Preparation and Evaluation of Transdermal Films of Oxybutynin

¹VASEEHA BANU TS^* and ²SUKHEN SOM

¹Department of Pharmaceutics, M.M.U College of Pharmacy,K. K. Doddi, Dist- Ramanagara- 571511, Karnataka (India)

²Department of Pharmaceutical Chemistry, M.M.U College of Pharmacy, K, K, Doddi, Dist. Ramanagara- 571511, Karnataka (India)

ABSTRACT

Overactive bladder (OAB) is a chronic and distressing medical condition characterized by urinary urgency and frequency with or without urge incontinence that often requires long term treatment to maintain control of symptoms. Oxybutynin is an anticholinergic drug used to treat OAB. The transdermal films of oxybutynin were formulated using solvent casting technique. Solutions containing polymers (HPMC, Ethyl cellulose) at different concentrations (2%, 3% and 4% w/w) were prepared. These solutions were then used to prepare films. Prepared films were then evaluated for various physicochemical properties like physical appearance, weight variation, thickness, drug content, folding endurance percentage elongation and tensile strength including in vitro studies. Between the two polymers used results showed that the formulation HE2 prepared in combination of HPMC: ethyl cellulose (3:1) with 30% propylene glycol was very flexible with highest folding endurance and uniform drug content. Further permeation study for HE2 shows 88.58% release across the rat abdominal skin for 24 hours.

Keywords: Overactive Bladder, Solvent Casting Technique, Oxybutynin

INTRODUCTION

More recent approach to drug delivery is to deliver the drug into systemic circulation at a predetermined rate which is known as controlled drug delivery, such system helps to overcome the side effects associated with conventional systems of medication which require multidose therapy¹. The development of technology which aims to deliver drugs into systemic circulation using skin as a port of entry has becoming increasingly popular for various reasons². Transdermal drug administration generally refers to topical application of agents to healthy intact skin either for localized treatment of tissues underlying the skin or for systemic therapy. For transdermal products the goal of dosage design is to maximize the flux through the skin into systemic circulation and simultaneously minimizes the retention and metabolism of the drug³. Transdermal drug delivery system has become an important means of drug administration. It present numerous advantages like (a) avoidance of variation in the absorption and metabolism associated with oral administration, (b) permits continuous zero order drug administration and the use of the drugs with short biological half lives, (c) increase the bioavailability and efficacy of drugs since hepatic first pass elimination is avoided and finally provides a simple therapeutic regimen leading to good patient compliance. With all the advantages still transdermal drug delivery system is limited by the small number of drugs with a suitable profile⁴.

Overactive bladder (OAB) is a chronic condition that often requires long term treatment to maintain control of symptoms which include frequent urination, an urge to urinate immediately and urinary incontinence^5. Antimuscarinic agents are the most popular treatment for OAB and their efficacy in man is well documented, producing decreased urinary frequency and an increase in bladder capacity⁶. Oxybutynin is anticholinergic agent used to suppress involuntary bladder contractions in urinary incontinence. In clinical practice initial dose of oxybutynin in tablet form is 5mg twice daily

and 2.5 mg twice daily in elderly patients ( average age of 59 years )⁷. It acts by inhibiting binding of acetylcholine to the muscarinic receptors in the detrusor muscle of the bladder. The same type of muscarinic receptors is found in the salivary gland. Thus it may decrease saliva production and cause dry mouth (78% patients) frequently seen with drugs given in tablet form⁸. The transdermal oxybutynin reduces the level of oxybutynin metabolites i.e. N- desethyl – oxybutynin resulting in a low incidence of anticholinergic side effects and provide efficacy ^{9, 10}.

Table-1 Formulation composition of transdermal films Containing HPMC and EC alone containing 3.9 mg of oxybutynin.

Serial number	Formulation code	HPMC	EC	P G
1	H1	2%	-	20%
2	H2	2%	-	30%
3	H3	2%	-	40%
4	H4	3%	-	20%
5	H5	3%	-	30%
6	H6	3%	-	40%
7	H7	4%	-	20%
8	H8	4%	-	30%
9	H9	4%	-	40%
10	E1	-	2%	20%
11	E2	-	2%	30%
12	E3	-	2%	40%
13	E4	-	3%	20%
14	E5	-	3%	30%
15	E6	-	3%	40%
16	E7	-	4%	20%
17	E8	-	4%	30%
18	E9	-	4%	40%

Table-2: Formulation composition of transdermal films with combination of polymers containing 3.9 mg of oxybutynin.

