Formulation design & evaluation of transdermal drug delivery system of an anti-inflammatory agent.

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ABOUT AUHTORS

  1. Das Ravindra Kumar

2. Arun Kumar

R.V. Northland Institute, Gr. Noida (India)

ABSTRACT

The aim of the present research was to develop matrix type transdermal patch containing diclofenac sodium with different ratios of HPMC and Eudragit RL100 by the solvent casting method. The prepared patch showed satisfactory physiochemical parameters like Thickness, Weight uniformity, Folding endurance, Moisture content, Moisture absorption for stability of the formulation and Drug content. In vitro study done by using Modified Franz diffusion cell for 20 hrs. Transdermal drug delivery system can improve the therapeutic efficacy and safety of the drugs because drug delivered through the skin at a predetermined and controlled rate. In different formulation on the basis of In vitro drug release F4 show satisfactory drug release pattern.

Keywords: Transdermal drug delivery system, Diclofenac sodium, HPMC, Eudragit RL100, Anti-inflammatory.

INTRODUCTION

Transdermal drug delivery systems (TDDS), also known as “transdermal patches,” are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin. In order to deliver therapeutic agents through the human skin for systemic effects, the comprehensive morphological, biophysical and physicochemical properties of the skin are to be considered. Transdermal delivery provides a leading edge over injectable and oral routes by increasing patient compliance and avoiding first pass metabolism respectively.

Advantages of TDDS

  • Avoidance of first pass metabolism of drugs.
  • Improved therapeutic effect, with decreased side effects.
  • Reduction of fluctuations in plasma levels of drugs, Utilization of drug candidates with short half-life and low therapeutic index.

Disadvantages of TDDS

  • The delivery system cannot be used for drugs requiring high blood levels.
  • The use of transdermal delivery may be uneconomical.
  • Big drugs molecules (>500 Dalton) usually difficult to penetrate the stratum cornea.

COMPONENTS OF TDDS

Polymer Matrix

Advances in transdermal drug delivery technology have been rapid because of the sophistication of polymer science that now allows incorporation of polymers in transdermal system (TDS) in adequate quantity. The release rate from TDS can be tailored by varying polymer composition.

Selection of polymeric membrane is very important in designing a variety of membrane permeation controlled TDS.

Drug

Transdermal route of administration cannot be employed for all types of drugs. It depends upon optimal physicochemical properties of the drug, its biological properties. In addition, consideration of the pharmacokinetic and pharmacodynamics properties of drug is necessary. The most important requirement of drug to be delivered trans dermally is demonstrated by need for controlled delivery, such as short half-life, adverse effect associated with other route or a complex oral or I.V. dose regimen.

Backing layer

The backing layer must be impermeable to drug and permeation enhancers. The backing membrane serves the purpose of holding the entire system together and at the same time protects the drug reservoir from exposure to the atmosphere, which could result in the breakage or loss of the drug by volatilization. The most commonly used backing materials are polyester, aluminized polyethylene terapthalate, siliconised polyethylene terapthalate and aluminum foil of metalized polyester laminated with polyethylene.

Release liner

The peel strip prevents the loss of the drug that has migrated into the adhesive layer during storage and protects the finished device against contamination. Polyesters foils and other metalized laminates are typical materials which are commonly used.

TYPES OF TRANSDERMAL DRUG DELIVERY SYSTEM

Reservoir System

In reservoir systems the drug is enclosed between a rate controlling microporous or nonporous membrane and an impermeable backing laminate (Figure 1). The drug is dispersed uniformly in solid polymer matrix and suspended in a viscous liquid medium making a paste. The release rate of the drug is determined by the abrasion rate, permeability, diffusion and thickness of the membrane. The whole system is supported on the impermeable metallic backing.

Figure 1: Reservoir system of drug delivery

Matrix diffusion system

In matrix diffusion system (Figure 2) drug is uniformly dispersed in hydrophilic or lipophilic polymeric material. The rate of erosion of the polymer, thickness of the layer and surface area of the film determines the release rate of the drug. No other rate controlling membrane is present in the matrix system. These are also known as the monolithic systems. Adhesive layer is spreaded and found the circumference of the polymer disc instead of spreading on the surface of the patch. Matrix system of drug delivery can be modified by adding drug directly in the adhesive layer. This may be formulated in single layer drug in adhesive system or multilayer drug in adhesive system.

Figure 2: Matrix diffusion system of drug delivery

Drug in adhesive system

In this system drug is dispersed in the adhesive layer of the patch (figure 3). The adhesive layer not only serves to adhere the components of the patch with the skin but also controls the rate of drug delivery to the skin. The adhesive layer is surrounded by the liner. In single layer patch a single drug in adhesive layer is present but in multilayer patch one layer is for immediate release of the drug and other layer is for controlled release of the drug.

