SK177598A3 - Oral composition comprising a triazole antifungal compound - Google Patents

Abstract

A pharmaceutical composition comprising: i) substantially inert beads; wherein said beads are coated with ii) an antifungal agent which is (-)-(2R-cis)-4-[4-[4-[4-[[-5-(2,4-difluorophenyl)-tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxypropyl]-3H-1,2,4-triazol-3-one; iii) a binder to enable the antifungal compound to adhere to said beads. The composition enables the antifungal compound, which has very low water solubility, to have enhanced bioavailability in mammals, such as humans.

Description

Technical field

The present invention relates to compositions enhancing or improving the bioavailability of a novel triazole antifungal compound.

BACKGROUND OF THE INVENTION

International patent application no. WO 95/17407, published June 29, 1995, discloses a new class of tetrahydrofuran / triazole antifungal compounds. In one of these, (2R-cis) -4- [4- [4- [4 - [[-5 (2,4-difluoro-phenyl) -tetrahydro-5- (1H-1,2,4-triazole-1)]] -ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl] 2-4-dihydro-2 - [(S) -1 ethyl-2 (S) -hydroxypropyl] -3H-1,2, 4-triazol-3-one ("antifungal compound"), a potent antifungal activity in suspension was found against opportunistic fungi such as Aspergillis, Candida, Cryptococcus and others. However, solid compositions in powder or granular form have shown reduced antifungal activity and / or bioavailability, possibly due to the extremely low water solubility of this compound. It would also be desirable to deliver this antifungal compound in a pharmaceutical composition that enhances or improves its antifungal activity and / or bioavailability.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising:

(i) a plurality of grains; (ii) an antifungal agent to which the grains are coated and having the formula I i

and (iii) a binder which allows the antifungal agent to adhere to said grains.

The pharmaceutical composition may also contain other excipients such as e.g. (iv) surfactants, (v) emollients, (vi) antifoams and dyes. It may be part of other delivery systems or dosage forms, such as capsules, tablets or grains for reconstitution.

Surprisingly and unexpectedly, it has been found that in the form of a coating bound to a grain by means of a suitable binder, the antifungal compound has an increased or equivalent bioavailability compared to when it is in the form of a suspension. These results are truly surprising and unexpected because known sources (e.g., Peter G. Welling: Pharmacokinetics, Processes and Mathematics, American Chemical Society, Washington DC, ACS Monograph 185, 1986, p. 57) report that solutions and suspensions generally provide more satisfactory bioavailability than capsules or tablets. See also J. G. Nairn in Remington's Pharmaceutical Sciences, 18th Edition, 1990, Mack Publishing Co., Chapter 83, p. 1519 that, as a result of drug absorption in the dissolved state, it is repeatedly found that the rate of absorption when administered orally decreases in the following order: aqueous solutions> aqueous suspensions> capsule or tablet.

It is an advantage of the present invention that the antifungal compound can be delivered in a pharmaceutical composition that can be part of solid, i.e., "dry" delivery systems or dosage forms such as capsules, tablets or loose grains having significant antifungal activity and / or bioavailability.

WO 95/17407, published June 29, 1995, discloses an antifungal compound of formula II

wherein R ¹ is alkyl (C 3 to C 8) straight or branched, substituted with one or more hydroxy, as well as esters, ethers or a pharmaceutically acceptable salt thereof. A particularly preferred compound of the group mentioned in Examples 24 and 32 of WO 95/17407 is the antifungal compound (-) - (2R-cis) -4- [4- [4- [4 - [[- 5 (2,4)] -difluoro-phenyl) -tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl] 2-4-dihydro-2- [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H-1,2,4-triazol-3-one (hereinafter the "antifungal compound"). Its total formula is C37H42F2N eO4l molar mass 700.2 g / mol, melting point 164165 ° C, [α] D ²⁵ = -29 ° + -3 ° (c = 1.0, CHCl 3) and its structure is as follows:

Micron particles of the antifungal compound can be obtained either at the final stage of production of the antifungal compound or by using conventional micronising techniques following the conventional crystallization procedure (s).

In micronizing, the antifungal compound can be milled to the desired particle size by conventional techniques, e.g. ball mill, ultrasonic or preferably fluid bed mills, such as a fluid bed mill from Plastomer Products, Newton, Pennsylvania 18940. Using a fluid bed mill, the desired particle size can be achieved by controlling the rate of addition of the antifungal compound to the mill.

