CONTROLLED RELEASE TABLET FORMULATIONS OF …€¦ · - Single punch Tablet Machine, Korsch-Berlin, Ek/0, Frankfort, Germany- Erweka tablet hardness tester, type TAB, G.m.b.H., Germany.

Bull. Pharm. Sci., Assiut University, Vol. 35, Part 1, 2012, pp. 83-95.

ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــReceived in 7/7/2012 & Accepted in 2/8/2012

*Corresponding author: Sayed I. Abdel- Rahman, E-mail: [email protected]

CONTROLLED RELEASE TABLET FORMULATIONS OFISOXSUPRINE HYDROCHLORIDE USING DIRECT COMPRESSIONTECHNIQUE

Ahmed A. Aboutaleb, Sayed I. Abdel- Rahman* and Jelan A. Abdel-Aleem

Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut 71524,Egypt

.

.

.

.)3.3430% ( .

15000RSPM30%ميثيل .)10%

()10% (RSPM) ن10%() 40%(

RSPM)10% (RLPO)40% ( .

.

Isoxsuprine hydrochloride is a peripheral vasodilator. It is advisable to prepare the drugin sustained release dosage forms to improve patient compliance and to achieve a steady stateblood level with minimum side effects. Different hydrophilic and hydrophobic polymers inaddition to their combinations were used in different ratios to select the best level of the matrixforming material that provides the most sustaining effect. The effect of different types andconcentrations of polymers on the release rate of the drug was investigated. The drug releasedecreased by increasing the concentration of the polymer in all the studied formulations. Tabletformula containing either 30% (w/w) HPMC 15000 or 30% (w/w) Eudragit RSPM gave themost sustaining effect among the single polymers. The drug release rate from tablets preparedusing polymer blends is slower compared to that from those containing single polymers. Theslowest drug release was obtained from tablet formulae containing: drug, 10% (w/w) HPMC15000 and 40% (w/w) Eudragit RSPM and drug, 10% (w/w) Eudragit RSPM and 40% (w/w)Eudragit RLPO. The release of isoxsuprine HCl from matrices prepared using single polymerfollowed Higuchi’s diffusion model. However, zero-order release kinetics was elucidated for therelease of isoxsuprine HCl from the investigated polymer blends in phosphate buffer (pH 6.8).

INTRODUCTION

Pharmaceutical methods for extendingdrug action involve the design of the dosageform in such a way that it affects the releaserate of the drug without affecting its chemicalor biological characteristics. Among the

methods used to formulate oral extendedrelease products is retardation of drug releaseby the use of polymeric materials1. Polymersare uniquely suited as materials of constructionfor oral delivery systems. The polymers offer awide range of properties such as diffusivity,permeability, and solubility that are important

Ahmed A. Aboutaleb, et al.

84

to achieve controlled delivery. These polymershave been broadly grouped into water-solublepolymers (hydrophilic polymers) and water-insoluble polymers (hydrophobic polymers)2.The increasing need for suitable polymers toachieve a desired drug release has facilitatedscreening of a large variety of both syntheticand natural polymers for their ability to retardthe release of specific drug substances. Sincethe cost of synthesizing a new polymericsubstance and testing for its safety is costly andtedious, a new focus has been directed towardsinvestigating the use of polymer blends ofpharmaceutically approved polymeric materialsas matrix excipients to retard drug release3.However, these systems are more complex thancoatings based on only one polymer and carehas to be taken when using this type offormulations. The use of polymer blends ascoating materials for controlled drug deliverysystems can offer major advantages, including:(i) facilitated adjustment of desired drugrelease patterns, mechanical properties anddrug release mechanism4, (ii) improved filmformation and storage stability5, and (iii) thepossibility to develop novel strategies for sitespecific drug delivery within thegastrointestinal tract6. Hence, isoxsuprine HClsustained release tablets were formulated usingdifferent hydrophilic polymers namely; methylcellulose (MC), sodium carboxymethylcellulose (NaCMC) and hydroxypropyl methylcellulose 15000 (HPMC 15000) in addition tohydrophobic polymers; ethyl cellulose (EC)and methacrylate copolymers; EudragitsRS100, RL100, RLPO and RSPM either singleor in combinations. The prepared tabletformulations were tested for their drug contentuniformity, weight uniformity, tablet diameter,tablet thickness, friability and hardness. Therelease of the drug from the prepared tabletswas also studied. The in-vitro release profilesof isoxsuprine HCl from the prepared tabletswere constructed and analyzed to determine therelease kinetics of the drug from theformulations.

MATERIALS AND METHODS

Materials- Isoxsuprine HCl was kindly supplied by

SEDECO Company, Cairo, Egypt.

