FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
PROVISIONAL SPECIFICATION
(SECTION 10 and Rule 13)
"PALATABLE PHARMACEUTICAL COMPOSITIONS"
Emcure Pharmaceuticals Limited.,
an Indian company, registered under the
Indian company's Act 1957 and having its registered office at
Emcure House, T-184, M.I.D.C,
Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

FIELD OF THE INVENTION
The present invention relates to an oral pharmaceutical dosage form, in particularly relates to an oral pharmaceutical dosage form comprising of a Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) and more particularly a oral pharmaceutical dosage form comprising of Efavirenz.
BACKGROUND
Millions of people around the world are suffering from HIV/AIDS, and millions more are likely to become infected each year. According to UNAIDS, AIDS Epidemic Update for the year 2005, one new HIV infection occurs every 6 seconds of every minute of every day, around 5 million new HIV infections occurred worldwide; approximately 14,000 every day and it has been estimated that around 3.1 million people worldwide have died of HIV/AIDS related illnesses. Globally, women represent half of all people living with HIV/AIDS. {UNAIDS/WHO "AIDS epidemic update: December 2005 "Special section on HIV Prevention " UNAIDS/05.19E)
Many medications are currently available for the treatment of HIV/AIDS including HIV protease inhibitors (Pi's), nucleoside/nucleotide reverse transcriptase inhibitors (NRTI's) and non-nucleoside reverse transcriptase inhibitors (NNRTI's). Most current treatment regimens require a combination of at least three medications, most commonly two NRTI's and either a PI or a NNRTI. (http://www.avert.ors/introtrt.htm)
Efavirenz is a known agent for the treatment of infection by HIV-1 (human immunodeficiency virus, type 1), which acts through specific inhibition of HIV-1 reverse transcriptase and is one of a class of drugs called Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (label insert of susutiva available on USFDA site). Reverse transcriptase, a part of HIV is required to infect cells in the body and make more virus and NNRTIs act by inhibiting said reverse transcriptase their by inhibiting the viral replication.
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Efavirenz i.e. 4(s)-6-chloro-4-(cyclopropylethynyl)-l ,4-dihydro-4-(trifluromethyl)-2//-3, l-benzoxazin-2-one was first disclosed by Young et. al. in US 5,519,021 and various methods of preparation have also been disclosed in US 5,663,169, US 5,665,720, and US 5,811,423. The recommended dosage of Efavirenz, which is available under the brand name SUSTIVA is 600 mg orally once a day in combination with a protease inhibitors (Pi's) and/or nucleoside/nucleotide reverse transcriptase inhibitors (NRTI's). For pediatric patients the recommended dose based on the body weight is in the range of 200 to 400 mg. SUSTIVA is available as hard gelatin capsule of 50 mg, 100 mg and 200 mg strength. Also it is available as a tablet in strength of 300 mg and 600 mg. Additionally liquid formulation of Efavirenz is under evaluation in US and as of date clinicians recommend opening and administering the contents of capsule with food or liquid (for instance apple sauce) for some patients and in particular children and elderly population.
In therapy, the simplicity of using tablets has always been considered as a major advantage in particular in the context of ambulatory treatments, as demonstrated by the fact that large number of drugs are formulated and made available in the form of tablets. Additionally for some patient population, especially the pediatric or geriatric population it is desirable to have a liquid composition such that it avoids the difficulty and consequent unpleasantness to ingest the tablet.
However in case of Efavirenz, the said compositions either solid or liquid dosage forms although preferred are associated with inherent properties of Efavirenz rendering them to be un-palatable. Efavirenz when administered produces a hot, burning sensation in the mouth which is similar to that produced by a jalapeno (a small to medium-sized chili) and hence termed as hot "jalapeno" taste. This burning sensation is even more unpalatable when Efavirenz is administered in the form of liquid formulation.
Conventional approach to make this kind of composition more palatable is by addition of flavors and sweeteners to mask the taste but these flavors and sweeteners do little to overcome the burning or scratching sensation in the throat.
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Humber et.al. in EP 0753296 entitled "Oral formulations of S (+)-ibuprofen" discloses a organoleptically acceptable composition wherein, its makes use of S(+)-ibuprofen which does not contain unpleasant bitter taste which is associated with the racemate ibuprofen, optionally it also discloses the use of acidic components such as Fumaric acid ,citric acid and tartaric acid.
Bunick et.al. in US 6,627,214 discloses a use of fumaric acid for the preparation of palatable composition of propionic acid derivatives and in particular the composition comprising ibuprofen.
