FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
"PALATABLE PHARMACEUTICAL PREPARATIONS"
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 PARTICULARLY DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

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/ADDS 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.ore/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 Sustiva® 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.


Efavirenz i.e. 4(s)-6-chloro-4-(cyclopropylethynyl)-1,4-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.


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
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/AIDS 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.
Traditionally phospholipids have been known for their role in protection of gastrointestinal tract (GIT) (Lichtenberger et. al, Science 219,1327-1329).EP 401952 and EP 287298 discloses composition comprising mixture of phospholipids and neutral lipids for the treatment of luminal lining of the GIT in the prevention and treatment of ulcerogenic process.
Katsuragi et.al. in US 5,407,921 entitled "Method For Suppressing Bitter Taste" discloses a taste masking composition wherein, its makes use of acidic phospholipids or an acidic lysophospholipid for suppressing a bitter taste of material to be placed in mouth or in contact with mouth, such as foods, drinks, pharmaceuticals.
However, there has so far been no effort being made for taste masking by using Neutral phospholipids, prior to the present invention. It has been surprisingly found that the neutral phospholipids used in the present invention afford a highly palatable composition of Efavirenz which is near to absolute taste masking of hot "jalapeno" taste accorded by Efavirenz.
Accordingly, the present invention provides a novel efavirenz palatable preparation comprising of neutral phospholipids and the process of preparing the same
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 Neutral phospholipids or the mixture 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 Neutral phospholipids either alone or the mixtures thereof in an amount of about at least 5 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.
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 "Neutral Phospholipids" as used herein means the phospholipids which are neutral in pH and are substantially free of any acidic phospholipids for example the Neutral phospholipids are the ones selected from but not limited to phosphatidyl choline (PC) and lysophosphatidylcholine (LPC). The said phospholipids might be used alone or in combination or such phospholipids might also be incorporated as a complex for example but not limited to Soluthin MD® (Phosphotidylcholine 28.5% and lysophosphotidylcholine 1.2%), Phospholipon® 90H (L) (Phosphotidylcholine 92.2% and lysophosphotidylcholine 2.0%) and Phospholipon® 100H (Phosphotidylcholine 95.1% and lysophosphotidylcholine 0.25%).


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 Neutral phospholipids or the mixture thereof in an amount of about at least 5 wt % based on the weight of Efavirenz which is sufficient to effectively mask the hot "jalapeno" taste of Efavirenz.
In the preferred embodiment, the Neutral phospholipids or the mixture thereof is in an amount of about at least 10 wt % of Efavirenz, preferably about 15 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 ready to use suspension. Optionally, the composition may also be extemporaneously prepared 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 Neutral phospholipids or the mixture 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 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 process for preparing a efavirenz composition free of hot "jalapeno" taste of Efavirenz, comprising of
a. Granulating the Efavirenz 40 wt% with spray granulation which optionally comprises of up to 2 to 4 wt % of a pharmaceutically acceptable disintegrant and about 5 to 20 wt% of diluent along with about 1 to 5 wt% of binder and about 1 to 2 wt% of water soluble anionic surfactant in a rapid mixture granulator under conditions suitable for producing uniform particle size granules after milling, sieving and drying in Fluidized Bed Dryer (FBD) to give first part of the dried Efavirenz granules with loss of drying, NMT 2.0%.