- Ethyl cellulose (EC), Hydroxypropyl methylcellulose 15000 (HPMC 15000), Methylcellulose (MC), and Sodium carboxymethylcellulose (NaCMC), were supplied fromAldrich Chemicals Co., USA.

- Eudragit RL100, Eudragit RS100, EudragitRLPO, and Eudragit RSPM, were suppliedfrom Röhm Pharma, Darmstadt, Germany.

- Anhydrous lactose was supplied fromShefield Chemical, N.J. USA.

- Microcrystalline cellulose (Avicel pH 101)was obtained from FMC O., Ireland.

- Magnesium stearate was obtained from El-Nasr Pharmaceutical Chemicals Co., Egypt.

- All other chemicals and solvents were ofanalytical grade, and were used as received.

Equipment- Single punch Tablet Machine, Korsch-Berlin,

Ek/0, Frankfort, Germany- Erweka tablethardness tester, type TAB, G.m.b.H.,Germany.

- Erweka friabilator apparatus, G.m.b.H.,Germany.

- Micrometer, Mitutoyo Corporation, Japan.- Electric sensitive balance (Precisa 205 A,

Switzerland).- UV-visible Spectrophotometer, JENWAY-

Model 6305, England.- pH meter, JENWAY-Model 3310, England.- Dissolution Apparatus, SR6 Dissolution Test

Station, Hanson Research Corporation,Chatsworth, California, USA.

MethodsPreparation of isoxsuprine HCl sustainedrelease tablets

Isoxsuprine HCl sustained release tabletswere prepared by mixing isoxsuprine HCl (20mg/tablet) with the different studied polymerseither single or in combinations in differentweight ratios and the other additives. Singlepolymers were added in the following weightratios, 3:1, 2:1, 3:2, 1:1, 1:2 and 1:3, drug :polymer and these polymer ratios represent thefollowing percentage from the tablet weight3.34%, 5.00%, 6.67%, 10.00%, 20.00% and30.00% respectively. In case of polymercombinations, four weight ratios were used1:1:1, 1:1:2, 1:1:3 and 1:1:4, drug : polymer 1 :polymer 2, respectively. Diluent was added andmixing was performed using the serial mixingprocedure in a mortar for at least five minutes

85

for each step. This was followed by tumblingmixing in a clean glass bottle for about fifteenminutes. Magnesium stearate was then added tothe blend and mixed for another five minutes.The produced mixtures were compressed intotablets using single punch tablet machineequipped with a flat faced 8 mm punch. Themachine was adjusted to produce tabletsweighing 200 mg.

Tables 1-4, show the composition of theprepared isoxsuprine HCl sustained releasetablet formulations and the amount of eachingredient in milligram (mg). Isoxsuprine HClsustained release tablet formulations preparedusing hydrophilic polymers are given thesymbols (D1-D19). The prepared isoxsuprineHCl sustained release tablet formulationscontaining hydrophobic polymers are given thesymbols (D20-D49). The symbols (D50-D69)are given to the tablets prepared using polymerblends.

The prepared isoxsuprine HCl sustainedrelease tablets were evaluated for the followingparameters7: tablet weight uniformity, drug

content uniformity, tablet friability, tabletdiameter, tablet thickness and tablet hardness.

In-vitro release of isoxsuprine HCl from theprepared sustained release tablets

The USP dissolution apparatus II (paddle-type) rotating at 100 rpm was utilized. Thedissolution medium was 500 ml of dilute HCl(pH 1.2) for the first 2 hrs, after which the pHof the dissolution medium was increased to pH6.8 by adding tribasic sodium phosphatepowder8. The dissolution medium waspreviously degassed and warmed to 37±0.5°C.At the specified time intervals, samples of 5 mlwere withdrawn from the dissolution mediumusing volumetric pipette with cotton plug at itstip and replaced immediately with the samevolume of the fresh dissolution mediummaintained at the same temperature. Theamount of isoxsuprine HCl was determinedspectrophotometrically at λmax 275 nm, usingthe same dissolution medium as a blank. Allassays were done in triplicates and the meanvalue and standard deviation (SD) werecalculated.

Table 1: Composition of 20 mg isoxsuprine HCl tablets prepared by direct compression techniqueusing hydrophilic polymers.