 Figure 3: Drug in adhesive layer system

Micro reservoir system

The micro reservoir system (Figure 4) is the combination of the matrix and reservoir system. In micro reservoir system the drug is first suspended in an aqueous solution of hydrophilic polymer (e.g. PEG) and then the above suspension is mixed with a lipophilic polymer (e.g. Silicon) by high shear mechanical stirrer. The cross linking of the polymer chains produced in-situ stabilizes the micro reservoir system and a medicated polymer disc of specific area and thickness is formed.

Figure 4: Micro reservoirs system

MATERIAL AND METHODS

Diclofenac sodium, HPMC and Eudragit RL100, PEG, Phosphate buffer pH 7.4, Disodium hydrogen phosphate, sodium hydroxide, sodium chloride, potassium di hydrogen orthophosphate, Aluminum foil, Double beam UV-Visible Spectrophotometer, FT-IR Spectrophotometer, Refrigerated centrifuge, Diffusion cell, Electronic balance, Digital pH analyzer, Stirrer, Vortex shaker, Digital melting point apparatus, Sonicator, Routine lab glass wares,  Orbital shaker, Vacuum oven, Water bath are used.

Preparation of transdermal patches

The diclofenac sodium transdermal patches were prepared by solvent casting technique. Composition of formulation of transdermal patches was showed in Table 1, Eudragit RL100 and HPMC were weighed in requisite ratios and they were then dissolved in phosphate buffer as solvent using magnetic stirrer. Diclofenac sodium (50mg) was added into homogenous dispersion under slow stirring with a magnetic stirrer. PEG 400 was used as plasticizer, added to the above dispersion under continuous stirring. The uniform dispersion was casted on aluminum backing membrane. The rate of evaporation of solvent was controlled by inverting cut funnel over the patches. After 24h, the dried films were taken out and stored in desiccator. Different concentration of propylene glycol as permeation was incorporated in the formulation.

Various parameters were studied for the performance of the prepared patches. Some parameters were kept constant and some of them were optimized. The optimal values were obtained after performing several experiments by trial and error method.

Table 1: Composition of formulation:

FORMULATION CODE RATIO OF POLYMER EUDRAGIT RL100 (mg) HPMC (mg) DRUG (mg) PLASTICIZER (ml)
F1 1:1 50 50 50 0.2
F2 1:2 50 100 50 0.2
F3 2:2 100 50 50 0.2
F4 2:1 100 50 50 0.2
F5 2:3 100 150 50 0.2
F6 3:2 150 100 50 0.2

PHYSICOCHEMICAL CHARACTERIZATION

Physicochemical properties such as thickness, weight uniformity, folding endurance, moisture content, percentage moisture uptake and content uniformity were determined on developed patches.

Thickness uniformity

The thickness of the formulated patches (1 cm2) were measured at 3 different points using a digital Caliper and average thickness of three reading was calculated.

 Weight uniformity

The prepared patches are dried at 60°C for 4hrs before testing. A specified area of patches (1 cm2) is cut in different parts of the patch and weigh in digital balance. The average weight and standard deviation values are calculated from the individual weights.

Folding endurance

A specific area of patch (1 cm2) is cut and repeatedly folded at the same place till it break. The number of times the film could be folded without breaking gave the value of folding endurance.

Percentage moisture content

The prepared patches (1 cm2) are weighed individually and to be kept in a desiccator containing fused calcium chloride at room temperature. After 24 h, the patches are reweighed and the percentage moisture content determined by below formula.

Percentage moisture content (%) = [Initial weight – Final weight / Final weight] ×100

Percentage moisture uptake

The prepared patches (1 cm2) are weighed individually and kept in a desiccator containing saturated solution of potassium chloride in order to maintain 84% Rhesus factor (RH). After 24 h, the films are reweighed and the percentage moisture uptake was determined by the formula.

Percentage moisture uptake (%) = (Final weight – Initial weight / initial weight) × 100

Drug Content Determination

The patches (1 cm2) was cut and added to a beaker containing 100 ml of phosphate buffered pH 7.4. The medium was stirred (500 rpm) with teflon coated magnetic bead for 5 hours. The contents were filtered using whattman filter paper and the filtrate was analyzed by U.V Spectrophotometer (UV-1700, Shimadzu) at 276.5 nm for the drug content against the blank solution.

In vitro drug released studies

The in-vitro drug released studies of the patches was carried using modified Franz diffusion cell. The cylinder consists of two chambers, the donor and the receptor compartment. The donor compartment was open at the top and was exposed to atmosphere. The temperature was maintained at 37 ± 0.5 C and receptor compartment was provided with sampling port. The diffusion medium used was phosphate buffer (pH 7.4).

