Enhancement of dissolution andbioavailability of water insolubledrug using liquisolid compact for oralapplication.

M.A.Hassan, H.M.El-Saghir

Department of Pharmaceutics, Faculty of Pharmacy, King Saud University

IntroductionNimesulide, a non-steroidal anti-inflammatorydrug (NSAID), is administered orally or rectallytwice daily for a variety of inflammation andpain states. This is a unique NSAID, not onlybecause of its chemical structure but alsobecause of its specific affinity to inhibitcyclooxygenase-2 (COX-2), thus exerting mildereffects on the gastrointestinal mucosa

Nimesulide is superior, or at leastcomparable in efficacy, to other NSAIDs,but is better tolerated and has lesspotential for adverse reactions. Thus,selective COX-2 inhibitors should haveanti-inflammatory effects devoid of sideeffects on the kidney and stomach.

They may also demonstrate newimportant therapeutic benefits asanticancer agents as well as helpprevention of premature labour andeven retard the progression ofAlzheimer's disease

Figure 1Nimesulide is N-(4-Nitro-2-phenoxyphenyl)methanesulfonamide Mol. Formula: C13H12N2O5S; Mol. Mass: 308.31

Several researchers have shown thatthe liquisolid technique is the mostpromising method for promotingdissolution rate of poorly water-soluble

From the historical point of view,liquisolid compacts were evolvedfrom ‘Powdered Solutions’ whichdepended on preparing a truesolution of the drug in a high boilingpoint, water-miscible solvent, whichwas carried out on the extensivesurface of an inert carrier such assilica

Aim of WorkThe aim of this study was to increasedissolution rate of nimesulide usingliquisolid technique. In this studynimesulide, a poorly water-soluble,non-steroidal anti-inflammatorydrug was formulated into 20 mgliquisolid tablets

Preparation of conventional tablet and liquisolid compacts

nimesulide conventional tablets wereproduced by mixing the drug withmicrocrystalline cellulose–Aerosil 200 andthe additive for a period of 10 min in a cubicmixer (Erweka, TypeUG, Germany).

The mixture was mixed with Ac-Di-Sol(5%, w/w, of the formulation) for 10min. The mixture was compressed on a10-mm punch and die using a manualtableting machine (Riken, Japan)Several liquisolid compacts, denoted asf1 to f8 were prepared as follows.

nimesulide was dispersed in PEG400,PG,and mixture of PEG400 or PEGand Tween 80 in a ratio 1:1.Then abinary mixture of carrier-coatingmaterials (microcrystalline cellulose asthe carrier powder and Aerosil 200 asthe coating material) was added to theobtained liquid medication undercontinuous mixing in a mortar.

Finally, 5 %( w/w) of Ac-Di-Sol as thedisintegrant, was mixed with themixture for a period of 10 min. Thefinal mixture was compressed usingthe manual tableting machine toachieve tablet hardness of 6-7kg.

Formula No

Drug %

Amount of liquid(mg)

Amount of carrier (mg)

Q

Amount of coating (mg)

q

Amount of disintegrant

(mg)

Total weight of

tabletF1F2F3F4F5F6F7F8

1020304050202020

200.00100.0066.6.0050.0040.00

100.00100.00100.00

1100600435350300600600600

55.0030.0021.7517.5015.0030.0030.0030.00

68.7537.5027.2021.8818.7537.5037.5037.50

1443.80787.50669.20459.40393.80787.50787.50787.50

Formulation characteristics of the prepared nimesulide liquisolid compacts.

Evaluation of nimesulide liquisolid tablets1. Differential Scanning Calorimetery (DSC) of the

prepared liquisolid powder 2. Determination of the drug content3. Determination of the friability, hardness, and

disintegration time4. Dissolution study5. Determination of anti-inflammatory effect of

nimesulide using liquisolid compact

RESULTS AND DISCUSSION

The very poor aqueous solubility andwettability of cox-2 inhibitors howevergives rise to difficulties in the design ofpharmaceutical formulations and leads toa variable oral bioavailability.

Solubility of nimesulide wasdetermined in different solvents aspropylene glycol, polyethylene glycol400, glycerol and water. The solubilityof the drug in different solvents was63.120, 1.760, 0.218, and 0.014mg/ml for PEG400, PG, glycerol andwater respectively15.

