Drug release optimization from microparticles of poly(ε-caprolactone) and hydroxypropyl methylcellulose polymeric blends: formulation and characterization

607

J. DRUG DEL. SCI. TECH., 24 (6) 607-612 2014

Drug release optimization frommicroparticles

of poly(ε-caprolactone) and hydroxypropylmethylcellulose polymeric blends:formulation and characterizationI. Javed1, N.M. Ranjha1, K. Mahmood1, S. Kashif2, M.

Rehman3, F. Usman4*1Faculty of Pharmacy, Bahauddin Zakariya University, Bosan

Road, Multan 60000, Pakistan2Department of Pharmacy, The University of Faisalabad, Sargodha

Road, Faisalabad 38000, Pakistan3Department of Pharmacy, The Islamia University of Bahawalpur,

Bahawalpur 63100, Pakistan4Department of Pharmacy, Faisalabad Institute of Cardiology,

Faisalabad 38000, Pakistan*Correspondence:

[email protected]

In this study, polymeric blend microparticles are prepared with tunable drug releasing behavior, imparted by using poly(ε-caprolactone) (PCL) as hydrophobic and hydroxypropyl methylcellulose (HPMC) as hydrophilic biodegradable polymericconstituents. Microparticles were prepared by simple oil in water emulsion-solvent evaporation method and evaluated for theirsustained release profile by using nifedipine (half-life is about2 h) as model drug. Hydrophilic PCL is added to optimize the drug release in simulated aqueous body fluid. Polyvinyl alcohol(PVA), used as emulsifier, was found to improve shape while HPMC increased surface smoothness of microparticles. Highencapsulation efficiency was achieved, controllable by HPMC concentration. In vitro dissolution studies in acidic and neutral pHshowed sustained release profile for all formulations. Synthesized microparticles, provided control over hydrophobic drug releaseby changing the proportion of HPMC and PCL in formulation at both acidic and intestinal pH.

Key words: Microparticles – Nifedipine – Poly-ε-caprolactone – Solvent emulsification – Sustainedrelease.

Microencapsulation has been one of the mostexplored novel technique for sustainedrelease dosage formulations [1, 2]. However,biodegradability and biocompatibility ofmicroparticles have been a major challenge intheir clinical application [3]. Polycaprolactone (PCL) has been evaluated assuccessful biodegradable and biocom- patiblepolymer for synthesis of microparticles [4-6]. Nifedipine is dihydropyridine classcalcium channel antagonist mainly prescribedin hypertension, angina and Raynaud’ssyndrome [7]. It has been reported to be aneffective therapeutic option in chronichypertension associated with pregnancy [8],pre-eclamptic hypertension and even in the

treatment of chronic anal fissures [9, 10].Its half-life is about2 h and it is prescribed in the dose of 10 mgthree times a day. Since all of theseindications are of chronic nature, it ishighly desirable to have a sustained releaseformulation of antihypertensive drugs forbetter disease control and reduced frequencyof administration.

In this study, nifedipine loaded poly (ε-caprolactone) (PCL) and hydroxypropylmethylcellulose (HPMC) blend microparticleswere prepared by oil in water emulsionsolvent evaporation technique using differentconcentrations of polyvinyl alcohol (PVA) asan emulsify- ing agent. HPMC was used to

608

optimize hydration rate, encapsulationefficiency and drug loading of microparticlesalong with emulsifier. Microparticles wereoptimized to be free flowing and evaluatedfor drug release kinetics. Surface morphologywas studied via scanning electron microscopywhile FTIR analysis was performed todetermine the stability of drug inmicroparticles.

I. MATERIALS AND METHODS1.Materials

Nifedipine was gifted by Standpharm (Pvt)Ltd., Lahore, Pakistan. All other chemicals,i.e. hydroxypropyl methylcellulose (HPMC),poly (ε-caprolactone) (PCL) (M.wt 10000)(Fluka), polyvinyl alcohol (PVA) (Merck),dichloromethane (RDH), potassium bromide ofIR grade (Fischer Scientific, UnitedKingdom), hydrochloric acid (RDH), sodiumhydroxide (BDH), potassium dihydrogenphosphate (Merck) and dialysis tube (M.wt.6491) (Sigma Aldrich) were used as received,without further modification.

