PHARMACEUTICAL COMPOSITIONS OF DEXIBUPROFEN

FIELD OF THE INVENTION

The present invention relates to formulations of pharmaceutical compositions and in particular to pharmaceutical composition of dexibuprofen and/ or salts thereof in oral dosage form. Also, the present invention relates to a process of manufacture of such pharmaceutical compositions comprising dexibuprofen and/ or salts possessing high in- vitro dissolution and enhanced bioavailability in humans. Importantly, the invention is directed to high in-vitro dissolution of a poor water soluble drug dexibuprofen by controlling the particle size of the active ingredient of the invention such as dexibuprofen, to enable a significant improvement in the in- vivo performance of the active.

BACKGROUND ART

Invention and first synthesis of Ibuprofen dates back to the year 1963 (US Patent 3,385,886) and was launched in UK (1969) as Nurofen TM, in USA (1983) and Canada (1974) as Advil TM. Ibuprofen is a racemate of S-Ibuprofen and R- Ibuprofen where S- Ibuprofen, commonly referred to as dexibuprofen, is the sole therapeutically active form in the class of NSAID' s (Non-steroidal anti-inflammatory drugs). About half of R- Ibuprofen is converted in- vivo into its S -isomer slowly, that does not add much to enhance the therapeutic effect. (Pharmaceutical Research Vol.l 1, No.6, 1994)

Therapeutic activity of all medicines depends upon the bioavailability of the active ingredient. Blood plasma levels of the drug depending upon the absorption of the drug, is a measure of bioavailability. Absorption of drugs can be affected by its solubility at the absorption site in the gastrointestinal tract (GIT). Poorly soluble drugs offer challenges to formulators in terms of achieving the desired dissolution of the drug at the pH of the target GIT to obtain the desired rate and extent of absorption. Hence, achieving high in- vitro dissolution in aqueous buffers with varied and defined pH's is an important parameter and is a prerequisite for achieving better bioavailability of an insoluble drug from a pharmaceutical composition.

The designation dexibuprofen or (S)-Ibuprofen or S-(+)-Ibuprofen as used in the present specification and claims is intended to denote the substantially pure S-(+) enantiomer of ibuprofen and are synonymous to (S)-(+)-2-(4-Isobutylphenyl) propionic acid of CAS no. 51146-56-6 which is free of R-(-)-Ibuprofen. In the working examples given herein S- (+)-Ibuprofen having an enantiomeric purity of > 99% and an analytical purity corresponding to that specified in British Pharmacopoeia was employed. Henceforth, the term dexibuprofen will be used for the active ingredient of this invention. It is the dextrorotatory or (+) stereoisomer of Ibuprofen racemate. The R (-)-isomer is partially, slowly and variably converted to the S-(+)-isomer in the body. Dexibuprofen is practically insoluble in water, but is readily soluble in most organic solvents like methanol, methylene chloride, and acetone, and is soluble in aqueous solutions of alkali hydroxides and carbonates (Martindale, 32 ^nd Ed.). It is slightly soluble in a buffer medium of pH 6.8 and very slightly soluble in a buffer medium of pH 4.5. Dexibuprofen is used in the relief of pain and inflammation. Therefore, it is thus vital for dexibuprofen for quick absorption in adequate amounts in early parts of gastrointestinal tract where pH is less than 6.8, after oral administration to initiate pain relief as early as possible.

One of the screening parameters used during the development of dosage forms to assess the physico-chemical properties of a pharmaceutical composition is in-vitro dissolution rate. Dexibuprofen is sparingly soluble in pH 7.2 buffer, slightly soluble in pH 6.8 buffer and very slightly soluble in pH 4.5 buffer. Hence pH 7.2 is the preferred medium to have a comparative study on the in-vitro dissolution performance of a formulation comprising dexibuprofen. Additionally, buffer of pH 4.5 with 0.5% sodium lauryl sulfate (SLS) can also be used as the dissolution media to find performance of the dosage form. Considering the higher solubility, USP describes Type 2 dissolution method with 900 ml buffer of pH 7.2 as the dissolution medium used for in-vitro dissolution of Ibuprofen tablets. Using the said USP dissolution method, Ibuprofen tablets (Motrin® tablets, Pharmacia & Upjohn Company., Division of Pfizer Inc, NY) releases more than 90% of the drug in 5 minutes which was determined by the concentration of liberated dexibuprofen spectrophotometrically by comparing the measured absorbance at 265.5 ran with that of a standard solution of dexibuprofen. Hence, a tablet formulation containing

dexibuprofen should have in- vitro dissolution of more than 90% in 5 minutes under Type 2 dissolution method to achieve the desired therapeutic efficacy both in terms of the rate and extent of absorption.

Dexibuprofen though more soluble than Ibuprofen, exhibits lower intrinsic dissolution rates as would be expected from the very small specific surface area (Drug Dev. and Industrial Pharmacy 1991, 17(5), 772-92) and particle size distribution. This coupled with its low melting point in the range of 52-54 ⁰ C ₅ low bulk density and poor flow properties imposes more than one problem to a formulator. Poor solubility/ low intrinsic dissolution of dexibuprofen in the pH of upper GIT can result in poor absorption, which in turn may result in low drug plasma levels and related low therapeutic activity.

U.S. Pat. No. 5, 631, 296 is directed to the production of pellets containing dexibuprofen combined with a basic compound. Techniques to prepare pellets are cumbersome, time consuming and need special equipments. Moreover, use of basic inorganic salt or dilute solution of alkali metal hydroxide solutions causes inversion of S to R isomer. These pellets dissolve to release over 90% of the drug in a time period of 20 minutes using USP in-vitro dissolution method.