b. Blending said first granular portion of step (a) with about 10 to 50 wt% of
diluent, about 3 to 7 wt% pharmaceutically acceptable disintegrant, 5 to 20 wt %
of neutral phospholipid, and 1 to 3 wt% of glidant in a blender along with about
0.01 wt% to 2 wt % of sweetners and flavors.
c. Blending the mixture of step (b) with 1 wt% to 2 wt% of lubricant.
d. Compressing a predetermined amount of the blended mixture of step (c) to
produce a tablet.
In yet another embodiment provided herewith is a process for preparing a Efavirenz composition free of hot "jalapeno" taste of Efavirenz, comprising of
a. Granulating the Efavirenz 25 to 50 wt% with spray granulation with about 5 to 20
wt% of neutral phospholipid dispersed in water, and composition also comprising
of up to 2 to 4 wt% of a pharmaceutically acceptable disintegrant and about 5 to
20 wt% of diluent along with about 1 to 5 wt% of binder and about 1 to 2 wt% of
water soluble anionic surfactant in a rapid mixture granulator under conditions
suitable for producing uniform particle size granules after milling, sieving and
drying in FBD to give first part of the dried Efavirenz granules with LOD NMT
2.0%.
b. Blending said first granular portion of step (a) with about 10 to 50 wt% of
diluent, 3 to 7 wt% pharmaceutically acceptable disintegrant, and 1 to 3 wt% of
glidant in a blender along with about 0.01 wt% to 2 wt % of sweetners and
flavors.
c. Blending the mixture of step (b) with 1 wt% to 2 wt% of lubricant.
d. Compressing a predetermined amount of the blended mixture of step (c) to
produce a tablet.
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 Neutral phospholipids or the mixture thereof, in an amount of about at least 5 wt % of Efavirenz in a final dosage form.


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.
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 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,


cellulose, sodium alginate, including ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose 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 carboxymethylceHulose, 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.
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, ammomum 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 ammomum 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, Cremophor (polyoxyethylene 35 castor oil) 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.
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.
EXAMPLE 1

Ingredients Qty/Tab(mg) %WAV
Efavirenz 100.43 50.215
1 Croscarmellose sodium (Ac-Di-Sol) 10.00 5.00
Microcrystalline cellulose (Avicel PH 101) 39.57 19.78
Hydroxypropyl cellulose (Klucel LF) 06.40 3.20
Sodium lauryl sulphate (Texpon K12P PH) 02.00 1.00
Purified water q. s.
Crospovidone (polyplasdone XL-10) 13.60 6.80
Talc 05.00 2.50
Colloidal silicon dioxide (Aerosil 200) 05.00 2.50
Aspartame granular 05.00 2.50
Strawberry flavor 04.00 2.00
Peppermint flavor 04.00 2.00
Magnesium stearate 05.00 2.50
Total tablet weight 200.00
Efavirenz, Avicel 101 and Sodium lauryl Suphate were mixed in a RMG and further blended with sifted Hydroxyl Propyl Cellulose and Croscarmellose Sodium. Said blend was mixed in a wet mass using RMG (spray granulation) and said wet mass was 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 crospovidone, talc and colloidal silicon dioxide was mixed with dried granules followed by addition of Aspartame, Peppermint and Strawberry flavor, 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

Ingredients Oty/Tab (mg) % WAV
Efavirenz 100.43 40.17
Croscarmellose sodium (Ac-Di-Sol) 10.00 4.00
Microcrystalline cellulose (Avicel PH 101) 39.57 15.83
Hydroxypropyl cellulose (Klucel LF) 06.40 2.56
Sodium lauryl sulphate (Texpon K12P PH) 02.00 0.80
Purified water q.s.
Crospovidone (polyplasdone XL-10) 13.60 5.44
Spray dried phospholipid with maltodextrin (Soluthin MD) 50.00 20.00
Talc 05.00 2.00
Colloidal silicon dioxide (Aerosil 200) 05.00 2.00
Aspartame granular 05.00 2.00
Strawberry flavor 04.00 1.60
Peppermint flavor 04.00 1.60
Magnesium stearate 05.00 2.00
Total tablet weight 250
Efavirenz, Avicel 101 and Sodium lauryl Suphate were mixed in a rotary mixer granulator (RMG) and further blended with sifted Hydroxyl Propyl Cellulose and Croscarmellose Sodium Said blend was mixed in a wet mass using RMG (spray granulation) and said wet mass was milled using multimill 1.0 mm screen by impact forward, Fast speed and dried using fluidized bed granulator at set loss on drying (LOD) of not more than 2.0 % to yield the granules which were crushed using multimill. A sifted blend of crospovidone, Soluthin MD, talc and colloidal silicon dioxide was mixed with dried granules followed by addition of Aspartame, Peppermint and Strawberry flavor, 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 3

