1. INTRODUCTION:

Transdermal delivery of drugs is a novel drug delivery system and this system breaks many barriers in drug therapy like need of assistance, intermediate dosing and uncomfortable administration. Transdermal delivery has many advantages over conventional modes of drug administration, it avoids hepatic first pass metabolism, potentially decreases side effects and improves patient compliance.

Transdermal therapeutics systems are defined as self-contained discrete dosage forms when applied to the intact skin, deliver the drugs through the skin, at controlled rate to the systemic circulation.

The advantages of delivering drugs across the skin for systemic therapy are well documented. Some of the main advantages of a transdermal drug delivery system are:

· Self-administration is possible with these systems.

· The drug input can be terminated at any point of time by removing transdermal patch.

· Longer duration of action resulting in a reduction in dosing frequency.

· Improved bioavailability.

· Improved patient compliance and comfort via non-invasive, painless and simple application.

Properties that influence Transdermal Delivery:

· Release of the medicament from the vehicle.

· Penetration through the skin barrier.

· Activation of the pharmacological response.

Kinetics of Transdermal Permeation: Knowledge of skin permeation kinetics is vital to the successful development of transdermal therapeutic systems. Transdermal permeation of a drug involves the following steps:

· Sorption by stratum corneum.

· Penetration of drug through epidermis.

· Uptake of the drug by the capillary network in the dermal papillary layer.

Selegiline is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B), increasing levels of dopamine in the brain. Administration of transdermal selegiline bypasses hepatic first pass metabolism. This avoids an inhibition of gastrointestinal and hepatic MAO-A activity resulting in an increase in blood of food-borne tyramine and possible adverse effects, while sufficient amount of selegiline reach the brain for an antidepressant effect.

In this, nine different formulations were formulated using different concentration of polymer and permeation enhancers by solvent casting technique. The transdermal patches were evaluated for their physicochemical characteristics such as thickness, weight variation, tensile strength, folding endurance, content uniformity, permeability characteristics and stability studies.

2. MATERIALS AND METHODS:

2.1. Materials:

Selegiline was received as a gift sample from Torrent Pharmaceutical Ltd., Gujarat, India. HPMC 100M, HPMC 15 MCR, and HPMC 4 CM were purchased from Yarrow Chem, Mumbai, India. Polyethylene glycol 400 and propylene glycol were obtained from Merck Specialities Private Ltd. (Mumbai) and Chemdyes Corporation (Ahmedabad, Gujarat) respectively. Cellulose acetate membrane was obtained from Sartorius Biotech GmbH (Germany). All other materials and chemicals used were of either pharmaceutical or analytical grade.

2.2. Methods:

2.2.1. Preparation of Transdermal Patch¹⁰:

Drug-loaded matrix-type transdermal patches of Selegiline were prepared by using solvent casting method. A petri dish with a total area of 44.15 cm2 was used. Polymers were accurately weighed and dissolved in 10mL of water, methanol (1: 1) solution and kept aside to form clear solution. Drug was dissolved in the above solution and mixed until clear solution was obtained. Polyethylene glycol 400 (30% w/w of total polymer) was used as plasticizer and propylene glycol (15% w/w of total polymer) was used as permeation enhancer. The resulted uniform solution was cast on the petri dish, which was lubricated with glycerin and dried at room temperature for 24 h. An inverted funnel was placed over the petri dish to prevent fast evaporation of the solvent. After 24 h, the dried patches were taken out and stored in a desiccator for further studies.

Table 1: Composition of formulated transdermal patches of Selegiline Hcl

Formulation code	HPMC grade	Conc. of HPMC (%)	PG
F1	100 M	0.5	5
F2	100 M	1	5
F3	100 M	1.5	5
F4	15 M CR	0.5	5
F5	15 M CR	1	5
F6	15 M CR	1.5	5
F7	4 CM	0.5	5
F8	4 CM	1	5
F9	4 CM	1.5	5

2.2.2 Evaluation Parameters of Transdermal Patch:

Physical Appearance and Surface Texture

Physical appearance and surface texture evaluation includes visual inspection and evaluation of texture by feel or touch.

Weight Variation:

Ten patches of 1cm² were weighed individually and average of those patches was measured.

Thickness¹¹

The thickness of the patch was measured using screw gauge with a least count of 0.01mm at different spots of the patches. The thickness was measured at five different spots of the patch and average was taken.

Flatness study:

Flatness study was conducted to appraise that the prepared transdermal patches possess a smooth surface and shall not constrict with time. Three longitudinal strips were cut from the film at three different portions. The length of each strip was measured and the variation in length because of non-uniformity in flatness by determining percent constriction, with 0% constriction equivalent to 100% flatness. Percent constriction was obtained as (l₁ − l₂)/l₁ × 100. Here, l₁ is the initial length of each strip, and l₂ is the final length of each strip.

Folding Endurance ¹¹

A strip of specific area (2 cm×2 cm) was cut evenly and repeatedly folded at the same place till it broke. The number of times the film was folded at the same place without breaking gave the value of the folding endurance.