Serial number	Formulation code	HPMC: EC(3:1)	HPMC: EC(2:1)	P G
1	HE1	2%	-	20%
2	HE2	2%	-	30%
3	HE3	2%	-	40%
4	HE4	3%	-	20%
5	HE5	3%	-	30%
6	HE6	3%	-	40%
7	HE7	4%	-	20%
8	HE8	4%	-	30%
9	HE9	4%	-	40%
10	HE10	-	2%	20%
11	HE11	-	2%	30%
12	HE12	-	2%	40%
13	HE13	-	3%	20%
14	HE14	-	3%	30%
15	HE15	-	3%	40%
16	HE16	-	4%	20%
17	HE17	-	4%	30%
18	HE18	-	4%	40%

The purpose of formulating oxybutynin into transdermal film is the suitability of the drug with respect to dose, solubility, molecular weight (393.95) and half life (2-3 hours). Here in this study an effort has been made to prepare the transdermal films of oxybutynin and to evaluate different physicochemical properties associated with it.

MATERIALS AND METHODS:

Oxybutynin was obtained as a gift sample from Jai Radhe sales, Gujarat; Hydroxy propyl methyl cellulose (HPMC) from NR chemicals, Mumbai; Ethyl cellulose (EC) from BPRL- Bangalore; Propylene glycol (PG) from Rankem, New Delhi. All others ingredients used were of analytical grade.

Graph 1:Comparative in vitro release study of the formulations containing 2% polymer with 30% PG

Preparation of transdermal film:

Method used for the preparation of film is solvent casting technique ¹¹. Table 1 and 2 Shows composition of transdermal films of Oxybutynin with HPMC, EC, alone and in combination. Polymer was dissolved in the mixture of alcohol: water (1:1). Drug was separately dissolved in 50% alcohol. Propylene glycol was added to this solution and mixed with help of magnetic stirrer for 30min. Then the solution containing drug and propylene glycol was added to the polymer solution and the resulting solution was stirred for 30min. The prepared solution was casted in petridish and dried at room temperature for 48 hours by covering petridish with inverted funnel, to avoid rapid evaporation of the solvent.

Physicochemical evaluation:

The prepared films were evaluated for physical appearance, weight variation, uniformity of thickness, folding endurance, tensile strength, drug content, water vapour transmission rate (WVTR) and in vitro release studies across the rat abdominal skin.

Weight variation:

Films having an area of 2 cm² each were cut uniformly and weighed in digital balance and result are reported in table-3 and 4.

Thickness of the film:

The thickness of the film was determined by screw gauge at three different position by placing the film in between two glass slides with known thickness and average thickness was calculated and the values are given in table-3 and 4.

Folding endurance: ¹²

The folding endurance was measured manually for the prepared films. A strip of film (2cm²) was cut evenly and repeatedly folded at the same place till it broken. The number of times the film could be folded at the same place without breaking/cracking give the exact value of folding endurance and the results are reported in table-3 and 4.

Tensile strength: ¹³

Tensile strength was measured using modified analytical two-pan balance method. A patch of 20 mm width and 50 mm length was cut from the film prepared and clamped between two clamps on one side. Weights were added to the pan on other side until the patch breaks. The weight required for breaking the patch was taken as a measure of tensile strength of the patch and the results are reported in table-3 and 4.

Table – 3: Physico chemical data of transdermal films of Oxybutynin prepared only with HPMC and EC