Amount of ingredient used in each tablet formula (mg)FormulaNo MC NaCMC HPMC 15000 Avicel pH101 Anhydrous lactoseD1 - - - 94.00 94.00D2 6.67 - - 85.67 85.67D3 10.00 - - 84.00 84.00D4 13.33 - - 82.34 82.34D5 20.00 - - 79.00 79.00D6 40.00 - - 69.00 69.00D7 60.00 - - 59.00 59.00D8 - 6.67 - 85.67 85.67D9 - 10.00 - 84.00 84.00D10 - 13.33 - 82.34 82.34D11 - 20.00 - 79.00 79.00D12 - 40.00 - 69.00 69.00D13 - 60.00 - 59.00 59.00D14 - - 6.67 85.67 85.67D15 - - 10.00 84.00 84.00D16 - - 13.33 82.34 82.34D17 - - 20.00 79.00 79.00D18 - - 40.00 69.00 69.00D19 - - 60.00 59.00 59.00

For all formulae: total tablet weight was 200 mg and magnesium stearate 1% of total tablet weight wasused as a lubricant.

Ahmed A. Aboutaleb, et al.

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Table 2: Composition of 20 mg isoxsuprine HCl tablets prepared by direct compression techniqueusing ethyl cellulose and Eudragit RL100.

Amount of ingredient used in each tablet formula (mg)FormulaNo Ethyl cellulose Eudragit RL100 Avicel pH101 Anhydrous lactoseD20 6.67 - 85.67 85.67D21 10.00 - 84.00 84.00D22 13.33 - 82.34 82.34D23 20.00 - 79.00 79.00D24 40.00 - 69.00 69.00D25 60.00 - 59.00 59.00D26 - 6.67 85.67 85.67D27 - 10.00 84.00 84.00D28 - 13.33 82.34 82.34D29 - 20.00 79.00 79.00D30 - 40.00 69.00 69.00D31 - 60.00 59.00 59.00

For all formulae: total tablet weight was 200 mg and magnesium stearate 1% of total tablet weight wasused as a lubricant.

Table 3: Composition of 20 mg isoxsuprine HCl tablets prepared by direct compression techniqueusing different Eudragits.

Amount of ingredient used in each tablet formula (mg)FormulaNo. Eudragit

RS100EudragitRSPM

EudragitRLPO

Avicel pH101

Anhydrouslactose

D32 6.67 - - 85.67 85.67D33 10.00 - - 84.00 84.00D34 13.33 - - 82.34 82.34D35 20.00 - - 79.00 79.00D36 40.00 - - 69.00 69.00D37 60.00 - - 59.00 59.00D38 - 6.67 - 85.67 85.67D39 - 10.00 - 84.00 84.00D40 - 13.33 - 82.34 82.34D41 - 20.00 - 79.00 79.00D42 - 40.00 - 69.00 69.00D43 - 60.00 - 59.00 59.00D44 - - 6.67 85.67 85.67D45 - - 10.00 84.00 84.00D46 - - 13.33 82.34 82.34D47 - - 20.00 79.00 79.00D48 - - 40.00 69.00 69.00D49 - - 60.00 59.00 59.00

For all formulae: total tablet weight was 200 mg and magnesium stearate 1% of total tablet weight wasused as a lubricant.

87

Table 4: Composition of 20 mg isoxsuprine HCl tablets using polymer blends.

Amount of ingredient used in each tablet formula (mg)FormulaNo. HMPC

15000Na CMC EC

EudragitRLPO

EudragitRSPM

AvicelPH101

Anhydrouslactose

D50 20 20 - - - 69 69D51 20 40 - - - 59 59D52 20 60 - - - 49 49D53 20 80 - - - 39 39D54 20 - 20 - - 69 69D55 20 - 40 - - 59 59D56 20 - 60 - - 49 49D57 20 - 80 - - 39 39D58 20 - - - 20 69 69D59 20 - - - 40 59 59D60 20 - - - 60 49 49D61 20 - - - 80 39 39D62 - - 20 - 20 69 69D63 - - 40 - 20 59 59D64 - - 60 - 20 49 49D65 - - 80 - 20 39 39D66 - - - 20 20 69 69D67 - - - 40 20 59 59D68 - - - 60 20 49 49D69 - - - 80 20 39 39

For all formulae: total tablet weight was 200 mg and magnesium stearate 1% of total tablet weight wasused as a lubricant.

Kinetic analysis of the drug release from theprepared sustained release tablets

The kinetic parameters for the in-vitrorelease of isoxsuprine HCl from the preparedsustained release tablets were determined andanalyzed in order to explain the mechanism ofthe drug release. The kinetic data were plottedby linear regression according to zero and first-order kinetics as well as simplified Higuchimodel.