U.S. Pat. No. 6, 066, 332 is related to the pharmaceutical compositions containing nanoparticles of dexibuprofen. Procedures used to prepare nanoparticles of the drug are difficult, complicated and expensive. Dexibuprofen 200 mg aqueous suspension of nanosol as compared to micronized dexibuprofen gave 15 mg/L and 11 mg/L plasma levels respectively. However, tablets comprising of dexibuprofen nanoparticles exhibited no observable difference in in-vitro dissolution when compared to tablets made by employing conventional techniques containing dexibuprofen.

WO 94/10993 describes a pharmaceutical particulate formulation comprising dexibuprofen, a water-soluble binder e.g. a protein preferably gelatin, colloidal silica of 0.05-0.15 % w/w (NMT 2% w/w) as lubricant or glidant, and microcrystalline cellulose 30-40 % w/w as a pharmaceutically acceptable excipient. The prior art discloses in-vitro

dissolution of drug starting from 10 minutes and also goes to show that the dissolution decreases on storage in blister packs. This prior art does not disclose the in-vitro dissolution value at 5 minutes time and also does not specify any particle size of the drug to be used while formulating the various examples described in this prior art patent.

U.S. Pat. No. 6, 713, 089 discloses a quick release of the active ingredient like dexibuprofen from a pharmaceutical composition of particle size such that: when the powder is subjected to a sieve analysis then at least 90 % w/w of the particles pass through the 180 micron sieve, and when the powder is contacted with an aqueous medium to form a particulate composition and when the particulate composition is subjected to a sieve analysis then at least about 50 % w/w of the particles passes through 180 micron mesh. The quick release composition claims the use of an alkalizing agent to achieve at least about 50 % w/w dissolution of the active substance in 0.07(N) HCl medium at 20 minutes. The claimed dissolution is achieved in this prior art due to the specific particle size and alkalizing agent in the composition, which imparts neutralizing effect to the acidic environment thereby increasing the drug release in acidic pH.

U.S. Pat. No. 4, 851, 444 is an attempt to achieve a fast and increased analgesic effect compared to racemic ibuprofen through compositions for oral administration which may be tablet, caplet, pill or capsule. Such compositions contain dexibuprofen and pharmaceutically acceptable carrier or diluents thereof. This patent does not disclose any particle size of dexibuprofen in the compositions.

U.S. Pat. No. 4, 877, 620 discloses an ibuprofen containing medicament, characterized in the medicament where ibuprofen is present as S-(+) Ibuprofen only whereby it was discovered that by the sole use of this S-(+) enantiomer a substantial reduction of the dosage is possible and thus the S-(+) isomer in the absence of R-(-) isomer had a greater pharmacological potential as was expected. It was surprisingly discovered by the analgesia test on the monkeys that the same analgesic activity caused by a given dose of racemic ibuprofen can not only be achieved by half a dose of S-(+)-ibuprofen, but that

even less than half as much S-(+)-ibuprofen as racemic ibuprofen is required to exhibit a given analgesic activity.

U.S. Pat. No. 5, 519, 057 which is the continuation of the prior art U.S. Pat. No. 4, 877, 620 is directed to the use of pure S-(+) enantiomer of Ibuprofen in a substantially free form from R-(-)-Ibuprofen as an analgesic formulated using other pharmaceutically acceptable diluents. This prior art patent does not describe the particle size of the drug used in these pharmaceutical compositions

WO 93/20809 describes pharmaceutical compositions of dexibuprofen to reduce adverse side effects when compared to compositions of Ibuprofen. In particular, the adverse side effects of gastrointestinal toxicity or irritation and kidney toxicity are reduced. S-(+)~ enantiomer was administered along with inactive substances such as diluents or fillers in pharmaceutical compositions. The dose of S-(+) enantiomer is half or even less than half of racemic ibuprofen.

U.S. Pat. No. 5, 560, 926 describes a process for the production of tablet containing S- Ibuprofen which rapidly releases the active agent, comprising, admixing dry binders to a compact powder mixture of active agent and customary tabletting auxiliaries, thereby compressing the dry binders with the compact active agent. The patent defines neither particle size of the drug nor in-vitro dissolution or bioavailability of these compositions.

U.S. Pat. No. 5, 631, 296 is directed to tablets comprising enteric coated pellets containing dexibuprofen and a basic compound. 90% dexibuprofen is released within 20 minutes. Capsules containing pellets/ tablets have plasma levels of the active comparable to those of the racemate on administration of at least 25 % less dexibuprofen than the racemate.

U.S. Pat. No. 5, 780, 046 claims an oral pharmaceutical composition comprising an organoleptically acceptable acidic component to maintain the pH of the formulation between 2 and 6. The composition is contained within a powdered or granular

formulation, liquid formulation, chewable tablet formulation, effervescent formulation, lozenge formulation, rapidly disintegrating solid dosage formulation, a chewable veterinary formulation or a chewing gum formulation. This patent does not provide any information about a particle size, in-vitro dissolution or bio availability of the drug in these compositions.

In an endeavor to prepare S-(+)-ibuprofen, U.S. Pat. No. 5, 869, 101 achieves the production of irregularly shaped spheroid crystalline particles of diameter < 1 mm having improved flow properties, comprising coarse-crystalline S-(+)-ibuprofen in a molten form, finely distributing it in chilled water, filtering out and drying the agglomerate suitable for tablets.