Approximately 99% of the micronised antifungal particles have a size less than or equal to 100 gm, of which 95% have a size less than or equal to 90 gm. It is preferred that approximately 99% of the micronised particles have a size less than or equal to 50 μηη, of which 95% have a size less than or equal to 40 µm. Preferably, 99% of the micronised particles have a size less than or equal to 20 μηη, of which 95% have a size less than or equal to 10 μηη.

The antifungal compound is used in the composition in amounts effective to suppress the above-mentioned organisms or fungi. These amounts may vary from 2 to 50 wt. % of the composition, preferably from 6 to 40 wt. %, more preferably from 5 to 33 wt. %. The amount of composition in a particular dosage form, e.g. in a capsule, tablet, and the like, from 10 to 300 mg of the antifungal compound per unit dosage form, preferably from 50 to 200 mg, can be varied.

The compositions of the present invention may be prepared by dissolving or suspending the antifungal compound in a suitable solvent system comprising a binder and optionally also one or more additives such as a surfactant, emollient, antifoam and / or coloring agent and applying the solution or suspension to an inert solvent. grains.

The pharmaceutical composition of the present invention may be incorporated into any suitable dosage form, such as capsules, tablets, or loose grains, to obtain the structure. For example, the composition may be compressed into a tablet form using a suitable buffering agent, such as microcrystalline cellulose, and optionally a disintegrant, a lubricant, a glidant and the like.

The following terms are used to describe the present pharmaceutical compositions, the ingredients that may be used in their formulation, and the methods for achieving their bioactivity or bioavailability.

The grains or loops are discrete particles, preferably spherical in shape, serving as a solid substrate for coating the antifungal compound and forming the largest portion of the compositions or dosage form. The grains can be made from sugars (carbohydrates and their derivatives) of the lactose, sucrose, mannitol and sorbitol type. They may also be prepared from starches derived from wheat, rice grains and potatoes, or from celluloses such as microcrystalline cellulose. The non-pareil seed source is known as Nu-pareil PG, a trademark of Crompton and Knowles Ingredient Technology Corporation in Mahawah, New Jersey. The microcrystalline cellulose grain source is known as Celphere, a trademark of FMC Corporation, Philadelphia, Pennsylvania. Grains of different mesh sizes can be used, e.g. 18/20 mesh, 25/30 mesh and 40/50 mesh. This mesh size refers to particles or grains with diameters ranging from 1.0 to 0.297 mm. Preferably, the grain dimensions or diameters lie in a relatively narrow interval, such as e.g. 1.0-0.84 mm (18/20 mesh) or 0.71-0.59 mm (25/30 mesh) or 0.42-0.297 mm (40/50 mesh). The grains should be "inert", which means that the grains themselves have little or no antifungal activity. The amount of grains in the composition may vary from 50 to 90 wt. % of the total composition, preferably from 60 to 80 wt. %, preferably from 65 to 75 wt. %.

The term "binder" refers to substances which bind or "stick" an antifungal compound and other grain additives to allow their coating. Suitable binders include sucrose-type carbohydrates, starches derived from wheat, rice grains and potatoes, natural acacia-type gelatin, gelatin and tragacanth, alginic acid-derived seaweed derivatives, sodium alginate and ammonium calcium alginate, methylcellulose-type cellulose materials, hydroxypropyl cellulose, hydroxypropylmethylcellulose , hydroxyethylcelluloses and sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidones), protein hydrolysates, methacrylic acid and its salts, as well as inorganic compounds such as magnesium aluminum silicate. A commercially available binder composition is known as Opadry powers, a trade name of Coloron Corporation, West Point, Pennsylvania. Opadry powders may contain hydroxypropylmethylcellulose together with a plasticizer such as polyethylene glycol and a surfactant such as polysorbate-80. The amount of binder in the composition may range from 1 to 10 wt. % of the composition, preferably from 2 to 8 wt. %. more preferably from 3 to 6 wt. %.

