FIELD OF THE INVENTION
The present invention relates to a co-precipitate of Atovaquone with a pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide and pharmaceutical composition comprising said coprecipitates.
BACKGROUND OF THE INVENTION
Many orally-administered drugs display poor bioavailability when administered in conventional dosage forms. With several drugs, absorption may be as little as 30 per cent or less of the orally administered dose. To compensate for this effect, a very large dose is often administered so that absorption of the therapeutically required quantity of the drug can occur. This technique may prove costly with expensive drugs, and the non-absorbed drug may also have undesirable side effects within the gastrointestinal tract. In addition, the poorly absorbed drugs often display a great deal of variability between patients in bioavailability, and this can create dosing problems. This poor bioavailability is often associated with poor solubility of drugs. There are various techniques available to overcome solubility and bioavailability problem, and one such option is by modification of physical states by producing solid dispersions and/or coprecipitates.
Atovaquone, 2-[4-(4-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone is a widely used antiprotozoal and is potently active (in animals and in vitro) against Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii. Atovaquone, a highly lipophilic compound resembling ubiquinone, has a low aqueous solubility, and that is the reason for the poor bioavailability of atovaquone after oral administration. It is reported that after a single oral dose, absorption of the drug is slow and erratic; it is increased about three-fold by the presence of fatty food and is dose-limited above 750 mg.
US 4,981,874 disclose the use of Atovaquone against Pneumocystis carinii infection in a mammal. EP 123,238 and US 5,053,432 discloses the use of atovaquone against Plasmodium falciparum and also against Eimeria species such as E. tenella and E.acervulina which are causative organisms of coccidiosis. Further, use of Atovaquone against Toxoplasmosis and Cryptosporidiosis is disclosed in EP 445,141 and 496,729 respectively.
Currently, Atovaquone Suspension marketed under trade name Mepron is an aqueous suspension of micro-fine particles of Atovaquone. The Atovaquone particles are reduced in size to facilitate absorption. These particles are significantly smaller than those in the previously marketed tablet formulation. Further, US 6,018,080 and US 6,649,659 discloses microfluidized particles of Atovaquone having improved bioavailability, wherein at least 90% of atovaquone particles have a volume diameter in the range of 0.1-3 micron.

Several possibilities of increasing solubility and improving dissolution rate of poorly soluble drugs are known; one of the options is the preparation of coprecipitates thereof. In the present invention, we have prepared coprecipitates of Atovaquone with a pharmaceutically acceptable carrier that result in modification of physical state of Atovaquone leading to increase in solubility.
SUMMARY OF THE INVENTION
The present invention relates to a coprecipitate of Atovaquone with a pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide and to a pharmaceutical composition comprising said coprecipitates.
Hence, according to one of the aspects, there is provided a coprecipitate of Atovaquone with a pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide.
In another aspect, there is provided a coprecipitate of Atovaquone with polyvinylpyrrolidone.
In another aspect, there is provided a coprecipitate of Atovaquone with colloidal silicon dioxide.
In another aspect, there is provided a process of preparation of a coprecipitate of Atovaquone, comprising the steps of:
a) Dissolving Atovaquone and dissolving or dispersing the pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide in an organic solvent or a mixture of organic solvents; and
b) spray-drying the obtained solution to obtain desired Atovaquone coprecipitate.
In another aspect, there is provided a pharmaceutical composition of Atovaquone comprising coprecipitate of Atovaquone with a pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide.
In another aspect, there is provided a process of preparation of a pharmaceutical composition comprising a coprecipitate of Atovaquone, comprising the steps of:
a) preparing the coprecipitate of atovaquone and pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide,
b) dispersing/dissolving a portion of surfactant mixture in water,
c) dispersing Atovaquone coprecipitates of step a) in dispersion of step b),
d) dispersing other pharmaceutically acceptable excipients in water,
e) adding slowly atovaquone dispersion of step c) in the dispersion of step d)
f) stirring / homogenizing the dispersion of step e) for a suitable period of time till a uniform suspension is formed and filling into suitable sized bottles.

