Microsoft word - rps_transdermal.doc
TRANSDERMAL FORMULATION OF
Rathore RPS*, Chauhan C S, Naruka P S, Tanwar Y S and Chauhan L S B. N. College of Pharmacy, Udaipur, Rajasthan –313001,INDIA. e-mail : [email protected]
Transdermal matrix type patches of terbutaline sulphate were fabricated using
ethyl cellulose and cellulose acetate polymer. The highest release rate was
observed from CP3 and EP2 patches. Transdermal patches CP3 and EP2 were
found to be physically stable with regard to drug content, tensile strength,
folding endurance, thickness, and weight variation. The drug permeation from
both the patches follows diffusion controlled drug permeation. INTRODUCTION
Terbutaline Sulphate is widely used for the therapeutic management of chronic
as well as prophylaxis of asthma and nocturnal asthma in particular. It is a drug
of choice for the treatment of asthma but it has several drawbacks such as
short biological half-life of about 3.6 hours1, it is readily metabolized in the gut
wall and liver when given orally. It has a short duration of action, low peak
plasma level of 1.2 µg/ml and poor bioavailability of only 14.8%. These factors
necessitated formulation of controlled release transdermal drug delivery system
for terbutaline sulphate, as this route of drug administration would reduce the
dosing frequency hence better patient compliance. MATERIALS AND METHODS
Terbutaline Sulphate was obtained as a gift sample from Gitra Lab., Ahmedabad, Cellulose Acetate and Poly Vinyl Pyrrollidone from OTTO KEMI, Ethyl Cellulose from Ases Chem.Works, Jodhpur and Propylene Glycol from E- Merck India Ltd. Mumbai. All the chemicals and reagents used were of analytical reagent grade.
PREPARATION OF TRANSDERMAL PATCHES
The transdermal patches of terbutaline sulphate were prepared by solvent
casting technique employing a mercury substrate. Two types of polymeric
patches were prepared; cellulose acetate 5% in combination with PVP 5% and
Ethyl cellulose 5% in combination with PVP 5%. The polymeric solution was
prepared by dissolving the cellulose acetate and PVP combination in acetone in
the ratio 1:4, 1:3 and 3:2 respectively using 2% propylene glycol as plasticizer.
Similarly the polymeric solution of ethyl cellulose and PVP combination was prepared by dissolving the combination in alcohol: toluene mixture (1:4) in the ratio 1:4, 1:3 and 3:2 respectively using 2% propylene glycol as plasticizer. Weighed amount of drug was dispersed in each of the polymeric solutions while stirring to ensure the uniform distribution of drug.
A measured volume of each of the polymeric solutions (10 ml) was
poured into Borosil® Petri dish and dried at room temperature. To prevent the
fast evaporation from the patches a funnel was placed inverted on the mould. After ensuring the complete evaporation of the solvent, patches of 2.5 cm diameter were cut with a borer and packed in aluminum foil and stored in desiccators for future study.
EVALUATION OF TRANSDERMAL PATCHES
The physical parameters such as thickness, weight variation, folding endurance,
tensile strength, water vapor transmission2 and drug content were determined.
Patch thickness was measured using digital micrometer screw gauge (Mitutoyo,
Japan) at three different places and the mean value was calculated. The
patches were weighed using a Fisher brand digital balance. Folding endurance
of patches was determined by repeatedly folding a small strip of film (2 cm x 2 cm) at the same place till it broke3. The number of times, the film could be folded at the same place without breaking gave the value of folding endurance. The tensile strength was determined by using a modified pulley system. Weight was gradually increased so as to increase the pulling force till the patch broke. The percentage elongation4 before the patch broke was noted with the help of a
magnifying glass on a graph paper and the tensile strength was calculated as Kg/mm2. Water vapour transmission studies were carried out using pre-weighed glass vials of 5ml containing 1 gm of fused calcium chloride. Polymeric films were fixed on the brim of the vials with a adhesive and stored in a humidity chamber at RH 80C with temperature of 25C for 24 hours and weight gained
was determined. STABILITY STUDY
The prepared patches were subjected to stability study by storing the patches
at different storage conditions. The patches were stored for three months at
different temperatures 40C, 60C, and 80C and at room temperature as well
and at relative humidity of 55%, 65% and 75%. The stability study was conducted with regard to tensile strength, moisture content and drug content. The patches, which retained their physical properties, were further subjected to in-vitro permeation studies.