Disintegrants are materials that are added to the composition to facilitate disintegration and release the drug. Disintegrants include starches, cold water soluble modified starches of the sodium carboxymethyl starch derivative type, natural and synthetic gelatins such as e.g. carob, guar, tragacanth and agar, cellulose derivatives of methylcellulose type and sodium carboxymethylcellulose, microcrystalline croscarmellose cellulose, alginates of alginic acid and sodium alginate, bentonite clays and effervescent mixtures. The amount of disintegrant in the composition may range from 2 to 15 wt. % of the composition, preferably from 4 to 10 wt. %.

A surfactant is a compound capable of reducing the surface tension between two immiscible phases, due to the fact that its molecule consists of two parts, one of which is hydrophilic in nature and the other hydrophobic in nature.

Non-ionic surfactant refers to a surfactant which lacks the true ionic charge and is not subject to visible dissociation in an aqueous environment. The properties of the nonionic surfactant are highly dependent on the ratio of hydrophilic and hydrophobic groups in the molecule. Hydrophilic groups include an oxyethylene group (-OCH ₂ CH ₂ -) and a hydroxyl group. By varying the number of these groups in a hydrophobic molecule such as a fatty acid, substances ranging from strongly hydrophobic and water-insoluble such as glycerol monostearate to highly hydrophilic and water-soluble such as macrogels can be obtained. Between these two extreme types there are those in which the ratio of hydrophilic and hydrophobic groups is equally balanced, such as macrogel esters and sorbitan ethers and derivatives. Suitable nonionic surfactants can be found in Martindale, The Extra Pharmacopoeia, 28th Edition, 1982, The Pharmaceutical Press London, UK, p. Such nonionic surfactants include block copolymers of ethylene oxide and propylene oxide, glycolic and glycerol fatty acid esters, polyoxyethylene fatty acid esters (macrogel esters), polyoxyethylene fatty acid ethers and derivatives thereof (macrogel ethers) and sorbitol esters. Preferably, the nonionic surfactant is a block copolymer of ethylene oxide and propylene oxide.

Suitable block copolymers of ethylene oxide and propylene oxide have the common name "poloxamers" with the following chemical structure

CH ₃

HO- (CH ₂ CH 2 O) _a (CH 2 Cl) b (CH 2 CH ₂ O) _a H wherein a is an integer of 10-110, preferably 12-101, more preferably 12-80, and b is an integer of from 20 to 60 , preferably from 20 to 56, also from 20 to 27. The most preferred values are for a 80 and for b 27, which has a surfactant otherwise known as Pluronic ® F68, a trademark of BASF Corporation, Mount Olive, New Jersey , USA. Pluronic® F68 surfactant is also known as Poloxamer 188. This surfactant has a molar mass of 8,400 g / mol, is a solid at 20 ° C, and has a Brookfield viscosity of 1000 cP (1 Nm ² s) at 77 ° C. Other suitable block copolymers of ethylene oxide and propylene oxide include Pluronic F87, also known as Poloxamer 237, in which a is 64 and b is 37, and Pluronic F127, also known as Poloxamer 407, in which α 101 and 56.

Suitable glycol and glycerol fatty acid esters and derivatives thereof include glycerol monooleate and similar water-soluble derivatives.

Suitable polyoxyethylene fatty acid esters (macrogel esters) include polyoxyethylene castor oil and hydrogenated castor oil derivatives.

Suitable polyoxyethylene fatty acid ethers and derivatives thereof (macrogel ethers) include Cetomacrogel 1000, Lauromacrogels (a series of chain length lauryl ethers), e.g. Laureth 4, Laureth 9 and Lauromacrogel 400.

Suitable sorbitan esters (esters of one or more hydroxyl groups in sorbitans with fatty acids such as stearic, palmitic, oleic or lauric) include e.g. Polysorbate 20, Polysorbate 60, Polysorbate 65, Polysorbate 80, Polysorbate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate and sorbitan tristearate.

The amount of surfactant in the composition may range from 0.5 to 25 wt. % of the total composition, preferably from 5 to 15 wt. %.

Anionic surfactant is a surfactant which has its own negative ionic charge and dissociates to a large extent in the aqueous environment. The present composition can optionally also contain an anionic surfactant, e.g. sodium lauryl sulfate, the amount of which may range from 1 to 10 wt. % of the total composition, preferably from 3 to 8 wt. %.

The term plasticizer refers to substances which soften the binder. Suitable plasticizers include propylene glycol, glycerol, diethyl phthalate, dibutyl sebacate, triethyl citrate, hydrogenated glycerides, polyethylene glycols, polyethylene oxides, triacetin and the like. The amount of plasticizer in the composition may range from 1 to 2 to 5 wt. %.