RESULTS AND DISCUSSION

Standard calibration curves of isoxsuprineHCl in 0.1 N HCl solution of pH 1.2 andphosphate buffer of pH 6.8 were found to obeyLambert-Beer's law within the concentrationrange (2-20 µg/ml). Isoxsuprine HCl sustainedrelease tablets prepared using differentpolymers were uniform in weight and tabletweights of all the studied formulations werefound to be within the Pharmacopeial limits.Isoxsuprine HCl sustained release tablets were

uniform in thickness and diameter. The valuesof friability (% loss) were ranged from 0.364 to0.611%, which are acceptable values as the %loss must not be more than 1%. The hardnessvalues of tablets were within the range of 4.5-7.1 kg which is also accepted range of hardnessvariation9.

In-vitro release of isoxsuprine HCl from theprepared sustained release tablets

Figures 1-3 show the efect of differentratios of the investigated hydrophilic polymerson isoxsuprine HCl release from the preparedtablets using pH-shift method.

Figure 1 shows the release profiles ofisoxsuprine HCl from the prepared tabletscontaining different ratios of MC. The releaseof isoxsuprine HCl from tablets containing thedrug alone (Formula D1) is rapid and completedrug release is obtained after 45 min. Theincorporation of MC in isoxsuprine HCl tabletswith different ratios (Formula D2-D7) resultedin a decrease in the release rate of isoxsuprine

Ahmed A. Aboutaleb, et al.

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HCl from these tablets than that from tabletscontaining the drug alone (Formula D1). Thissustaining in the drug release may be attributedto the presence of MC, which is a non-ionicswelling hydrophilic polymer. The process ofrelease of the drug from the hydrophilicpolymer-drug matrix involves waterpenetration into the dry matrix, hydration andgel formation of this polymer followed by thediffusion of the dissolved drug in the gel9. Asshown in figure 1, the release rate ofisoxsuprine HCl was slowed upon increasingthe concentration of MC from 3.34 to 30%(w/w). About 88% of the drug was releasedfrom the tablets containing 3.35% (w/w) MC,formula D2, after 90 min., while the tabletscontaining 30% (w/w) MC, formula D7released about 69% of the drug after the sametime. This decrease in the drug release rate maybe due to the increase in the thickness of thegel layer upon increasing the concentration ofthe polymer in the tablets.

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D1:drug alone

D2:3.34% MCD3:5%MC

D4:6.67%MC

D5:10%MC

D6:20%MCD7:30%MC

Fig. 1: Release profiles of isoxsuprine HCl fromtablets containing different ratios of methylcellulose.

Figure 2 shows the release profiles ofisoxsuprine HCl from tablets prepared usingdifferent ratios of NaCMC. It is clear that thedrug release rate decreased as the percent ofNaCMC in the matrix is increased. Thepresence of 30% (w/w) NaCMC in the tablet(formula D13) sustained the release ofisoxsuprine HCl to 5 hrs. This sustaining effectof the drug release can be attributed to thepresence of NaCMC, which is swellablecellulose ether. Upon hydration, tabletscontaining NaCMC, behaved as a gel-likesystem, thereby creating a gelatinous barrierthrough which the drug diffuses during the

dissolution process. The formation of such agel layer around the drug particles mightaccount for the retardation of the drug releasefrom the prepared tablets10. Similar behaviourwas observed with matrix tablets containingdiltiazem HCl and NaCMC11.

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D1:drug aloneD8:3.34%NaCMCD9:5%NaCMCD10:6.67%NaCMCD11:10%NaCMCD12:20%NaCMCD13:30%NaCMC

Fig. 2: Release profiles of isoxsuprine HCl fromtablets containing different ratios of sodiumcarboxymethyl cellulose.

Figure 3 represents the drug releaseprofiles of isoxsuprine HCl from tabletscontaining different ratios of HPMC 15000.The release of isoxsuprine HCl markedlydecreased with increasing HPMC 15000concentration. An increase in HPMCconcentration resulted in an increase in theviscosity of the gel layer as well as theformation of a gel layer with a longerdiffusional path, decreasing the drug release12.Similar results were obtained with tabletsprepared from diclofenac sodium and HPMC13.

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D1: drug alone

D14:3.34% HPMC

D15:5% HPMC

D16:6.67% HPMC

D17:10% HPMC

D18:20% HPMC

D19:30% HPMC

Fig. 3: Release profiles of isoxsuprine HCl fromtablets containing different ratios of HPMC15000.

Time (h)

pH 6.8pH 1.2

% d

rug

rele

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Time (h)

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% d

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Time (h)

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89

Figure 4 shows the release profiles ofisoxsuprine HCl from tablets containing 30%(w/w) of different hydrophilic polymers. Asshown from this figure, HPMC 15000 (formulaD19) shows the most sustaining effect(complete drug release was obtained after 7hrs) when used in the attributed to its nature asa highly swellable non-ionic hydrophilicpolymer. The sustaining effect of the threetested hydrophilic polymers on drug releasewas found to be in the following descendingorder: HPMC 15000 > NaCMC > MC.

