DESC:The following specification describes the invention and the manner in which it has to be performed:

FIELD OF INVENTION
The present invention relates to the field of solid dispersions of in situ salts of poorly water soluble triazole drugs with improved bioavailability, to processes for their preparation and to use the solid dispersion in pharmaceutical composition. Specifically, the present invention relates to solid dispersions with improved bioavailability resulting from incorporation of poorly water soluble triazole class of drugs into acidic environment in presence of pharmaceutically acceptable carriers.
BACKGROUND
Poorly water soluble triazole drugs often exhibit incomplete and irregular absorption, resulting in low and erratic bioavailability. Although these drugs are often soluble in a low pH environment, such as the stomach (pH 1-2), these drugs are largely insoluble at a higher pH environment, as found in the small intestine (pH 5-7). Consequently, such drugs generally precipitate out of solution as they pass from the low pH environment of the stomach into the higher pH environment of the small intestine.
Thus far, the development of these drugs has been problematic as their solubility in aqueous solution is highly pH-dependent which results in difficulties in providing sufficient and easily controlled bioavailability.
Salt formation or “salification” is the most common approach for improving the solubility, and hence, bioavailability of poorly water soluble drugs. A pharmaceutical salt is a newly engineered molecule produced by chemically fusing two moieties: the active drug molecule, which is either weakly acidic (or basic), and a corresponding basic (or acidic) counterion. With the progress in medicinal chemistry and, especially due to the recent introduction of combinatorial chemistry and high-throughput screening in identifying new chemical entities (NCE), the solubility of new drug molecules has decreased sharply. This has resulted in an upsurge in interest for salt formation approach.
Owing to the attractive advantages offered by salt formation process, the pharmaceutical salts of poorly water soluble triazole drugs can be expected to provide better formulation opportunities in comparison to their free base counterparts. However, the salification process is also associated with several drawbacks. The salt formation and its isolation steps may add several unit operations in the already tedious pharmaceutical product development process. Other limitations include, low reaction yield of the pharmaceutical salts, physicochemical stability concerns and involvement of hazardous solvents.
It is therefore preferable to develop a technique, which circumvents the salt isolation steps, physiochemical stability issues and reaction yield concerns while utilizing an ecofriendly alternative green solvent for difficult to dissolve drugs.
SUMMARY OF INVENTION
The present invention relates to a solid dispersion comprising a pharmaceutically acceptable salt of a poorly water soluble triazole drug prepared in in situ condition and at least one hydrophilic polymer.
In another aspect, the present invention relates to a process for preparing the solid dispersion comprising: 1) preparing drug solution by adding the triazole drug into acidified solvent, 2) adding dispersion of hydrophilic polymer to drug and, 3) isolating and drying of the solid dispersion.
In another aspect, the present invention relates to a process for preparing the said solid dispersion comprising the use of green solvent. In another aspect, the present invention relates to a pharmaceutical dosage form comprising the said solid dispersion of the poorly water soluble triazole drug.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts the morphology of the precipitated Posaconazole solid dispersion particles, observed using scanning electron microscopy (SEM).
DETAILED DESCRIPTION
As used herein, the term “solid dispersion”, refers to a group of solid formulations generally consisting of a pharmaceutically acceptable carrier matrix and the poorly water soluble triazole drug homogeneously dispersed therein. The matrix may be either crystalline or amorphous. The drug may be dispersed molecularly, in amorphous particles (clusters), or in crystalline particles.
As used herein, the term “pharmaceutically acceptable salt” may include a variety of available pharmaceutical salts prepared by organic or inorganic acids. The inorganic acid may be selected from the group comprising hydrobromic acid, chlorous acid, hypobromous acid, hydrochloric acid, hypochlorous acid, nitric acid, nitrous acid, pernitric acid, sulfuric acid, sulfurous acid, hyposulfurous acid, chloric acid, bromous acid, bromic acid, persulfuric acid, pyrosulfuric acid, disulfurous acid, dithionous acid, peroxydisulfuric acid, hydrosulfuric acid, perchloric acid, phosphoric acid, phosphorous acid, hypophosphous acid, perchromic acid, boric acid and arsenic acid. The organic acid may be selected from the group comprising citric acid, fumaric acid, malic acid, lactic acid, glycolic acid, tartaric acid, succinic acid, ascorbic acid, aspartic acid, acetic acid, formic acid, oxalic acid, gallic acid, malonic acid, methane sulfonic acid, proprionic acid, pthalic acid, thioacetic acid, thioglycolic acid, thiobromoacetic acid, thiochloroacetic acid, trichloroacetic acid and trifluoro acetic acid.
As used herein, the term “poorly water soluble” refers to an active pharmaceutical agent or drug in an amount equal to its maximum dose strength that is not fully soluble in about 250 mL or less of an aqueous media across a pH range of about 1 to about 7.5.