2. Preparation ofmicroparticles

Microparticles were prepared by oil inwater emulsification solvent evaporationmethod with little modification [11]. PCLand HPMC in various ratios from 15:2 to 8:6were dissolved in 20 mL dichlo- romethane andthen 100 mg of nifedipine was added to thissolution to form organic phase (Table I). Theorganic phase was poured drop wise to the 160mL aqueous solution (0.5 or 1 %) of PVA (Figure1). Dichloromethane was removed in laminarflow hood by stirring at1000 rpm at room temperature for 2 h. Aftercomplete evaporation of dichloromethane,microparticles were washed by repeatedcentrifu- gation (Himac CS150GXL, Hitachi,Japan) at 1000 rpm for 30 min, usingdeionized water, to remove the unreactedimpurities.

Table I - Formulations of PCL/HPMC blends with PVAand nifedipine.Formula-

Drug/polymer/

Drug/polymer

Concentration of

F1F2F3F4F5F6F7

NFD/PCL/HPMCNFD/PCL/HPMCNFD/PCL/HPMCNFD/PCL/HPMCNFD/PCL/HPMCNFD/PCL/HPMCNFD/PCL/HPMC

1:15:2

1:12:2

1:10:4

1:8:6

0.5 %0.5 %0.5 %0.5 %1 %1 %1 %

Figure 1 - Microparticles preparation scheme anddrug releasing behavior showing dissolution ofmicroparticles content along with drug release.

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J. DRUG DEL. SCI. TECH., 24 (6) 607-612 2014

Drug release optimization from microparticles of poly(e-caprolactone) and hydroxypropyl methylcellulose polymeric blends: formulation andcharacterization I. Javed, N.M. Ranjha, K. Mahmood, S. Kashif, M. Rehman, F. Usman

3. Recovery of formed microparticlesMicroparticles were collected on filter

paper and dried over-night at roomtemperature. Large sized irregular aggregatesand precipitates were separated by passingthe particles through sieve 500 mesh (poresize 25 µm), except formulation G1, whichcontained majority of particles greater than25 µm.

Recovery is the ratio of weight ofmicroparticles obtained (mean output) tototal weight of solid contents used (meaninput) at the begin- ning of themicroencapsulation process. Recovery ofmicroparticles was calculated by followingequation:Microparticle recovery = {[weight of microparticles

over a frequency range of 400 to 4000 cm-1 andthe resolution was2 cm-1.

8. Scanning electron microscopy (SEM)Scanning electron microscope Hitachi S-3400

was used for the surface characterization ofthe microparticles. Samples were prepared onaluminum stub with Au coating via sputtercoater. Scanning was performed at 5 kv.

9. Drug release and release kineticsIn vitro release behavior of nifedipine from blend microparticles

obtained (mean output)]/[(weight of solid contents used (mean input)]} × 100

4. Microparticle hydration

Eq. 1

was determined using a USP dissolutionapparatus (Pharmatest).About 100 mg of microparticles were taken incellulose dialysis bag containing 4 mL ofdissolution medium and tied to the paddle.The in vitro release study was conducted at apaddle rotation of 100 rpm

At the end of each microencapsulationprocess, microspheres were weighedimmediately before (M1) and after drying to aconstant weight (M2). The percentage ofmicroparticle hydration was calculated byfollowing formula (Equation 2):

in 500 mL of release medium (37 ± 1 °C). Analiquot of the releasemedium (5 mL) was withdrawn at pre-determinedtime intervals and then an equivalent volumeof fresh dissolution medium was added.Collected samples were suitably diluted,passed through 0.45 mL

Microparticle hydration % = (M1/M2) × 100

5. Determination of drug loading capacity

Eq. 2

syringe filter and analyzed for nifedipine content by measuring theabsorbance at 238 nm using an UV-Vis spectrophotometer (IrmecoU2020). Drug release was conducted in USP phosphate buffer solu-

