Journal of Scienti fic & Industrial Research

Vol. 62 , October 2003, pp 985-989

Release of Ketoprofen from Alginate Microparticles' Containing Film Forming Polymers

K S Rajesh, A Khanrah and Biswanath Sa*

Department of Pharmaceutica l Technology. Jadavpur Uni versity. Kolkat;1 700 OJ2

Received: 27 February 2003 ; acce pted: 19 May 2003

Ketoprofen-Ioaded alginate microparti cles were prepared by dropping alginate-drug suspension, with or without aqueous coll oidal pol ymer di spersions, into calci um chloride so lution. The effect of various formulati on var~a bles on the physical characteristi cs of the mieroparticies was studi ed. While increase in the concentration of sodium alginate and aqueous polymer dispersions increased the spheri ci ty of the microparricles, no appreciable change in the morphology was observed with variation in the concentrat ion of calcium chl oride and curing time. The mean diameters of the mi cropanicles were influenced by all the variables. Drug entrapment erlici ency approached nearl y 100 per cent , except in those mi cropan icles prepared by curing for longer time. III vitro release showed that drug release from the mi cropanicies depended onl y on the

concentration of alginate and the nature of aqu eous colloidal polymcr dis persions.

Keywords: Ketoprofen, Alginate microparti cles, Mi croparti cles , Co ll oidal pol ymer, Di spersions

Introduction

Sodium alginate, an anionic block copolymer of

~-D-manuronic acid and a-L-guluronic ac id, is a readily avail ab le, non-toxic pol ysaccharide which is ex tensivel y used in pharmaceutical industri es as suspending and emul sifying agent l. Its property to form ge l with divalent and multi va lent cati ons has been used to immobilize cells2

.3. Sodium a lginate has

a lso been used to prepare sustained re lease tab le ts4.5

.

However, microparticulate drug de livery system provides severa l advantages over sing le unit susta ined release tabl ets6

.8

. Recently the use of calcium a lginate gel beads as a vehicle for controlled drug de li very system has attracted cons iderable attention because of the ir property of reswelling which is susceptible to environmenta l pH. Consequently, ac id-sensiti ve drugs incorporated into the beads would be protected from gas tric juice9

. Alginate ge l beads loaded with various drugs have been prepared and various factors which affect the drug release rate from the beads have been in vestigated intens ive lylo.ll. However, maj or di s­advantages of a lg inate beads are the ir fast disintegration in s imul ated intest ina l fluid and hi gh

" Author for correspondence

. h' I I ' 'd I I 11 porosIty w IC 1 resu t In rap l C rug re ease -. Currentl y, aqueous co ll o ida l polymer dispersions like latex and pseudo latex are ava il ab le as film forming mate ria ls to coat solid dosage forms in aqueous system l3.

The study aims at de ve loping ke toprofen-I oaded micropartic les by ionotropic gelati on of sodium alginate contatntl1g aqueous co ll o ida l po lymer di spersions (Acrycoats·R

). Ke top rofen, a non-steroidal anti-infl ammatory agent has been used as mode l drug and acrycoats have been used as re lease rate modifiers.

Materials and Methods

Mctlerials

Ketoprofen (Rh one-Po Lll e nc, Ind ia) , acrycoat LJOD (v iscos ity !5CPS, so li d content 30 per cent) and ac rycoat E30D (v iscos ity 19CPS , so lid content 30 per ce nt , C hore l P harma-c hem. India) were obta ined as g ift samples . Acrycoat L30D is ani onic and contai ns methacrylic acid copolymer. Acrycoat E30D is a neutra l po lyac ry late dispers ion. Sodium alginate (SD F ine C hemical s. Indi a), ca lcium chloride d ihydrate (Ranchemical s, India) and a ll other chemical s were obta ined comme rc ia ll y.

986 J SCI INO RES VOL 62 OCTOBER 2003

Preparation of Sodium Alginate Microparticles

In 30mL aqueous soluti on of sodium alginate, required amount of ketoprofen (30 per cent of the dry polymer) was di spersed uniformly. Bubble-f ree dispers ion was dropped through a 24 bore g l.ass syringe in gentl y agitated calc ium chl oride so lu tion. After curing fo r predetermined times the ge lled beads were separated by fi ltrati on, washed with di stilled water, a ir dri ed and finall y dried at 60°C fo r 6h. T he fo ll owing experimenta l parameters were varied :

(i) Cu ring time : 0.5, I and 2h.