The diffusion was carried out for 20 hours at an interval one and two hour for20 hours (1, 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 hour). 5 ml sample was withdrawn from the same volume of phosphate buffer pH 7.4 was added to receptor compartment to maintain sink conditions and the samples were analyzed at 276.5nm in UV spectrophotometer.

RESULT AND DISCUSSION

Evaluation of Formulated transdermal patch

The thickness, folding endurance, weight uniformity, moisture content, moisture uptake and drug content of the patches were measured. And all the results are showed in Table 2.

Table 2: Evaluation parameters:

Formulation

      Code

Thickness

    (mm)

Folding

Endurance

Weight

Uniformity     (mg/cm2)

Moisture

 Content

    (%)

Moisture

Uptake

(%)

Drug content (%)
F1

 

    0.11

 

       14 11.5 5.3 3.2 96.25
F2

 

    0.08        15

 

12.4 3.6 4.6 92.02
F3

 

    0.12        15 11.8 8.9 4.1 91.55
F4

 

    0.08        16 13.6 5.6 3.8 87.45
F5

 

    0.10        14 14.5 9.2 4.8 90.12
F6

 

    0.09        13 15.0 4.4 3.7 89.63

 

Fourier transforms infrared spectroscopy

                                   Figure 5: FTIR Spectra of diclofenac sodium

Table 3: Peaks of diclofenac sodium:

 

PEAKS RANGE (cm-1)
 

FUNCTIONAL GROUPS
 

3385

 

(N-H Stretching vibrations) Secondary amine

 

1574

 

(C=O Stretching vibrations) Carboxyl ion

 

1557

 

(C=C Ring Stretching vibrations)

 

746

 

(C-Cl Stretching vibrations)

 

Table 4: Percentage drug release of transdermal patches batch (F1-F6):

 

Percentage drug release

Time (hrs.)  

F1

 

F2

 

F3

 

F4

 

F5

 

F6

1 4.06 3.15 4.69 3.60 3.00    2.10
2 6.34 5.21 6.10 5.25 5.26 4.20
4 17.81 18.50 16.59 14.55 15.50 11.58
6 19.67 22.62 17.50 18.11 18.91 17.26
8 21.72 28.53 34.65 35.62 22.06 21.25
10 39.80 45.71 59.78 55.81 36.58 34.11
12 55.12 69.11 66.53 73.51 48.11 58.62
14 67.52 75.31 82.21 85.22 64.33 75.96
16 78.19 83.22 86.89 90.96 79.49 88.01
18 80.36 88.29 92.26 95.25 83.25 90.09
20 82.56 89.03 93.01 96.04 90.07 91.12

CONCLUSIONS

In this study Diclofenac sodium loaded transdermal patches were prepared using  Eudragit RL 100 and HPMC in different combination as matrix forming agent and polyethylene glycol 400 (PEG 400) is used as plasticizer. The patches were prepared by varying the ratio of two polymers in each formulation and also by varying the quantity of plasticizer to understand their impact on the responses. Preformulation studies of drug were undertaken concerning melting point, solubility analysis, UV-spectrophotometric analysis and FTIR analysis to identify and assessment of purity of drug. Possibility of drug-excipient interaction was checked by FTIR analysis. The formulation were characterized for thickness, weight uniformity, folding endurance, moisture content, percentage moisture uptake and drug content uniformity.

Preformulation studies revealed the purity of the drug. UV-spectrophotometric analysis of drug in phosphate buffer pH 7.4 (y = 0.267x + 0.010, R2 = 0.999) revealed the suitability of the standard curve for further calculation. FTIR analysis revealed that there are no potential chemical interaction between the drug and the polymers.

The thickness of all formulations was found to be at the range 0.09-0.11 mm (table no.4.4). The weight of 1 cm2 of every patch was in between 11.5–15.0 mg (table no. 2), ensuring the uniformity of the weight. The folding endurance of all formulations was found to be range between 13-15 (table no. 2). Which ensure the moisture content of patches were found to be range 3.6-9.2% (table no.4.7) and the moisture absorption study revealed 3.2- 4.8% (table no. 2)  increase in weight at 84% relative humidity. The drug content analysis revealed the uniformity of drug content in all formulations (table no. 2).

In vitro release of Diclofenac sodium patches were carried out in diffusion cell. The phosphate buffer (pH 7.4) used as diffusion medium. The release profile data of Diclofenac sodium were given in table 4.10 for patches F1 to F6. From the diffusion studies it was observed that, at the end of 20 hour drug diffusion from formulation F4 (96.04) was maximum than F1 (82.56), F2 (89.03), F3 (93.01), F5 (90.07), and F6 (91.12), presented in Figure 6.

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