The drug loading of the microparticles wasdetermined by dis- solving an accuratelyweighed amount of microspheres (20 mg) indichloromethane (5 mL) and then diluting themixture with 20 mL phosphate buffer (pH 6.8,0.01 M). Dichloromethane was removed bystirring the solution for 1 h. After passingthe solution through

tions (0.01 M, pH 1.2 and 6.8).Mode of drug release was determined by

mathematical models [12] including zero order(Equation 10), first order (Equation 11),Higuchi’s model (Equation 12), Hixon-Crowell(Equation 13) and Korsmeyer-Peppas (Equation 14):

0.45 µm syringe filter, drug concentrationwas measured by taking absorbance ofnifedipine at 238 nm with UV-Visspectrophotometer (Irmeco U2020).

Qt = k0t

log Qt = log Q0- k1 tQt = KHt

Eq. 10Eq. 11Eq. 12

Drug loading capacity was determined by following formula

1/3 o

- Qt

1/3= KHCt

Eq. 13

(Equation 3):Drug loading = (Mass of drug in microparticles/Mass of

micr

oparticles) × 100Eq. 3

Mt/Mo = kKPt II. RESULTS AND DISCUSSION Eq. 14

Percent encapsulation efficiency was calculated as follows (Equa-

tion 4):Encapsulation efficiency = (Entrapped amount

In this study, oil in water solvent evaporation technique was used

to encapsulate nifedipine using different ratios of PCL and HPMC, in order to optimize the release characteristics of microparticles. This

of drug per g of microparticles/Theoratical amount of drug per g of microparticles) × 100

6. Rheological studies of microparticles

Eq. 4

preparation technique is commonly used for microencapsulationof water-insoluble drugs in hydrophobic polymeric systems [13]. Polymeric blends of PCL and HPMC in various ratios ranging from15:2 to 8:6 were used to form 8 formulations (Table I). These ratios

Compressibility index, Hausnner’s ratio andangle of repose were determined as indices ofrheological properties of microparticles.Microparticles (20 g) were taken involumetric cylinder and tapped on flatsurface to determine bulk (Equation 5) andtapped densities (Equation 6):

of PCL and HPMC were designed to have ascanning view of theirimpact on drug release pattern. However, inall formulations, HPMC concentration isrelatively lesser than polymer, otherwisedisintegrating effect of HPMC dominatesresulting in particles disruption and burstrelease of drug.

Bulk density = Sample weight/Sample volume Tapped density = Weight of microparticles/Volume of microparticles after 100 tappings

Eq. 5Eq. 6

1. Recovery of microparticlesMean input, mean output and percent recoveryare shown in Table II.

The Carr’s Compressibility Index (Ci) was calculated as follows

(Equation 7):

This is evident from the results that recovered total weight markedlyincreased from 71.2 to 74.3 % with an increasein the concentration

Ci = [(Initial volume - Final volume)/Initial volume] × 100

Eq. 7

of the PVA from 0.5 to 1.0 %. Higher PVA concentration minimized

The Hausnner’s ratio was calculated by following formula (Equa-

tion 8):

the formation of irregular and undesired microparticles, and increasedthe recovery of microparticles. In addition, high concentration of PVA

Hausner’s ratio = Volume before tapping/Volume after tapping

Eq. 8

could keep droplets dispersed and prevent agglomeration [14]. On the

Angle of repose was measured by passingmicroparticles through a funnel on thehorizontal surface. Angle of repose wascalculated as (Equation 9):

other hand, increasing the concentration of HPMC from 15:2 to 8:6suppressed microparticles recovery from 71.2 to 53.7 %. This lowrecovery is due to affinity and transfer of hydrophilic HPMC to external

Tanθ = Hight of heap/Radius of cone

7. FTIR studies

Eq. 9

aqueous phase. It can be explained as when a hydrophilic co-polymerlike HPMC or PEG is used in combination with hydrophobic polymers beyond a certain concentration, the co-polymer starts to diffuse into

Infrared spectrum of pure drug, polymersalone, and polymer drug mixture were obtainedto evaluate drug-polymer interaction. KBrdisc method was used in which KBr wasincorporated with the drug and polymers.Scans were obtained with Nicolet iS10 FT-IRSpectrometer

external aqueous phase of emulsion. Thisphenomenon also encour-ages precipitation of other polymericconstituent and aggregation of microparticlesinto large irregular aggregates which werefiltered out through sieve [15, 16].

