non-ionic surface-active agent containing a polyethylene oxide and polypropyleneoxide, along with the required amount of diluent and, if necessary, disintegrator, lubricant, a binder, a substance that gives the composition fluidity, and/Il composition can be compressed into a tablet.

The following examples describe compositions of the present invention, but not limit its scope.

Example 1. The composition of the capsules (see tab. 1).

Example 2. The composition of the capsules (see tab. 2).

Getting the capsules in examples 1, 2, 4, 5, 10-12, and 15
Mixed antifungal compound, Pluronic F68, the diluent in the form of microcrystalline cellulose, disintegrator in the form of (a) croscarmellose (Na+-form) and, if necessary, sodium lauryl sulfate, as in examples 10-12, in an appropriate mixer for 5-10 minutes was Dissolved binder in the form of polyvinylpyrrolidone in water and granulated above mixture with a solution of polyvinylpyrrolidone. Dried granulated mixture in the cradle oven at 45-50oWith over night or in a fluidized bed dryer to a moisture content of less than 2%. Sieved granules through a sieve of 20 μm and mixed the crushed granules within 5 minutes was Selected portion of the milled granules were mixed with magnesium stearate as a lubricant, sieved and then mixed sifted granules with the remaining crushed granules. Added (b) croscarmellose (Na+-form) and was stirred for 5-10 minutes Capsules of the appropriate size were filled hyaluronic F68 in 4 ml of distilled water. To the suspension was added 200 mg of antifungal compounds and mixed, obtaining a homogeneous suspension.

Comparative example. Capsules (see tab. 3).

Getting the capsules in comparative example
Mixed antifungal compound, lauryl sulfate, magnesium as surface-active compounds, microcrystalline cellulose and modified glycolic acid starch (Na+-form) in the mixer for 10 minutes was Added magnesium stearate and was stirred for 5 min. Capsules of the appropriate size were filled to a specified weight.

Determination of bioavailability
Dogs were administered 200 mg of antifungal compounds in the form of two capsules or suspension. Serum samples were collected at specific time and analyzed using high-performance liquid chromatography with detection by ultraviolet (HPLC/UV). The following table of values Formaxand AUC (0-72 h) are indicators of the bioavailability of antifungal compounds. The higher the value of CPD, the greater the total number of antifungal compounds accumulated in plasma serum for 72 hours (see next table. 4).

The results above show that the capsules in the NGO when compared to the capsules in the comparative example.

Example 4. The composition of the capsules (see tab. 5).

Example 5. The composition of the capsules (see tab. 6).

Example 6. The composition of the tablets (see tab. 7).

Example 7. The composition of the tablets (see tab. 8).

Example 8. The composition of the tablets (see tab. 9).

Example 9. The composition of the tablets (see tab. 10).

Preparation of tablets in examples 6-9 and 13-14
Mixed antifungal compound, Pluronic F68, the diluent in the form of microcrystalline cellulose, disintegrator in the form of (a) croscarmellose (Na+-form) and, if necessary, sodium lauryl sulfate, as in examples 13-14, in an appropriate mixer for 5-10 minutes was Dissolved binder in the form of polyvinylpyrrolidone in water and granulated above mixture with a solution of polyvinylpyrrolidone. Dried granulated mixture in the cradle oven at 45-50oWith over night or in a fluidized bed dryer to a moisture content of less than 2%. Sieved granules through a sieve of 20 μm and mixed the crushed granules within 5 minutes was Selected portion of the milled granules were mixed with magnesium stearate as a lubricant, sieved and then mixed sifted granules with the remaining crushed granules. Added (b) croscarmellose (Na+-form) and stirred the nl. 11).

Example 11. The composition of the capsules (see tab. 12).

Example 12. The composition of the capsules (see tab. 13).

Example 13. The composition of the tablets (see tab. 14).

Example 14. The composition of the tablets (see tab. 15).

Example 15. The composition of the capsules (see tab. 16).

Examples 16-23. The composition of the capsules.

Received as described in examples 1, 2, 4, 5 and 10-12, replacing Pluronic F68 on Pluronic F87.

Examples 24-29. The composition of the tablets.

Received as described in examples 6-9 and 13-14, replacing Pluronic F68 on Pluronic F127.


Claims

1. Pharmaceutical composition comprising (a) an antifungal agent of the formula

b) a diluent, characterized in that it further contains at least one nonionic surfactant in an amount of about 9.5 to 25 wt.%.

2. The pharmaceutical composition according to p. 1 wherein the nonionic surfactant is a copolymer of ethylene oxide and propylene oxide.

3. The pharmaceutical composition under item 1 or 2, where the nonionic surfactant, which is a copolymer of ethylene oxide and propylene oxide represented by the following chemical structure:

in which a represents a number in Ernesto-active substances and mean number of approximately 12 80, b refers to the number of about 20 to 56.

5. The pharmaceutical composition according to p. 3, where for nonionic surfactants and means 80, b means 27.

6. The pharmaceutical composition according to any one of paragraphs.1-5, where the diluent is microcrystalline cellulose.

7. The pharmaceutical composition according to any one of paragraphs.1-6, including advanced g) disintegrator.

8. The pharmaceutical composition according to p. 7, where the cage is croscarmellose (Na+-form).

9. The pharmaceutical composition according to any one of paragraphs.1-8, including optionally d) a binding agent.

10. The pharmaceutical composition according to p. 9, where the binder is polyvinylpyrrolidone.

11. The pharmaceutical composition according to any one of paragraphs.1-10, including additional f) lubricating substance.

12. The pharmaceutical composition according to p. 11, where the lubricant is magnesium stearate.

13. The pharmaceutical composition according to any one of paragraphs.1-12 in the dosage form in the form of capsules, tablets or powder for systemic use.

14. The pharmaceutical composition according to any one of paragraphs.1-12 in the dosage form in the form of capsules containing about 50-200 mg of the antifungal agent.

15. The pharmaceutical composition according to any one of paragraphs.1-12 in the dosage form in the form of AC is 2 in the dosage form in the form of tablets, containing about 50-200 mg of the antifungal agent.

17. The pharmaceutical composition according to any one of paragraphs.1-12 in the dosage form in the form of tablets containing about 50, 100 mg or 200 mg of the antifungal agent.

18. Pharmaceutical composition comprising approximately 18-50 wt.% antifungal agent of the formula

about 9.5 to 25 weight. % of at least one nonionic surfactant, about 12-60 wt.% the diluent, which is microcrystalline cellulose, about 4-10 wt.% cage mill, which is croscarmellose (Na+-form), about 3-6 wt.% the binder, which is polyvinylpyrrolidone, about 0.3 to 1.5 wt.% the lubricant, which is magnesium stearate.

19. The pharmaceutical composition according to p. 18, including, if necessary, about 3-8 wt.% lauryl sodium.

 

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