U.S. Pat. No. 5, 869, 102 discloses a solid pharmaceutical composition consisting of dexibuprofen, macrocrystalline cellulose (30-50 % w/w), colloidal silica (less than 0.3%w/w) and wetting agent (3-6 % w/w) or surfactant (0.01-2 % w/w of sodium lauryl sulfate, Tween, Span) whereby the dissolution time for 90 % of dexibuprofen was 3 to 9 minutes as compared to 19 minutes for Seractil (dexibuprofen tablets of Gebro). This patent does not speak about the particle size of the active dexibuprofen directed to achieve the unique behaviour of the tablets in dissolution medium which in turn influence the bioavailability of the drug.

U.S. Pat. No. 6, 551, 615 describes the preparation of soft gelatin capsules as a clear solution. In 20 minutes time 77.23 %, 93.28 % and 90 % of the drug dose was dissolved at pH's of 6.5, 7.5 and water respectively.

WO 2007/069874 discloses a fused solid dispersion comprising active ingredient having lower melting point and a pharmaceutically acceptable absorbent for immediate release and controlled release formulations. Pharmaceutically acceptable absorbent is selected from the group comprising silicates, bentonite, lactose, dextrin, starch, celluloses, PEG, and cross linked PVP. For immediate release formulation, highest in-vitro release obtained was 66.7% and 89.15% in 5 and 10 minutes respectively.

WO2007/025488 is related to a method of production of a fine-crystalline mixture containing a non-steroidal antiinflammatory drug and an auxiliary substance like microcrystalline cellulose. The coarse crystalline substance from the group of nonsteroidal anti-inflammatory drugs is dissolved in a solvent at an increased temperature, the solution is subsequently distributed at rapid chilling into a cooling liquid containing the auxiliary substance, said cooling liquid being placed in an ice bath, and the product is then filtered off and dried. The said application uses NSAID' s and auxiliary agent as co- mixture or adsorbed to form a fine-crystalline mixture containing NSAID 's and auxiliary agent, which contribute to the improved flow properties and compressibility of the mixture and is used to formulate as capsules or tablets.

Therefore it remains important to address the need for good in-vitro dissolution by exploring other improved pharmaceutical compositions to favour/ achieve effective bioavailability of the active ingredient in humans

Slower in-vitro dissolution can increase T _max (Time required to attain maximum concentration in plasma) and possibly decrease C _max . Thus slower and incomplete dissolution are expected to give lower plasma levels and increased T _max . Reported C _max of Seractil 400 mg tablets is 24.1 mg per liter (International J CHn Pharmacol & Therapeutics 1998, 36, 414-417). T _max for Seractil® 400 mg tablets (Gebro Pharma GmbH) is 2.2 hours. The reported C _max of dexibuprofen in Ibuprofen 800mg tablets (which contains 400 mg dexibuprofen initially) is 28 mg per liter and T _max is 1.80 hours (Eur J Clin Pharmacol 1995, 48, 505-511). The last reference also gives C _max values of 23.5 mg per liter for S-Optifen® (dexibuprofen) 400 mg tablets, which is another marketed product in Switzerland by Spring Pharma. AUC for Seractil® tablets 400 mg is 98.4 μg. hr/ mL as compared to 113.2 μg. hr/ mL for Ibuprofen 800 mg.

Hence, there exists a continuous need in the art to improve on the in-vitro dissolution whereby enhanced bioavailability in terms of improved and lower T _max (Time required to attain maximum concentration in plasma), increased C _max and extent of absorption in the

blood plasma denoted by AUC of dexibuprofen from pharmaceutical compositions can be achieved.

In the instance, for poor water soluble drug such as dexibuprofen, achieving faster release of the drug is challenging and for such a purpose increasing the in- vitro dissolution with a consequential improvement in the in-vivo performance of the pharmaceutical composition is always desirable.

Also, there is need for an improved and selective manufacturing process for the production of such a pharmaceutical composition that would take care of the serious disadvantages associated with the active ingredient, dexibuprofen, like low melting point, low bulk density and poor flow properties thereby making it easily to process.

OBJECTS OF THE INVENTION

It is thus the basic object of the present invention to provide for pharmaceutical compositions of dexibuprofen that would achieve faster drug release by way of increasing the rate of in-vitro dissolution to thereby bring about improvement in the in-vivo performance of the product.

Another object of the present invention is to provide a process for the preparation of pharmaceutical composition comprising dexibuprofen that would achieve faster release of dexibuprofen particles and prevent the aggregation of such released particles in the dissolution medium and thereby achieve a faster dissolution rate.

Yet another object of the present invention is to provide a pharmaceutical composition comprising dexibuprofen with in-vitro dissolution of at least about 80 % of the active at pH 7.2 at 5 min and not more than 30 % in 0.07 (N) HCl at 20 min.

It is another object of the present invention to provide a pharmaceutical composition comprising dexibuprofen devoid of an alkalizing agent and yet achieving an in-vitro

dissolution of at least about 80 % at pH 7.2 at 5 min and not more than 30% in 0.07(N) HCl at 20 min.

It is yet another object of the present invention to provide a pharmaceutical composition comprising dexibuprofen in combination with pharmaceutically acceptable excipients such as disintegrant and superdisintegrant in a selective ratio ranging from 1:4 - 4:1 respectively, distributed evenly or unevenly in intra and extra granular form or both to achieve faster drug release by way of increasing the in- vitro dissolution and enhance the in- vivo performance of the product.

Another object of the present invention is to provide a pharmaceutical composition comprising dexibuprofen in combination with at least one diluent, at least one disintegrant and other pharmaceutically acceptable excipients without the use of any alkalizing agent that would help in achieving the above said in-vitro dissolution parameter of at least about 80 % at pH 7.2 at 5 min and not more than 30 % in 0.07(N) HCl at 20 min.