2

Drug release optimization from microparticles of poly(e-caprolactone)and hydroxypropyl methylcellulose polymeric blends: formulation and characterizationI. Javed, N.M. Ranjha, K. Mahmood, S. Kashif, M. Rehman, F. Usman

J. DRUG DEL. SCI. TECH., 24 (6) 607-612 2014

Table II - Recovery of microspheres.

Table III - Microspheres hydration.

Formula- tions

Input(mean)

Output

Recovery

(%)Mean ± SD

F1F2F3F4F5F6F7

16161616161616

11.4

10.610.18.611.911.

0.034

0.085

0.040.065

0.01

71.266.263.153.774.369.366.2

Cellulose ethers are water soluble polymersbut they also have solubility in organicsolvent like dichloromethane and used insynthesis of pharmaceutical formulations bydissolving in organic solvent [17,18]. When organic solvent evaporates, if HPMCis not entrapped inside microparticles alongwith other polymer constituents, it tends todiffuse in aqueous phase due to its greatertendency to dissolve in water [19].

2. Degree of hydration ofmicroparticles

Degree of hydration is affected bymiscibility of polymers and water. Duringmicroencapsulation process, water poorlypenetrates into dispersed phase due to verylow aqueous miscibility of dichlorometh- ane(internal phase). Therefore, resultantmicroparticles were poorly hydrated and lessprone to aggregation upon drying [20].Results of hydration studies (Table III)indicated that all microparticle formula-tions had absorbed water, depending upon HPMCconcentration. Degree of hydration increasedfrom 138.65 to 317.97 % as the proportion ofHPMC was increased from 15:2 to 8:6. Theseresults can be explained on the basis of thefact that HPMC is a water miscible polymerand its incorporation in the polymer blendsincreases water penetration intomicroparticles.

3. Drugloading

Effect of HPMC and PVA on drug loading andentrapment ef- ficiency (Table IV) wereinvestigated. Drug loading and encapsu-lation efficiency of microparticles decreasedwith increase in the concentration of HPMC.Drug loading decreased from 9.10 to 8.30 %and encapsulation efficiency decreased from

91.25 to 83.00 % as HPMC proportion wasincreased from 15:2 to 8:6. These results arein accordance with the study of Yeo et al. [21]who concluded that encapsulation efficiencycan be enhanced by decreasing hydrophiliccomponent of microparticles. This reductionin loading efficiency can be attributed toincreasing hydrophilic proportion whichlimits the incorporation of hydrophobic drug[22]. The results also showed that entrapmentefficiency of formulation increased withincrease in concentration of PVA from 0.5 to1.0 %. A probable reason for this is theformation of more compact particles andreduced partitioning of drug into continuousphase during formulation [23]. Nifidipine hasa partition coefficient of 3.17 (logPoctanol/water

) [24].

4. Rheological studies ofmicroparticles

Rheological properties of all sixformulations are expressed in terms of bulkdensity, tapped density, compressibilityindex, Hausner’s ratio and angle of repose.Compressibility index of all six formulationswas below 15 %, Hausner’s ratio was below1.2, and angle of repose was below 30°. Allthese parameters indicate that all theformulations are of free flowing nature (TableV).