Fig. 4: Release profiles of isoxsuprine HCl fromtablets containing 30% (w/w) of differenthydrophilic polymers.

In order to highlight the differences foundin the release profiles of the three differentformulae (D7, D13 and D19) in addition toformula D1 containing drug alone, t50% and t90%

have been calculated and their values arereported in table 5. t50% and t90% are the timeneeded for the release of 50% and 90% of thetotal amount of drug contained in the tablet.Formula (D19), containing 30% (w/w) HPMC15000, showed the highest values of t50% andt90% and this confirmed that isoxsuprine HCltablets prepared using 30% (w/w) HPMC15000 gave the most sustaining effect ofisoxsuprine HCl release among the studiedhydrophilic polymers. Generally, it could beobserved that the release of isoxsuprine HClfrom all the prepared formulations in acidicmedium was pronouncedly more rapid than inphosphate buffer (pH 6.8). This initial rapidrelease of isoxsuprine HCl from the sustainedrelease tablets in pH 1.2 may be attributed tothe presence of the drug in higherconcentration in the ionized form (salt form),which has higher solubility than the base,

hence the drug particles close to the tabletsurface might be released first giving thisinitial higher release of the drug14. Moreover,the viscosity of the gel layer around the drugmay decrease in acidic medium. By increasingthe pH of the dissolution medium, moresustaining drug release was obtained and thismay be due to the increase in the viscosity ofthe gel layer14.

Table 5: t50% and t90% of isoxsuprine HCltablets containing 30% (w/w) ofdifferent hydrophilic polymers.

Formulanumber

Polymert50%

(hour)*t90%

(hour)**D1 --- 0.04 0.50D7 MC 0.50 3.50

D13 Na CMC 0.75 3.75D19 HPMC 15000 2.58 6.25

*t50%: Time for release 50% of the drug contained inthe tablet.

**t90%: Time needed for release 90% of the drugcontained in the tablet.

Figures 5-9 show the effect of differentratios of the investigated hydrophobic polymerson isoxsuprine HCl release from the preparedtablets using pH-shift method8.

Figure 5 shows the release profiles ofisoxsuprine HCl from the prepared tabletscontaining different ratios of EC. The drugrelease decreased upon the incorporation ofEC. This decrease may be attributed to thenature of EC, which is a hydrophobic celluloseether that forms a thick coat around the drugparticles.

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D1:drug alone

D20:3.34% ECD21:5% EC

D22:6.67% EC

D23:10% EC

D24:20% ECD25:30% EC

Fig. 5: Release profiles of isoxsuprine HCl fromtablets containing different ratios of ethylcellulose.

Time (h)

pH 6.8pH 1.2

% d

rug

rele

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Ahmed A. Aboutaleb, et al.

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Upon contacting with the dissolutionmedium, diffusion and dissolution of the drugthrough water filled capillaries within thepore15. The release rate of isoxsuprine HCldecreased as the percent of EC increased from3.34 to 30% (w/w). This increase in thesustaining of the drug release may be due to theincrease in the thickness of the insoluble ECcoat formed around the drug particles. Themaximum sustaining, about 5 hrs, of the drugrelease was obtained from formula D25containing 30% (w/w) EC.

Figure 6 illustrates the release profiles ofisoxsuprine HCl from tablets prepared usingEudragit RL100. It is clear from this figure thatthe drug release decreased as the percent ofEudragit RL100 increased and the maximumrelease duration (5 hrs) was obtained in case offormula D31, containing the drug and 30%(w/w) Eudragit RL100. This decrease in thedrug release may be attributed to the nature ofEudragit RL100, which is an acrylic copolymerthat forms water-insoluble coat with definedpermeability to water and to dissolved drugs.

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D1:drug aloneD26:3.34%Eudragit.RL100D27:5%Eudragit RL100D28:6.67%Eudragit RL100

D29:10%Eudragit RL100D30:20%Eudragit RL100D31:30%Eudragit RL100

Fig. 6: Release profiles of isoxsuprine HCl fromtablets containing different ratios of EudragitRL100.

Figure 7 shows the release profiles ofisoxsuprine HCl from tablets containingdifferent ratios of Eudragit RS100. As shownin this figure, drug release is markedlydecreased due to the presence of EudragitRS100 that forms a low permeable coat aroundthe drug particles. This coat has a relativelystrong sustaining effect on drug release and themaximum retardation was obtained in case offormula D37 which contains 30% (w/w)Eudragit RS100.