It is another object of the present invention to provide a pharmaceutical composition comprising dexibuprofen and a pharmaceutically acceptable excipient with optional use of surfactants and/ or wetting agents to achieve faster drug release by way of increasing the dissolution and thereby obtain improvement in the in-vivo performance of the product.

Yet further object of the present invention is to provide a pharmaceutical composition of dexibuprofen with high in-vitro dissolution involving amorphous dexibuprofen having untapped bulk density of 0.1 to 0.7 g/ ml and tapped bulk density of 0.3 to 1.0 g/ml and pharmaceutically acceptable diluents.

It is another object of the present invention to provide a pharmaceutical composition comprising amorphous dexibuprofen of bulk density of 0.30 to 0.65 g/ ml and Tapped density of 0.4 to 1.0 g/ml in combination with pharmaceutically acceptable diluents

directed to achieve high in vitro dissolution of at least about 80 % at pH 7.2 at 5 min and not more than 30% in 0.07 (N) HCl at 20 min.

A further object of the present invention is directed to a pharmaceutical composition comprising dexibuprofen salt preferably lysinate or sodium salt and pharmaceutically acceptable diluents directed to achieve high in vitro dissolution of at least about 80 % at pH 7.2 at 5 min.

In yet further object of the present invention to provide a pharmaceutical composition comprising dexibuprofen with high in-vitro dissolution not limited to tablets, capsules, granules, powders, suspensions and suppositories.

Yet further object of the present invention is directed to provide a process for preparing a pharmaceutical composition comprising dexibuprofen with high in-vitro dissolution, wherein the formulation would show no substantial enantiomeric conversion of S form to R form even after exposing the tablets to accelerated instability conditions.

Still another object of the present invention is to provide a selective manufacturing process for dexibuprofen tablets, wherein the active has associated disadvantages of possessing low melting point i.e., 52-54 ⁰ C, lower bulk density and poor flow properties and yet would achieve high in-vitro performance of the formulation.

SUMMARY OF THE INVENTION

Thus according to the basic aspect of the invention there is provided a pharmaceutical composition comprising dexibuprofen having high in-vitro dissolution with dexibuprofen, of mean particle size ranging from 1 to 450 microns, preferably ranging from 25 to 150 microns and more preferably ranging from 30 to 100 microns; and pharmaceutically acceptable diluent/ excipients thereof.

In accordance with a preferred aspect a pharmaceutical composition comprising dexibuprofen is provided in preferable amounts of 100 mg, 200 mg, 300 mg, 400 mg & 600 mg.

In accordance with another aspect a pharmaceutical composition comprising dexibuprofen particles is provided with specific surface area ranging from 0.01 to 3 m ² / gm

Importantly, a pharmaceutical composition comprising dexibuprofen wherein the specific ratio of disintegrant and superdisintegrant is 1 :4, which is distributed uniformly or non- uniformly in-intra or extra-granular form or both along with pharmaceutical acceptable excipient.

Advantageously, a pharmaceutical composition comprising dexibuprofen wherein in- vitro dissolution of at least 80% in buffer of pH 7.2 at 5 minutes and not more than 30% in 0.07 (N) HCl at 20 minutes is obtained free of any alkalizing agent.

In another aspect the said pharmaceutical composition comprises film coated or sugar coated tablets of different dosage form along with pharmaceutically acceptable excipients in various forms including coated or uncoated tablets, capsules, granules, powder blends, orally disintegrating tablets, dispersible tablets, chewable tablets, effervescent tablets, soft gelatin capsules, gels and any such solid or semi solid dosage forms for human administration.

In accordance with yet another aspect, a process preferably, direct compression and dry granulation and more preferably wet granulation are provided for the above said pharmaceutical composition in the form of tablets.

In accordance with yet further aspect, the above said composition was formulated into a tablet dosage form by direct compression process, as per following process, dexibuprofen of specified particle size is co-sifted with a adsorbent and then was blended in a tumbling

blender, then with sifted ingredients of starch or pregeletinised starch, starch derivatives, cellulose or cellulose derivatives, combination of disintegrant & super disintegrant, glidant, with optional use of solubiliser and then finally with lubricant in a tumbling blender. Then the blend is compressed to get tablets of desired strengths

In accordance with yet further aspect, the above said composition was formulated into a tablet dosage form by dry granulation process, as per following process, dexibuprofen of specified particle size is co-sifted with a adsorbent and then was blended in a tumbling blender, then with sifted ingredients of starch or pregeletinised starch or starch derivatives, cellulose or cellulose derivatives, with super disintegrant, glidant, with optional use of solubiliser, part of disintegrant and of lubricant. Then the blend was slugged using specific punches in compression machine. Then the slugs are milled, sifted. Then the sized granules are blended with remaining part of disintegrant and of lubricant in a tumbling blender. Then the blend is compressed to get tablets of desired strengths.