As used herein, the term “triazole drug” refers to a free base drug containing at least one heterocyclic ring of three nitrogen and two carbon atoms, in particular each of five isomeric compounds containing such a ring with two double bonds. The two isomeric forms of triazole include 1,2,3-triazole and 1,2,4-triazole. The poorly water soluble triazole drug according to this invention may be selected from a group comprising but not limited to Fluconazole, Isavuconazole, Itraconazole, Voriconazole, Pramiconazole and Posaconazole or a combination thereof.
As used herein, the term “hydrophilic polymer” refers to a group of polymers, which may dissolve, disperse or swell in water and modify the physical properties of aqueous systems in the form of gelation, thickening or emulsification/stabilization. These polymers usually have repeating units or blocks of units; the polymer chains contain hydrophilic groups that are substituents or are incorporated into the backbone. The hydrophilic groups may be of synthetic or natural origin and may be selected from a group comprising but not limited to methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, sodium carboxymethylcellulose, pottasium carboxymethyl cellulose, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, poly(meth)acrylic acid polymers, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohol, polyethylene glycol, gelatin, sodium alginate, starch, gum acacia, dextrin, hyaluronic acid, sodium chondroitin sulfate, propylene glycol alginate, agar, tragacanth, xanthan gum, macrogol, polyethylene oxide, polypropylene oxide, copolymer of ethylene oxide and propylene oxide, carrageenans, d-galactomannans and a mixture thereof.
As used herein, the term “in situ condition” refers to a state of a component in the reaction mixture. More specifically, it denotes that isolating pharmaceutically acceptable salt of the poorly water soluble triazole drug is not required.
As used herein, the term “acidified solvent” refers to a solution prepared by dissolving an organic or inorganic acid into a polar solvent.
As used herein, the term “isolating” refers to one or more methods related to removal of solvent by techniques known in the art, which include evaporation, distillation, filtration, cooling, concentrating the reaction mass, and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolating.
As used herein, the term “drying” refers to one or more methods including use of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer and flash dryer.
As used herein, the term “green solvent”, refers to type of solvent, which when used in chemical production, can minimize the environmental impact. The green solvents according to this invention may include water, short C-chain alcohols, ketones, esters, acetic acid and a mixture thereof. Alcohols may be selected from a group comprising but not limited to methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, propylene glycol and a mixture thereof. Ketones may be selected from a group comprising but not limited to acetone, methylethyl ketone, 2-propanone, 2-butanone a mixture thereof. Esters may be selected from a group comprising but not limited to ethyl acetate, propyl acetate, isopropyl acetate a mixture thereof.
As used herein, the term “pharmaceutical dosage form”, refers to any acceptable dosage form, such as a powder, effervescent powder, sachet, tablet, capsule, pill, suppository, implant, wafer, cream, ointment, syrup, gel, suspension, and the like. The dosage form may be an orally deliverable dosage form, such as a tablet or capsule, and typically a capsule. The pharmaceutical dosage form may be prepared using the usual pharmaceutically acceptable excipients.
In one embodiment, the composition comprises the poorly water soluble triazole drug and the hydrophilic polymer in a ratio by weight of about 10:1 to about 10:1. In a further embodiment, the composition comprises the poorly water soluble triazole drug and the hydrophilic polymer in a ratio by weight of about 8:1 to about 1:8. In a further embodiment, the composition comprises the poorly water soluble triazole drug and the hydrophilic polymer in a ratio by weight of about 4:1 ratio to 1:4.
In one embodiment, the solid dispersion of present invention comprises at least one poorly water soluble triazole drug in a therapeutically effective amount. In a further embodiment, the solid dispersion of present invention comprises one poorly water soluble triazole drug in a therapeutically effective amount.
In one embodiment, the solid dispersion of present invention comprises the one poorly water soluble triazole drug in the range of about 0.1 to about 80% w/w. In a further embodiment, the solid dispersion of present invention comprises the one poorly water soluble triazole drug in the range of about 0.5 to about 70% w/w. In a further embodiment, the solid dispersion of present invention comprises the one poorly water soluble triazole drug in the range of about 0.75 to about 50% w/w. In a further embodiment, the solid dispersion of present invention comprises the one poorly water soluble triazole drug in the range of about 1 to about 30% w/w. In a further embodiment, the solid dispersion of present invention comprises the one poorly water soluble triazole drug in the range of about 1 to about 10% w/w.
In one embodiment, the process of preparing the solid dispersion of the present invention comprises the steps of: a) preparing drug solution by adding the triazole drug into acidified solvent; b) adding polymer dispersion to drug; and c) isolating and drying of the solid dispersion.
In one embodiment, the process of preparing the solid dispersion of the present invention comprises the steps of: a) preparing a polymer solution into acidified solvent; b) adding drug into the polymer solution; and c) isolating and drying of the solid dispersion.
In one embodiment, the process of preparing the solid dispersion of the present invention comprises the steps of: a) preparing a polymer and drug solution; b) adding acid to the solution; and c) isolating and drying of the solid dispersion.