Bahal et. al. in US 6,235,733 discloses one such oral liquid composition of Efavirenz, which makes use of liquid vehicle composed of polyol esters of medium chain fatty acids supplemented with sweetening and flavoring agents to make it palatable. Despite of this, said liquid composition suffers from oily taste imparted by polyol esters of medium chain fatty acids.
Accordingly, the Efavirenz compositions available in market are associated with problems of un-palatability and lack of a suitable dosage form for administration to a pediatric or geriatric population. Although the tablets dosage form are provided with a coat to overcome the un-palatability, this approach does not address the present need of pediatric and geriatric population.
The issue of dose regimen palatability and patient compliance is also an major problem for the patients under treatment for HIV/AIDS related illnesses, since the patient needs to undergo a therapy wherein an individual has to take several unit dosage forms over a course of a given day, further the treatment becomes more complicated for an individual undergoing a combination therapy. More over, these individuals often need to administer additional medications such as antibiotics, lipid lowering agents or multivitamin preparations to control opportunistic infections and other related diseases or conditions they may be afflicted with. Consequently, these patients might need to take an extraordinary number of medications in a variety of dosage form per day
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Despite the disclosures of prior art and numerous efforts to find an effective means to eliminate this hot "jalapeno" taste, there is a continuing need for a method to effectively eliminate the burning sensation associated with Efavirenz, preferably in the form of oral dosage form wherein the hot "jalapeno" taste can be significantly reduced.
That is the why it is desirable to have palatable efavirenz composition suitable for all group of patient population ensuring taste masking, patient compliance and reduce the unnecessary burden of the patients under treatment for HIV/ADDS related illnesses and provide the required medicament with universal acceptance. This can be achieved by formulating an oral dosage form substantially free of hot "jalapeno" taste either as a chewable/mouth dissolving/dispersible tablets or dry powder for reconstitution (ready to use sachet) which are readily acceptable, simpler and cost effective.
SUMMARY OF INVENTION
The present invention relates to a pharmaceutical composition of Efavirenz, which is substantially free of hot "jalapeno" taste and the process for preparation of said pharmaceutical composition.
The Efavirenz composition of the present invention comprises of fumaric acid or citric acid or a combination thereof, formulated as either a solid oral dosage form or a liquid oral dosage form which is substantially free of hot "jalapeno" taste.
The use of a fumaric acid or citric acid or a combination thereof in an amount of about 25 wt % to 75 wt % based on the weight of Efavirenz, unexpectedly provides Efavirenz composition, which is substantially free of hot "jalapeno" taste and can be formulated as either a solid oral dosage form or a liquid oral dosage form which is substantially free of hot "jalapeno" taste
In another embodiment the composition of the present invention may further comprise of another active agent as well.
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DEFINITIONS
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any method and material similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
The term "pharmaceutically acceptable" as used herein means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and especially for human pharmaceutical use.
The term "therapeutically effective amount" means the amount of a compound that, when administered for treating or preventing a disease, is sufficient to effect such treatment or prevention for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.
The term "subject" or "a patient" or "a host" as used herein refers to mammalian animals, preferably human.
As used herein unless otherwise stated, all percentages for ingredients are weight percentages, based on the total weight of the pharmaceutical composition.
OBJECT OF THE INVENTION
The present invention provides with a pharmaceutical composition of Efavirenz which is substantially free of hot "jalapeno" taste.
The Efavirenz composition of the present invention comprises of fumaric acid or citric acid or a combination thereof in an amount of about 25 wt % to 75 wt % of Efavirenz which, is sufficient to effectively mask the hot "jalapeno" taste of Efavirenz.
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In the preferred embodiment, the fumaric acid is in an amount of about 40 wt % of Efavirenz, preferably about 50 wt %.
In one embodiment, the present invention provides a composition to be formulated as either a solid oral dosage form or a liquid oral dosage form. The solid oral dosage form may be in the form of a tablet such as a chewable/mouth dissolving/dispersible tablet. The taste masked liquid oral dosage form may be in the form of syrup, a ready to use suspension. Optionally, the composition may also be extemporaneously prepared liquid syrup or suspension such as for example dry powder for reconstitution with water, liquid concentrate for dilution, dispersible tablet or capsule.
Another embodiment of the present invention is simple incorporation of fumaric acid or citric acid or a combination thereof and Efavirenz as a mixture within a tablet or capsule. The composition of the present invention may also be provided in liquid or semisolid form such as syrup, suspension, gel or an elixir or other desirable form.
In yet another embodimant provided is a Efavirenz composition suitable for use in pediatric or gediatric population.
In yet another embodiment the composition of the present invention may further comprise of another active agent selected from the group comprising of protease inhibitors (Pi's), nucleoside/nucleotide reverse transcriptase inhibitors (NRTI's) or non-nucleoside reverse transcriptase inhibitors (NNRTI's).
