FIELD OF THE INVENTION The present invention relates to solid oral pharmaceutical compositions comprising spinosad for treating an ectoparasite infestation on a companion animal. It provides a process for the preparation of said compositions. It also provides a method for controlling such infestations by administering said compositions to the companion animal.

BACKGROUND OF THE INVENTION

Fleas are common ectoparasites of companion animals such as cats and dogs. They are responsible for the production of flea-allergy dermatitis, serve as vectors of various bacterial pathogens and are the intermediate hosts for filarid and cestode parasites. Ctenocephalides felis ( C.felis ) is one of the most common flea species parasitizing cats and dogs.

Spinosad is a member of the spinosyns class of insecticides, which are non-antibacterial tetracyclic macrolides. Spinosad contains two major factors, spinosyn A and spinosyn D, derived by fermentation from the naturally occurring bacterium, Saccharopolyspora spinosa. Spinosyn A and spinosyn D have the chemical compositions 2-[(6-deoxy-2,3,4 tri-O- methyl-a-L-mannopyranosyl) oxy]-l3- [[5 (dimethylamino)tetrahydro-6-methyl-2H- pyran-2-yl]oxy]- 9 ethyl-2, 3, 3a, 5a, 5b, 6, 9, 10,11,12, 13,14, l6a,l6b tetradecahydro-l4- methyl-lH-as-indaceno[3,2-d] oxacyclododecin-7,l5-dione and 2-[(6-deoxy-2,3,4-tri- Omethyl- a-L-mannopyranosyl)oxy] l3-[[5- (dimethylamino) tetrahydro-6-methyl-2H- pyran-2 yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,l0,l 1,12,13,14,16a, 16b tetradecahydro-4,l4- dimethyl-lH-as-indaceno[3,2 d]oxacyclododecin-7,l5-dione, respectively.

The primary target of action of spinosad in insects is an activation of nicotinic acetylcholine receptors (nAChRs). Insects treated with spinosad show involuntary muscle contractions and tremors resulting from activation of motor neurons. Prolonged spinosad-induced hyperexcitation results in prostration, paralysis, and flea death.

Elanco Animal Health Co. markets spinosad tablet in the USA under the brand name Comfortis ^® for the prevention and treatment of flea infestations ( C.felis ) on cats and dogs. Comfortis ^® chewable tablet for cat is available in strengths of 90, 140, 270 and 560 mg. Comfortis ^® chewable tablet for dog is available in strengths of 90, 140, 270, 560, 810 and 1620 mg. Comfortis ^® chewable tablet is given orally once a month to cats and dogs. Comfortis ^® tablet contain microcrystalline cellulose, artificial beef flavour, hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate.

U.S. Patent No. 6,664,237, assigned to Eli Lilly and Company, discloses a single-dose oral formulation for controlling an ectoparasite infestation on a dog or cat comprising spinosad and a carrier for administration once every at least 7 days at a dose of 10 to 100 mg of spinosad per kg of body weight.

U.S. Patent No. 9,220,719, assigned to Eli Lilly and Company, discloses a composition comprising spinosad and the following excipients: microcrystalline cellulose (diluent), hydroxypropyl cellulose (binder), croscarmellose sodium (disintegrant), colloidal silicon dioxide (glidant) and magnesium stearate (lubricant). It mentions a spinosad composition with binder specifically hydroxypropyl cellulose. However, the addition of excess binder in the formulation is likely to adversely impact palatability and may further affect the other desired technical attributes such as such as hardness, thickness, disintegration time and dissolution. There is a continuing need of alternate dosage forms of spinosad with desired formulation. The inventors of the present invention have prepared alternate compositions of spinosad that exhibit desirable technical attributes such as assay, hardness, thickness, disintegration time and dissolution.

SUMMARY OF THE INVENTION The present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient.

One embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising: i) about 30% to about 80% by weight of spinosad,

ii) about 10% to about 50% by weight of diluent, iii) about 0% to about 10% by weight of glidant,

iv) about 1% to about 30% by weight of disintegrant, and

v) about 0.5% to about 3% by weight of lubricant.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the composition is free of binder.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad, wherein the composition is free of hydroxypropyl cellulose. Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the composition is free of glidant.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the composition is free of glidant and free of hydroxypropyl cellulose.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the composition is free of binder and exhibits an in-vitro release of not less than 90% spinosad release in 15 minutes in 900 mL of 0.1 N

Hydrochloric acid with 0.02% Tween 80 using a USP II apparatus (paddle) at a temperature of 37°±0.5°C and a rotation speed of 100 revolutions per minute.

In yet another embodiment, the high drug load solid oral pharmaceutical composition is a tablet or chewable tablet or granule or capsule. Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from the group comprising diluent, glidant, lubricant, disintegrant, surfactant, flavor and colorant. Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the spinosad is present in an amount ranging from about 50 mg to about 1800 mg. Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the composition is prepared by dry blending, dry granulation, wet granulation or direct compression.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the composition is free of binder and is prepared by dry blending, dry granulation, wet granulation or direct compression.

Another embodiment of the present invention relates to a process for the preparation of high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient for veterinary administration comprising: i) mixing spinosad with at least one diluent, glidant and/or disintegrant;

ii) lubricating the mixture of step i); and

iii) compressing the lubricated mixture of step ii) into a tablet or chewable tablet.

Another embodiment of the present invention relates to a process for the preparation of high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient for veterinary administration comprising: i) mixing spinosad with at least one pharmaceutically acceptable excipient;

ii) granulating the mixture of step i) to form granules;

iii) lubricating the granules of step ii); and

iv) compressing the lubricated granules of step iii) into a tablet or chewable tablet.

Another embodiment of the present invention relates to a process for the preparation of high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient for veterinary administration comprising: i) dissolving spinosad in a solvent; ii) granulating at least one pharmaceutically acceptable excipient with the spinosad solution of step i) to form granules;

iii) optionally adding one or more pharmaceutically acceptable excipients to the granules of step ii);

iv) lubricating the granules of step iii); and optionally

v) compressing the lubricated granules of step iv) into a tablet or chewable tablet or filling the lubricated granules into a capsule or filling the lubricated granules into a sachet.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, for use in the treatment of an ectoparasite infestation on a companion animal.

In yet another embodiment, the high drug load solid oral pharmaceutical composition is used in the treatment of C.felis infestation. Another embodiment of the present invention relates to a solid oral pharmaceutical composition comprising spinosad in combination with one or more compounds that have activity against ectoparasite or endoparasite selected from the group comprising milbemycins, avermectins, synthetic pyrethroids, natural pyrethrins, organophosphates, organochlorines, carbamates, foramidines and insect growth regulators. DETAILED DESCRIPTION OF THE INVENTION

The present invention can be more readily understood by reading the following detailed description of the invention.

As used herein, the term“composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising spinosad or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and the other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with“formulation” and“dosage form”. Pharmaceutical composition of the invention include, but is not limited to, tablets, chewable tablets, capsules, granules, pellets, beads, minitabs, spherules, beadlets, soft chews, powders, sachets, animal feed and the like. Preferably, the pharmaceutical composition refers to tablets including chewable tablet. Pharmaceutical compositions of the invention are meant for veterinary use.

The term“excipient” means a pharmacologically inactive component such as a diluent, glidant, lubricant, disintegrant, binder, surfactant, colorant, flavor or the like. Co- processed excipients are also covered under the scope of present invention. Further, excipient may be in the form of powders or in the form of dispersion. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.

The term“spinosad” as used herein, refers to combination of spinosyn A and spinosyn D in any ratio as known to the person skilled in the art and includes its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof.