In one embodiment, the process of preparing the solid dispersion of the present invention comprises the steps of: a) preparing an acidified solution; b) adding drug and polymer to the solution; and c) isolating and drying of the solid dispersion.
In one embodiment, the process of preparing the solid dispersion of the present invention comprises the use of one green solvent. In a further embodiment, the process of preparing the solid dispersion of the present invention comprises the use of a combination of green solvents.
In a further embodiment, the process of preparing the solid dispersion of the present invention comprises the use of water as green solvent. In a further embodiment, the process of preparing the solid dispersion of the present invention comprises the use of water and alcohol combination as green solvent.
In one embodiment, the isolating of the solid dispersion of the present invention may include evaporation, distillation, filtration, cooling, concentrating the reaction mass, and the like.
In one embodiment, the isolating of the solid dispersion of the present invention may include stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolating.
In one embodiment, the isolating of the solid dispersion of the present invention may include addition of an anti-solvent.
In one embodiment, the isolating of the solid dispersion of the present invention may include distillation performed at atmospheric pressure or above, or under reduced pressures and at a temperatures less than about 120°C, less than about 100°C, less than about 90°C, or any other suitable temperatures.
In a further embodiment, the isolating of the solid dispersion of the present invention may include the use of any temperature with vacuum conditions as long as there is no increase in the impurity levels of the product due to decomposition.
In one embodiment, the drying of the solid dispersion of the present invention may include use of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like.
In one embodiment, the drying of the solid dispersion of the present invention may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 1 20°C, less than about 100°C, less than about 80°C, or any other suitable temperatures.
In one embodiment, the drying of the solid dispersion of the present invention may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
In one embodiment, the solid dispersion of the present invention is stable for a period of at least one year when subjected to storage conditions of from about 15 °C to about 25 °C and from about 50% relative humidity to about 60% relative humidity, and is stable for a period of at least about 3 months when subjected to storage conditions about 40 °C and about 75% relative humidity.
In one embodiment, the solid dispersion of the present invention is meant for administration through oral, sublingual, buccal, nasal, inhalational, rectal and parenteral route. In a further embodiment, the solid dispersion of the present invention is meant for administration through oral, sublingual and buccal route. In a further embodiment, the solid dispersion of the present invention is meant for administration through oral route.
In one embodiment, the solid dispersion of present invention under fed conditions is therapeutically similar to the reference composition under fed conditions. In one further embodiment, the solid dispersion of present invention exhibits an absorption profile under fed conditions which is similar to the absorption profile of the reference composition under fed conditions. In one further embodiment, the solid dispersion of present invention exhibits an absorption profile under fed conditions which is bioequivalent to the reference composition under fed conditions.
In one embodiment, the solid dispersion of present invention under fasting conditions is therapeutically similar to the reference composition under fasting conditions. In one further embodiment, the solid dispersion of present invention exhibits an absorption profile under fasting conditions which is similar to the absorption profile of the reference composition under fasting conditions. In one further embodiment, the solid dispersion of present invention exhibits an absorption profile under fasting conditions which is bioequivalent to the reference composition under fasting conditions.
In one embodiment, the dosage form comprising the solid dispersion of present invention may be formulated for immediate release or sustained release. A "sustained release formulation" is a formulation which is designed to slowly release a therapeutic agent in the body over an extended period of time, whereas an "immediate release formulation" is a formulation which is designed to quickly release a therapeutic agent in the body over a shortened period of time. In one further embodiment, the immediate release formulation may be coated such that the therapeutic agent is only released once it reached the desired target in the body (e.g. the stomach). In one further embodiment, the pharmaceutical composition is formulated for immediate release.
In one embodiment, the dosage form comprising the solid dispersion of present invention may further comprise pharmaceutical excipients such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizers, and combinations thereof.
While this invention has been described with reference to specific embodiments, the scope of the invention is not limited to these embodiments alone. Further some of the embodiments are illustrated as examples below and are meant to be representative only. The invention may be construed in any other forms and embodiments which may be understood and applied by a person skilled in the art within the scope of the present invention.

