INTRODUCTION:

Topical gel preparations remain one of the most popular and widely used pharmaceutical dosage forms because therapeutic effects are achieved effectively and systemic side effects can be avoided (2). Role of in-vitro diffusion cell to assess skin permeability provides key insights into the relationships between skin, drug, and formulation (3). Normally biological membranes are used, but when not available synthetic membranes are employed. In the past two decades, much research has been carried out in the assessment of topical drug diffusion using porous membranes.

A wide range of synthetic membranes is available in the market. The membranes used in this study are Cellulose Acetate Nitrate, Mixed cellulose ester, polyether sulfone, cellulose acetate. In lodge to have a fair evaluation of drug diffusion through each membrane, the most appropriate method would be to evaluate each membrane under standardized experimental conditions on in vitro diffusion cell apparatus (4). The main aim of this study is to compare the 4 different types of synthetic membranes and their effect on diclofenac sodium drug diffusion using in vitro drug diffusion cell apparatus (5). Transdermal drug delivery systems (skin patches) Dosage forms which provide controlled and continuous delivery of drugs directly into systemic circulation through the hide (6). Following skin permeation the drugs first reach the systemic circulation (7). Then they are transferred to the target site to produce therapeutic action. Carbopol polymers are polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol and used as bioadhesives for drug delivery (8). Because the pKa of these polymers is between 6.0 to 6.5, the carboxylategroups on the polymer backbone ionize, resulting in repulsion between the negative charges, which adds to the swelling of the polymer (9). Diclofenac sodium is an Analgesic and Anti-Inflammatory drug. The anti-inflammatory effects of diclofenac are believed to be due to inhibition of leukocyte migration and the enzyme Cyclo-oxygenase (COX-1 and COX-2), leading to the peripheral inhibition of prostaglandin synthesis (10). As prostaglandins sensitize pain receptors, inhibition of their synthesis is responsible for the analgesic effects of diclofenac. Antipyretic effects may be due to action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat dissipation (11).

The evaluation was done by in vitro drug release system. The Membranes used in this study are

· Cellulose Acetate Nitrate (0.45 micron)

· Mixed Cellulose Ester (0.45 micron)

· Poly-Ether Sulfone (0.45 micron)

· Cellulose Acetate (0.45 micron).

MATERIALS AND METHODS USED:

All materials used were of either analytical grade or pharmaceutical form.

Diclofenac sodium (free sample provided by M/S. Elam pharmaceuticals, Gujarat, MFG LIC NO- G/1092), Carbopol 934, Methanol, Phosphate buffer, Distilled Water, Sigma Membrane, 4 synthetic membranes (provided by lupin pharma company Ltd.)

Preparation of 1% w/v diclofenac sodium gel-

Accurately weighed 0.5g of Diclofenac sodium and 0.5g of carbopol 934 and split up in 50ml of water with continuous stirring. 45ml of water is first added slowly (12). The mixture is stirred continuously until gel formation. Then append the remaining 5ml of water, mixed thoroughly and keep it away for a few hours. The gel is formed (13).

Preparation of standard solutions for the standard plot-

1% diclofenac gel was prepared. Accurately weighed 50mg of gel into a 100ml volumetric flask. If needed to dissolve the gel in a few drops of methanol for solubility. Made up the volume with distilled water and shook the flask till solubility (A). Sonicate if necessary. 2ml was accurately pipetted from the above solution (A) into another 100ml volumetric flask. Accurately made up the volume with distilled water. From the above solution 2, 4, 6, 8, 10ml were withdrawn into a 10ml volumetric flask respectively, and concentrations obtained were 2, 4, 6,8,10 microgram/ml respectively (7).

Preparation of phosphate buffer PH 6.8

28.8g of disodium hydrogen phosphate and 11.45g of potassium dihydrogen phosphate was dissolved in 1000ml of water with continuous stirring. The pH of the solution was confirmed using a pH meter (14).

IN VITRO DIFFUSION CELL APPARATUS:

Cell apparatus consists of donor and recipient compartment. Donor compartment consists of a glass tube with open ends tied with a membrane on one end (15). Recipient compartment consists of beaker consisting of buffer solution (13). Accurately weighed 1g of gel for sigma membrane and 0.25g for the synthetic membranes and dipped 1cm into the recipient compartment. Recipient compartment has a magnetic bead and set along a magnetic stirrer. For every time interval, 5ml of sample is pipetted out and replaced with 5ml of the buffer.

DRUG CONTENT:

0.101g of the gel was transferred in a 100mL volumetric flask and Buffer pH 6.8 was added. The solution was mixed well and made up the volume with buffer(16). Read the absorbance at 276nm i.e. Lambda max of Diclofenac drug (17). Blank was prepared utilizing the same buffer and the values were entered. Absorbance = 0.355.

Percentage Drug Content = 94.55% w/w.

RESULTS:

CALIBRATION CURVE:

All the respective concentrations were analyzed by UV, visible spectroscopy and wavelengths were found out. Lambda max was found to be 287.6nm (18).

Table no. 1 Details of the concentration of drug in the medium and their respective absorbance.

Sample concentration (Microgram/ml)	Absorbance
0	0
2	0.120
4	0.185
6	0.242
8	0.299
10	0.357

Plot-1: Percentage Cumulative Drug Release.