In another aspect, there is provided a method for the treatment of protozoal infection, the method comprising: orally administering to a subject a pharmaceutical composition comprising a coprecipitate of Atovaquone with a pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide.
DETAILED DESCRIPTION
"Atovaquone" as employed herein is intended to include isomers, cis and trans forms of atovaquone or mixture thereof or any pharmaceutically acceptable salts thereof. Atovaquone may be used in any of the Polymorphic forms such as Form I or III. It may be used alone or in combination with Proguanil.
As used herein, the term "pharmaceutically acceptable salts" refers to inorganic base salts such as alkali metal (e.g. sodium and potassium) salts and alkaline earth metal (e.g. calcium) salts; organic base salts e.g. phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine and diethanolamine salts; and amino acid salts e.g. lysine and arginine.
The term "coprecipitate" as used herein refers to a solid substance that results from dissolving atovaquone and dissolving or dispersing the pharmaceutically acceptable carrier in organic solvent and removing the solvent. Lipophilic substances incorporated in the coprecipitates show improved drug release in simulated gastric fluid in vitro and enhance oral bioavailability in vivo. Coprecipitation may be carried out using freeze-drying, spray-drying orfluidized bed drying.
Organic solvent that can be used for coprecipitation should be able to dissolve Atovaquone as well as pharmaceutically acceptable carrier. Examples include chloroform, ethanol, N-methyl 2 pyrrolidinone, tetrahydrofuran, Acetone or mixtures thereof.
Polyvinylpyrrolidone (PVP) is a water-soluble linear polymer of 1-vinyl-2-pyrrolidone and has average molecular weight ranges from several thousands to several millions. The viscosity contribution of povidone ranges from high viscosity to low viscosity and is a function of the average molecular weight of the polymer. Polyvinylpyrrolidones having an average molecular weight of 25000, 40000 and 1200000 are described as polyvinylpyrrolidone K25, polyvinylpyrrolidone K30 and polyvinylpyrrolidone K90, respectively. They are easily available as Kollidon, the trade name. Certain organic solvents have a particular effect on the viscosity contribution of povidone, the intensity of which is related to the polarity of the particular organic solvent.
Colloidal silicon dioxide is submicron fumed silica prepared by the vapor-phase hydrolysis (e.g., at 1110°C.) of a silicon compound, such as silicon tetrachloride. Variety of commercial grades of colloidal silicon dioxide are produced by varying the manufacturing process. These modifications do not affect the silica content, specific gravity, refractive index, color or amorphous form. How

ever, these modifications are known to change the particle size, surface areas, and bulk densities of the colloidal silicon dioxide products. It is commercially available from a number of sources, including Cabot Corporation (under the trade name Cab-O-Sil); Degussa, Inc. (under the trade name Aerosil); Huber Engineered Materials (Huber GL100 and GL200); Wacker (Wacker HDK ®); and E.I.
Ratio of pharmaceutically acceptable carrier to Atovaquone ranges from about 0.025:1 to about
2:1.
Pharmaceutical composition as used herein includes liquid dosage forms such as suspension.
The suspension dosage form should have suitable properties such as viscosity, taste and flavor. The pharmaceutical^ acceptable excipients for suspension may be selected from suspending agent, solvents, surfactants, preservatives, colouring agents, antioxidants, flavoring agents and sweeteners.
5
The surfactants may be selected from sodium lauryl sulfate (SLS), polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate; dialkyl sodium sulfosuccinates such as bis-(2-ethylhexyl) sodium sulfosuccinate; polyglycolized glycerides such as Gelucire and Labrasol; polyoxyethylene-polyoxypropylene block co-polymer such as Poloxamer; fatty acid esters of polyethylene glycol such as PEG600 monooleate, PEG400 dioleate, PEG 600 dioleate, PEG400 monostearate, PEG600 monostearate, PEG8000 distearate, PEG 10000 distearate, PEG200 monolaurate, PEG400 monolaurate and PEG600 monolaurate; polyethoxylated alkyl ethers such as Cremophors, polyethylene glycol monostearate (Myrj 45), Polyoxyethylene stearate (Myrj 52) polyoxyethylene lauryl ether, such as that sold under the name Brij, particularly Brij-35 and Brij-700.
Poloxamer (polyoxypropylene-polyoxyethylene block copolymer) surfactants are non-ionic block copolymer surfactants having a structure composed of two blocks or chains of hydrophilic polyoxyethylene (POE) flanking a single block of hydrophobic polyoxypropylene (POP). They are considered to be among the least toxic of known surfactants and are available in different grades such as poloxamer®124, poloxamer®188, poloxamer®237, poloxamer®338, poloxamer® 407. The amount may vary from 1 to 15mg/ml.
Cremophors (Polyoxyl 35 castor oil) are non-ionic emulsifiers obtained by causing ethylene oxide to react with hydrogenated castor oil particularly in a molar ratio of about 35 moles to 1 mole. Polyethoxylated castor oil known as Cremophor® is available in different grades such as Cremophor® A6, Cremophor® A25, Cremophor® RH 410, Cremophor® RH 40, Cremophor® RH