In accordance with yet further aspect, the above said composition was formulated into a tablet dosage form by wet granulation process, as per following process, dexibuprofen of specified particle size is co-sifted with a adsorbent and then was blended in a high shear mixer granulator with impeller at fast speed, then with sifted ingredients of cellulose or cellulose derivatives and with super disintegrant and part of disintegrant. The above mix in high shear mixer granulator was granulated using a paste was made using starch or pregelatinised starch or starch derivatives, with optional use of part of solubiliser. The wet mass was dried in fluidized bed drier, to achieve required LOD. Then the dried granules were sized by milling in multi mill of specific screen and mesh. The sized granules are blended with remaining part of disintegrant and then with glidant, finally with lubricant. Then the blend is compressed to get tablets of desired strengths.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises dexibuprofen or its salts with mean particle size ranging from 1 - 450 microns, preferably ranging from 25-150 microns, more preferably ranging from 30-100 microns; at least one diluent, at least one disintegrant in intra-granular or

extra-granular or both intra-granular and extra-granular form, at least one super- disintegrant in intra-granular or extra-granular or both intra-granular and extra-granular form along with optional use of solubility enhancers such as SLS, Tween 80, etc. The unit dosage is coated using low viscosity hydrophilic or hydrophobic polymers either alone or along with other suitable pharmaceutical ingredients used as coating aids.

The intrinsic dissolution profile of dexibuprofen particles of mean particle size ranging from 500, 400, 250 and 100 microns showed only about 15%, 40%, 47% and 54%, respectively. These dissolution profiles were incomplete because of gel formation of API in contact with the dissolution media.

The present invention is directed to a pharmaceutical composition and a process to prepare such a pharmaceutical composition that provides a quick release of dexibuprofen particles to thereby achieve a faster in-vitro dissolution rate by a preferred range of particle size of dexibuprofen and preventing the aggregation of released dexibuprofen particles in the dissolution medium. The above said objective was achieved by providing a unique composition comprising optimum amount of water insoluble diluents along with the unique ratio of two different types of disintegrants used in intra-granularly and extra- granularly form to formulate the pharmaceutical composition.

This unique pharmaceutical composition initially allows aqueous fluids to imbibe quickly onto the tablet surface followed by faster hydration of the inner layer of the tablet due the above said unique composition which eventually leads to disintegration of the tablet in a relatively much lesser time suitable for achieving the desired high dissolution profile which leads to higher C _max and shorter T _max , as is desired for dexibuprofen as NSAID.

However, the above said pharmaceutical composition of this invention shows no substantial enantiomeric conversion of S form to R form even after exposing the composition under accelerated instability conditions.

The above said pharmaceutical composition exhibits faster and efficacious pain relief in acute painful disorders during the first hour after intake compared to the pain relief exhibited by a composition equivalent thereto. The painful disorders relates to surgical and non-surgical dental pain, headache, dysmenorrhea!, lower back pain and musculoskeletal pain.

Further, the present invention details a specific manufacturing process for tablets out of dexibuprofen that circumvents the difficulties in its manufacture, wherein the active, dexibuprofen, has low melting point in the range of 52-54 ⁰ C, has lower bulk density and poor flow properties thereby posing serious process problems to a manufacturer.

The composition according to the above, said invention further comprise of a pharmaceutically acceptable excipient that can be used in dosage forms selected from the group of fillers, binders, disintegrants, antiadherents, suspending agents, stabilizers, coating materials among others.

Fillers comprise of and are preferably selected from starch and starch derivatives, cellulose and cellulose derivatives, microcrystalline cellulose, lactose, mannitol, sorbitol, sucrose, dicalcium phosphate, tricalcium phosphate/ sulphates and silicon dioxide.

Binders comprise of and are preferably selected from starch paste, starch derivatives, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, alginate, sorbitol, glucose, polyvinyl pyrrolidone (PVP) and gum.

Disintegrants/ super disintegrants comprise of and are preferably selected from starch and starch derivatives such as, sodium starch glycollate, cellulose and cellulose derivatives such as croscarmellose sodium, calcium carboxymethyl cellulose, alginates and crospovidone.

Suitable lubricants/ Antiadherents/ glidants are selected from but are not limited to a group comprising colloidal silicon dioxide (such as Aerosil(R) 200), talc, stearic acid,

magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oil and the like or mixtures thereof.

Stabilizers are selected from the group of methyl paraben and propyl paraben.

Coating materials comprise of and are preferably selected from hypermellose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methyl cellulose, methacrylic acids, ethyl acrylates, saccharides and mixtures thereof.

Solubility enhancers to improve in-vitro dissolution are preferably selected from sodiun lauryl sulphate, sorbitan monolaurate, docusate sodium, polysorbate 80/20, polyvinyl pyrrolidone, polyethylene glycol, propylene glycol, cyclodextrin and its derivatives, poloxamer, ethylene oxide-propylene oxide copolymer surfactants, polyalkylene glycol and their derivatives, polyoxyethylene alkyl ethers and polar solvents or mixtures thereof.

The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations as per the following Examples:

EXAMPLES:

The following process is used to prepare the compositions as discussed in the below mentioned examples. Materials of batch size of around 0.9 kg were blended, granulated if applicable in planetary mixer and blended in Y Blender. Materials of batch size of around 2.0 kg were blended granulated in Rapid Mixer Granulator if applicable and blended in V Blender. The Granules were dried in Fluid Bed Drier at inlet temperature of 45 ⁰ C to obtain LOD below 1.5 %. Compression was done using 17.5 x 6.5 mm caplet shape, standard concave punches except for Example 1. Film coating process was done using conventional coating pan. In-vitro dissolution test was performed using USP Type 2 Apparatus on six tablets at 50 r. p. m. ₅ using 900 ml of buffer of pH 7.2 and the in vitro release values given are average of 6 readings. Using the said USP dissolution method, the tablets releases more than 90% of the drug in 5 minutes which was determined by the concentration of liberated dexibuprofen spectrophotometrically by comparing the measured absorbance at 265.5 nm with that of a standard solution of dexibuprofen.

EXAMPLE !

