Permeability studies of cellulose acetate free films for transdermal use: Influence of plasticizers

PHARMACEUTICA ACTA HEIJETIAE ELSEVIER

Pharmaceutics Acta Helvetiae 72 (1997) 47-51

Permeability

studies of cellulose acetate free films for transdermal use: Influence of plasticizers P. Rama Rao, Prakash V. Diwan

*

Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India

Received 7 February

1996; revised 29 May 1996; accepted

16 June 1996

Abstract Permeability of cellulose acetate (CA) free films casted from chloroform solution containing different plasticizers were studied with a view to developing a suitable rate controlling membrane for transdermal use. Dibutyl phthalate (DBP), polyethylene glycol 600 (PEG 600) and propylene glycol (PG) were used as plasticizers at a concentration of 40% w/w of dry polymer weight. The free films were prepared by mercury substrate method and evaluated for uniformity of thickness, tensile strength and percentage elongation and water vapour transmission. Permeability characteristics of free films were studied using the drugs such as diltiazem hydrochloride (DLT) and indomethacin (Ind). The variation in film thickness was less than 2% which ensured uniformity. Tensile strength of films plasticized with DBP is more compared with other plasticized films. Water vapour transmission and drug diffusion through the free films followed zero order kinetics and decreased with increasing the film thickness. The films plasticized with PEG600 showed higher permeability for both drugs compared with other films. The order of decrease of permeability of plasticized films with plasticizers is PEG600 > PG > DBP. Diffusion of drugs through the free films of CA was extended over a longer period of time at a controlled rate and thus, these can be used as rate controlling membranes for the development of a transdermal drug delivery system. Keywords: Cellulose systems

acetate free films; Transdermal

use; Plasticizers;

Diltiazem hydrochloride;

1. Introduction Formulation of cellulose polymer films which are used as rate controlling membranes for transdermal drug delivery system requires plasticizers. The plasticizer will interpose itself between the polymer chains and interact with the forces held together by extending and softening the polymer matrix (Entwistle and Rowe, 1979). These are incorporated into the films for various reasons such as to reduce brittleness, impart flexibility, increase strength and also to improve adhesiveness of the film with other surfaces or membranes. The commonly used plasticizers in the formulation of films include phthalate esters, phosphate

* Corresponding 673387/673757.

author. Tel.: +91-40-673874

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Indomethacin;

Permeability

characteristics;

Drug delivery

esters, fatty acid esters and glycol derivatives (Spitael and Kinget, 1977; Entwistle and Rowe, 1979). The selection of a suitable plasticizer and its concentration has a profound influence on the mechanical properties as well as on the permeability of drugs (Crawford and Esmerian, 1971). In the present study, plasticized free films of cellulose acetate were prepared and evaluated for various parameters like

uniformity

of thickness,

elongation and water vapour include dibutyl phthalate,

tensile

strength,

percentage

transmission. Plasticizers propylene glycol and

used poly-

glycol 600. All the plasticizers were incorporated at a concentration of 40% w/w of dry polymer weight. Further, plasticized films were subjected to permeability studies, using diltiazem hydrochloride and indomethacin, in order to study the influence of the above mentioned plasticizers on the permeability of films. ethylene

0 1997 Elsevier Science B.V. All rights reserved.

