Chitosan microspheres prepared by spray dying method

Relating to Invited Lecture 5-Material

Sl73

Science (P3.031-P3.089)

The importance of vesick size and drug entrapment control in the use of liposomcs in drug delivery

and targeting is well established ‘.

microfluidization

of solub-containing

leads to

the formation of smaller

originally

entrapped solute.

Previous wo&

dehydration-rchydmtion vesicles retaining

(“washed”

of DRV

or “unwashed”

mathematical

considwabk

liposomes)

amounts

of the

The size of, and soIu(e retention by, such vesicles was

found’ to depend on the number of microfluidization microfluidization

hss shown that

vesicks (DRV

WBS carrkd DRV).The

cycles and on whether or not

out in the presence of non-entrapped solute aim

of the present study was to establish

correlations which would allow the prediction of such characteristics es

size and polydispenity the microfluidization

index and solute retention values in vnicks of solute-containing

those behveen the above characteristics

DRV

liposomes.

and operational

generated through

Correlations studied were variabks

such as pressure

applied (P, 20-60 psi), number of cycles (N; I -I 0) and the presence or absence of nonentrapped material during the process ofmicmfluidization Preparations (Microfluidizer

of

“C-labelled

S-l IO; Micmfluidics,

sucrose-containing

(W). DRV

were

micmfluidizcd

USA) according to a compkte factorial

designof

thethreevariables at hvo levels, with interactions. Results show that all three operational variables exerted a significant effect on the vesicle characteristics studied. By carving out five unperformed experiments (with unwashed DRV liposomes) in the factorial design ofthe two variables (P. N) at three levels of P (20.40.66 psi) and N (I, end IO cycles) and using regression analysis (SPSS PC’ sofhvare) the following correlations were established:

5

% of initial 82.2094*5.34

entrapment ??SE = 0.3988

N’ + 0.01440

P’

_ 6.3338 N -I ,303s P +

(~0.9252)

size (nm) f SE = 0.07268 NP - I .0759P - 6.3874N + 204.6885i 16.86(r-0.8136) Polydispenity index ?? SE = 0.001713 P + 0.008872 N - 0.0003508 NP

+

0.159240+0.022 (1=0.8595)

(1) MC. Woodle & D. L&c, Biochim. Biop s.Acro,1113, 171299, (1992) (2) J.H. Cmwe C L.M. Crowe, in Li some P c&nolo Vol I 2 ed., CRC Press, Boa Raton, 229-252 &3). ISBN 0-883-67Oi-7 (3)M.Diim,J.Ha&er &!&hr, Ew~JPharmBiopharm 40(3) 147-156 (1994) (4) R.R.C. New (ed.) in Liposomes - a practical a pro&h, O;ford University Press, pp. 33-104, (1990). ISBN O-19-96307&3

Chitosan is a polycationic poiysaccharide. it has the advantages of being non-toxic, biodegradable, and positively charged. During recent years, it has found increasing kppliiation as a drug carrier. In the present study, chitosan microspheres with entrapped Hz-receptor antagonists (cimetidine and famotidine) have been prepared by a spray drying method. The inlet air spray drying conditions were set up as follows: Chitosan temperature, 150 “C; spray flow rate, 5-15 mllmin. microspheres so prepared have good sphericity, convoluted surfaces, narrow size distribution and are positively charged (20 mv). Particle size was 3-5 pm. An in vitro release study was carried out in a USP-2 dissolution apparatus. Cimetidine was rapidly released from the microspheres. There was a clear ‘burst effect” during the first stage of dissolution. and most of the drug was released in few minutes. This is most likely due to (1) the small size and porous morphology; (2) hydrophillic nature of the polymer and drug (cimetidine) which both have a high affinity with water. When famotidine was used (its solubilii in water is 10 times tower than that of cimetidiie). the release rate was reduced. Differential scanning calorimetry(DSC) was used to evaluate the cimetidine and chitosan materials, blank chitosan microspheres. a cimetidine/chitosan physical mixture and cimetidine-loaded microspheres. The endothermic peak of cimetidine. due to the melting of the drug at 417 K, which was present in the DSC scan for the physical mixture of chitosan and cimetidine, no longer appeared in that for the drug-loaded microspheres. This suggests that the drug has been molecularly dispersed as a solid solution inside the microspheres. The microspheres could be used mucoadhesive delivery such as nasal or gastric muco-delivery.

These

correlations

have been used successfully

for the prediction

of vesicle

characteristics as above under a set of given conditions of micmfluidization. I. Gregoriadis. G., (I 995) Trends m Biok~hno/ogy, 13: 527-537 2. Gregoriadis, G. et al, (I 990) Inr. J Phorm., 65: 235-242

One of the most significant side affects of oral dosage forms is their irritative effect cn stomach mumsa. This problem can be solved intmducing entefic coating. In thtt shrdy. entark microcapsules were prepared for this purpose acccrding to the solvent evaporation technique using a new polymer, CAT. Tenoxicam (TNX). an antinflammatory drug causing irrttation on stomach mucosa upon p.o. administratton in the form of a tabtet or a hard gelatin capsule, was selected as a model drug. There are not any published reports on the prepatatton of entertc mlaocapsules of TNX or any other drug using CAT. Particle size, drug loading capacity, disintegration and dissolution rates in both simulated gastric and intestinal media were determined. plsaolutton studii were performed according to the methods statad in the USP XXlt (paddele and basket methods). Entertc coat+d miaocapwles showed insignificant dlsintegratbn in simulated gaatrtc media. Dissotution rate of enteric m&ocapsules wae compared to that of commercially available hard geMn capsufes and conventbnai tablets of TNX. in simulated inteatinal meua at dIffereM pH values (6.0, 6.4, 6.6 and 7.2) 100 96 of TNX in en&c rndissolved in two hours wMreas TNX i n unntnenMy avatlable conventtonal gelattn capsules and tablets didnot ctissohrsd at all.