In yet another embodiment provided herewith is a method of reducing the burning and hot "jalapeno" taste of efavirenz composition comprising providing a mixture of therapeutically effective amount of efavirenz and fumaric acid or citric acid or a combination thereof, in an amount of about 25 wt % to 75 wt % of Efavirenz in a final dosage form.
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DETAILED DESCRIPTION OF THE INVENTION
With regards to prior art teachings, the present invention does not require complex process or operation which involves coating or use of fatty acid ester for taste masking rather involves simpler and cost effective process in manufacturing of said composition.
fumaric acid or citric acid or a combination thereof is capable of reducing the pH of the mouth sufficeint to lower the hot "jalapeno" taste of Efavirenz..Although not firmly, but it can be postulated that by reduction in pH there is increase in salivary secretion from salivary ducts and these salivary secretions continuoesly washout the mucous membarne of oral cavity and throatThis mechanism might helps to reduce the burning sensation activity of efavirenz, which makes it more palatable.
Composition of the present invention may be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The "carrier" refers to all the components present in the pharmaceutical composition other than the active ingredient or ingredients. As generally used herein, "carrier" includes, but is not limited to fillers/diluents, disintegrants, binders, stabilizers, surfactants, suspending agents, sweeteners, flavorings agents or colorants.
Solvents may be chosen from those known in the pharmaceutical art. In a preferred embodiment, the solvents are water, alcohol, acetone, isopropanol, dichloromethane or combinations thereof.
Diluents, also referred to as "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed
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starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.
Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone or a combination thereof.
Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp).
The term "detackifier" as used herein means agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to reduce the tackiness of granules. Such compounds include, by way of example and without limitation, magnesium stearate, calcium sulphate, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
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The term "glidant" as used herein means agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.
Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer.RTM. 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
If desired, the tablets, beads, granules, or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, anti-oxidants, or preservatives.
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Most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.
The invention is described in by way of the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
EXAMPLES
Example 1
EFAVIRENZ DISPERSIBLE TABLET

Ingredients Qty/Tab (mg) %WAV
Efavirenz 50 15.4
Microcrystalline Cellulose 20 6.15
Sodium Lauryl Sulphate 1 0.3
Hydroxyl Propyl Cellulose (Klucel LF) 3.2 0.98
Croscarmellose sodium 20 6.15
Avicel pH 102 86.8 26.7
DCL-11 100 30.8
Polyplasdone-xl-10 6 1.8
Fumaric Acid 25 7.7
Aspartame 5 1.54
Peppermint flavor 2.5 0.77
Strawberry flavor 2.5 0.77
Magnesium stearate 3.0 0.9
Total 325.0
Process for the preparation of Efavirenz Dispersible tablet Composition
Efavirenz, Avicel 101 and Sodium lauryl Suphate were mixed in a RMG and further blended with Hydroxyl Propyl Cellulose and Croscarmellose Sodium bed granulator. Said blend was mixed in a wet mass using RMG and said wet mass was
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milled using multimill 1.0 mm screen by impact forward, Fast speed and dried using fluidized bed granulator at set LOD of not more than 2.0 % to yield the granules. Said granules were crushed in multimill. A sifted blend of Croscarmellose sodium, Microcrystalline Cellulose (Avicel pH 102), Lactose Monohydrate (DCL-11) and Cross-PVP was mixed with dried granules followed by addition of Aspartames, Peppermint flavor, Strawberry flavor and Fumaric acid ,mixed well and lubricated using magnesium stearate to provide a granular efavirenz composition ready for tableting.
The granular efavirenz composition was compressed using a rotary tablet press fitted with punches having predefined dimension.
Example 2
EFAVIRENZ SACHET: Powder for reconstitution

Ingredients Qty/Tab(mg) %WAV
Efavirenz 50.13 5.01
Aerosil 200 3 0.30
Avicel R591 100 10.00
SLS 1 0.10
Sucrose (processed) 795.82 79.60
Fumaric acid 25 2.50
Aspartame 10 1.00
Peppermint flavor 10 1.00
Strawberry flavor 5 0.50
Total 1000
Process for the preparation of Efavirenz Sachet: Powder for reconstitution.
Efavirenz and sucrose were mixed and sifted through a sieve and the blend was granulated using water to yield desired granules in and further blended with sucrose Avicel R591, Aerosil 200, SLS and Fumaric acid. Said blend was mixed with Aspartames, Peppermint flavor and Strawberry flavor to provide a granular efavirenz composition in the form of powder for reconstitution.
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Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All patent and non-patent publications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.
Dated this day of April, 2007
Umesh Zope
Registered patent agent
For, Emcure Pharmaceuticals Ltd.
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