Table No- 2 SM (Sigma Membrane), MCE (Mixed Cellulose)

TIME	MEMBRANE
TIME	SM	MCE	PES	CAN	CA
0 hr.	0	0	0	0	0
1 hr.	5.725	10.35	12.18	14.7	9.12
2hr	9.865	20.44	20.42	17	18
4.5 hr.	14.07	20.42	26.86	20.6	23.1
6 hr.	18.2275	25.91	33.32	24.3	27
8 hr.	22.4875	27.35	37.31	26.5	29.9
23.5 hr.	35.995	43.07	53.87	42	45.5
26 hr.	37.435	44.42	57.67	45.9	51.7
29 hr.	41.275	46.31	59.11	46.8	52.8
47.5 hr.	50.555	61.55	64.34	63.7	66.7
50 hr.	52.66	62.69	66.54	63.1	69.6
53 hr.	53.445	68.04	66.2	67.5	70.1
71.5 hr.	61.145	83.63	70.8	75.6	78.1

R²VALUE:

The R²value is important in determining the order of reaction the drug diffusion follows (19). It is also needed to determine if drug diffusion across various membranes follows Higuchi’s model of diffusion (20).

Plot-2: SM (Sigma Membrane), MCE (Mixed Cellulose Ester), PES (Poly Ether Sulfope), CAN (Cellulose Acetate Nitrate), CA (Cellulose Acetate).

RELEASE EXPONENT:

Table no- 4- Release exponent values of the membranes along with their drug transport mechanism

Membrane Name	Release Exponent (n)	Drug Transport Mechanism
Sigma Membrane	1.24	Super Case II Transport
Mixed Cellulose ester	0.968	Super Case II Transport
Poly Ether Sulfone	0.83	Non Fickian Transport
Cellulose Acetate Nitrate	0.963	Super Case II Transport
Cellulose Acetate	0.89	Case II Transport

DISCUSSION:

Comparative studies showed that Mixed Cellulose Ester membrane showed the highest %CDR in 71.5 hours i.e. 83.63%. Cellulose Acetate showed the second highest %CDR at 78.1% in 71.5 hours. Cellulose Acetate nitrate showed the third highest %CDR at 75.6% in 71.5 hours. Poly-Ether Sulfone showed the least %CDR at 70.8% in 71.5 hours (21) (Table-2). All membranes show 1^st order release indicating release depends on contribution of drug remaining. All membranes followed Higuchi's model of diffusion From Korsmeyer-Peppas model, results indicated that polyether sulfone follows non-fickian transport (does not obey Fick's laws) (22). Cellulose acetate follows case II transport which could be due to polymer erosion (23). Sigma membrane, mixed cellulose ester, and cellulose acetate nitrate follow super case II For system exhibiting Super case II transport, the dominant mechanism for drug transport is due to polymer relaxation as the gel swells (24). Drug release is a process by which a drug leaves a drug product (25). It involves the study of drug release rate, dissolution/diffusion/erosion studies (26). Drug release kinetics is the application of mathematical models to the drug release process. Drug release could be due to drug diffusion, polymer degradation or polymer swelling (27). Various kinetic models were used to study diffusion parameter(28). All membranes showed the first order release and Higuchi's model. From the Korsmeyer-Peppas model, various diffusion mechanisms of drug diffusion were reported (29).

CONCLUSION:

Drug release mechanism in the polyether-sulfone membrane is 1.5 times faster than sigma membrane it shows release up to 60% within 48 hrs. (First order) so, this can be used for fast release of drug and for immediate therapeutic effect (30). Mixed cellulose ester membrane showed 1.6 times faster drug release than sigma membrane, follows Higuchi’s diffusion mechanism. Cellulose acetate and cellulose acetate nitrate membranes show almost similar profile for a full period of time i.e. Sustained release pattern. Hence, can be used in conditions where the therapeutic effect requires long-lasting action (31).

The Release Pattern of Drug is Different Rates Despite Using Same Gel Polymer Complex Since:

Carboplol (polyacrylic acid) reacts with cellulose fiber enhances ion exchange and fluid absorbance due to which polyether-sulfone membrane which is PH sensitive when combined with polyacrylic acid undergo modification in pore sizes results in a faster release. Hence shows the fast release rate in a short period of time(32).The mixed ester cellulose membrane is made up of a nonionic polymer when combines with polyacrylic acid forms hydrogen-bonded interpolymer complex cause diffusion type of release(33).

Cellulose acetate and cellulose acetate nitrate membranes made up of acetic acid and nitrate as the main component when comes in contact with polyacrylic acid forms polycomplexes and show sustained release type of drug release mechanism(34).

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Received on 08.08.2019 Modified on 13.10.2019

Research J. Pharm. and Tech. 2020; 13(7): 3098-3102.

DOI: 10.5958/0974-360X.2020.00549.1

Membrane/Kinetic Model	Zero Order	First Order	Higuchi's Diffusion	Korsmeyer-Peppas
Sigma Membrane	0.953	0.99	0.997	0.878
Mixed Cellulose ester	0.95	0.983	0.954	0.658
Poly Ether Sulfone	0.796	0.918	0.95	0.628
Cellulose Acetate Nitrate	0.94	0.996	0.993	0.639
Cellulose Acetate	0.913	0.994	0.994	0.682