DSC studyOne of the most classic applications of DSCanalysis is the determination of the possibleinteractions between a drug entity and theexcipients in its formulation; it is veryimportant to establish the existence of anyincompatibilities during the preformulationstage to ensure the success of thesubsequent stability studies.

Figure 1 reveals the thermal behaviorsof the pure components together withthe thermal behavior of the finalliquisolid system prepared. Nimesulidepeak is clear in its DSC thermogram(Fig. 1A) demonstrating a sharpcharacteristic endothermic peak at149.25°C corresponding to its meltingtemperature (Tm);

The liquisolid system thermogram infigure 2 displayed completedisappearance of characteristic peak ofnimesulide a fact that agrees with theformation of drug solution in theliquisolid powdered system, i.e., thedrug was molecularly dispersed withinthe liquisolid matrix.

Such disappearance of the drug peaksupon formulation of the liquisolidsystem declared that the completesuppression of all drug thermalfeatures, undoubtedly indicates theformation of an amorphous solidsolution.

Fig1 DSC thermogram of nimesulide (A), Avicel PH102 (B),Aerosil 200 (C), physical mixture (D), liquisolid compact mixturecontaining PEG400 (E), liquisolid compact mixture containing PG(F), and liquisolid compact mixture containing Tween 80 (G).

Dissolution study of nimesulide liquisolidcompacts

In-vitro dissolution profiles of nimesulideshowed that the liquisolid compacts producedhigher dissolution rates in comparison with theconventional tablet. For example, thepercentages of drug released from F1, F6, F7,F8, and conventional tablets after 1 hr were100%, 80%, 100%, 88%, and 50% at pH 1.2respectively.

Fig.2The dissolution profile of nimesulide from different liquisolid compacts compared with conventional tablets.

Figure 3 shows the dissolution rates ofdifferent liquisolid compacts usingdifferent solvents (PEG400, PG,PEG+Tween, PG+Tween) incomparison with conventional tablets.The figure shows that dissolution ratesdecreased in the following order:PEG400 > PEG400+Tween >PG+Tween > PG > compressedtablets.

Fig. 3: The dissolution rates (DR) of nimesulide fromdifferent liquisolid compacts and conventional tablets.

The drug concentration in the liquidmedication is one of the main factorson the performance of a liquisolidcompact. The effect of drugconcentration (Cd) in the liquidmedication (PEG400) on dissolutionprofile of nimesulide from theliquisolid compacts in 0.1 N HCldissolution media is shown in figure 4.

The figure shows that the increase ofdrug concentration from 20-50% inthe liquid medication a liquisolidcompact has no considerable effect onthe dissolution rate. It can be seenthat dissolution rate has no significantincrease with an increase in theconcentration of drug.

This result can be attributed to that thedrug in low concentrations is in amolecular form which is more solublethan the drug in higherconcentrations3.

Fig. 4: Effect of different concentrations of drug on the dissolution from liquisolid compacts containing PEG.

The anti-inflammatory effect of nimesulidefrom liquisolid compact

The anti-inflammatory effect of nimesulidefrom two formulae of liquisolid compactscompared with conventional tablets. Thepercent inhibition observed with any formulaeconsidered the maximum possible response foranti-inflammatory effect of nimesulide in thisformula during the 4 hrs observation period.

Figure 5 showed the percentinhibition of paw edema plottedagainst time. From the figure it wasobserved that the order ofsuppression of swelling (percentageinhibition) was as follows: LSC (PEG)> LSC (PG) > conventional tablets.

Fig. 5: The percentage inhibition of swelling from nimesulide liquisolid compacts compared with conventional tablets.

Conclusion

The liquisolid technique is the most promisingmethod for promoting dissolution rate ofpoorly water-soluble drugs. The results showedthat the optimum loading factor which givesgood flowability and compressibility is 0.2, andthe liquisolid compact containing PEG400 givesthe highest dissolution rate than otherformulae.

Also the results showed no increasein the amount of the drug dissolvedas the concentration of the drugincreases. Liquisolid compacts give apronounced anti-inflammatory effectwhen compared with conventionaltablets.

Acknowledgment

The authors are greatly thankful to researchcenter, King Saud University, FemaleSection, Riyadh, KSA, for financial support inform of research fellowship.

THANK YOU FOR YOUR ATTENTION