EXAMPLES
Example 1. Solid dispersion of Itraconazole
S. No. Ingredient Weight (per unit dose)
1. Itraconazole 100 mg
2. HPMC 200 mg
3. HCl Concentrated 0.025 ml
4. Methanol 1.875 ml
5. Purified water 0.100 ml

1. To a stirred mixture of methanol (97.5 ml) and concentrated hydrochloric acid (2.5 ml), Itraconazole (10 g) was added and a clear solution was obtained after 10 min.
2. In a separate container, HPMC was dispersed in a mixture of methanol and water (90:10 v/v) and stirred for 30 min to give a clear dispersion (100 mg/ml).
3. Solution obtained in step 1 was gradually added with stirring to clear dispersion obtained in step 2. After continuing stirring for 15 min, the final dispersion is spray dried. The powder was analyzed for assessing the solid state of the composition.

Example 2. Evaluation of pharmacokinetic parameters in Rat studies
The solid dispersion of itraconazole (Example 1) was orally administered to Wistar rats (n=3) maintained under fasting conditions.
Pharmacokinetic parameter Treatment groups
(values expressed as Mean±SD; n=3)
Itraconazole free base Itraconazole hydrochloride Solid dispersion of Example 1
Tmax (h) 7.33±1.15 5.33±2.31 8.00±0.00
Cmax (ng/ml) 40.0±15.1 195±66.7 1006±263
AUC(0-last) (ng.h/ml) 326±37 2199±498 14690±3680

The values of the pharmacokinetic parameters, i.e., Cmax and AUC(0-last) achieved by the solid dispersion of present invention were found to be enhanced by factors of approximately 25 and 45 folds to those of itraconazole free base. Similarly, the values of Cmax and AUC(0-last) achieved by the solid dispersion of present invention were found to be enhanced by factors of approximately 10.5 and 6.7 folds to those of itraconazole salt.

