DESC:FIELD OF THE INVENTION
The present specification relates to a stable controlled release formulation of zileuton. The present specification is particularly related to a bilayer pharmaceutical composition of zileuton comprising an immediate release portion and a controlled release portion. Further, the present specification also relates to manufacturing processes for stable controlled release formulations of zileuton.

BACKGROUND OF THE INVENTION
Zileuton is an orally active inhibitor of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Chemically, Zileuton is ((±)-1-(1-Benzo[b]thien-2-ylethyl)-1-hydroxyurea) and has the following structure:

Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro and in vivo systems, and inhibit leukotriene (LTB4, LTC4, LTD4 and LTE4) formation. 5-Lipoxygenase is responsible for the first enzymatic step in the production of leukotrienes, a family of inflammatory mediators that can trigger asthma symptoms. In addition to asthma, leukotrienes have been shown to play a role in other diseases including rheumatoid arthritis, allergic rhinitis, acne, atherosclerosis, aortic aneurysm, sickle cell disease, nasal polyposis and inflammatory bowel disease, among others. Accordingly, compounds which inhibit lipoxygenase activity are useful in the treatment and/or prevention of such diseases. Because zileuton selectively inhibits the activity of 5-lipoxygenase, it may have broader therapeutic utility than other leukotriene inhibitors.

Zileuton was introduced in 1996 by Abbott Laboratories and is now marketed in two formulations by Cornerstone Therapeutics Inc. under the brand names ZYFLO® and ZYFLO CR®. ZYFLO CR® and ZYFLO® are the only FDA-approved leukotrienes synthesis inhibitors for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. The recommended dose of ZYFLO CR® is two 600 mg extended-release tablets twice daily, within one hour after morning and evening meals, for a total daily dose of 2400 mg. The recommended dose of ZYFLO® is one 600 mg immediate-release tablet four times a day for a total daily dose of 2400 mg.
Pharmacodynamic studies reveal that the inhibition of LTB4 formation in whole blood is directly related to zileuton plasma levels. Given the short elimination half life (3hrs) of zileuton, it is difficult to maintain peak plasma concentration of the drug for longer periods.
ZYFLO CR® is a triple layered tablet, and is prepared by utilizing a proprietary drug delivery technology, which controls the amount and rate of drug released into the body, thereby providing effective concentration of the drug in blood for relatively long periods of time. It has a unique mechanism of action which, combined with its twice-daily dosing regimen, has fundamentally expanded the treatment options available to asthma patients as well as improved patient compliance.
U.S. Pat. No. 5,681,583 discloses controlled release formulations of antihistaminic and/or antiasthmatic drugs. It discloses multilayered controlled-release solid pharmaceutical compositions in tablet form comprising at least two layers containing active material in association with excipients and additives.
U.S. Pat. No. 6,372,255 discloses multilayered tablets for the instant and prolonged release of active substances, specifically for the treatment of asthma.
Despite the availability of prior art for different types of controlled release compositions; because of the low solubility of zileuton, it is cumbersome, inconvenient and expensive to manufacture controlled release compositions of the drug.
Thus, there remains a need for stable controlled release formulations of zileuton, which would be bioequivalent to ZYFLO CR®. Ideally, such formulations would be simple, convenient to prepare, commercially viable and would exhibit enhanced storage stability.
SUMMARY OF THE INVENTION
The inventors, by the judicious selection of excipients in specific amounts, have developed stable controlled release formulations of zileuton. In general aspects these formulations are bilayer pharmaceutical compositions comprising an immediate release portion and a controlled release portion.