(ii ) Concentrati on of calc ium chl oride so luti on : 1,4 and 8 per cent w/v.

(iii ) Concentrati on of sodium a lginate solution : 2,3 and 4 per cent w/v.

Preparation of Sodium A 19inate-Acrycoat Microparticles

In 30 mL of 2 per cent sodium algi nate solu tion, ketoprofen (30 per cent of the po lymer) was dispersed. Required volume of acrycoat di spersions (equi va lent to 0.03, 0.06 and 0 . 12 per cent d ry acrycoat of total so lids) were added and homogeni zed fo r 5 min . T he resulting di spersion was dropped in I per cent calc ium chl oride so luti on and cured fo r 0 .5h. T he micropartic les were separated , washed with di stilled water, a ir dried and then dried at 60°C for 6h.

Weight Loss of A lginate Particles

Bubble-free sodium .a lg inate so lution wi thout conta ining any drug or collo idal polymer dispersions was dropped th rough 24 bore g lass syringe in gentl y agitated 4 per cent calc ium chl oride soluti on. Twenty beads were removed at predetermined times and weighed in e lectronic balance (Precisa, XB-600MC) after removal of surface water with ti ssue paper. We ight loss of the beads was determined as fo llows :

(Weight of the beads at zero lime -Weight of the beads at time t)

x 100 Weighl of the beads at zero time

Scanning Electron Microscopy

Dried microparticles were mounted onto stubs, using double sided adhesive tape and vacuum coated with gold film using putter coater (Bio Rad Sc 502). The coated particles were observed under scanning

e lec tron mI croscope (Jeo l JSM 5200) for surface characte ri sti cs.

D rug Ellt rapmell t Efficien.cy -

Accurate ly we ighed amount of microparti c les were d issolved in 250 mL of USP phosphate buffer so lut ions (pH 7.4) by shaking on a mechanical shaker fo r 24h. T he so luti on was filtered. An ali quot follow ing suitab le diluti on was assayed spectrophotometrica ll y at 260nm. The re liability of the method was j udged by reco very ana lys is, using 25 mg of ketoprofen with or without sodi um a lg inate and

ac rycoats. T he recovery averaged 98.4 ± 2.03 per cent. Th e drug entrapment effi c iency was determ ined usi ng the fo ll ow ing re lati onship .

Drug entrapment effic iency =

Experimenta l drug con tent

x 100. T heoretica l drug content

III Vit ro Dissolutioll S tudy

T he in vitro re lease of ketoprofen from the mic roparti c les was moni tored in LISP phosphate buffer so lution (pH 6 .8, 37 ± 1°C) u ing USP padd le type d issol uti on rate tes t apparatu s. SO mg, accurate ly weighed, micropartic les were st irred in 900 mL d isso luti on med ium at 75 r.p. m. Samples were wi thdrawn after predetermined peri ods and were repleni shed immedi ate ly with the same vo lume of fres h mediu m. A liqu ots, fo ll ow ing su itab le d iluti on, were ana lyzed spectrophomet ri ca ll y at 260 nm .

Results and Discussion

Ketoprofen (30 per cent) loaded a lginate micro­pa~ti c l es whi ch were cured fo r 0.5 to 2h in I per cent calcium chl oride so luti on were not spherical and had a flattened base at the po ints of contact with the drying vesse l. Vari ati on in the concentration of calcium chloride ( I to 8 per cent) did not improve the spheric ity apprec iably (Figure I ). However, increase in the concentrati on of sodium alginate tended to make the particles more spherical (Figure 2). This . indicates that at low a lginate concentration the parti cles were composed of loose network structure wh ich co ll apsed during drying. O n the other hand, higher alg inate concentrati on fo rmed dense matrix structure whic h prevented co ll apse of micropartic les .

