INTRODUCTION:

Arthritis is the tenderness and swelling of one or more of our joints. The main symptoms of arthritis are joint pain and stiffness, which typically worsen with age. The most common types of arthritis are osteoarthritis and rheumatoid arthritis.¹Gout is a form of inflammatory arthritis that develops in some people who have high level of uric acid in blood. The acid can form needle like crystals in a joint and cause sudden, severe episode of pain tenderness, redness, warmth and swelling.^2,3.

A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body.⁴In almost all transdermal patch designs, the drug is stored in a reservoir that is enclosed on one side with an impermeable backing and has an adhesive that contacts the skin on the other side.^5,6

MATERIAL AND METHOD:

Material:

Febuxostat was obtained as a gift sample from Alembic Pharmaceutical Pvt. Ltd. Vadodara Gujarat, India. Hydroxypropyl methylcellulose (HPMC), Oleic acid (OA), dibutyl-phthalate (DBP), were received from smriti college of pharmaceutical education, Indore Other materials used in the study (chloroform, methanol, ethanol, acetone, dichloromethane, etc.) were of analytical grade. Double-distilled water was used throughout the study.

Method:

PreformulationStudies:^7,8,

Organoleptic properties:Color, odour, taste, and state were determined.

Identification of Drug and Excipients:

Determination of melting point:

The melting point was determined by the capillary method. The temperature at which the drug melted was recorded.⁹

Determination of UV absorption maxima:

The identification of drug was done by UV spectrophotometric method. From the spectra, λ max of febuxostat was observed at 315nm. The spectral data from this scan was used for the preparation of a calibration curve of febuxostat.^10,11

Fourier transform infrared analysis:

FTIR analysis of the sample was employed for compound identification (FTIR-8400S Shimadzu). The powdered drug was scanned from 400 to 4000 cm⁻¹.

Determination of solubility:

The solubility analysis for febuxostat was done by solubility determination in different solvents like Water, PBS 7.4 pH, 0.1 M NaOH, 0.1M HCl, ethanol by saturated solubility method using UVspectrophotometer.^12,13

Determination of partition coefficient:

The partition coefficient was determined by dissolving 10mg of drug in separating funnels containing 10ml portion of each of n-Octanol and PBS pH 7.4. The separating funnels were shaken on mechanical shaker for 24hours. Two phases were separated and aqueous phase was filter through Whatman filter paper and the amount of the drug in aqueous phase was determined spectrophotometrically at 315nm.^14,15,16

Differential Scanning Calorimetry Analysis of Febuxostat:

The febuxostat was given to B.R. Nahata college of Pharmacy and Research Centre, Mandsaur for the analysis.^17,18

Calibration ofFebuxostat:

100mg of Febuxostat powder was accurately weighed and transfer to a 100ml volumetric flask. It was dissolved by progressive dilution with volume made up to 100mL with 7.4 PBS.¹⁹The stock solution of 100µg/ml was prepared by diluting 10ml of above solution up to 100mL from the above stock solution appropriate dilution were prepared with 7.4 PBS and analysed on UV Visible spectrometer (Shimadzu 1800) at 315 nm.^20,21,23

Preparation of transdermal patch:

Transdermal patches containing Febuxostat were prepared by the solvent evaporation technique in Petri dish. The backing membrane was cast by pouring a 2.5 % (m/v) polyvinyl alcohol (PVA) solution followed by drying at 60°C for 6h, forming a smooth, uniform and transparent backing membrane. The drug reservoir was prepared by dissolvingHPMC in Ethanol: Water (1:2) mixture.^24,25,26The drug was added slowly into polymeric solution and mixed thoroughly, Dibutyl phthalate 15% (w/w of dry polymer composition) was used as a plasticizer and oleic acid was used as permeation enhancer. The uniform dispersion was cast on a PVA backing membrane and dried at room temperature.

Table 1: Composition of transdermal patch

S. No	Ingredients	TD1	TD2	TD3	TD4	TD5	TD6
1	Febuxostat	40(mg)	40(mg)	40(mg)	40(mg)	40(mg)	40(mg)
2	HPMC	200(mg)	150(mg)	-	50(mg)	100(mg)	125(mg)
3	Eudragit L 100	-	50(mg)	200(mg)	150(mg)	100(mg)	75(mg)
4	Dibutyl phthalate	15%	15%	15%	15%	15%	15%
5	Oleic acid	1%	1%	1%	1%	1%	1%

Evaluation of transdermal patch:²⁷

Physical appearance: Formulated transdermal patches were physically examined forColour, Clarity andSurface texture

Thickness:

The thicknesses of the patches were measured by using Vernier caliper in mm.