The term“high drug load” as used herein refers to a solid pharmaceutical composition, wherein the composition includes about 30% w/w or more of spinosad. The composition includes about 30% w/w to about 95% w/w of spinosad. The composition includes particularly about 30% w/w to about 80% w/w of spinosad, particularly about 45% w/w to about 90% w/w of spinosad, particularly about 45% w/w to about 80% w/w of spinosad, particularly about 45% w/w to about 70% w/w of spinosad, particularly about 50% w/w to about 90% w/w of spinosad, particularly about 60% w/w to about 90% w/w of spinosad, particularly about 65% w/w to about 90% w/w of spinosad and particularly about 70% w/w to about 90% w/w of spinosad.

Unless otherwise stated the weight percentages expressed herein are based on the final weight of the composition or formulation.

The term“about” as used herein, means ± approximately 10% of the indicated value, such that“about 10 percent” indicates approximately 08 to 12 percent. The term “free of binder” as used herein, refers to a high drug load solid oral pharmaceutical composition of spinosad, which does not contain a binder.

The term “free of glidant” as used herein, refers to a high drug load solid pharmaceutical composition of spinosad, which does not contain a glidant. The term“free of hydroxypropyl cellulose” as used herein, refers to a high drug load solid pharmaceutical composition of spinosad which does not contain hydroxypropyl cellulose.

One embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising: i) about 30% to about 80% by weight of spinosad,

ii) about 10% to about 50% by weight of diluent,

iii) about 0% to about 10% by weight of glidant,

iv) about 1% to about 30% by weight of disintegrant, and

v) about 0.5% to about 3% by weight of lubricant.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the composition is free of binder.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad, wherein the composition is free of cellulose derivatives including but not limited to hydroxypropyl cellulose.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the composition is free of glidant. Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the composition is free of glidant and free of hydroxypropyl cellulose.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the composition is free of binder and exhibits an in-vitro release of not less than 90% spinosad release in 15 minutes in 900 mL of 0.1 N Hydrochloric acid with 0.02% Tween 80 using a USP II apparatus (paddle) at a temperature of 37°±0.5°C and a rotation speed of 100 revolutions per minute. Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad, wherein the composition is free of hydroxypropyl cellulose.

In yet another embodiment, the high drug load solid oral pharmaceutical composition is a tablet or chewable tablet or granule or capsule.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from the group comprising diluent, glidant, lubricant, disintegrant, surfactant, flavor and colorant.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the spinosad is present in an amount ranging from about 50 mg to about 1800 mg. Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, wherein the composition is prepared by dry blending, dry granulation, wet granulation or direct compression.

Another embodiment of the present invention relates to a process for the preparation of high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient for veterinary administration comprising: i) mixing spinosad with at least one diluent, glidant and/or disintegrant;

ii) lubricating the mixture of step i); and

iii) compressing the lubricated mixture of step ii) into a tablet or chewable tablet. Another embodiment of the present invention relates to a process for the preparation of high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient for veterinary administration comprising: i) mixing spinosad with at least one pharmaceutically acceptable excipient;

ii) granulating the mixture of step i) to form granules;

iii) lubricating the granules of step ii); and iv) compressing the lubricated granules of step iii) into a tablet or chewable tablet.

Another embodiment of the present invention relates to a process for the preparation of high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient for veterinary administration comprising: i) dissolving spinosad in a solvent;

ii) granulating at least one pharmaceutically acceptable excipient with the spinosad solution of step i) to form granules;

iii) optionally adding one or more pharmaceutically acceptable excipients to the granules of step ii);

iv) lubricating the granules of step iii); and optionally

vi) compressing the lubricated granules of step iv) into a tablet or chewable tablet or filling the lubricated granules into a capsule or filling the lubricated granules into a sachet.

Another embodiment of the present invention relates to a high drug load solid oral pharmaceutical composition comprising spinosad and at least one pharmaceutically acceptable excipient, for use in the treatment of an ectoparasite infestation on a companion animal.