Anti-foaming agents are substances used to limit the formation of foam, which occurs as a result of mechanical agitation or as a result of the formation of gases from nitrogenous materials or other substances, which is a problem during processing. Examples include sodium chloride metal salts, octanol C6-C12 alcohols, sulfonated oils, simethicone-type silicone ethers, organic phosphates and the like. The amount of antifoam in the composition may range from 0.05 to 5 wt. %, preferably from 0.1 to 2 wt. %.

Glidants are materials that prevent caking and improve the flow characteristics of the granulates so that the flow is smooth and even. Suitable glidants include, for example, silica. Their amount in the composition may range from 0.1 to 5 wt. % of the total composition, preferably from 0.5 to 2 wt. %.

Lubricant refers to a substance added to the dosage form of a composition so that tablets, granules, and the like, after being compressed, can be released from the mold or die by reducing friction or wear. Suitable lubricants include metal stearates such as magnesium, calcium or potassium stearate, stearic acid, high melting waxes and water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, polyethylene glycols and D, L-leucine. Lubricants are generally added in the very last step prior to compression, as they must be present on and between the granule surfaces as well as on the tablet press components. The amount of lubricant in the composition may range from 0.2 to 5 wt. % of the composition, preferably from 0.5 to 2 wt. %.

Dyestuffs are excipients which impart color to the composition or dosage form. These excipients include food colors alone and food colors adsorbed on a suitable adsorbent such as clay or alumina.

The amount of dye can vary from 0.1 to 5 wt. % of the composition, preferably from

0.1 to 1 wt. %.

A dosage form is a composition comprising an antifungal compound formulated into a delivery system, e.g. tablets, capsules, oral gel, powder for adjustment or suspension in conjunction with inactive ingredients.

A capsule is a special container or capsule made of methylcellulose, polyvinyl alcohol or denatured gelatin or starch for the maintenance of compositions containing the active antifungal compound. The hard shell capsules are usually made of a mixture of bone and skin pork gelatin with a relatively high gel strength. The capsule itself may contain small amounts of colorants, opacifiers, opacifiers, emollients and preservatives.

The term tablet refers to a compressed or cast solid dosage form containing the active ingredient (antifungal compound) with preferred diluents. A tablet may be prepared by compressing the mixture or granules obtained by wet granulation, dry granulation, upsetting, or by compressing the mixture containing the coated active grains.

The grains for treatment are loose, coated grains which can be suspended in water, juices and musts such as apple cider.

Bioavailability is the term for the rate and extent of absorption of an active drug or therapeutic agent in the systemic circulation from the administered dose as compared to a standard or control.

As the value of x _{m and} c are indicated maximum ( "peak"), the concentration of the antifungal compound measured in plasma (serum).

AUC values (0-72 h) are areas under the plasma concentration-time curves (serum) versus time for the indicated time.

Conventional methods for preparing tablets are known. These include dry methods, such as direct compression or compression of granules obtained by tamping, as well as wet methods or other special processes.

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In the following examples, compositions of the present invention comprising an antifungal compound are described. However, these examples are not to be construed to limit the scope of the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Coated grains in capsules

component grams in the handle weight. % Antifungal compound, micronised 135 20.3 Opadry YS-1-7006 30 4.5 simethicone 1.42 0.2 Water Purified, USP (Evaporates) 700 ml - Non-Pareil Mesh (25/30 mesh) 500 75 Total (without water) 666.42 100

Example 2 Coated grains in capsules component milligrams in the handle weight. % Antifungal compound, micronised 75 11.0 Opadry YS-1-7006 30 4.4 Pluronic F68 surfactant 75 11.0 simethicone 0.7 0.1 Water Purified, USP (Evaporates) 500 ml - Non-Pareil Mesh (25/30 mesh) 500 73.5 Total (without water) 680.7 100

Preparation of Coated Grains in Capsules of Examples 1, 2 and 5.

Dissolve in water Opadry YS-1-7006 and Pluronic F68 or sodium lauryl sulfate. Add Simethicone with stirring. Add the antifungal compound with slow stirring until a homogeneous suspension is formed. Pass the suspension through a 25 mesh screen. Spray the suspension onto non-pareil meshes using a fluid bed coater. Dry the coated grains overnight and determine the amount of antifungal compound. Fill coated capsules of appropriate size to the required fill weight.