Surface pH:

Patches were left to swell for 1 hour on the surface of the agar plate, the agar plate was prepared by dissolving 2% (w/v) agar in warmed isotonic phosphate buffer of pH 6.6 under stirring and the solution was poured into the petridish, it was allowed to stand until it solidified to form a gel at room temperature. The surface pH was measured by means of pH paper placed on the surface of the swollen patch.

Tensile Strength¹⁰:

The tensile strength of buccal patch refers to tension or force required to tear of the patch apart into two pieces. The instrument used to measure the tensile strength designed in our laboratory especially for this project work. The instrument is a modification of chemical balance. One pan of the balance was replaced with one metallic plate having a hook for attaching the film. The equilibrium of the balance was adjusted by adding weight to the right pan of balance. The instrument was modified in such a way that the patch can be fixed up between two hooks of horizontal beams to hold the test film. A film of 2.5cm length was attached to one side hook of the balance and the other side hook was attached to plate fixed up to the pan. The weights are added to the other side pan of the balance. Thus, tensile strength,

T = M x g Dynes/cm²

B x t

T= force at break/ initial cross-sectional area of sample.

Where,

m = mass in grams

g = acceleration due to gravity 980 cm/sec²

b = breadth of the specimen in cm

t = thickness of sample in cm.

Percentage Elongation Break Test ¹²

The percent elongation at break is defined as the elongation at the moment of rupture of the specimen divided by the initial gauge length of the specimen and multiplying by 100.

LB – L0

Percent elongation at break = -------------------- ×100

LB = length of the specimen in cm when it breaks.

L0 = original length of the specimen in cm.

The instrument and procedure is similar to that used for tensile strength.

Drug Content^9,14

A specified area of patch (2cm×2cm) was dissolved in 100ml methanol and shaken continuously for 24 h. Then the whole solution was ultrasonicated for 15 min. After filtration, the drug was estimated spectrophotometrically at wavelength of 281nm and determined the drug content.

Percentage Moisture Content¹¹

The prepared films were weighed individually and kept in a desiccator containing anhydrous calcium chloride at room temperature for 24 h. After 24 h, the films were reweighed and determined the percentage moisture content from the below mentioned formula:

(Initial weight−Final weight) X100

Percentage moisture content = Final weight

Percentage Moisture Uptake ¹¹:

The weighed films were kept in a desiccator at room temperature for 24 h containing saturated solution of potassium chloride in order to maintain 84% RH. After 24 h, the films were reweighed and determine the percentage moisture uptake from the below mentioned formula:

(Final weight−Initial weight)

Percentage moisture uptake = -------------------------×100.

Initial weight

In vitro Drug Release Studies⁹:

In Vitro drug release studies were performed by using a Franz diffusion cell with a receptor compartment capacity of 60ml. The cellulose acetate membrane was used for the determination of drug from the prepared transdermal matrix-type patches. The cellulose acetate membrane having a pore size 0.45μ was mounted between the donor and receptor compartment of the diffusion cell. The prepared transdermal film was placed on the cellulose acetate membrane and covered with aluminum foil. The receptor compartment of the diffusion cell was filled with phosphate buffer pH 7.4. The whole assembly was fixed on a hot plate magnetic stirrer, and the solution in the receptor compartment was constantly and continuously stirred using magnetic beads, and the temperature was maintained at 32±0.5°C, because the normal skin temperature of human is 32°C. The samples were withdrawn at different time intervals and analyzed for drug content spectrophotometrically. The receptor phase was replenished with an equal volume of phosphate buffer at each sample withdrawal.

Stability studies:

Stability studies are to be conducted according to the ICH guidelines by storing the TDDS samples at 40±0.5°C and 75±5% RH for 6 months. The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyze suitably for the drug content.

3. RESULTS AND DISCUSSION:

Physicochemical characterization of selegiline hydrochloride The melting point of selegiline hydrochloride was found to be in the range of 138 to 142 °C (melting point literature 141 to 142°C) (http://www.drugbank.ca/drugs/DB01037)

Evaluation of transdermal patches:

The prepared transdermal patches were evaluated to study the effect of different grades of HPMC polymer (with varied concentration) and the presence of PEG 400 as plasticizer on the release kinetics of drug and on the physical characteristics of the film. These were evaluated for their physical appearance, weight uniformity, thickness uniformity, surface pH, moisture content, moisture uptake, folding endurance, tensile strength, elongation break test, drug content uniformity and in vitro drug release.

Physical parameters:

All the films were evaluated for their physical parameters (weight, thickness, folding endurance, diameter, area, flatness and surface pH), and they were found to be flexible, uniform, smooth, and transparent (Table 2). The weight of the prepared transdermal patches for different type of formulations ranged between 169.11mg and 235.60mg. The thickness of the patches varied from 0.08mm to 0.21mm.

Folding endurance values varied between 301.1 and 308.9. The folding endurance number gives the mechanical property of the patches; high folding endurance number indicate that the patches have high mechanical property.

The flatness study showed that all the formulations had the same strip length before and after their cuts, indicating 100% flatness. Thus, no amount of constriction was observed which indicated that all patches had smooth flat surface which would be maintained when the patches are applied to the skin.