60, Cremophor® CO 40, Cremophor® CO 410, Cremophor® CO 455, Cremophor® CO 60, Cremophor® EL. The amount of Cremophor may vary from 1-70mg/ml.
The polyglycolyzed glyceride may be saturated or unsaturated and include ethoxylated glycerides and polyethylene glycol esters. The hydrophilic-lipophilic balance value of the polyglycolized glycerides is adjusted by the length of the PEG chain and the melting point is adjusted by the length of the chains of the fatty acids, of the PEG and by the degree of saturation of the fatty chains. A particularly preferred polyglycolyzed glyceride is a glyceryl ca pry I ate/caprate and PEG-8 (polyethylene glycol) caprylate/caprate complex known as LABRASOL™. The amount of Labrasol may vary from 1-30mg/ml.
Gelucire® are polyglycolyzed glycerides that are prepared by the alcoholysis reaction of natural oils with polyethylene glycols (PEG). They are a well-defined mixture of mono-, di- and triglycerides and mono- and di-fatty acid esters of polyethylene glycol, wherein the predominant fatty acid is lauric acid. It is available in various grades like Gelucire®33/01, Gelucire® 37/02, Gelucire®39/01, Gelucire®43/01, Gelucire®44/14, Gelucire®50/02, Gelucire®50/13 and Gelucire® 53/10. The amount of Gelucire may vary from 1-70mg/ml.
Suspending agent is selected from the group consisting of polysaccharide, (tragacanth; xanthan gum; bentonite; acacia and lower alkyl ethers of cellulose (including the hydroxy and carboxy derivatives of the cellulose ethers), vinyl polymers such as povidone, a mixture of cellulose and of xanthan gum, a mixture of polyethylene glycol and of sodium carboxymethyl cellulose, a mixture of xanthan gum and of pregelatinized starch, a mixture of microcrystalline cellulose and of sodium carboxymethyl cellulose (Avicel RC 591), dispersed silicon dioxide (Aerosil 200). The amount of suspending agent may range from 0.01-5% w/v.
The preservatives may be selected from benzyl alcohol, propylparaben, methylparaben, sorbic acid, sodium benzoate and sodium bisulphate.
Sweeteners may be selected from sucrose, lactose, sucralose, acesulfame potassium, glucose, aspartame, saccharine, and sorbitol solution.
The suitable flavoring agents may be selected from yellow plum lemon, tutti frutty, aroma, peppermint oil, oil of wintergreen, cherry, orange or raspberry flavor.
The suspension may be in ready for administration form or as powder which is to be reconstituted at the time of administration.

The suspension for oral administration is usually aqueous based wherein the suspension may comprise water, or a mixture of one or more water-miscible solvents. Suitable water-miscible solvents include propylene glycol, benzyl alcohol, ethanol and other commonly used solvents known to the skilled in the art. These solvents also act as preservatives.
According to one of the embodiment, there is provided a process for the preparation of a coprecipitate of Atovaquone, comprising the steps of:
a) dissolving Atovaquone and dissolving or dispersing the pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide in an organic solvent or a mixture of organic solvents; and
b) spray-drying to obtain desired Atovaquone coprecipitate.
According to yet another embodiment, the coprecipitate of Atovaquone may be prepared by a process comprising the steps of:
a) dissolving Atovaquone and dissolving or dispersing the pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide in an organic solvent or a mixture of organic solvents; and
b) removing the solvent in a fluidized bed drier to obtain desired Atovaquone coprecipitate.
According to one of the embodiment, there is provided a process of preparation of a pharmaceutical composition comprising a coprecipitate of Atovaquone, comprising the steps of:
a) preparing the coprecipitate of Atovaquone and pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide by spray drying;
b) dissolving/dispersing a portion of surfactant mixture of PEG8 caprylic/capric glycerides, polyoxyl 35 castor oil and lauroyl polyoxylglycerides by stirring till a clear solution is obtained;
c) dispersing the obtained Atovaquone coprecipitates from step a) in dispersion of step b);
d) dissolving/dispersing remaining portion of surfactants and other pharmaceutically acceptable excipients in water;
e) adding the dispersion of step c) to the solution of step d) under continuous stirring;
f) homogenizing the dispersion of step e) for a suitable period of time till a uniform suspension is formed and filling into suitable sized bottles.
The following examples are provided to enable one of ordinary skill in art to prepare dosage forms of the invention and should not be construed as limiting the scope of invention.