Ingredients Oty/Tab(mg) %w/w
Efavirenz 100.43 40.17
Croscarmellose sodium (Ac-Di-Sol) 10.00 4.00
Microcrystalline cellulose (Avicel PH 101) 39.57 15.83
Hydroxypropyl cellulose (Klucel LF) 6.40 2.56
Sodium lauryl sulphate (Texpon K12P PH) 2.00 0.80
Purified water q.s.
Crospovidone (polyplasdone XL-10) 13.60 5.44 1
Phosphotidylcholine [Phospholipon 90 H (L)] 15.00 6.00 1
Talc 5.00 2.00
Colloidal silicon dioxide (Aerosil 200) 5.00 2.00
Microcrystalline cellulose (Avicel PH 102) 35.00 14.00
Aspartame granular 5.00 2.00
Strawberry flavor 4.00 1.60
Peppermint flavor 4.00 1.60
Magnesium stearate 5.00 2.00
Total tablet weight 250.00 |
Efavirenz, microcrystalline cellulose (Avicel 101) and Sodium lauryl Suphate mixed in RMG with chopper and mixer set at fast speed. The said blend was then mixed with sifted hydroxypropyl cellulose and croscarmellose sodium. The said blend was then granulated with water addition by spraying in RMG and said wet mass was 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. Sifted blend of crospovidone, talc, phospholipon 90H (L), microcrystalline cellulose (Avicel 102) and colloidal silicon dioxide was mixed with dried granules followed by addition of Aspartame, Peppermint and Strawberry flavor, 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 4

Ingredients Qty/Tab(mg) %w/w
Efavirenz 100.43 40.82
Croscarmellose sodium (Ac-Di-Sol) 10.00 4.07
Microcrystalline cellulose (Avicel PH 101) 39.57 16.09
Hydroxypropyl cellulose (Klucel LF) 6.40 2.60
Sodium lauryl sulphate (Texpon K12P PH) 2.00 0.81
Purified water q.s.
Crospovidone (polyplasdone XL-10) 13.60 5.53
Phosphotidylcholine [Phospholipon 100 H] 15.00 6.10
Talc 5.00 2.03
Colloidal silicon dioxide (Aerosil 200) 5.00 2.03
Microcrystalline cellulose (Avicel PH 102) 35.00 14.23
Aspartame granular 5.00 2.03
Peppermint flavor 4.00 1.63
Magnesium stearate 5.00 2.03
Total tablet weight 246.00 1
Efavirenz, microcrystalline cellulose (Avicel 101) and Sodium lauryl Suphate is mixed in RMG with chopper and mixer set at fast speed. The said blend was then mixed with sifted hydroxypropyl cellulose and croscarmellose sodium. The said blend was then granulated with water by spraying it on the blend in RMG and said wet mass was 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. Sifted blend of crospovidone (polyplasdone XL 10), talc, phospholipon 100H, microcrystalline cellulose (Avicel 102) and colloidal silicon dioxide was mixed with dried granules followed by addition of Aspartame, Peppermint and Strawberry flavor 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 5

1 Ingredients Qty/Tab(mg) %W/W
1 Intragranular
1 Efavirenz 100.00 28.99
I Croscarmellose sodium (Ac-Di-Sol) 10.00 2.90
1 Microcrystalline cellulose (Avicel PH 101) 40.00 11.59
1 Hydroxypropyl cellulose (Klucel LF) 6.40 1.85
Sodium lauryl sulphate (Texpon K12P PH) 2.00 0.58
Phospholipon 100H 15.00 4.35
Purified water q.s.
I Efavirenz granules 173.40
1 Lubrication or extragranular excipients
Lactose monohydrate (DCL-11) 108.35 31.40
Talc 5.00 1.45
Colloidal silicon dioxide (Aerosil 200) 5.00 1.45
Polyplasdone XL 10 25.00 7.25
Neotame 0.25 0.07
Peppermint 5.00 1.45
Strawberry flavor 8.00 2.32
Sodium steryl Fumarate 15.00 4.35
Total tablet weight 345
Phospholipon 100H was dispersed in the sufficient quantity of water and was homogenized for 30 min using homogenizer the said dispersion was used as granulating fluid for Efavirenz granulation. Efavirenz, microcrystalline cellulose (Avicel 101) and Sodium lauryl Suphate was mixed in RMG with chopper and mixer set at fast speed. The said blend was then mixed with sifted hydroxypropyl cellulose and croscarmellose sodium. The said blend was then granulated with the phospholipids dispersion by spraying the dispersion on blend in RMG and said wet mass was 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. Sifted blend of DCL-11, polyplasdone XL 10, talc, and colloidal silicon dioxide was mixed with dried granules followed by addition of Neotame, Peppermint and Strawberry flavor 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 6