In yet another embodiment, the high drug load solid oral pharmaceutical composition is used in in the treatment of C.felis infestation. Another embodiment of the present invention relates to a solid oral pharmaceutical composition comprising spinosad in combination with one or more compounds that have activity against ectoparasite or endoparasite selected from the group comprising milbemycins, avermectins, synthetic pyrethroids, natural pyrethrins, organophosphates, organochlorines, carbamates, foramidines and insect growth regulators. The term“controlling C.felis infestation” as used herein, refers to prevention, treatment or prevention and treatment of C.felis infestations.

The amount needed to control the C.felis infestation will vary depending upon a number of factors such as the breed of companion animal being treated, its weight, and general physical condition. The high drug load solid oral pharmaceutical compositions comprise an effective amount of spinosad and is suitable for administration to mitigate the risk of disease.

The high drug load solid oral pharmaceutical composition is a tablet, chewable tablet, soft chew, capsule or granules. The granules may be sprinkled on food particularly soft food before administration.

The high drug load solid oral pharmaceutical composition of the present invention is prepared by wet or dry process. The wet and dry processes include, but are not limited to, wet granulation, dry granulation, dry blending, direct compression, extrusion and spheronization. Soft chew compositions can be prepared by molding or extrusion techniques. Other formulation techniques are also contemplated within the scope of the present invention.

Any pharmaceutically acceptable granulating solvent or mixture of granulating solvents can be used for wet granulation. Suitable granulating solvents include aqueous or organic solvents. Granulating solvents include, but are not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and combinations thereof. Particularly, the granulating solvent used during wet granulation is water, isopropanol or combinations thereof. The wet granulation can be performed using Rapid mixer granulator, Fluid bed granulator, Planetary mixer and the like; dry blending can be performed in V-blender or key blender; dry granulation can be performed using roller compacter or slugging techniques; spheronization can be performed using Fuji Paudal spheronizer or by any other method known in the art.

Suitable pharmaceutically acceptable excipients are selected from at least one of diluent, glidant, binder, disintegrant, lubricant, surfactant, flavor, colorant and other pharmaceutical excipients.

Diluents or fillers are substances which usually provide bulk to the composition. Various useful fillers or diluents include, but are not limited to mannitol, microcrystalline cellulose, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, cellulose acetate, compressible sugar, confectioner’s sugar, dextrates, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, sodium alginate, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof. Diluents are present in the range from about 10% to about 95% by weight of the uncoated composition.

Glidants improve flowability and accuracy of dosing. Since the present invention relates to an oral pharmaceutical composition, it is imperative to use glidant(s) to achieve desirable flowability of the active. Glidants used in the composition include, but are not limited to, colloidal silicon dioxide, tribasic calcium phosphate, calcium silicate, cellulose, powdered, magnesium silicate, magnesium trisilicate, starch and talc or mixtures thereof. Glidants are present in the range from about 0% to about 15% by weight based on the total weight of the uncoated composition.

Binders impart cohesiveness to formulation. Various useful binders include, but are not limited to hypromellose, acacia, alginic acid, carbomer, sodium carboxymethyl cellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, maltose, methylcellulose, povidone (polyvinylpyrrolidone), copovidone, hydroxypropyl cellulose, starch, polyvinyl alcohol, polyethylene oxide, or mixtures thereof. Binders are present in the range from about 0% to about 30% by weight of the uncoated composition. Particularly, the composition is free of binder. Various useful disintegrants include, but are not limited to, croscarmellose sodium, pregelatinized starch, crospovidone, alginic acid, carmellose calcium, potassium polacrilin, sodium starch glycolate, low substituted hydroxypropyl cellulose and starch, or mixtures thereof. Disintegrants are present in the range from about 0% to about 45% by weight of the uncoated composition. Various useful lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, zinc stearate, sucrose stearate, hydrogenated vegetable oil type I, talc, poloxamer, adipic acid, glyceryl palmitostearate, glycerine monostearate, medium- chain triglycerides, sodium stearyl fumarate, glyceryl behenate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate and polyethylene glycol. Lubricants are present in the range from about 0% to about 10% w/w of the uncoated composition. Surfactants or surface-active agents improve wettability of the dosage form and/or enhance its dissolution. Surfactants contemplated in the present invention include but are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants and macromolecular surfactants. Suitable examples of anionic surfactants include but are not limited to sodium lauryl sulphate, sodium cetyl stearyl sulphate or sodium dioctyl sulphosuccinate etc. Suitable example of an amphoteric surfactant include but is not limited to lecithin. Suitable examples of non-ionic surfactants include but is not limited to cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acid esters such as sorbitan mono-oleate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 20, polyoxyethylene fatty acid glycerides such as macrogol 1000 glycerol monostearate, polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyethylene fatty alcohol ethers such as polyoxyl 10 oleyl ether, glycerol fatty acid esters such as glycerol monostearate, commercially available Sepitrap ^® 80 or Sepitrap ^® 4000, etc. Surfactants are present in the range from about 0% to about 0.5% w/w of the uncoated composition.