Moisture content:

The prepared patches were weighed individually and kept in adesiccator containingactivated silica at room temperature for 24h. After 24h patches were reweighed.²⁸

Initial weight - Final weight

% Moisture content ------------------------------- × 100

Final weight

Moisture Uptake:

Weighed patches were kept in desiccator at room temperature for 24h. Then exposed to 84% relative humidity using saturated solution of Potassium chloride in a desiccator until a constant weight was achieved.²⁹

Final weight - Initial weight

% Moisture uptake = --------------------------------- × 100

Initial weight

Folding endurance:

The folding endurance of patches was determined by repeatedly folding a small strip of the patch (2x2) at the same place. The number of times the patch was folded at the same place without breaking gave the exact value of folding endurance.³⁰

% Elongation break:

Longitudinal strips were cut out from the prepared transdermal patches. The percentage elongation was determined by noting the length just before the break point and calculated by the formula:

L1 – L2

% Elongation = ----------× 100

Weight variation:

Three patches from three different batches were selected randomly, were cut and weighed on digital balance for weight variation test. The test was done to check the uniformity of weight and thus check the batch to batch variation.³¹

Drug content uniformity:

The prepared patch was cut into small pieces and put 100ml dissolution or diffusion medium used respectively and stirred continuously using a magnetic stirrer and sample was withdrawn at the end of three hours and the drug content was determined, spectrophotometrically at 315nm.³²

In vitro Drug diffusion studies:

The drug release from the febuxostat transdermal patch is investigated by using Franz diffusion cell. At predetermined time intervals, samples are withdrawn and taken and then analyzed with UV Spectrophotometer at λ max at 315nm.^33,34

RESULTS AND DISCUSSION:

Preformulation Studies:

Physical appearance/Organoleptic studies:

Appearance of Febuxostat was visually identified and compared with reference data.

Table 2: Physical appearance/Organoleptic studies

S. No.	Properties	Standard	Drug
1.	Colour	White Amorphous powder	White Amorphous powder
2.	Odour	Odourless	Odourless

Melting point: Melting point of drug was found to be 210-211 0c±1◦C which compared with previously reported value (209-211⁰C) indicated that the drug sample was pure.

UV absorption maxima:

The maximum absorbance of drug in methanol was found to be at λ max 315nm. The spectrum of absorption maxima for pure drug is shown in figure 1.

Figure 1: Absorption maxima of Febuxostat at 315 nm

Fourier transform infrared analysis:

The FTIR analysis of the drug was carried out for compound identification. The powdered drug was placed carefully over sample holder for scanning. The FTIR spectrum for pure drug is shown in figure 2.

Figure 2: FTIR spectrum of Febuxostat

Differential Scanning Calorimetry Analysis of Febuxostat:

Figure 3: Differential Scanning Calorimetry Analysis of Febuxostat

Solubility:

The solubility study revealed that the drug sample were Practically insoluble in water, slightly soluble in pH 7.4 PBS, Very Slightly soluble in 0.1M NaOH, soluble in 0.1M HCl and freely inethanol.

Partition coefficient:

The logarithmic value of partition coefficient value was experimentally found to be 3.2. This revealed the hydrophobic nature of febuxostat and further indicated that it is a suitable candidate for transdermal drug delivery.

Table 3: Calibration of febuxostat in pH 7.4 PBS

S. No.	Drug Concentration (µg/ml)	Absorbance(nm)
1	2	0.086
2	4	0.153
3	6	0.237
4	8	0.328
5	10	0.410

Figure 4: Calibration curve of Febuxostat in 7.4 PBS at 315 nm

Evaluation of Transdermal Patches:

Physical appearance:

The formulated patches were found to be clear, smooth, uniform, flexible in their physical appearance and free from entrapment of air bubble.

Thickness:

The thickness of the prepared patches varies between 0.120±0.007 to 0.184±0.013. Low standard deviation values show uniformity of the patches.

Weight variation:

The weight of the prepared transdermal patches for different formulations ranged between 286±0.008 to 566±0.017mg. The variation in weight uniformity of the prepared patches was within acceptable range.