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6070

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0 1 2 3 4 5 6 7 8

D1:drug aloneD32:3.34%Eudragit RS100

D33:5%Eudragit RS100D34:6.67%Eudragit RS100

D35:10%Eudragit RS100D36:20%Eudragit RS100

D37:30%Eudragit RS100

Fig. 7: Release profiles of isoxsuprine HCl fromtablets containing different ratios of EudragitRS100.

The effect of different percentages ofEudragit RSPM on the release of isoxsuprineHCl from the prepared tablets is shown infigure 8. It is clear that the drug release wasmarkedly decreased when the percentage ofEudragit RSPM increased in the tabletformulation. The complete drug release wasobtained after 8 hrs in case of formula D43containing 30% (w/w) of this polymer.

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D1:drug alone

D38:3.34%Eudragit RSPM

D39:5%Eudragit RSPM

D40:6.67%Eudragit RSPM

D41:10%Eudragit RSPM

D42:20%Eudragit RSPM

D43:30%Eudragit RSPM

Fig. 8: Release profiles of isoxsuprine HCl fromtablets containing different ratios of EudragitRSPM.

Figure 9 shows the release profiles ofisoxsuprine HCl from tablets prepared usingdifferent ratios of Eudragit RLPO. The releaseof isoxsuprine HCl from these tabletsdecreased by increasing the polymer content inthe tablet.

Time (h)

pH 6.8pH 1.2

% d

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% d

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D1:drug alone

D44:3.34%Eudragit RLPO

D45:5%Eudragit RLPO

D46:6.67%Eudragit RLPO

D47:10%Eudragit RLPO

D48:20%Eudragit RLPO

D49:30%Eudragit RLPO

Fig. 9: Release profiles of isoxsuprine HCl fromtablets containing different ratios of EudragitRLPO.

Figure 10 shows the drug release profilesof isoxsuprine HCl from tablets containing30% (w/w) of different hydrophobic polymers.It is clear that the sustaining effect of theinvestigated hydrophobic polymers on the drugrelease can be arranged in the followingdescending order: Eudragit RSPM > EudragitRLPO > Eudragit RS100 > Eudragit RL100 >EC. The maximum retardation effect on thedrug release was obtained in case of EudragitRSPM and this may be attributed to its pH-independent solubility properties and the lowpermeability to water-soluble drugs16.

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0 1 2 3 4 5 6 7 8 9 10 11 12

D1:drug alone

D25:EC

D31:Eudragit RL100

D37:Eudragit RS100

D43:Eudragit RSPM

D49:Eudragit RLPO

Fig. 10: Release profiles of isoxsuprine HCl fromtablets containing 30% (w/w) of differenthydrophobic polymers.

Table 6 shows t50% and t90% values ofisoxsuprine HCl release from tablets containing30% (w/w) of different hydrophobic polymers.It is clear that tablet formula (D25) containingEC has the least t50% and t90% values among thestudied hydrophobic polymers. Tablet formula(D43) containing Eudragit RSPM shows the

highest t50% and t90% values and this confirmedthat isoxsuprine HCl tablets prepared using30% (w/w) Eudragit RSPM gave the mostsustaining effect on the drug release among thestudied hydrophobic polymers. IsoxsuprineHCl tablets containing 30% (w/w) EudragitRS100 (formula D37) show more sustaining ofdrug release than those containing 30% (w/w)Eudragit RL100 (formula D32) and this may beattributed to that Eudragit RS100 has lowerpermeability to the aqueous solution and theactive ingredient than Eudragit RL100.Generally, RS type of Eudragits has lowpermeability to aqueous solutions due to itslower content in quaternary ammoniumfunctional groups which give rise to thepermeability of the coat and theammonium/meth-acrylic acid ester values are1/40 and 1/20 for Eudragit RS- type andEudragit RL- type, respectively16.

Table 6: t50% and t90% of isoxsuprine HCltablets containing 30% (w/w) ofdifferent hydrophobic polymers.

Formulanumber

Polymert50%

(hour)*t90%

(hour)**D1 --- 0.04 0.50

D25 EC 0.75 3.50D31 Eudragit RL100 1.00 4.00D37 Eudragit RS100 1.40 5.25D43 Eudragit RSPM 2.00 6.58D49 Eudragit RLPO 1.50 5.50

*t50%: Time for release 50% of the drug contained inthe tablet.

**t90%: Time needed for release 90% of the drugcontained in the tablet.

The release profiles of isoxsuprine HClfrom the prepared tablets containing differentpolymer blends are shown in figures 11-15.