IN-VITRO DRUG PERMEATION STUDIES
The in-vitro permeation studies were carried out using a modified Keshary-
Chein diffusion cell. A 2.5 cm diameter patch was placed in intimate contact
with the stratum corneum side of the skin; the topside was covered with
aluminum foil as a backing membrane. Teflon bead was placed in the receptor
compartment filled with 75 ml of normal saline solution, the whole assembly
was kept on a magnetic stirrer, at a speed of 100 rpm and the temperature conditions controlled at 37± 2C . The cell contents were stirred with a
magnetic stirrer. Sample of 1 ml was withdrawn at time interval of 1, 2, 3, 4, 5, 6 and 8 hour simultaneously replaced with equal volume of fresh normal saline
solution. The samples were withdrawn and filtered through Whatman filter paper. The absorbance of the solution was measured by UV at 276 nm5.
In the present investigation various polymeric transdermal patches of
terbutaline sulphate were prepared. The effect of permeability enhancer (PVP)
on the permeability of drug from cellulose acetate and ethyl cellulose patches
were studies. The physicochemical characteristics of the patches of terbutaline sulphate in the polymeric matrix were satisfactory with respect to weight variation thickness, folding endurance, water vapour transmission and tensile strength. The polymeric combinations showed good film forming properties the method of casting on mercury substrate was found to give good films. Low SD values were found in the patches, which ensured uniformity of thickness of each
film. Water vapour transmission studies indicated that the films were permeable to water vapour and followed Higuchi kinetics. The diffusion studies reveled that as the concentration of PVP increases the rate of drug diffusion also increases. The stability studies conducted reveled that polymeric patches prepared in the
combination of Cellulose acetate and PVP in the ratio of 3:2 (CP3) and combination of Ethyl cellulose and PVP in the ratio of 2:3 (EP2) with 1% plasticizer were found to be most stable with respect to drug content and all the physical parameters evaluated (Table-1). Hence the patches CP3 and EP2 were considered for further in-vitro permeation studies. Table 1: Physical evaluation of transdermal patches of Terbutailne sulphate.
The in-vitro release data from the most stable patches CP3 and EP2 in terms of
thickness, tensile strength, weight variation, folding endurance and water
transmission, were subjected to zero order and Higuchi model. The kinetic
treatment revealed that the drug release from the patch CP3 followed Higuchi model as the correlation coefficient of linear relation ship between the cumulative percent drug released and the square root of time was found to be 0.9966 and for EP2 it was 0.9943, where as the correlation coefficient of linear
relation for zero order was found to be 0.9803 for CP3 and for EP2 it was 0.9812.Thus the comparison of coefficient of linear relation ship between the zero order and Higuchi model suggests that the drug permeation is controlled by diffusion in both the transdermal patches (Fig1 & Fig.2).
Figure 1: In-Vitro permeation profile (Zero order) of Terbutaline sulphate from CP3 and EP2 patches through human cadaver skin.
Figure 2: In-Vitro permeation profile (Higuchi Model) of Terbutaline sulphate from CP3 and EP2 patches through human cadaver skin. The diffusion coefficient of terbutaline sulphate from CP3 was calculated to be 0.2145 ± 0.25 cm2/h where as for EP2 it was calculated to be 0.1421± 0.28 cm2/h, from figure 2.
The present investigation suggests that the drug release from both the system
follows Higuchi kinetics and the higher rates were achieved from CP3 patch as
compared to EP2 patch. Thus it could be concluded that higher release rates
can be achieved from cellulose acetate patches in combination with PVP where
as the same phenomenon was not observed in case of ethyl cellulose patches.
Higher drug permeability was observed from cellulose acetate patches as
1. Shargel, L. and YuBc, A., In; Applied Biopharmaceutics and
Pharmacokinetics, Appleton and Lang, Stanfoard, 1992, 3rd ed., 595.
2. Murthy, S.N. and Hiremeth, S.R.R., Int.J.Pharm.Excip., 2002,34.
3. Nafee, N., Acta Pharm., 2003, 53, 199. 4. Agarwal, A.K., Seth, A.K. and Saini, T.R., Indian Drugs, 1985, 23(1), 45. 5. Moffat, A.C., Osselton, M.D. and Widdop, B., Clark’s Analysis of Drugs
and Poisons, 200, 3rd ed., Pharmaceutical Press, Chicago, 1607.
Copyright Priory Lodge Education Limited 2006 First Published April 2006 www.priory.com
FOR THE SIX MONTH PERIOD ENDED JUNE 30, 2006 EnerVest Natural Resource Fund Ltd. Statements of Net Assets Proceeds receivable for portfolio assets sold Subscriptions receivable for shares issued Accounts payable and accrued liabilities Approved by the Board of EnerVest Natural Resource Fund Ltd. EnerVest Natural Resource Fund Ltd. Statements of Operations for the Six Month Periods End
Clinica Chimica Acta xxx (2009) xxx–xxxj o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n c h i mAcquired Pelger–Huët anomaly associated with ibuprofen therapyand basophils carry chromatin hypercondensation The secondsuggests that pseudo PHA is not actually an abnormality in neutrophilmaturation but represents an apoptotic cell, since ultrastructurally