RAJESH el al .: FILM FORMING POLYMERS 987

Figure I - Effect of: (a) Curing time (2 h) and (b) Calcium chloride solution (8 per cent) on the morphology of mi cropartic les containing 2 per cent sodium alginate and 30 per cent ketoprofen

Figure 2 - Morphology of 30 per cent keloprofcn loaded microparti cles prepared with : (a) 4 per cent alginate. (b) 2 per cenl alginate + 0. 12 per cenl acrycoat L30D, (c) 2 per cent alginate + 0. 12 per celll acrycoat E30D and cured for I h in I per cent calci um chl oride solution

The mean di ameters of the microparti c les were found to decrease with inc rease in curing time and calc ium chloride concentrati on (T ab le I). Inc rease in the concentrat ion of sodium alginate , however, increased the diamete rs of the pa rti c les (Table 2) . It has been stated that w hen a drop of alginate soluti on comes in contact with calc ium ions, ge lat ion occurs instantaneous ly. As Ca+2 ions pene trate into the interior of droplets, water is al so squeezed out of the interior, resulting in contraction of the beads <) Thus, at a fixed concentrati on of alginate , e ithe r increase in curing time or in the concentration of calc ium chloride solution resulted in the contract ion of the beads, leading to decrease in di ameter. However, increase in a lg inate concentrat ion increased the viscos ity of the di spe rse phase. In additi on, wate r loss , during curing, fro m the blank mic roparticles hav ing highe r alginate concentration was found to be less than that from the mic ropa rti c les havi ng lowe r alginate concentration (Figure 3). These factors resulted in the formation of bigger particles.

80

• •

o~~~~~~~~~~ o 20 40 60 80 100

Time (minute)

Figu re ::I - Loss of waler frolll hl<lIlk micropa rticles co ntaining 2 per cenl alginale ( 0) and 4 per celll alginate ( e ) as a function of

time in 4 per cenl calciulll chl oride Soluli on

Drug e ntrap ment e ffi c ie ncy as a fu nction of curing time was found to be mo re c riti ca l than the concentrat ion of C{' iOIl (Table I ). Since the solubility of ketoprofen was s li ght ly hi ghe r in ca lc ium chloride so lu t ion th an in d ist ill ed wate r, pro longed ex posure caused greate r loss of d ru g in the curing medium. Jnc rease in a lg in ate cO llcenrati on reduced the loss of d ru g in the curing med ium due to the fo rmati on of dense matri x s tru c ture. It has been reported th at diffu sio n coe ffi c ient o f a drug dec reases with increase in al g in ate concentrati o n')

Re lease o f ke to profe n fro m the mi croparticles was compl eted w ithin I h, irrespec ti ve of curing time and concentrati on o f ca lc ium c hl o ride so lu tion . Ne ithe r the prol onga ti on of curing time nor inc rease in ca lc ium chl oride concent rati on prov ided ex tended re lease as ev ide nt by ins ign i ficalll differences in t sO%

va lues (time required fo r 50 pe r cent re lease of drug) (Tabl e I). Inc rease in initi a l a lg in ate concentration, however, ex tended the re lease to some ex tent (Tabl e 2). A lg ini c ac id is composed of D-manuroni c ac id and L-guluro ni c ac id res idues at varying proportion of GG-, MM -, and MG-b locks I4

. Cross­linking takes place onl y be twee n the carboxy late res idue of GG-bl oc ks and Ca+1 io ns via egg-box mode l to g ive a ti ght ge l ne twork struc ture l5 The toughness o f the ne two rk struc ture and subsequent di s integrati on and di sso lu ti on o r a lg inate part ic les, taking place th rough io n-exc hange be t ween the bound Ca+2 ions and Na+ io ns present in the di ssolution medium, is onl y dependent o n initi a l a lg inate concentrat ion and no t o n the curin g time or calc ium

988 J SCIIND RES VOL 62 OCTOB ER 2003

Table I - Effect of curing time and calcium chloride cOlllcentrati on on the characteri sti cs of ketoprofen (30 per cent) loaded alginate (2 per cent) microparticles

Variables Mean di am

(!-1m)

Drug entrapment efti ciency (per cent)

Ti me required for 50 per cent release of ketoprofen (t,n per cent) (min)

Curing time (h)