The effect of different ratios of NaCMCon isoxsuprine HCl release from tabletscontaining 10% (w/w) HPMC 15000 isillustrated in figure 11. It is clear that theisoxsuprine HCl matrix tablet prepared with acombination of Na CMC (ionic hydrophilicpolymer) and HPMC 15000 (non ionichydrophilic polymer) gave slower release of thedrug than tablets prepared using 10% (w/w)HPMC 15000 alone, formula (D17). This maybe due to the fact that, when the matrix tabletprepared using hydrophilic polymer comes into

Time (h)

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Ahmed A. Aboutaleb, et al.

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contact with water, it swells and forms aporous gel barrier, the pores near the surface ofmatrix are filled with water. The drug release isinitially controlled by the dissolution of thedrug in the water filled pores and then bydiffusion17&18. The presence of NaCMC in thepolymer blend resulted in the formation of ahighly viscous solution in the pores up ondissolution, which in turn slowed down thedrug release by the formation of an additionalgel-like barrier. As shown in figure 11, as thepercentage of NaCMC increased in the polymerblend used for the preparation of isoxsuprineHCl matrix tablets, the synergistic retardationeffect of the polymer blend increased and avaluable decrease of drug release rate can beachieved.

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0 1 2 3 4 5 6 7 8 9 10 11 12

D17:0%NaCMC

D50;10%NaCMC

D51:20%NaCMC

D52:30%NaCMC

D53:40%NaCMC

Fig. 11: Release profiles of isoxsuprine HCl fromtablets containing 10% (w/w) HPMC15000 and different ratios of sodiumcarboxymethyl cellulose.

Figure 12 shows the release profiles ofisoxsuprine HCl from tablets containing 10%(w/w) HPMC 15000 and different ratios of EC.The drug release from tablets containing thepolymer blend was less than that from tabletscontaining HPMC 15000 alone and this may beattributed to the presence of EC, which is ahydrophobic polymer, the admixture of HPMCwith EC could change the permeability of theprepared matrix and consequently modify therelease rate of the drug19. The maximumsustaining drug release was obtained fromtablet formula: D57 that contains isoxsuprineHCl, 10% (w/w) HPMC 15000 and 40% (w/w)EC.

0

10

2030

40

50

60

7080

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

D17:0%EC

D54:10%EC

D55:20%EC

D56:30%EC

D57:40%EC

Fig. 12: Release profiles of isoxsuprine HCl fromtablets containing 10% (w/w) HPMC15000 and different ratios of ethylcellulose.

Figure 13 illustrates the drug releaseprofiles of isoxsuprine HCl from tabletscontaining 10% (w/w) HPMC 15000 anddifferent percentages of Eudragit RSPM. It isclear from the figure that there was a markeddecrease in the release of isoxsuprine HCl fromthe prepared sustained release tabletscontaining the blend of HPMC and EudragitRSPM. Eudragit RSPM is a pH independentpolymer with poor surface wettability and lowswelling properties. Therefore, its combinationwith HPMC 15000 can result in a pronouncedsustaining of drug release. As the percentage ofEudragit RSPM increased, the drug releasedecreased and the maximum drug releaseretardation was obtained when the blend of10% (w/w) HPMC 15000 and 40% (w/w)Eudragit RSPM (formula D61) was used. Thetotal drug release from this tablet formula wasobtained after 12 hrs.

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

D17:0%Eudragit RSPM

D58:10%Eudragit RSPM

D59:20%Eudragit RSPM

D60:30%Eudragit RSPM

D61:40%Eudragit RSPM

Fig. 13: Release profiles of isoxsuprine HCl fromtablets containing 10% (w/w) HPMC15000 and different ratios of EudragitRSPM.

Time (h)

pH 6.8pH 1.2

% d

rug

rele

ased

pH 1.2

Time (h)

pH 6.8pH 1.2

% d

rug

rele

ased

Time (h)

pH 6.8pH 1.2

% d

rug

rele

ased

93

The effect of different weight ratios of ECon the drug release from tablets containing10% (w/w) Eudragit RSPM is shown in figure14. Results showed that the blend of EC andEudragit RSPM at different percents reducedthe drug release more than Eudragit RSPMalone (formula D41). It is clear from the figurethat as the percentage of EC increased, the drugrelease from the prepared tablets decreased.The maximum time for total drug release (9hrs) was obtained when 40% (w/w) EC wasadded to isoxsuprine HCl tablets containing10% (w/w) Eudragit RSPM (formula D65).

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

D41:0%EC

D62:10%EC

D63:20%EC

D64:30%EC

D65:40%EC

Fig. 14: Release profiles of isoxsuprine HCl fromtablets containing 10% (w/w) EudragitRSPM and different ratios of ethylcellulose.