EXAMPLES Example-1
FORMATION OF A COPRECIPITATE OF ATOVAQUONE WITH POVIDONE

(Table Removed)

Procedure:
1. Povidone was dissolved in a mixture of chloroform and ethanol to form a clear colorless solution.
2. Atovaquone was added to the solution of step 1) under stirring till a yellow colored clear solution was obtained.
3. The obtained solution was spray dried to obtain the desired Atovaquone-povidone coprecipitate.
Example 2

FORMATION OF A COPRECIPITATE OF ATOVAQUONE WITH COLLOIDAL SILICON DIOXIDE

(Table Removed)
Atovaquone was dissolved in chloroform. Colloidal silicon dioxide was added to the drug solution and dispersed uniformly. The obtained dispersion was spray dried to obtain the desired Atovaquone-silicon dioxide coprecipitate.
Example-3
Atovaquone suspension may be prepared using coprecipitates of Atovaquone and povidone of Example 1

(Table Removed)
Procedure:
1. Heat a part of Cremophor EL, labrasol and Gelucire and stir till a clear solution is obtained.
2. Add Ethanol and benzyl alcohol to the solution of step 1.
3. Disperse Atovaquone coprecipitates (of example 1) in the solution of step 2.
4. Dissolve remaining portion of Cremophor EL, Poloxamer 188 and saccharin sodium in a portion of water.
5. Disperse xanthan gum with stirring in another portion of water.
6. Slowly add Atovaquone dispersion of step 3 to solution of step 4.
7. Add xanthan gum dispersion of step 5 to Atovaquone dispersion of step 6 under continous stirring.
8. Add flavors to dispersion of step 7 and make up the final volume with purified water.
9. Homogenize the dispersion of step 8) for a suitable period of time till a uniform suspension is obtained.
While particular formulations have been described above, it will be apparent that various modifications and combinations detailed in the text can be made without departing from the spirit and scope of the invention.

WE CLAIM:
1. A coprecipitate of Atovaquone with a pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide.
2. The coprecipitate of Atovaquone according to claim 1 wherein the ratio of pharmaceutically acceptable carrier to Atovaquone is 0.025:1 to 2:1
3. The coprecipitate of Atovaquone according to claim 1 wherein coprecipitate is prepared by the process of spray drying, fluidized bed drying or freeze drying.
4. The coprecipitate of Atovaquone according to claim 3 wherein the coprecipitate is prepared by a process, comprising the steps of:
i) dissolving Atovaquone and dissolving or dispersing the pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide in an organic solvent or a mixture of organic solvents; and
ii) spray-drying to obtain desired Atovaquone coprecipitate.
5. The coprecipitate of Atovaquone according to claim 4 wherein the organic solvent is selected
from chloroform, ethanol, N-methyl 2 pyrrolidinone, tetrahydrofuran, Acetone or mixtures thereof.
6. The coprecipitate of Atovaquone according to claim 1 wherein the coprecipitate is incorporated
into a suspension dosage form.
7. The coprecipitate of Atovaquone according to claim 6 wherein the suspension dosage form
comprises pharmaceutically acceptable excipients selected from the group consisting of surfactants, preservatives, suspending agents, coloring agents, flavoring agents and sweeteners.
8. The coprecipitate of Atovaquone according to claim 6 wherein the suspension is prepared by a
process comprising the steps of:
a) preparing the coprecipitate of atovaquone and pharmaceutically acceptable carrier selected from polyvinylpyrrolidone and colloidal silicon dioxide,
b) dispersing/dissolving a portion of surfactant mixture in water,
c) dissolving Atovaquone coprecipitates of step a) in dispersion of step b),
d) dispersing other pharmaceutically acceptable excipients in water,
e) adding slowly atovaquone dispersion of step c) in the dispersion of step d)
f) stirring the dispersion of step e) for a suitable period of time till a uniform suspension is formed and filling into suitable sized bottles.
9. The coprecipitate of Atovaquone as used and exemplified herein.