Moisture content and moisture uptake:

The moisture content in the patches ranged from 3.13±0.55 to 6.36±2.83% and moisture uptake in the patches ranged from 5.88±0.009 to 8.98±0.013%. The lower moisture content in the formulations helps them to remain stable and become a completely dried and brittle film. Again, low moisture uptake protects the material from microbial contamination and bulkiness.

% Elongation Break Test:

Folding endurance:

Folding endurance values varied between 47±3.63 and 60±5.12. The result was found satisfactory indicating that the patches would not break and would maintain their integrity when used.

Drug content:

The drug content was found to be ranging between 82±1.56 and 92±0.89mg.

In-vitro drug release study:

The cumulative percentage of the drug released in 24 h was found between 85% (TD2) to 93% (TD5) for transdermal films. The formulation TD5 showed a better in vitro drug release profile across the cellulose membrane, when compared to the other formulations. This might be attributed to the nature of polymer; plasticizers and even the permeation enhancer used. Thus, formulation TD5 is considered as optimized formulation. The results are depicted in Table 5.

Evaluation of transdermal patch:

Table4: Evaluation of transdermal patch:

Batch No.	Physical appearance		Thickness (mm) ±SD	Weight Variation (%)± SD	% Moisture Content ± SD	% Moisture Uptake ± SD	% Elongation Break Test	Folding Endurance (No. of folds) ± SD	Drug content (%) ±SD
TD1	Transparent	Smooth	0.52±0.08	0.054±0.011	3.13±0.55	6.12±0.006	8.01±0.24	7.66±0.31	88±1.02
TD2	Transparent	Smooth	0.45±0.06	0.078±0.02	3.88±0.89	5.88±0.009	7.08±0.26	8±0.001	85±0.98
TD3	Transparent	Smooth	0.60±0.02	0.120±0.02	4.28±1.14	8.98±0.013	7.10±0.48	7.33±1.15	82±1.56
TD4	Transparent	Smooth	0.66±0.04	0.138±0.014	4.28±1.14	8.17±0.016	6.21±0.41	7.33± 0.47	84±1.66
TD5	Transparent	Smooth	0.64±0.13	0.123±0.030	6.36±2.83	7.76±0.035	5.26±0.32	7.66±0.57	92±0.89
TD6	Transparent	Smooth	0.49±0.07	0.098±0.023	5.16±1.65	6.85±0.048	4.22±0.30	7.33±1.15	86±1.37

Table 5: Drug release profile of formulated transdermal patch

Time (hrs)	Cumulative Drug Release of Prepared Formulation(%) ± SD
Time (hrs)	TD 1	TD 2	TD 3	TD 4	TD 5	TD 6
1hr	18±0.04	16±0.62	18±1.43	14±0.25	15±0.078	13±1.72
2 hr	25±0.92	27±0.09	36±1.95	39±0.44	35±0.054	32±0.32
3 hr	38±1.29	37±0.48	47±0.27	45±0.38	42±1.67	39±0.64
4hr	57±1.34	54±0.08	56±0.87	55±0.43	53±0.89	48±0.72
5 hr	69±1.38	66±1.78	63±0.03	64±1.65	65±0.09	62±0.63
6 hr	76±0.56	72±1.54	69±0.65	73±0.09	70±0.73	67±0.08
18 hr	80±0.67	78±1.23	72±1.99	77±0.53	75±0.31	73±0.76
20 hr	88±0.89	80±0.96	82±0.32	80±1.32	82±1.62	86±0.065
24 hr	92±1.82	85±0.25	86±0.76	90±1.34	93±0.09	89±1.43

Figure 5: In-vitro drug release graph

CONCLUSION:

Transdermal patches of febuxostat have been successfully by solvent evaporation technique. Evaluation of the prepared patches in terms of physical appearance, weight, thickness, flatness, tensile strength moisture absorption, moisture uptake and drug content uniformity recommend that the method employed for formulation of the transdermal patches was reproducible and assured outstanding quality and uniformity in patch characteristics with least variability. Further, in vitro drug release studies for all the formulations exhibited the drug release and nearly complete release (93%) was achieved in 24 h. These results show that transdermal delivery of febuxostat can have probable applications in therapeutic areas providing advantages by reducing dosing frequency, improving patient compliance, non-invasive character, improved bioavailability, and easy termination of therapy.

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Received on 14.11.2022 Modified on 17.06.2023

Research J. Pharm. and Tech 2024; 17(1):373-378.

DOI: 10.52711/0974-360X.2024.00058