Ingredients Qty/Tab(mg) %W/W
Intragranular
Efavirenz 100.00 23.92
Croscarmellose sodium (Ac-Di-Sol) 10.00 2.39
Microcrystalline cellulose (Avicel PH 101) 40.00 9.57
Hydroxypropyl cellulose (Klucel LF) 6.40 1.53
Sodium lauryl sulphate (Texpon K12P PH) 2.00 0.48 |
Purified water q. s. E
Efavirenz granules 158.40
Lubrication or extragranular excipients
Microcrystalline cellulose (Avicel PH 200) 97.00 23.21
Lactose monohydrate (Flowlac 100) 118.35 1 28.31
Talc 3.00 0.72
Colloidal silicon dioxide (Aerosil 200) 8.00 1.92
Polyplasdone XL 15.00 3.59
Neotame 0.25 0.06 |
Peppermint 5.00 1.20
Strawberry flavor 8.00 1.92
Magnesium stearate 5.00 1.20
Total tablet weight 418 |
Efavirenz, microcrystalline cellulose (Avicel 101) and Sodium lauryl Suphate mixed in RMG with chopper and mixer set at fast speed. The said blend was then mixed with sifted hydroxypropyl cellulose and croscarmellose sodium. The said blend was then granulated using purified water in the form of spray in RMG and said wet mass was 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. Sifted blend of polyplasdone XL, talc, microcrystalline cellulose (Avicel 200), lactose monohydrate (flowlac 100) and colloidal silicon dioxide was mixed with dried granules followed by addition of Neotame, Peppermint and Strawberry flavor, 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.


EXAMLE 7

Ingredients Oty/Tab(mg) %W/W
Intragranular
Efavirenz 100.00 23.92
Croscarmellose sodium (Ac-Di-Sol) 10.00 2.39
Microcrystalline cellulose (Avicel PH 101) 40.00 9.57
Hydroxypropyl cellulose (Klucel LF) 6.40 1.53
Sodium lauryl sulphate (Texpon K12P PH) 2.00 0.48
Phospholipon 90H (L) 15.00 3.59
Purified water q.s.
Efavirenz granules 173.40
Lubrication or extragranular excipients
Microcrystalline cellulose (Avicel PH 200) 97.00 23.21
Lactose monohydrate (Flowlac 100) 98.35 23.53
Talc 3.00 0.72
Colloidal silicon dioxide (Aerosil 200) 8.00 1.92
Polyplasdone XL 20.00 4.78
Neotame 0.25 0.06
Peppermint 5.00 1.20
Strawberry flavor 8.00 1.92
Magnesium stearate 5.00 1.20
Total tablet weight 418
Phospholipon 90H (L) was dispersed in the sufficient quantity of water and was homogenized for 30 min using homogenizer the said dispersion was used as granulating fluid for efavirenz granulation. Efavirenz, microcrystalline cellulose (Avicel 101) and SLS mixed in RMG with chopper and mixer set at fast speed. The said blend was then mixed with sifted hydroxypropyl cellulose and croscarmellose sodium. The said blend was then granulated with the phospholipids dispersion by spraying the dispersion on blend in RMG and said wet mass was 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. Sifted blend of polyplasdone XL, talc, microcrystalline cellulose (Avicel 200), lactose monohydrate (flowlac 100) and colloidal silicon dioxide was mixed with dried granules followed by addition of Neotame, Peppermint flavor, and Strawberry flavor, 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
DETERMINATION OF TASTE MASKING
Method: Efavirenz tablet (with or without neutral phospholipids were dispersed in 10 ml of water and were labeled as Test Sample 1 (Composition of Example 1) and Test Sample 2. (Composition of Example 2). Said dispersions were subject to Taste evaluation by volunteers (Cross over blind technique) wherein, a time gap of 30-60 min was kept between the two cross over test for each volunteer. After tasting samples volunteers were asked to grade the samples on a 0 to 5 scale. The grading from 0 to 5 was classified as below. Grade Description:
? 0: Pepper or jalapeno taste immediately after ingestion (Not Acceptable)
? 1: Pepper or jalapeno taste after some times of ingestion (Not acceptable)
? 2: Slight sweet taste with pepper or jalapeno taste after some times of ingestion.(Not
acceptable)
? 3: Sweet taste with slight pepper or jalapeno taste (Partially acceptable or Average)
? 4: Sweet taste with negligible pepper or jalapeno taste after few minutes (Acceptable)
? 5: Sweet taste with no pepper or jalapeno taste (Acceptable)
TABLE-I
Volunteers Grading (Example 1 and Example 2)