A pharmaceutical formulation having the following composition was prepared: dexibuprofen (450 micron mean particle size) 400 mg (67.2 %), macrocrystalline cellulose 130 mg (21.8 %), sodium starch glycollate 10 mg (1.7 %), colloidal silicon dioxide 20 mg (3.4 %) were dry mixed and granulated using binder prepared by dissolving HPC LF 25 mg (4.2 %) in water under stirring. Granules were dried, milled through multi mill and sized through #24, blended with sodium starch glycollate 10 mg (1.7 %) compressed using 17.5 x 7.5 mm caplet shaped punches for average weight of 595 mg. Tablets were coated to get 2.5 % weight gain. The in-vitro release of the active from core tablets was 38.2 % and from coated tablet was 27.7% in 5 minutes.

EXAMPLE-2

Dexibuprofen (200 micron mean particle size) 400 mg (69.6 %), microcrystalline cellulose 130 mg (22.6 %), colloidal silicon dioxide 10 mg (1.7 %) were dry mixed, and granulated using binder prepared by dissolving hydroxypropyl cellulose LF 23 mg (4.0 %) in water. Granules were dried, milled through multi mill and sized through #24 and then blended with sodium starch glycollate 5 mg (0.9 %), and then lubricated with talc 7 mg (1.2 %). Lubricated blend compressed for average weight of 575 mg. Tablets in-vitro release of the uncoated tablet was 36.2 % in 5 minutes.

EXAMPLE-3

Dexibuprofen of different particle size (details given in the below mentioned table) 400 mg (65.5 %), microcrystalline cellulose 140 mg (22.9 %), colloidal silicon dioxide 10 mg (1.6 %), sodium starch glycollate 10 mg (1.6 %), croscarmellose sodium 20 mg (3.3 %) were dry mixed, and granulated using binder prepared by making starch paste 15 mg (2.4 %) with sodium lauryl sulphate 3 mg (0.5 %) in water. Granules were dried, milled through Co-mill sized through #24 and then blended with colloidal silicon dioxide 3 mg (0.5 %) and then lubricated with talc 10 mg (1.6 %). Lubricated blend compressed for average weight of 611 mg. The in-vitro release of the uncoated tablet is given in the table below according to the particle size.

Table 1

EXAMPLE-4

Dexibuprofen (200 micron mean particle size) 400 mg (65.1 %), macrocrystalline cellulose 140 mg (22.9 %), colloidal silicon dioxide 10 mg (1.6 %), sodium starch glycollate lOmg (1.6%), croscarmellose sodium 20 mg (3.3 %) were dry mixed, and granulated using binder prepared by making starch paste 15 mg (2.4 %) with sodium lauryl sulphate 6 mg (1.0 %) in water. Granules were dried, milled through Co-mill, sized through #24 and then blended with colloidal silicon dioxide 3 mg(0.5 %) and then lubricated with talc 10 mg (1.6 %). Lubricated blend compressed for average weight of 614 mg. The in-vitro release of uncoated tablet was 80.1% in 5 minutes.

EXAMPLE-5

Dexibuprofen (100 micron mean particle size) 400 mg (67.1 %), microcrystalline cellulose 150 mg (25.2 %), colloidal silicon dioxide 10 mg (1.7 %), sodium starch glycollate 10 mg (1.7 %) were dry mixed and granulated using binder prepared by making starch paste 20 mg (3.3 %) in water. Granules were dried, sized through #24 and then blended with colloidal silicon dioxide 3 mg (0.5 %), and then lubricated with talc 5 mg (0.8 %). Lubricated blend compressed for average weight of 596 mg. The in-vitro release of uncoated tablet was 92.1 % in 5 minutes.

EXAMPLE-6

Dexibuprofen (30 micron mean particle size) 400 mg (64.9 %), microcrystalline cellulose 150 mg (24.3 %), colloidal silicon dioxide 10 mg (1.6 %), sodium starch glycollate 10 mg (1.6 %), croscarmellose sodium 10 mg (1.6 %) were dry mixed, and granulated using binder prepared by making starch paste 22 mg (3.6 %) in water. Granules were dried,

milled through multi mill and sized through #20 mesh and then blended with colloidal silicon dioxide 4 mg (0.6 %), and then lubricated with talc 10 mg (1.6 %). Lubricated blend compressed for average weight of 616 mg. The in- vitro release of uncoated tablet was 90.6 % in 5 minutes. However, flow during compression was poor, tablets were softer, with sticking observed, wherein friability was high.

EXAMPLE-7

Dexibuprofen of different particle size (Details given in the table below) 400 mg (65.8 %), microcrystalline cellulose 140 mg (23.0 %), colloidal silicon dioxide 10 mg (1.6 %), sodium starch glycollate 10 mg (1.6 %), croscarmellose sodium 20 mg (3.3 %) were dry mixed, and granulated using binder prepared by making starch paste 15 mg (2.5 %) in water. Granules were dried, milled through Co-mill sized through #24 and then blended with colloidal silicon dioxide 3 mg (0.5 %) and then lubricated with talc 10 mg (1.6 %). Lubricated blend compressed for average weight of 608 mg. The in- vitro release of the active from uncoated tablets is given in the table below particle size wise.