0.5

1.0

2.0

Calci um chloride concentration (per cent )

4

8

743.60

703.55

670.36

703.55

645.62

616.46

Figu res in the parentheses indicate standard deviation

99.73 (± 3.83)

98.53 (± 1.74)

88.00 (± 5. 13)

98.53 (± 1.74)

100.02 (± 3.42)

97.52 (± 4.28)

19.50(±2.04)

16.92 (± 2.24)

20.0 (± 2.94)

16.92(±024)

22.67 (± 0.26)

20.92 (± 0.72)

-------------~----------------------------------------

Tabl e 2 - Effec t of concentrations of sodium alginate a.nd acrycoats on the characteri stics of 30 per cent ketoprofen - loaded microparticies cured for I h in I per cent calcium chloride solution

Vari ables Mean di am (!-1m)

Drug entrapment eftl ciency (per cent)

Time required fo r 50 per cent release of ketoprofen (lsn per cent) (min )

Sodi um alginate (per cent)

2

3

4

2 per cent sodium algina te containing acrycoat L 300

0.03 per cent

0.06 per cent

0.12 per cent

2 per cent sodium algi nate containing acrycoat E 300

703.55

870.0

980.15

11 62.5

1236. 12

1511. 12

98.53 (± 1.74)

98.63 (± 2.04)

100.25 (± 2.05 )

97.03 (± 2.67)

100 (± 3.56)

100 (± 4.6 1)

16.92 (± 0.24)

55.33 (± 2.49)

62.67 (± 3.30)

21.67 (± 287)

30.0 (± 2.94)

36.0 (± 3.74)

0.03 per cent

0.06 per cent

O. 12 per cent

11 44.69

11 68.50

11 92.83

99. 15 (±3.96)

100.00 (± 3.40)

99.89 (± 3.(9)

55.0 (± 4.55)

68.0 (± 6.98)

88.0 (± 5.89)

Figures in the parentheses indi cate Sl.andard deviation

chloride concentration. Thus the release profiles of ketoprofen did not appear to be modul ated signifi cantl y with curing time and concentration of Ca+2 ions. However, an increase in initi al a lginate concentration, leads to the formati on of network stmcture of greater toughness which might have hindered the penetrati on of di ssolution medium into the a lginate particles, leading to ex tended re lease to some extent .

Dmg-Ioaded a lginate particles contammg ac rycoat L30D and ac rycoat E30D appeared to be spherical , a lthough the surface was not as smooth as alginate partic les (Figure 2). T hi s was due to coalescence and fu s ion of the collo ida l aqueous polymer di spers ions in the a lg inate matri x. T he average di ameter of the particles increased with increase in the amount of acrycoats due to added viscos ity imparted by acrycoats. The dm g entrapment

RAJESH et al.: FILM FORMING POLYMERS 989

100 '(f<

"E 80 (f) co ~

~ C

~ Q 40 Q.

j

1 2 3 4 5 6 TIme( hour)

Figure 4 - Release protiles of ketoprofen from microparticles containing 2 per cent alginate ( 0 ), 2 per cent alginate + 0.12 per

cent acrycoat L30D (t.), 2 per cent alginate + 0.12 per cent acrycoat E30D (0) in phosphate buffer solution (pH 6.8)

efficiency of all the particles was close to the theoretical drug load (Table 2).

Although incorporation of acrycoat L30D did not extend the release appreciably, acrycoat E30D significantly prolonged the release of keteprofen (Figure 4) . As acrycoat L30D is pH sensitive, dissolution of acrycoat L30D in pH 6.8 buffer leads to di sintegration of microparticies and thus shows faster release as compared to acrycoat E30D which is insoluble over the entire physiological pH. Thus, re lease of ketoprofen from alginate microparticles containing acrycoat E30D was significantly prolonged.

Conclusion

The results sugges t that ketoprofen-Ioaded alginate micropartic les containing acrycoat E30D can be prepared by ionotropic gelation method in a completely aqueous environment and the microparticles could be used for extended re lease of the drug.

Acknowledgement

The authors are grateful to MIS Rhon-Poulenc, India, and Mis Corel Pharma-chem, India for their

generous gifts of keteprofen and acycoats, respectively.

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