Volunteer No Test sample 1* Test sample 2#
1 0 4
2 1 3
3 1 5
4 0 4
5 2 5
* Example 1: Efavirenz tablet without phospholipids;# Example 2 : Efavirenz tablet with Neutral phospholipidSpray dried phospholipid with maltodextrin i.e. Soluthin MD.
Similarly, Example 6 and Example 7 were subjected to Taste evaluation and volunteers grading are as provided in Table II.


TABLE-II
Volunteers Grading (Example 6 and Example 7)

Volunteer No 1 Test sample 3* Test sample 4#
1 I 0 5
2 1 5
3 1 4
4 0 5
5 1 4
* Example 6# Example 7 : Efavirenz tablet without phospholipids; : Efavirenz tablet with Neutral phospholipids Phospholipon 90H (L).
The above results clearly demonstrate the effect of Neutral Phospholipid in Taste masking of Efavirenz. As a comparison, the above data for Test sample 2 and 4 clearly demonstrates a well correlated, desirable Taste masking effect of Neutral Phospholipid used in compositions of the invention, as compared to Test sample 1 and 3.
Conclusion: The comparative taste evaluation data of Example 1 and Example 6 with Example 2 and Example 7 shows that the composition of the present invention comprising of Neutral Phospholipid provides with a desired and palatable Efavirenz composition.
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 and the claims as given below.
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.


We claim
1. An oral palatable pharmaceutical composition comprising a therapeutically effective amount of efavirenz or a pharmaceutically acceptable salt thereof, wherein said composition contains at least 5 wt % of neutral phospholipids based on the weight of Efavirenz.
2. A pharmaceutical composition as claimed in claim 1, wherein said composition contains about 10 wt % to 20 wt % of neutral phospholipids based on the weight of Efavirenz.
3. A pharmaceutical composition as claimed in claim 1, wherein said neutral phospholipids are selected from the group comprising of phosphatidylchloine or lyso phosphatidyline or the mixture thereof.
4. A pharmaceutical composition as claimed in claim 3, wherein the neutral phospholipids is selected from Soluthin MD, Phospholipon 90H (L) or Phospholipon 100H.
5. A pharmaceutical composition as claimed in claim 1 further comprises of a pharmaceutically acceptable carrier.
6. A pharmaceutical composition as claimed in claim 1 is provided in a solid dosage form.
7. A pharmaceutical composition as claimed in claim 4 is provided in a tablet dosage form.
8. A pharmaceutical composition as claimed in claim 1 is provided in a liquid dosage form.
9. A pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical dosage form comprises about 50-600 milligrams of efavirenz..
10. A palatable pharmaceutical composition of efavirenz, substantially as described herein with respect to the foregoing examples and accompanying drawings.





ABSTRACT
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 Neutral phospholipids or the mixture thereof, formulated as either a solid oral dosage form or a liquid oral dosage form which is substantially free of hot "jalapeno" taste.