Formulation code	Polymer concentration	Plasticizer concentration	Physical appearance	Thickness (mm) n = 5	Weight (mg) n = 5	Drug content (%) n = 3	Tensile Strength Gm/10^2cm n = 5	Percent elongation n = 5	Folding endurance n = 5	WVTR g/cm^2 at 72hrs	Invitro release studies
Films prepared only with HPMC
H1	2%	20%	uniform	0.014 ±0.005	4.816 ±0.46	98.78 ±0.56	40.72 ±0.47	15 ±0.082	164 ±6.8	0.14326	83.56
H2	2%	30%	Uniform	0.019 ±0.006	4.921 ±0.52	97.68 ±0.85	46.26 ±0.23	15 ±0.078	168 ±9.5	0.16253	85.67
H3	2%	40%	Uniform	0.016 ±0.004	4.864 ±0.42	96.23 ±0.56	46.06 ±0.32	16 ±0.065	186 ±9.4	0.16821	85.23
H4	3%	20%	Uniform	0.015 ±0.004	4.984 ±0.31	97.85 ±0.42	41.58 ±0.33	15 ±0.075	188 ±8.4	0.13563	82.12
H5	3%	30%	Uniform	0.018 ±0.002	5.024 ±0.33	97.67 ±0.52	47.88 ±0.28	16 ±0.082	200 ±6.5	0.13854	81.31
H6	3%	40%	Uniform	0.018 ±0.004	5.019 ±0.28	96.83 ±0.53	47.68 ±0.35	16 ±0.069	190 ±7.8	0.13729	80.05
H7	4%	20%	Uniform	0.021 ±0.007	5.116 ±0.41	98.23 ±0.52	43.63 ±0.29	14 ±0.073	175 ±7.8	0.13117	80.26
H8	4%	30%	Uniform	0.024 ±0.008	5.184 ±0.25	96.32 ±0.53	45.06 ±0.31	15 ±0.065	169 ±6.8	0.13408	79.23
H9	4%	40%	Uniform	0.022 ±0.005	5.156 ±0.36	97.54 ±0.52	47.32 ±0.28	15 ±0.069	190 ±6.5	0.13342	79.89
Films prepared only with EC
E1	2%	20%	Uniform	0.017 ±0.004	4.896 ±0.49	97.59 ±0.42	40.23 ±0.26	11 ±0.065	88 ±5.8	0.`3829	66.52
E2	2%	30%	Uniform	0.021 ±0.006	5.008 ±0.58	97.59 ±0.42	43.88 ±0.42	12 ±0.065	98 ±8.6	0.14156	68.39
E3	2%	40%	Uniform	0.019 ±0.004	4.984 ±0.46	96.81 ±0.52	39.99 ±0.48	12 ±0.062	98 ±9.3	0.14532	67.91
E4	3%	20%	Uniform	0.018 ±0.007	5.071 ±0.39	97.88 ±0.42	39.76 ±0.42	13 ±0.069	77 ±8.4	0.13112	64.02
E5	3%	30%	Uniform	0.022 ±0.005	5.184 ±0.36	97.35 ±0.48	42.26 ±0.62	12 ±0.058	79 ±4.5	0.13245	64.56
E6	3%	40%	Uniform	0.020 ±0.006	5.135 ±0.51	98.81 ±0.68	40.01 ±0.37	13 ±0.067	71 ±9.2	0.13136	63.15
E7	4%	20%	Uniform	0.028 ±0.007	5.289 ±0.29	97.34 ±0.72	39.62 ±0.42	12 ±0.059	69 ±6.9	0.12632	59.72
E8	4%	30%	Uniform	0.029 ±0.004	5.407 ±0.37	96.36 ±0.42	41.80 ±0.48	12 ±0.062	66 ±7.2	0.12858	58.81
E9	4%	40%	Uniform	0.028 ±0.005	5.304 ±0.41	96.82 ±0.52	39.82 ±0.52	13 ±0.055	64 ±5.8	0.12969	56.93

Values expressed in mean ±SD, n = number of samples used

Percentage elongation:

Percentage elongation was calculated by measuring the increase in length of the film after tensile strength measurement by using the following formula.

Percentage elongation = (L_F- L_O) X 100 / L_O. Where L_F = final length, L_O= initial length.

Water vapour transmission studies:^{12, 13}

For this study vials of equal diameter were used as transmission cells. These cells were washed and dried in an oven. About one gram of fused calcium chloride was taken in the cell and the polymeric patches were fixed over the brim with the help of an adhesive. Then the cells were weighed accurately and kept in a closed dessicator containing saturated solution of potassium chloride (200ml). The humidity inside the dessicator was measured by a Hygrometer and it was found to be 80-90% relative humidity. The cells were taken out and weighed after 2, 8, 12, 24, 48 and 72 h. From the increase in weights, the amount of water vapor transmitted and rate of water transmitted was calculated using the formula, Water Vapor Transmission Rate = W L /S. where W = Gm of water transmitted, L = Thickness of the patch and S = Exposed surface area of the patch.