5. FTIRstudies

The FTIR spectra of nifedipine showed N-Hstretching vibration at 3330.46 cm-1, C=Ostretching at 1683.55 cm-1, C-O esterstretching at 1227.47 cm-1, and 1120.44 cm-1.Sharp peak of NO stretching was

Formula- tion

Mean weight ofwet

Mean weight ofwet

Micro-spherehydrati

onMean ± SD Mean ± SD

F1F2F3F4F5F6F7

1.651.722.282.831.751.892.11

0.030.050.060.060.030.050.07

1.191.111.060.891.141.061.01

0.020.020.030.030.050.070.6

138.65154.95215.09317.97153.50178.30208.91

Table IV - Drug loading ofmicrospheres.Formula- tion

Massof

micro-spheres (mg)

Theoretical

amountof

drug

Encap-sulatio

nefficiency (%)

Drug load- ing (%)

F1F2F3F4F5F6F7

20202020202020

2.002.002.002.002.002.002.00

91.2588.0083.5083.0098.5597.1094.44

9.108.808.358.309.859.709.40

Table V - Rheological properties ofmicrospheres.Formula- tions

Bulkdensity

Tapped densi

Com-pressibil- ity

Haus-ner’

Angle of repose

F1F2F3F4F5F6F7

0.410.380.280.240.380.350.29

0.460.430.330.280.440.410.33

12.212.115.114.215.714.612.1

1.151.141.191.181.161.161.15

26.226.927.329.224.725.427.6

seen at 1529.27 cm-1 (Figure 2).Thesecharacteristics peaks of drug can be seen inpolymer blend showing stability and chemicalstability in mixture (Figure 2).

6. Scanning electronmicroscopy

Microparticles prepared with 0.5 % PVA wereof aggregated rough surface and somewhatamorphous (Figure 3A, B, C), while those with1 % PVA were spherical (Figure 3D, E, F). Whenused as emulsify- ing agent, PVA is reportedto impart good spherical surface to themicroparticles [25]. Smoothness of surfaceincreased by increasing the ratio of HPMC,whereas, microparticles with lower HPMCpropor- tions showed rough and poroussurface. Decreasing the concentration of PCLand increasing the concentration of HPMC inmicroparticles resulted in aggregation ofparticles. No drug crystal was observed onsurface of microparticles.

7. In vitro drugrelease

At pH 6.8, all formulations showed asustained release pattern (Figure 4) up to 10h. PCL is a hydrophobic polymer and itsrelease retarding effect is due to lowpenetration of water into sphere matrix [26].However this effect, in addition with otherrelease promoting agents e.g. HPMC, is usedto control the over release profile of

formula- tions. Formulation F1 showed maximumsustainability as 83 % drug

Drug

Relese

(%)

Drug R

elease

(%

)

J. DRUG DEL. SCI. TECH., 24 (6) 607-612 2014

Drug release optimization from microparticles of poly(e-caprolactone) and hydroxypropyl methylcellulose polymeric blends: formulation andcharacterization I. Javed, N.M. Ranjha, K. Mahmood, S. Kashif, M. Rehman, F. Usman

Figure 2 - FTIR spectra of A) nifedipine, B) PCL, C) HPMC, D) PCL + HPMC, E) PCL + HPMC + nifedipine.

Figure 3 - SEM images of formulation G1 (A), G2 (B), G3 (C), G4 (D), G5 (E) and G6 (F).

120 25

100

80

60

40

20

F120 F1

F2

F2F3

F315F4

F4F5 F5F6 10

F6F7 F7F8 5 F8

00 2 46 8 10

12Time

00 0.5 1 1.5 2 2.5 3 3.5

Time

Figure 4 - Release of all formulations at pH 6.8. Figure 5 -

Release of all formulations at pH 1.2.

was released in 10 h. Drug release was foundto increase by increasing HMPC concentration.This increase in release rate was due toincor- poration of hydrophilic polymer HPMCwhich facilitates penetration of water intomicroparticles. Drug release rate increasedfrom 83 to94 % as HPMC ratio was increased from 15:2 to8:6. Drug release was sustained modestly byincreasing PVA concentration from 0.5 to 1.0%. Increasing concentration of PVA asemulsifying agent leads to the hard

and compact microparticles that tend toresist penetration of water. This effect wasmore evident in formulations containinghigher proportion of HPMC. Initial burstrelease was observed in all formulations dueto the presence of HPMC, more evident informulation containing higher HPMC ratio.During synthesis, some drug and HPMCpartition to the outer shell ofmicroparticles. Due to enhanced swelling,owing to increased proportion of HPMC andreduced diffusion path length, the