Thus, in one embodiment, the present specification provides a stable controlled release formulation, in the form of a bilayer tablet comprising a) an immediate release portion containing zileuton and one or more pharmaceutically acceptable excipients; and b) a controlled release portion containing zileuton, one or more pharmaceutically acceptable rate-controlling agents and one or more additional pharmaceutically acceptable excipients.
These and other advantages of the compositions disclosed herein, as well as additional inventive features, will be apparent from the description of the invention provided herein.
DETAILED DESCRIPTION OF THE INVENTION
The present specification is directed to stable controlled release formulations of zileuton, in the form of bilayer compositions comprising an immediate release portion and a controlled release portion.
The present specification provides a bilayer pharmaceutical composition comprising a) an immediate release portion containing zileuton and one or more pharmaceutically acceptable excipients; and b) a controlled release portion containing zileuton, one or more pharmaceutically acceptable rate-controlling agents and one or more pharmaceutically acceptable excipients.
As used herein, the term "zileuton" includes the compound zileuton, pharmaceutically acceptable salts of zileuton, isomers, solvates, complexes and hydrates, anhydrous forms thereof, and any polymorphic or amorphous form or combinations thereof.
As used herein, the term "stable compositions" refers to any preparation of zileuton having sufficient stability to allow storage at a convenient temperature, such as between about 0°C and about 60°C, for a pharmaceutically acceptable duration of time. Preferably, the composition are stable for a period of time, such as at least about one week, at least about one month, at least about three months, at least about six months, at least about one year, or at least about 2 years.
The term "immediate release" shall mean that the release of the majority of the active material content occurs within a relatively short time, for example within 1 hour, preferably within 30 minutes, after oral ingestion. Immediate release can also be referred to as instant release.
The term "controlled release" refers to the release of a drug substance from a pharmaceutical formulation, at a slower rate than from an immediate release formulation. Controlled release can also be referred to as sustained release, prolonged release, extended release, or modified release.
The term "rate controlling agent" refers to an excipient which can control the release of a drug from the dosage form for a prolonged period of time. The rate controlling substance may include a hydrophilic and/or a hydrophobic excipient.
The ratio of the amount of zileuton in the immediate release portion to the controlled release portion may be in the range of from about 1:1 to about 1:10 parts by weight. The amount of zileuton that is incorporated in a tablet may range between about 400 mg and about 1200 mg.
The present specification relates to zileuton API particles with specific surface area ranging from about 0.9 - 3.1 m2/g.
The pharmaceutically acceptable excipients as per present specification are selected from diluents, binders, disintegrants, surfactants, lubricants, glidants, colorants, or combinations thereof.
Suitable diluents are selected from, but are not limited to microcrystalline cellulose, starches and starch derivatives, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol, erythritol and the like. The diluents or fillers may be present in an amount from about 5% w/w to about 50% w/w based on the total weight of composition.
Suitable binders are selected from, but are not limited to hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinylpyrrolidone, sodium alginate, gums, synthetic resins or combination thereof. The binders may be present in an amount from about 0.1% w/w to about 10% w/w based on the total weight of composition.
Suitable disintegrants are selected from, but are not limited to starch or its derivatives, croscarmellose sodium, sodium starch glycolate, clays, celluloses, alginates, crospovidone, gums and the like used either alone or combination thereof. The disintegrants may be present in an amount from about 0.1% w/w to about 10% w/w based on the total weight of composition.
Suitable surfactants are selected from, but are not limited to oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan fatty acid esters, poloxamer, sodium oleate, sodium lauryl sulphate and the like or combination thereof. The surfactant may be present in amount from about 0.1% w/w to 10% w/w based on the total weight of the composition.
Suitable lubricants are selected from, but are not limited to metallic stearates such as magnesium stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin; or combinations thereof. The lubricants may be present in amount from about 0.01% w/w to 10% w/w based on the total weight of composition.
Suitable glidants are selected from, but are not limited to talc, colloidal silicon dioxide, finely divided silicon dioxide, or combinations thereof. The glidants may be present in amount from about 0.01% w/w to 10% w/w based on the total weight of composition.
Suitable colorants are selected from, but are not limited to iron oxides, titanium oxide, aluminium lakes or combination thereof. As per the present specification colorants may be incorporated in any of the portions.

The pharmaceutically acceptable rate-controlling agents as per present specification are selected from the group consisting of one or more of hydrophilic and/or hydrophobic substances.
Suitable hydrophilic substances are selected from, but not limited to one or more of cellulosic polymers/copolymers or its derivatives including methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose; polyacrylates, methyl acrylates, polyethylene oxides, polyethylene glycols, chitosan, gums, starch derivatives, and the like. Preferred hydrophilic substance is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose or mixture thereof.
The hydrophilic substances may be present in an amount from about 1% w/w to about 30% w/w based on the total weight of the composition.
Suitable hydrophobic substances are selected from, but not limited to one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnauba wax, hydrogenated vegetable oil and its derivatives, e.g. hydrogenated castor oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, acrylate and phthalate polymers and copolymers such as poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly (ethylene terephthalate) and the like.
In one of the embodiment, the bilayer pharmaceutical composition of the present specification may optionally comprise a non-functional coating.
The non-functional coating may comprise polymers like hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copolymer of vinyl pyrrolidone and vinyl acetate; plasticizers like polyethylene glycol, triacetin, dibutyl sebecate and diethyl tartrate; opacifying agents like titanium dioxide and talc; and coloring agents. Examples of such non-functional coat are commercially available Opadry compositions.
The process for preparation of bilayer pharmaceutical composition of the present specification may involve wet granulation, dry granulation and fluidized bed granulation. The wet granulation process involves use of water or any other suitable solvent. The dry granulation may involve use of roller compacter or any suitable technique.
In one embodiment, the bilayer pharmaceutical composition of the present specification may be prepared by the steps of:
a) preparing an immediate release component, wherein the method comprises the steps of blending zileuton with one or more pharmaceutically acceptable excipients; granulating the blend with the help of aqueous binder solution to produce granules; drying and milling the granules; further mixing the dried granules with one or more pharmaceutically acceptable excipients and lubricating the granules to form the immediate release portion which is ready to compress;
b) preparing a controlled release component, wherein the method comprises the steps of blending zileuton with one or more pharmaceutically acceptable rate-controlling agents and one or more additional pharmaceutically acceptable excipients; granulating the blend with the help of aqueous binder solution to produce granules; drying and milling the granules; further mixing the dried granules with one or more pharmaceutically acceptable excipients and lubricating the granules to form the controlled release portion which is ready to compress;
c) compressing the controlled release blend and the immediate release blend using bilayer machine to form a bilayer compressed tablet; and
d) Optionally, film coating the bilayer tablet using film forming compositions.
The following examples further illustrate the invention but should not be construed as in any way limiting its scope. In particular, the processing conditions are merely exemplary and can be readily varied by one of ordinary skill in the art.
Example 1:
Sl. No. Ingredients %w/w
a) Immediate release portion
1. Zileuton 5 - 25
2. Pregelatinized Starch/Microcrystalline cellulose 0.5 - 10
3. Sodium Starch Glycolate/Crosspovidone 0.1 - 5
4. Hydroxypropyl Cellulose 0.1 - 5
5. Iron Oxide Red 0.01 - 1
6. Magnesium Stearate 0.01 - 1
7. Purified Water q.s.
b) Controlled release portion
1. Zileuton 30 - 60
2. Mannitol 10 - 30
3. Hypromellose 10 - 20
4. Polysorbate 80 0.1 - 5
5. Povidone 0.5 - 5
6. Hydroxypropyl Cellulose 0.1 - 5
7. Magnesium Stearate 0.5 - 5
8. Purified Water q.s.
c) Coating layer (optional)
1. Opadry 1 - 5
2. Purified Water q.s.
Total 100