Figure 15 shows the drug release profilesof isoxsuprine HCl from tablets containing10% (w/w) Eudragit RSPM and different ratiosof Eudragit RLPO. It is clear that there was amarked decrease in the drug release fromtablets containing different ratios of thepolymer blend than the drug release fromtablets containing 10% (w/w) Eudragit RSPMalone. This may be attributed to the synergisticretardation effect of the two hydrophobicpolymers used.

As shown from figure 15, as the ratio ofEudragit RLPO increased from 10% (w/w) to40% (w/w), the sustaining effect on the drugrelease increased. Tablets containing 10%(w/w) Eudragit RSPM and 40% (w/w) EudragitRLPO (formula D69) gave the least drugrelease and the total drug release was achievedafter 12 hrs.

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

D41:0%Eudragit RLPOD66:10%Eudragit RLPOD67:20%Eudragit RLPOD68:30%Eudragit RLPOD69:40%Eudragit RLPO

Fig. 15: Release profiles of isoxsuprine HCl fromtablets containing 10% (w/w) EudragitRSPM and different ratios of EudragitRLPO.

Table 7 shows t50% and t90% values ofisoxsuprine HCl release from tablets containingdifferent polymer blends. It is clear thatisoxsuprine HCl sustained release tabletscontaining single polymers (formulae D17 andD41) have the least values of t50% and t90%.Isoxsuprine HCl sustained release tabletscontaining the blend of 10% (w/w) HPMC15000 and 40% (w/w) Eudragit RSPM(formula D61) as well as those containing thepolymer blend of 10% (w/w) Eudragit RSPMand 40% (w/w) Eudragit RLPO (formula D69)have the highest value of t50% and t90% amongthe studied formulae. From the results obtainedit is clear that these two types of polymerblends are preferable for the design of the oralsustained release product of isoxsuprine HCl,where the rate of the drug release wasremarkably prolonged.

Table 7: t50% and t90% of isoxsuprine HCl tabletscontaining different polymer blends.

Formulanumber

Polymert50%

(hour)*t90%

(hour)**D17 10% (w/w) HPMC 15000 0.20 4.00D41 10% (w/w) Eudragit RSPM 0.70 3.75

D5310% (w/w) HPMC + 40%

(w/w) Na CMC 3.50 7.75

D5710% (w/w/) HPMC + 40%

(w/w) EC 2.75 7.00

D6110% (w/w) HPMC + 40%

(w/w) Eudragit RSPM 6.07 10.85

D6510% (w/w) Eudragit RSPM +

40% (w/w) EC 2.50 7.75

D6910% (w/w) Eudragit RSPM +40% (w/w) Eudragit RLPO 5.42 10.54

*t50%: Time for release 50% of the drug contained in the tablet.**t90%: Time needed for release 90% of the drug contained in

the tablet.

Time (h)

pH 6.8pH 1.2

% d

rug

rele

ased

Time (h)

pH 6.8pH 1.2

% d

rug

rele

ased

Ahmed A. Aboutaleb, et al.

94

The kinetic parameters for the in-vitrorelease of isoxsuprine HCl from the preparedsustained release tablets were determined andanalyzed in order to explain the mechanism ofthe drug release It is clear that the release ofisoxsuprine HCl from all the preparedsustained release tablets containing singlepolymers in the both dissolution media are bestfitted to simplified Higuchi model as indicatedfrom the highest regression coefficient (r2).This means that the release rate of isoxsuprineHCl from the prepared sustained release tablets(formulae D2-D49) is dependent on thediffusion mechanism.

The release data of isoxsuprine HCl fromtablets containing different polymer blends indissolution medium of pH 1.2 were best fittedto simplified Higuchi model indicating that therelease of the drug is dependent on thediffusion of the drug through the polymer gellayer. In dissolution medium of pH 6.8, therelease of isoxsuprine HCl from sustainedrelease tablets containing the blend of HPMC15000 with either NaCMC or Eudragit RSPM,in addition to the blend of Eudragits RSPM andRLPO followed zero-order release mechanism.This may be attributed to the sufficientsustaining of the drug release due to thepresence of polymer blends that leads toincrease in the total polymer content resulted inhighly viscous gel layer around the drugleading to zero-order drug release. As one ofthe major objectives in the development ofsustained release drug delivery system is toprepare devices, which release drugs at aconstant rate for extended period of time. Inorder to obtain a constant blood level forcertain desired period. In this study, Tabletformulae D61 and D69 sustained isoxsuprineHCl release for 12 hrs and the mechanism ofthis drug release is zero-order release kinetics.

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