Example 3. Solid dispersion of Posaconazole
S. No. Ingredient Weight (per unit dose)
1. Posaconazole 100 mg
2. HCl Concentrated 0.2 ml
3. Methanol 2.5 ml
4. HPMCAS 200 mg
5. NaOH 10% 0.23 ml
6. Purified water 5.0 ml

1. To a stirred mixture of methanol (250 ml) and concentrated hydrochloric acid (20 ml), Posaconazole (10 g) was added and a clear solution was obtained after 15 min.
2. In a separate container, HPMCAS (20 g) was dispersed in 230 ml of 10% NaOH and stirred for 15 min to give a clear dispersion.
3. Solution obtained in step 1 was gradually added with stirring to clear dispersion obtained in step 2. Additional 270 ml purified water was added and stirring continued for 15 min.
4. The uniform suspension obtained in step 3 was then used for fluid bed granulation on microcrystalline cellulose particles.

Example 4.
The granules of Example 3 were blended with pharmaceutical excipients, croscarmellose sodium, silicon dioxide and magnesium stearate, and the blend was compressed into tablets. The dissolution study on the Posaconazole solid dispersion tablets was performed for 2 hours in 0.01 N HCl followed by pH 6.8 phosphate buffer.
Time % Dissolution
0.01 N HCl
60 min. Not detected
120 min 2.3%
pH 6.8 buffer
10 93
15 94
30 94
45 94
50 96

The dissolution study results suggest that the Posaconazole solid dispersion could be utilized to prepare delayed release pharmaceutical dosage forms.

The processes similar to that described in Example 1 and Example 3 may be utilized to prepare the solid dispersions of Voriconazole, Fluconazole and Isavuconazole, which may be utilized in a variety of pharmaceutical dosage forms. This approach provides benefit of in situ salification as an alternative to use of solvents like DMSO. While the manufacturing process is simplified by eliminating isolating step at various stages like salt, precipitated polymer particles etc., it also ensures that amorphous base drug is available for therapeutic action.
,CLAIMS:Claims:
1. A solid dispersion comprising a pharmaceutically acceptable salt of a poorly water soluble triazole drug and a hydrophilic polymer, wherein the solid dispersion is prepared in in situ condition using a triazole drug.
2. The solid dispersion of claim 1, wherein the poorly water soluble triazole drug comprise a drug selected from a group comprising Fluconazole, Isavuconazole, Itraconazole, Voriconazole, Pramiconazole, Posaconazole, and a combination thereof.
3. The solid dispersion of claim 1, wherein the poorly water soluble triazole drug is Itraconazole.
4. The solid dispersion of claim 1, wherein the poorly water soluble triazole drug is Posaconazole.
5. The solid dispersion of claim 1, wherein the hydrophilic polymer comprise a polymer selected from a group consisting of methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, sodium carboxymethylcellulose, pottasium carboxymethyl cellulose, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, poly(meth)acrylic acid polymers, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohol, polyethylene glycol, gelatin, sodium alginate, starch, gum acacia, dextrin, hyaluronic acid, sodium chondroitin sulfate, propylene glycol alginate, agar, tragacanth, xanthan gum, macrogol, polyethylene oxide, polypropylene oxide, copolymer of ethylene oxide and propylene oxide, carrageenans, d-galactomannans and a mixture thereof.
6. The solid dispersion of claim 1, wherein the hydrophilic polymer is hydroxypropylmethylcellulose.
7. The solid dispersion of claim 1, wherein the hydrophilic polymer is hydroxypropylmethylcellulose acetate succinate.
8. A process for preparing the solid dispersion of claim 1 comprising:
a) Dissolving the triazole drug into acidified solvent;
b) Preparing a homogenous aqueous dispersion of the hydrophilic polymer;
c) Adding the polymer dispersion of b) into the drug solution of a); and
d) Isolating and drying the solid dispersion.
9. The process of claim 8, wherein the acidified solvent comprise a green solvent selected from a group consisting of water, alcohols, ketones, esters, acetic acid and mixture thereof.
10. The process of claim 9, wherein the green solvent is water.