The surface pH of all the films exhibited uniformity in their values and they were found to be 6 which shows neutral pH. So it will not cause any kind of irritation to the skin.

Moisture content and moisture absorption studies:

The moisture content in the patches ranged from 3.01 to 4.26%. The moisture content in the formulations was found to be increased by increase in concentration of polymer. Low moisture content in the formulations helps them to remain stable from being a completely dried and brittle film.

The prepared patches showed minimal moisture absorption rates ranging from 0.21 to 0.84%. The low moisture uptake protects the patches from microbial contamination and bulkiness.

Tensile strength:

The tensile strength of the patches prepared with HPMC 100M and PG were found in between 0.53Kg/cm²to 0.82Kg/cm², which were 0.16 Kg/cm²to 0.38Kg/cm²for the patches composed of HPMC 15 M CR and were 0.36 Kg/cm²to 0.61Kg/cm²for the patches composed of HPMC 4 CM. It was observed that with the increase of concentrations, the tensile strength of the patches gradually increased.

Percent elongation at break:

The elongation at break test provides an indication of the strength and elasticity of the film which is reflected by the elongation of the break. The % elongation was found to be in the range of 33.92% to 35.90%. It indicates inverse relation between tensile strength and % elongation.

Table 2: Characterization data for the transdermal patches

Code	Texture	Thickness mm	Weight mg	Folding endurance	Surface pH
F1	Flexible	0.08	235.60	308.9	5.69
F2	Flexible	0.12	208.12	308.6	5.71
F3	Flexible	0.14	184.20	306.6	5.74
F4	Flexible	0.15	209.42	307.2	5.62
F5	Flexible	0.18	202.34	306.3	5.81
F6	Flexible	0.21	169.11	304.6	5.62
F7	Flexible	0.13	215.42	302.8	5.58
F8	Flexible	0.15	203.71	302.6	5.63
F9	Flexible	0.16	198.32	301.1	5.82

Code	% Moisture content	% Moisture uptake	Tensile strength Kg/cm²	Percentage elongation at break
F1	3.26	0.72	0.53	33.92
F2	3.41	0.84	0.74	34.15
F3	3.68	0.81	0.82	34.78
F4	3.01	0.21	0.16	34.80
F5	3.24	0.42	0.28	35.3
F6	3.31	0.37	0.38	35.90
F7	3.98	0.45	0.36	34.23
F8	4.12	0.63	0.48	34.83
F9	4.26	0.54	0.61	35.12

Drug content:

Drug content analysis was performed for all the prepared transdermal patches and the results are showed in table. A near uniform drug content was noted for the prepared transdermal films ranging from 96.28 to 99.73%. This suggests that the process employed to prepare the films was capable of affording uniform drug content and minimum variability.

In vitro release studies:

The drug release characteristics of the formulation were studied in in-vitro conditions by using artificial semipermeable membrane. The in vitro release profile is an important tool that predicts in advance how a drug will behave in vivo. Release studies are required for predicting the reproducibility of rate and duration of drug action. The in vitro drug release profiles of the formulations prepared from the three grades of HPMC, i.e., HPMC 15 M CR, HPMC 100 M, and HPMC 4 CM are showed in Table.The cumulative percentage of the drug released in 24 h was found to be satisfactory for all types of transdermal films and drug release ranged from 80.12% to 84.74%. The formulation with 100 M displayed an overall lower drug release in 24 h compared to patches formulated with 15 M CR and 4 CM.

A statistically significant difference was seen for varying concentration of the polymer (lower concentration leading to increased drug release) for all the three polymer series. Further presence of plasticizer (PEG 400) was seen to significantly improve the drug release profile.

Code	Drug content %	Drug release %
F1	89.62	81.64
F2	90.13	80.82
F3	90.82	80.12
F4	92.90	83.92
F5	94.30	83.53
F6	94.86	82.15
F7	92.26	84.74
F8	93.11	84.16
F9	94.62	83.64

Stability study of selected patches:

Patches that were placed in specified temperature and humidity conditions for stability studies were withdrawn and analysed for their drug content. Percentage drug present in the patches was determined spectrometrically. It was found that the drug loss was less through the patches stored for 6 months. The patches were also observed for their appearance and texture.

4. CONCLUSIONS:

Transdermal films of Selegiline hydrochloride have been successfully formulated by solvent casting technique. The prepared transdermal drug delivery system of Selegiline using different grades of HPMC had shown good promising results for all the evaluated parameters. These results show that transdermal delivery of Selegiline hydrochloride can have good potential applications in therapeutic area offering advantages in terms of reduced dosing frequency, improved patient compliance, non-invasive characteristics, improved bioavailability, and easy termination of therapy.

5. ACKNOLEDGEMENT:

The authors are thankful to the Management and Principal of Al-Azhar College of Pharmacy, Thodupuzha, Kerala, for providing various facilities to complete the work.

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Received on 04.08.2021 Modified on 14.01.2022

Asian J. Pharm. Tech. 2022; 12(2):96-100.

DOI: 10.52711/2231-5713.2022.00016