Drug content:¹²

A film of size 2cm² was cut into small pieces and put in a 100ml buffer (pH 7.4). This was then shaken in a mechanical shaker for 2 hrs to get a homogenous solution and filtered. Then sample solutions from this was prepared by diluting to different concentrations and determined spectroscopically at 344 nm ¹⁴. The determinations were carried out in triplicates and the average of three readings were recorded and reported in table 3 and 4.

In vitro release studies across the rat skin:^{11, 15}

Permeation studies of the transdermal film were carried out using rat abdominal skin. The Franz diffusion cell assembly having 100 ml capacity in receptor chamber was used. The skin was washed with plenty of water and trimmed in to circular section of about 3 cm diameter. The patch was then placed over the skin facing the stratum corneum side and mounted with cap of the diffusion cell and clamped securely on to the receptor compartment with dermis side of the skin facing the receptor solution containing 100 ml pH 7.4 phosphate buffer solution. The area of the film exposed for release was 2 cm².

Table – 4: Physico chemical data of transdermal films of oxybutinin prepared in combination of HPMC and EC

Formulation code	Polymer Concentration	Plasticizer concentration	Physical appearance	Thickness (mm) n = 5	Weight (mg) n = 5	Drug content (%)n = 3	Tensile Strength Gm/10^2cm n = 5	Percent elongation n = 5	Folding endurance n = 5	WVTR g/cm^2 at 72hrs	Invitro release (%)
HPMC: ETHYL CELLULOSE = 3:1
HE1	2%	20%	uniform	0.016 ±0.006	4.957 ±0.52	97.25 ±0.72	36.48 ±0.52	11 ±0.072	142 ±7.5	0.14512	85.32
HE2	2%	30%	Uniform	0.018 ±0.007	5.102 ±0.48	99.35 ±0.56	38.65 ±0.52	14 ±0.062	145 ±8.2	0.15012	88.58
HE3	2%	40%	Uniform	0.020 ±0.006	5.110 ±0.32	98.45 ±0.62	38.72 ±0.56	12 ±0.058	144 ±9.5	0.15234	85.45
HE4	3%	20%	Uniform	0.021 ±0.005	5.123 ±0.56	98.68 ±0.65	40.23 ±0.65	11 ±0.057	142 ±6.2	0.12834	82.32
HE5	3%	30%	Uniform	0.023 ±0.008	5.128 ±0.52	97.34 ±0.65	43.19 ±0.48	13 ±0.042	143 ±5.8	0.12945	81.45
HE6	3%	40%	Uniform	0.023 ±0.008	5.128 ±0.47	98.84 0.58±	43.22 ±	11 ±0.038	140 ±6.2	0.12902	78.68
HE7	4%	20%	Uniform	0.026 ±0.005	5.141 ±0.38	98.73 ±0.74	44.98 ±0.54	11 ±0.085	135 ±9.2	0.12625	81.45
HE8	4%	30%	Uniform	0.029 ±0.007	5.156 ±0.45	99.02 ±0.72	45.12 ±0.56	12 ±0.075	132 ±8.2	0.12812	80.58
HE9	4%	40%	Uniform	0.030 ±0.006	5.158 ±0.72	97.32 ±0.56	45.16 ±0.61	12 ±0.065	130 ±10.8	0.12845	80.32
HPMC: ETHYL CELLULOSE = 2:1
HE10	2%	20%	Uniform	0.018 ±0.005	5.202 ±0.81	96.23 ±0.72	35.56 ±0.52	10 ±0.074	70 ±13.4	0.13714	79.21
HE11	2%	30%	Uniform	0.021 ±0.004	5.224 ±0.58	97.45 ±0.65	37.62 ±0.58	12 ±0.071	75 ±14.2	0.13821	81.21
HE12	2%	40%	Uniform	0.022 ±0.008	5.228 ±0.62	97.32 ±0.62	37.69 ±0.59	12 ±0.078	73 ±11.5	0.13852	78.45
HE13	3%	20%	Uniform	0.024 ±0.006	5.408 ±0.71	98.45 ±0.72	39.98 ±0.49	13 ±0.085	62 ±10.2	0.12932	79.45
HE14	3%	30%	Uniform	0.026 ±0.004	5.450 ±0.74	96.87 ±0.68	42.82 ±0.47	12 ±0.075	68 ±8.6	0.12641	80.16
HE15	3%	40%	Uniform	0.027 ±0.007	5.461 ±0.56	97.32 ±0.58	41.34 ±0.48	11 ±0.069	68 ±7.8	0.11984	78.32
HE16	4%	20%	Uniform	0.033 ±0.008	5.480 ±0.65	98.18 ±0.56	43.59 ±0.52	12 ±0.052	59 ±8.7	0.11832	79.01
HE17	4%	30%	Uniform	0.036 ±0.005	5.501 ±0.52	98.68 ±0.63	44.94 ±0.56	12 ±0.069	59 ±10.2	0.11645	76.45
HE18	4%	40%	Uniform	0.037 ±0.006	5.508 ±0.48	98.72 ±0.72	44.96 ±0.78	12 ±0.068	54 ±8.2	0.11652	78.58