Table 2

Mean Particle Average % Drug release in pH 7.2 Buffer

S.No

Size (microns) 5 min 10 min 15 min

1 30 94.9 98.6 99.7

2 100 90.7 95.6 96.4

3 150 86.5 97.8 98.0

4 200 85.6 98.4 99.9

5 450 61.8 87.1 94.4

EXAMPLE-8

Dexibuprofen of different particle size (Details given below table) 400 mg (65.5 %), microcrystalline cellulose 140 mg (22.9 %), colloidal silicon dioxide 10 mg (1.6 %), sodium starch glycollate 10 mg (1.6 %), croscarmellose sodium 20 mg (3.3 %) were dry mixed, and granulated using binder prepared by making starch paste 15 mg (2.4 %) with

sodium lauryl sulphate 3 mg (0.5 %) in water. Granules were dried, milled through Co- mill sized through #24 and then blended with colloidal silicon dioxide 3 mg (0.5%) and then lubricated with talc 10 mg (1.6 %). Lubricated blend compressed for average weight of 611 mg. The in- vitro release of uncoated tablet is given in the table below as per the particle size.

Table 3

EXAMPLE-9

Dexibuprofen (100 micron mean particle size) 400 mg (63.5 %), microcrystalline cellulose 102 grade 150mg (23.8%), colloidal silicon dioxide 10 mg (1.6 %), pregelatinised starch 25 mg (4%), Sodium starch glycollate 10 mg (1.6 %), cros carmellose sodium 20 mg (3.2 %) were blended for 5 mins and then lubricated with talc 15 mg (2.4 %). Lubricated blend compressed for average weight of 630 mg. The in- vitro release of uncoated tablet was 93.8% in 5 minutes.

EXAMPLE-10

Dexibuprofen (60-100 micron mean particle size) 400 mg (54.42 %), microcrystalline cellulose 211 mg (28.71 %), colloidal silicon dioxide 15 mg (2.04 %), sodium starch glycollate 5 mg (0.68 %), croscarmellose sodium 25 mg (3.40 %) were dry mixed, and granulated using binder prepared by making starch paste 10 mg (1.36 %) and sodium lauryl sulfate 4 mg (0.54 %) in water. Granules were dried and sized through #20 mesh and then blended with colloidal silicon dioxide 5 mg (0.68 %), corn starch 10 mg (1.36 %) and then lubricated with talc 15 mg (2.04 %). Lubricated blend compressed for average weight of 700 mg. The tablets were film coated using conventional coating pan

using 15 % w/w concentration coating suspension, to get the weight build up of 5.0 % w/w.

EXAMPLE-Il

Dexibuprofen (60-100 micron mean particle size) 400 mg (55.75 %), microcrystalline cellulose 182 mg (25.36 %), colloidal silicon dioxide 20 mg (2.79 %), sodium starch glycollate 10 mg (1.39 %), croscarmellose sodium 40 mg (5.57 %) were dry mixed, and granulated using binder prepared by making starch paste 15 mg (2.09 %) and sodium lauryl sulfate 4 mg (0.56%) in water. Granules were dried and sized through #20 mesh and then blended with colloidal silicon dioxide 5 mg (0.56 %), corn starch 9 mg (1.25 %) and then lubricated with talc 15 mg (2.09 %). Lubricated blend compressed for average weight of 700 mg. The tablets were film coated using conventional coating pan using 15 % w/w concentration coating suspension, to get the weight build up of 2.5 % w/w. The in- vitro release at 5 minutes was 94.3 % for uncoated tablet and was 94.5 % for coated tablet.

EXAMPLE-12

Dexibuprofen (60-100 micron mean particle size) 400 mg (54.42%), microcrystalline cellulose 182 mg (24.76 %), colloidal silicon dioxide 20 mg (2.72 %), sodium starch glycollate 10 mg (1.36 %), croscarmellose sodium 40 mg (5.44 %) were dry mixed, and granulated using binder prepared by malting starch paste 15 mg (2.04 %) and sodium lauryl sulfate 4 mg (0.54 %) in water. Granules were dried and sized through #20 mesh and then blended with colloidal silicon dioxide 5 mg (0.68 %), corn starch 9 mg (1.22 %) and then lubricated with talc 15 mg (2.04 %). Lubricated blend compressed for average weight of 700 mg. The tablets were film coated using conventional coating pan using 15 % w/w concentration coating suspension, to get the weight build up of 5.0 % w/w. The dissolution profile of the coated tablets was compared against dissolution profile of different particle size of the API.

Table 4

EXAMPLE-13

Dexibuprofen (60-100 micron mean particle size) 600 mg (54.42 %), microcrystalline cellulose 273 mg (24.76 %), colloidal silicon dioxide 30 mg (2.72 %), sodium starch glycollate 15 mg (1.36 %), cros carmellose sodium 60 mg (5.44 %) were dry mixed, and granulated using binder prepared by making starch paste 22.5 mg (2.04 %) and sodium lauryl sulfate 6 mg (0.54 %) in water. Granules were dried and sized through #20 mesh and then blended with colloidal silicon dioxide 7.5 mg (0.68 %), corn starch 13.5 mg (1.22 %) and then lubricated with talc 22.5 mg (2.04 %). Lubricated blend compressed for average weight of 1050 mg. The tablets were film coated using conventional coating pan using 15 % w/w concentration coating suspension, to get the weight build up of 5.0 % w/w.

EXAMPLE-14

Dexibuprofen (60-100 micron mean particle size) 300 mg (54.42 %), microcrystalline cellulose 136.5 mg (24.76 %), colloidal silicon dioxide 15 mg (2.72 %), sodium starch glycollate 7.5 mg (1.36 %), cros carmellose sodium 30 mg (5.44 %) were dry mixed, and granulated using binder prepared by making starch paste 11.25 mg (2.04 %) and sodium lauryl sulfate 3 mg (0.54 %)in water. Granules were dried and sized through #20 mesh and then blended with colloidal silicon dioxide 3.75 mg (0.68%), Corn starch 6.75 mg (1.22 %) and then lubricated with talc 11.25 mg (2.04 %). Lubricated blend compressed for average weight of 525 mg. The tablets were film coated using conventional coating pan using 15 % w/w concentration coating suspension, to get the weight build up of 5.0 % w/w.