Colorants include but are not limited to iron oxides such as red ferric oxide, yellow ferric oxide, black iron oxide, titanium oxide beta-carotene, food blue No. 2 and food blue No. 2 aluminium lake.

Flavors are commonly added to the veterinary compositions to enhance their palatability. Suitable animal product based flavors include uncooked dried meat parts such as beef, pork, chicken, turkey, fish and lamb; organ meats such as liver; meat meals, bone meals and ground bone; and animal-derived food such as casein, milk (which may include dry forms and lowered fat forms, such as dry skim milk), yogurt, gelatin, cheese and egg.

EXAMPLES

The following examples are intended to further illustrate certain preferred embodiments of the invention and are not limiting in nature. Example 1

Table 1

Procedure:

1. Spinosad, microcrystalline cellulose, sodium lauryl sulphate, crosscarmellose sodium, colloidal silicon dioxide and optionally flavor were blended.

2. Magnesium stearate was mixed with the blend of step 1.

3. The mixture of step 2 was compressed into a chewable tablet.

Example 2

Table 2

Procedure:

1. Spinosad and microcrystalline cellulose were blended.

2. A solution of Polysorbate 80 was prepared in isopropyl alcohol.

3. The blend of step 1 was granulated with the solution of step 2 to form granules.

4. The granules of step 3 were mixed with mannitol, crosscarmellose sodium, colloidal silicon dioxide and optionally beef flavor.

5. Magnesium stearate was mixed with the mixture of step 4.

6. The mixture of step 5 was compressed into a chewable tablet. Example 3

Table 3

Procedure:

1. Spinosad and microcrystalline cellulose are blended.

2. A solution of Polysorbate 80 is prepared in isopropyl alcohol.

3. The blend of step 1 is granulated with the solution of step 2 to form granules.

4. The granules of step 3 are mixed with lactose, crosscarmellose sodium and beef flavor.

5. Magnesium stearate is mixed with the mixture of step 4.

6. The mixture of step 5 is compressed into a tablet or chewable tablet or filled into a capsule or filled into a sachet. Table 4 shows the properties of tablets obtained in Examples 1 and 2. Disintegration test was performed using water as a test liquid. The method and equipment for testing of disintegrating time is provided in the ETnited States Pharmacopeia (USP 42).

Table 4

Assay

The spinosad content of tablet of Example 1 was determined by HPLC method [Inertsil ODS column (250x4.6 mm, 5 pm); mobile phase- ammonium acetate buffer (pH 5.3):methanol:acetonitrile (20 : 30 : 50 v/v); flow rate of 1.5 mL/min; UV detection at 245 nm]. The assay was found to be more than 93%.

In-Vitro Dissolution Study

Dissolution test was performed on spinosad tablet of Example 1 using ETSP apparatus type-II (paddle) apparatus at a rotation speed of 100 rpm with 900 mL of 0.1 N Hydrochloric acid with 0.02% Tween 80 as dissolution medium at 37±0.5°C. More than 95% spinosad release was observed in 15 minutes (Table 5) Table 5