P. Rama Rao, P.V. Diwan /Pharmaceutics

48

2. Materials

Acta Helwtiae

72 (1997) 47-51

2.5. Determination

and methods

2.1. Materials Cellulose acetate (having acetic acid content of 53.5 to 56.0%, Loba Chemie) was used as the film former, dibutyl phthalate (Ranbaxy), polyethylene glycol 600 (S.d. Fine Chem.) and propylene glycol (Loba Chemie) were used as plasticizers, diltiazem hydrochloride (kind gift from M/s Torrent Pharmaceuticals, Ahmedabad) and indomethacin (kind gift from M/s Invinex, Hyderabad) as model drugs, chloroform (HPLC grade, Qualigens, Glaxo India) as solvent and mercury (E. Merck) was also used. The above mentioned chemicals were obtained from Indian firms. 2.2. Methods 2.2.1. Preparation of free jilms Free films of cellulose acetate were prepared employing the method of casting on mercury surface (Munden et al., 1964). A 2% w/w polymer solution was prepared using chloroform as solvent. Plasticizers were incorporated at a concentration of 40% w/w of dry polymer weight. Five ml of polymer solution was poured in a glass ring which was placed over the mercury surface in a glass petri dish. The rate of evaporation of the solvent was controlled by placing an inverted funnel over the petri dish. The film formation was noted by observing the mercury surface after complete evaporation of the solvent. The dry film was isolated and stored between the sheets of wax paper in a desiccator until use. Free films of different thicknesses were prepared by changing the volume of the polymer solution. The free films were evaluated for uniformity of thickness, tensile strength and percentage elongation, water vapour transmission, drug diffusion and permeability characteristics.

of water uapour transmission

The method of Munden et al. (1964) was adopted for the determination of water vapour transmission through free films. The film under investigation was cut using a circular glass template, its thickness was measured at five different places using the micrometer and the mean thickness of the film was calculated. The cut film was fixed over the brim of a glass vial (exposed surface area of 2.27 cm*>, containing 3 g of fused calcium chloride as desiccant, with an adhesive. The charged vial was kept in a desiccator for about 2 h to attain the equilibrium condition and vial was removed after 2 h, weighed and kept in desiccator containing either saturated solution of potassium chloride or sodium hydrogen sulfate monohydrate to provide the relative humidity of 84% and 52%, respectively. The relative humidity inside the desiccator was measured using a Barigo hygrometer (Germany). The whole assembly was kept on a flat surface without any disturbance. The vial was taken out and weighed at regular time intervals for a period of 72 h. The experiment was triplicated and average values were calculated. The water vapour transmission rate was calculated from the plots of amount of water vapour transmitted versus time. The WVT rate was calculated using the equation of Crawford and Esmerian (1971): rate = WL/S where W is g of water/24 h, L is thickness of the film in cm, S is exposed surface area of the film. The typical plots from which these values were calculated for various films at different relative humidities and with different thicknesses are shown in Fig. 1 and the respective values are depicted in Table 1. 2.6. Drug diffusion and permeability

studies

Diffusion of drugs such as diltiazem hydrocholoride and indomethacin through the free films was studied using

2.3. Film thickness The thickness of the free films was measured by a micrometer (Mitotoyo, Japan) at five different places on the film. The average of the five values was calculated. 2.4. Tensile strength and percentage

elongation

The tensile strength and percentage elongation measurements were made according to A.S.T.M. standards, using an INSTRON 1026, (Type 2512-119, Model M.A. 30-1014, England) instrument. The calculated values are given in Table 1.

Fig. I. Water vapour transmission profiles of various plasticized films at 84% (0, A, n ) and 52% (0, A, 0). Key: CA-DBP ((0) 46.8 qn; (I3 ) 46.5 pm); CA-PC (( A ) 3 1.4 pm; (0) 3 1.6pm); CA-PEG600 (( n ) 7Y.S pm; (A ) 46.4 pm).

P. Rama Rao, P.V. Diwan/Pharmaceutica Table 1 Mechanical

properties . .