EXAMPLE-15

Dexibuprofen (60-100 micron mean particle size) 100 mg (54.42 %), microcrystalline cellulose 45.5 mg (24.76 %), colloidal silicon dioxide 5 mg (2.72 %), sodium starch glycollate 2.5 mg (1.36 %), croscarmellose sodium 10 mg (5.44 %) were diy mixed, and granulated using binder prepared by making starch paste 3.75 mg (2.04 %) and sodium lauryl sulfate 1 mg (0.54 %) in water. Granules were dried and sized through #20 mesh and then blended with colloidal silicon dioxide 1.25 mg (0.68 %), corn starch 2.25 mg (1.22 %) and then lubricated with talc 3.75 mg (2.04 %). Lubricated blend compressed for average weight of 175 mg. The tablets were film coated using conventional coating pan using 15 % w/w concentration coating suspension, to get the weight build up of 5.0 % w/w.

The following examples are given by way of illustration of the present invention and therefore should not be construed to limit the scope of the present invention. All percentages are by weight.

The above exemplary illustration of the formulations of this invention to formulate a pharmaceutical composition with dexibuprofen as the active ingredient clearly and surprisingly reveals that when dexibuprofen with mean particle size of 30 to 100 microns was used in a particular composition, the same met with the desired in-vitro dissolution performance of more than 90 % release in just 5 minutes (Example 5 to 7).

As we move from Examples 1 -3 that are differentiated on the basis of mean particle size of 450 micron, 200 micron for Examples 1 and 2 and the addition of new pharmaceutically acceptable excipients like croscarmeilose sodium, colloidal silicon dioxide and talc in Example 3. It is clearly evident from Table -1 that the best in-vitro release of ~90 % in 5 minutes of the active is obtained from the uncoated tablet with a mean particle size of 150 micron of the active in the formulation of Example-3.

On comparison of the formulations under Example 2 and Example 4, both with 200 micron mean particle size of the active, it is clearly revealed that addition of

croscarmellose sodium, starch paste binder and sodium lauryl sulfate drastically enhances the in-vitro release of the active from the uncoated tablet from 36.2% to 80.1 % in 5 minutes.

Comparison of formulations under Example 5 and 6, with the noted absence of sodium lauryl sulfate shows that with mean particle size of the active of 100 micron (Ex.5) and 30 micron (Ex. 6), the in-vitro release of the active from the uncoated tablet of > 90 % can be thereby achieved.

However, for 30 micron mean particle size of the active, flow during compression was poor, tablets were softer, with sticking observed, wherein friability was high.

It is clearly apparent from Table-2, illustrating the % drug release from the formulations with different mean particle size of the active under Example 7, that the best in-vitro release of the active of —94 % in 5 minutes is obtained from the uncoated tablet with a mean particle size of 30 micron of the active.

Once the 30 and 100 micron mean particle size of the active was selected as the best particle size of choice of dexibuprofen, incorporation of sodium lauryl sulfate in the formulation under Example 8 along with the diminished particle size of the active of 30 and 100 micron was explored. It is concluded from Table 3, that in the presence of sodium lauryl sulfate, 100 micron mean particle size of the active was the best particle size to obtain a maximum % of in-vitro release of the drug.

Example 9 chooses the best mean particle size of 100 micron and demonstrates that in the absence of sodium lauryl sulfate the % average release of the active goes down by only about 1 % which again goes to prove that the particle size remains the sole criterion to get an enhanced value of % in-vitro release of the active.

Example 10 and Example 11 comprises a coated tablet formulation of the mean particle size of the active in the range of 60-100 micron wherein the in- vitro release at 5 minutes was 94.3% for uncoated tablet and 94.5% for coated tablet.

Example 12 reveals a formulation at the onset of a comparative study being conducted on those formulations as specified under Table 4, wherein the dissolution profile of coated tablet comprising API of 100 micron particle size and the dissolution profile of different particle size of the API alone without any pharmaceutically acceptable excipients are compared. It is clearly evident from the comparison under Table 4 that 100 micron mean particle size of the API alone gives the best dissolution performance that is similarly expressed and greatly enhanced in a coated tablet form using 100 μm API along with other suitable pharmaceutically acceptable excipients.

Example 13-15 illustrates to provide a process for preparing film coated tablets of oral dosages of 600, 300, 100 mg respectively with dexibuprofen as the active ingredient.

Therefore it is thus possible by way of the present invention to meet the desired and improved in-vitro dissolution whereby enhanced bioavailability of active such as dexibuprofen from the formulations of pharmaceutical compositions could be achieved.

Thus it is surprisingly found by way of the present invention that by controlling the mean particle size of the active pharmaceutical ingredient for a poorly water soluble drug such as dexibuprofen, it is thereby possible to achieve the challenging task of faster drug release or faster in-vitro dissolution to bring about improvement in the in-vivo performance leading to the enhanced bioavailability of the active such as dexibuprofen from the pharmaceutical compositions as disclosed herein.

Also, by way of the present invention, the in-vitro dissolution for an insoluble drug such as dexibuprofen at 5 minutes and 10 minutes time is thus achieved and is highly significant from the perspective of the extent and rate of drug absorption from GIT to favour its wide scale use and application with enhanced efficacy.