Values expressed in mean ± SD, n = number of samples used

The receptor solution was constantly stirred over magnetic stirrer maintaining temperature at 37⁰ ± 1⁰C. At hourly Intervals, 1ml of the sample was withdrawn and replaced immediately with fresh media. Amount of drug in the withdrawn samples was determined spectrophotometrically at 344 nm and reported in table 3 and 4.

RESULTS AND DISCUSSION:

Prepared films were thin, flexible, smooth and transparent. The method used to prepare film (solvent casting technique) on the petridish was found to be satisfactory. The physicochemical evaluation data for the films (table 3 and 4) reveals that there were no physical changes like appreance, colour and flexibility when the films stored at room temperature.

The thickness found to be least for the films prepared with 2% w/v polymers alone and in combination with 20% plasticizer (table 3 and 4). Same observation was attributed for weights and tensile strength of the films prepared. The drug content for all the formulations varied in the range of 96.23% to 98.78%. In case of folding endurance the formulations prepared only with HPMC that is H1 to H9 (irrespective of the percentage of HPMC used) shown more values than formulation prepared with EC (E1 to E9). In some cases it shows increase by about 2 to 3 fold (table 3 and 4). The reason may be due to the fact that elasticity of HPMC is more than EC. This observation is again supported by the tensile strength and percent elongation measured for formulations containing HPMC and EC.

The water vapour transmission (WVT) pattern was found to be in the order of HPMC > EC > HPMC: EC – 3: 1 > HPMC: EC- 2: 1. Further investigation revealed that at 30% and 40% concentration of plasticizer (PG) the W V T rate was maximum in case of combination of polymers as well as when they were singly used (table 3 and 4).

In vitro release study shows that HPMC at the concentration of 2% with 30% PG as plasticizer gives maximum release. Where as HPMC 2% with 40% PG has not shown much difference. In this regard likewise EC 2% with 30% PG showed maximum in vitro release when compared among all the percentage of polymers used with different concentration of plasticizers. When used in combination, the 3:1 ratio of polymers at 2% concentration with 30% PG showed maximum in vitro release up to 88.58%. From this study it is evident that 2% polymer alone or in combination with 30% plasticizer had shown to have maximum in vitro release irrespective of any other films prepared in any percentage of polymers and plarticizers. Thus it may be stated that 2% w/v polymer with 30% PG seems to be the optimum ratio to prepare transdermal films of oxybutynin for maximum in vitro release.

CONCLUSION:

Oxybutynin holds good promise for administration via transdermal route for the treatment of OAB. The various parameters that were evaluated helps to understand the suitability and usefulness of oxybutynin to be formulated as a transdermal film with different concentration of polymers. Based on its physical appreance, folding endurance, thickness, weight variation, tensile strength, uniform drug content and good release pattern 2% polymer concentration with 30% PG as plasticizer in each type of polymer used was found to be best. As the polymer concentration increases to 3% and 4% the drug release was found to be decreased. HPMC: EC (3:1) films gave satisfactory release rate. Other polymers can also be tried to formulate the transdermal film of oxybutynin.

Thus in this perspective it can be concluded that oxybutynin, in the form of transdermal film, which is characterized by low incidence of anticholinergic side effects that is dryness of mouth, observed when served in tablet form, can be used as an efficient drug delivery tool for treating OAB for long term therapy.

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Received on 23.06.2009

Accepted on 25.08.2009

© A & V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 1(2): Sept.-Oct. 2009, 130-134