Example 2:
Sl. No. Ingredients %w/w
a) Immediate release portion
Refer to example 1
b) Controlled release portion
1. Zileuton 30 - 60
2. Lactose Monohydrate 10 - 30
3. Hypromellose 10 - 20
4. Sodium Lauryl Sulphate 0.1 - 5
5. Povidone 0.5 - 5
6. Hydroxypropyl Cellulose 0.1 - 5
7. Magnesium Stearate 0.5 - 5
8. Purified Water q.s.
c) Coating layer (optional)
1. Opadry 1 - 5
2. Purified Water q.s.
Total 100

The method of preparation of bilayer pharmaceutical composition comprises the following steps:
a) preparing granules for the immediate release, wherein the method involves the blending of zileuton with one or more pharmaceutically acceptable excipients; granulating the blend with aqueous binder solution to produce granules; drying and milling the granules; further mixing the dried granules with one or more pharmaceutically acceptable excipients and lubricating the granules to form the immediate release portion which is ready to compress;
b) preparing granules for the controlled release, wherein the method involves the blending of zileuton with one or more pharmaceutically acceptable rate-controlling agents and one or more additional pharmaceutically acceptable excipients; granulating the blend with the help of aqueous binder solution to produce granules; drying and milling the granules; further mixing the dried granules with one or more pharmaceutically acceptable excipients and lubricating the granules to form the controlled release portion which is ready to compress;
c) compressing the immediate release granules and the controlled release granules using suitable punches to form a bilayer compressed tablet; and
d) Optionally, film coating the bilayer tablet using film forming compositions.
The bilayer controlled release tablet was found to be stable.
The pharmaceutical compositions of present specification were characterised by dissolution studies compiled in Table – 1

Table-1: Dissolution Data
Time
(in hrs) Average % of drug released
1 NLT 20
4 NLT 40
8 NLT 50
12 NLT 80

The pharmaceutical compositions of present specification was found to be bio-equivalent against ZYFLO CR® tablets in normal, healthy, adult human subjects.
,CLAIMS:1. A stable controlled release formulation, in the form of a bilayer tablet comprising:
a.) an immediate release portion containing zileuton and one or more pharmaceutically acceptable excipients; and
b.) a controlled release portion containing zileuton, one or more pharmaceutically acceptable rate-controlling agents and one or more additional pharmaceutically acceptable excipients.
2. The bilayer tablet according to claim 1, wherein ratio of the amount of zileuton in the immediate release portion to the controlled release portion is in the range from about 1:1 to about 1:10 parts by weight.
3. The additional pharmaceutically acceptable excipients in said controlled release portion according to claim 1, comprises one or more surfactants selected from oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan fatty acid esters, poloxamer, sodium oleate, sodium lauryl sulphate and the like or combination thereof.
4. The surfactant according to claim 3, is polyoxyethylene sorbitan fatty acid ester.
5. The bilayer tablet according to claim 1, wherein pharmaceutically acceptable rate-controlling agents in said controlled release portion are selected from the group consisting of hydrophilic and/or hydrophobic substances.
6. The hydrophilic rate-controlling agents according to claim 5 are selected from one or more of cellulosic polymers/copolymers or its derivatives including methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose; polyacrylates, methyl acrylates, polyethylene oxides, polyethylene glycols, chitosan, gums, starch derivatives.
7. The hydrophobic rate-controlling agents according to claim 5 are selected from one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnauba wax, hydrogenated vegetable oil and its derivatives, e.g. hydrogenated castor oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, acrylate and phthalate polymers and copolymers such as poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly (ethylene terephthalate).
8. The bilayer tablet according to claim 1, exhibits an in-vitro release such that at least about 20% of zileuton is released after 1 hour, at least about 40% of zileuton is released after 4 hours, at least about 50% of zileuton is released after 8 hours, and at least about 80% zileuton is released within 12 hours.