Plasticizer

DBP PG PEG600

and WVT rates of cellulose

Acta Helvetiae 72 (1997) 47-51

49

acetate free films

Tensile strength (dyn/cm*)

Percent elongation

2.85 x 10’ 2.23 x lo* 2.03 x 10’

23.3 38.6 45.5

Keshary-Chein diffusion cell (Kakuji Tojo, 1987) designed and fabricated in our laboratory. The cell consists of two compartments, namely donor and receptor, each has a volume of 25 ml capacity. Phosphate buffer of pH 7.4 was used as receptor fluid. The polymer film was sandwiched between the two compartments. 10 ml of drug solution (2% w/v> was poured into the donor compartment. The receptor fluid was agitated using a magnetic stirrer and a temperature of 37 k 1°C was maintained. Periodical samples (1 ml) were collected through the sampling port over a period of 6-10 h and drug content was assayed spectrophotometrically, at 236 nm and 318 nm, for diltiazem hydrochloride (Mazzo et al., 1994) and indomethacin (O’Brien et al., 1984) respectively. After each sampling an equal volume of drug free phosphate buffer solution was added to maintain the constant volume of the receptor fluid. The amount of drug diffused at various time intervals was calculated, with necessary corrections for the loss of drug due to sampling, and plotted against time (Figs. 2 and 3). F rom the drug diffusion data, the permeability coefficient (P) for various films was calculated using the equation below (Chowdary and Naidu, 1992) and values are given in Table 2: p=- KWH A

Water vapour transmission

rate (g cm/cm*.

at 84% R.H.

at 52% R.H.

2.06~ 10m4 4.50x 1om4 1.19x 1om3

1.84X 1O-4 3.13x 1om4 6.13~ 1O-4

24 h)

where KaPP is diffusion rate obtained from the slope of the linear drug diffusion profiles, H is the thickness of the film in cm and A is the surface area of the film in cm’.

3. Results and discussion The plasticized films with DBP and PEG 600 did not differ significantly from unplasticized films with regard to transparency. However, films with PG were slightly opaque. Plasticized films with 40% w/w of plasticizer to the dry polymer weight were flexible than the unplasticized films and easily removed from the mercury surface without any rupture. Low and high concentration of plasticizer yielded brittle and soft films, respectively. The uniformity of film was ensured as the variation was only 2% during the measurements. Films of various thicknesses were obtained by changing the volume of the polymer solution. It is clear from Table 1 that the films plasticized with DBP have high tensile strength and low percentage elongation compared to other films. The tensile strength of the plasticized films decreased in the following order DBP > PEG 600 > PG; whereas, percentage elongation was in the order of PEG 600 > PG > DBP. The above results indicate that the films plasticized with DBP were tough compared with those plasticized with either PEG 600 or PG.

I

10

Fig. 2. Diffusion profiles of diltiazem hydrochloride through CA films: Influence of plasticizer and films thickness. Key: CA-DBP ((0) 28.2 pm; (0) 41.9 pm); CA-PG ((0) 31.3 wrn; (m) 50.0 pm); CA-PEG600 ((A) 45.8 pm; (A) 55.2 wm).

Fig. 3. Diffusion profiles of indomethacin through CA films: Influence of plasticizer and film thickness. Key: CA-DBP ((0) 42.2 pm; (0) 52.1 pm); CA-PG ((0) 35.6 Frn; (H) 49.3 pm); CA-PEG600 ((A) 93.9 pm; (A ) 49.0 Km).

P. Rama Rao, P.V. Diwan/

50 Table 2 Drug diffusion

and permeability

Drug Diltiazem hydrochloride

characterisitics

Dibutyl phthalate

Propylene

Indomethacin

of CA films: Influence

Plasticizer

Polyethylene

glycol 600

glycol

Dibutyl phthalate Polyethylene Propylene

Pharmaceutics

glycol 600

glycol

Acta Heluetiae 72 (1997) 47-51

of plasticizer

and film thickness (g/h)