Formula- tion codes

Zero order kinetics

First order kinetics

Hixson-Crowell kinetics

Higuchi kinetics

Korsmeyer-Peppas

R2 K R2 K R2 K R2 K R2 nF1F2F3F4F5F6F7

0.9760.9560.9500.9630.9540.9450.947

8.328.568.608.148.438.598.84

0.8820.9750.9780.9590.9920.9780.954

0.1960.2140.2430.2380.2060.2350.282

0.9070.8720.8510.8630.8860.850.84

0.280.270.260.230.270.260.26

0.9440.9710.9780.9840.9760.9710.975

36.8936.7137.1835.0236.8037.0138.12

0.9380.9550.9640.9740.9230.9520.957

1.121.181.100.941.171.121.15

Drug release optimization from microparticles of poly(e-caprolactone)and hydroxypropyl methylcellulose polymeric blends: formulation and characterizationI. Javed, N.M. Ranjha, K. Mahmood, S. Kashif, M. Rehman, F. Usman

J. DRUG DEL. SCI. TECH., 24 (6) 607-612 2014

Table VI - Release kinetics of microspheres.

0 1 HC H

drug entrapped in and near to the shell ofmicroparticles was released abruptly [27].Retarding effect of PCL on drug release isquite visible in second phase of drugrelease. The sustained drug release in thisphase was due to relatively slow penetrationof water in PCL matrix [28]. Similar releasepattern was observed at pH 1.2 (Figure 5) butoverall drug release was very low. Initialburst release was negligible for allformulation at acidic pH. Over 3 h studyperiod, drug release increased from 9 to 20 %as HPMC ratio was increased from 15:2 to8:6. However, increasing the PVA from 0.5 %to 1.0 % sustained the drug release from 9 to10 % in accordance with the drug releaseprofile at pH 6.8. The results of drugrelease demonstrate that PCL/ HPMC blendsbased microparticles will provide sustainedrelease of Nifedipine (t

1/2 = 2 h) at gastric

and intestinal pH when given orally. Inaddition, HPMC can be used to tune drugrelease from PCL or other hydrophobic polymerbased drug delivery systems. Single oral doseof 20 mg in immediate release capsulesprovides 6 h of therapeutic plasma levelsi.e. 15-30 mg/mL [29]. Microparticlesprepared in this study are able to providesustained release of drug up to 10 h whichstill can studied beyond this time untilcomplete exhaustion drug from particles. Itprovides an insight that preparedmicroparticles can maintain therapeutic bloodlevels of drug, with single oral dose up tosufficient, replacing multiple dosingregimen.

Kinetic modeling of all formulations wasperformed in order to estimate order andmechanism of drug release from particles (Ta-ble VI). Kosmeyer-Peppas model (R2 = 0.923-0.978) showed that release exponent (nvalues) for all formulations lied between0.94 to 1.19, which predicted anomalous andCase II drug release [30]. This indicatescontinuous matrix release behavior ofmicroparticles prepared in this study.

*

PCL/HPMC blends based microparticles showedexcellent rheo- logical properties. Allformulations exhibited sustained drug releasepattern with minimum release in acidic butsustained release pattern at intestinal pH.Microparticles prepared by 1 % PVA showedsmoother surface and more sustained releasepattern. Microparticle recovery increased byincreasing concentration of HPMC andemulsifier while hydration rate, drug loadingand encapsulation efficiency were increased byincreasing the concentration of polymer. HPMCincorporation into polymeric blends enhanceddrug release both at acidic and neutral pH.Drug release kinetics followed zero-order andHiguchi model while release mechanism wasfound to be anomalous and case II drugrelease. In conclusion, PCL-HPMC basedmicroparticles will provide sustained releaseof Nifedipine at gastric and intestinal pHand the release rate can be optimized bychanging PCL to HPMC ratio on polymericblends.

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CONFLICT OF INTEREST

The authors have no conflict of interest.

MANUSCRIPT

Received 6 August 2014, accepted for publication 10 November 2014.