Preparation of the aqueous suspension in Comparative Example 3

Prepare a suspension containing 59.8 mg of Pluronic F68 in four ml of distilled water. Add 400 mg of the antifungal compound to this mixture and mix until a homogeneous suspension is obtained.

Preparation of the powder mixture in capsules in Comparative Example 4

The milligram component in the capsule wt. %

Antifungal compound, micronised 100.0 28.6 Sodium lauryl sulphate (surfactant) 22.5 6.4 Microcrystalline cellulose 178.0 50.9 Acid sodium starch glycolic 45.0 12.8 Magnesium stearate 4.5 1.3 Pretty 350 100

In a blender, mix for 10 minutes a mixture of the antifungal compound, sodium lauryl sulfate (surfactant), microcrystalline cellulose and acid sodium salt. starch glycolic. Add magnesium stearate and mix for minutes to form a homogeneous powder. Fill the capsule with the appropriate size to the required fill weight.

Bioavailability tests

Dogs are given a two-milligram dose of the antifungal compound in either two capsules or in suspension. Serum samples are collected at certain time intervals and analyzed by HPLC / UV (high pressure liquid chromatograph equipped with ultraviolet detector). The c _max and AUC (0-72 h) values in the table below are indicators of bioavailability. The greater the AUC, the greater the total amount of antifungal compound that accumulated in plasma serum at 72 hours.

indicators bio usability coated grains in capsules, Example 1 coated grains in capsules of Example 2 Control suspension, Comparative Example 3 Powder mixture in capsules, Comparative Example 4 C max (gg / ml) 1:43 1:37 1.21 0.95 AUC (0-72 hrs) 50,21 50.17 47,98 29.72

The results shown show that the capsules of Examples 1 and 2 exhibit increased bioavailability over the aqueous suspensions of Comparative Example 3, and in particular the powder blends in the capsules of Comparative Example 4.

Example 5

Coated grains in capsules

component grams in the handle weight. % Antifungal compound, micronised 75 11.80 Opadry YS-1-7006 30 4.72 Sodium lauryl sulfate 30 4.72 simethicone 1.0 0.16 Water Purified, USP (Evaporates) 500 ml - Non-Pareil Mesh (25/30 mesh) 500 78.60 Total (without water) 636.0 100

Claims (19)

PATENT CLAIMS A pharmaceutical composition comprising (i) a plurality of grains, (ii) an antifungal agent by which the grains are coated and having the formula I, and (iii) a binder allowing adhesion of the antifungal agent to said grains. Composition according to claim 1, characterized in that the grains are made of carbohydrates, starch or microcrystalline cellulose. Composition according to claim 1, characterized in that the grains are made of carbohydrates. Composition according to claim 1, characterized in that the grains have a size ranging from 18/20 to 45/50 mesh. The composition of claim 1, wherein the concentration of the antifungal compound in the composition may be in the range of 5 to 33 wt. %. The composition of claim 1, wherein the binder is hydroxypropylmethylcellulose. The composition of claim 1, further comprising (iv) a surfactant. The composition of claim 7, wherein the surfactant is a nonionic surfactant. The composition of claim 7, wherein the surfactant is a block copolymer of ethylene oxide and propylene oxide. The composition of claim 7, wherein the surfactant is an anionic surfactant. The composition of claim 10, wherein the anionic surfactant is sodium lauryl sulfate. The composition of claim 7, further comprising (v) a plasticizer. The composition of claim 12, wherein the emollient is polyethylene glycol. The composition of claim 13, further comprising (vi) a defoamer. The composition of claim 14, wherein the antifoam is Simethicone. 16. The composition of claim 1, wherein the composition is in a capsule dosage form. The composition of claim 16, wherein the amount of antifungal compound in the capsule is in the range of 50 to 300 mg. The composition of claim 16, wherein the amount of antifungal compound in the capsule is in the range of 50 to 200 mg. The composition of claim 1, further comprising 11 to 20 wt. % antifungal compound, 73 to 75 wt. 0.5 to 15 wt. % surfactant, 4.7 to 5 wt. % binder which is hydroxypropylmethylcellulose and 0.5 to 1.5 wt. % defoamer.