28.2 * 0.57 41.9+0.42 45.8 i 1.09 55.2 f I .04 31.3io.57 50.0 f 1.22

0.182 0.125 0.288 0.266 0.281 0.188

9.78 x 1om8

42.2 52.1 93.9 49.0 35.6 49.3

0.092 0.075 0.094 0.175 0.175 0.138

7.35 x 1om8

All the films were permeable to water vapour and followed the zero order kinetics. The WVT rate was more in the case of films plasticized with PEG600 compared to other films (Table 1). Further, it is clear from Table 1 that the WVT rate increased as the relative humidity increased from 52 to 84%, which indicates the dependency of WVT on relative humidity as reported in the literature by Lachman and Drubulis (1964) and Sprockel et al. (1990). It was also observed that the WVT rate was decreased with increasing film thickness in all cases. The WVT of the films with different plasticizers was decreased in the following order PEG 600 > PG > DBP. Diffusion studies of the films with respect to diltiazem hydrochloride and indomethacin indicated that these were permeable to drugs and drug diffusion followed zero order kinetics. The diffusion rate of both drugs increased with decreasing film thickness in all the cases. The permeability coefficient of both drugs (Table 2) from plasticized films decreased in the following order of PEG 600 > PG > DBP. The higher permeability coefficients of both drugs in case of films plasticized with PEG 600 might be due to leaching out of PEG fraction from the films, which might have lead to the formation of small pores and hence high permeability.

4. Conclusions We achieved thin and uniform films by the mercury substrate method. The plasticizers used at a concentration of 40% w/w resulted in smooth and flexible films. Films plasticized with DBP yielded tough films compared with other plasticized films. All the plasticized films were permeable to water vapour, diltiazem hydrochloride and indo-

+ f f f i f

0.84 1.02 0.96 1.58 0.89 0.97

Diffusion rate

Average permeability coefficient

Film thickness ( pm) mean F s.d.

X IO3

2.63 X IOY’ 1.72X IO-’

1.64~ lo-’ 1.23~ 1O-7

methacin. Both WVT and drug diffusion through the films followed zero order kinetics. WVT was dependent on film thickness, relative humidity and plasticizer used. As the film thickness increased the WVT was decreased, However, it was increased with increasing relative humidity from 52% to 84%. Films plasticized with PEG 600 showed the highest WVT rate. Drug diffusion studies revealed that the rate of diffusion of drug through the film was dependent on film thickness and plasticizers used. The rate of diffusion was increased with decrease in film thickness. The permeability coefficient values for both drugs were high in case of films plasticized with PEG 600 and low in case of films plasticized with DBP. It was concluded from this study that the plasticizers have a significant influence on the mechanical properties of the films and also on the permeability to water vapour and drugs. The diffusion of the drugs through these films followed zero order kinetics and drug diffusion was extended over a longer period of time at a controlled rate. Hence, these films may be used as rate controlling membranes for the development of a transdermal drug delivery systems. The study is in progress with respect to the skin permeation studies in vitro and in vivo in animal models.

Acknowledgements One of the authors (P.R.R.) is thankful to the CSIR, New Delhi, India for the award of Senior Research Fellowship. The authors are grateful to Dr. Kaiser Jameel, Head, Biology Group, IICT, Hyderabad for her constant encouragement.

P. Rama Rao, P.V. Diwan / Pharmaceutics Acta Heluetiae 72 (19971 47-51

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vapour transmission of cellulose acetate phthalate films. J. Pharm. Sci. 53, 639-643. O’Brien, Mathew et al. (1984) Indomethacin. In: K. Florey (Ed.), Analytical Profiles of Drug Substances, Vol. 13. Academic Press, INC, California, pp. 21 l-238. Mazzo, D.J. et al. (1994) Diltiazem hydrochloride. In: K. Florey (Ed.), Analytical Profiles of Drug Substances and Excipients, Vol. 23. Academic Press, INC, California, pp. 53-98. Munden, B.J. et al. (1964) Evaluation of polymeric materials I. Screening of film coating agents. J. Pharm. Sci. 53, 395-401. Spitael, J. and Kinget, R. (1977) Preparation and evaluation of free films: Influence of plasticizers and filler upon the permeability. Pharm. Acta Helv. 52, 106-108. Sprockel, O.L. et al. (1990) Permeability of cellulose polymers: Water vapour transmission rates. J. Pharm. Pharmacol. 42, 152-157.