Formulation and Evaluation of Celecoxib Transdermal Patches
Lama Alhaushey, Ranin Darwish Ahmad*
Department of Pharmaceutics and Pharmaceutical Technology,
Faculty of Pharmacy, Tishreen University, Lattakia, Syria.
*Corresponding Author E-mail: ranindarwishahmad@gmail.com
ABSTRACT:
This study aims to prepare prolonged-release Celecoxib transdermal patches due to the multiple advantages of patches. Several formulations were prepared using Ethylcellulose (EC) as a hydrophobic polymer with different plasticizers such as Span 60, Silicon oil, Oleic acid, or Polyethylene Glycol 400 (PEG400). Different properties of the prepared patches (in terms of weight uniformity, content uniformity, folding endurance, and in vitro drug release) were studied. The effect of changing polymer concentration and type of plasticizer and its concentration on patch properties were investigated. The results showed that ≈90% of Celecoxib was released after 24 hours by using EC at a concentration of 0.5% with PEG 400(25% w/w with respect to dry weight of polymer). The prepared films were transparent, visually homogenous, and flexible as the folding endurance value was 500±1.52 folds and Celecoxib release followed Higuchi model, meaning that the diffusion of Celecoxib through the EC chains is the main mechanism of release.
KEYWORDS: Celecoxib, transdermal patches, plasticizers, Ethylcellulose, prolonged release.
INTRODUCTION:
Several pharmaceutical forms are applied to the skin to treat skin disorders such as creams, ointments, gels, etc…, but the need to ensure prolonged transdermal release has led to the formulation of transdermal drug delivery systems (TDDS), which are known as patches. Patches are adhesive treatment systems applied to the surface of the skin in order to release the drug into the skin continuously and at a controlled rate1,2,3,4.
Transdermal drug delivery systems have many advantages compared to oral pharmaceutical forms, eg.improving patient compliance, avoiding variables that affect drug absorption along the gastrointestinal tract such as pH changes, presence of food and fluids, gastric emptying time, and avoiding first-pass metabolism. The transdermal route can be used when the oral route is not possible or undesirable in cases of vomiting, or when drugs have short half-lives or narrow therapeutic windows.
Since the drug is continuously entering the skin, there will be no fluctuations in plasma concentration and thus fewer undesirable side effects and the patch applied to the skin can be removed directly if any side effects appear1,2,5,6,7,8,9,10,11,12,13.
Celecoxib is a non-steroidal anti-inflammatory drug (NSAIDs) that is used as a pain reliever and antipyretic 14,15, as well as for the treatment of osteoarthritis, rheumatoid arthritis, dysmenorrhea pain, and others 16,17,18,19,20,21,22. The mechanism of action of Celecoxib is to inhibit the production of prostaglandins through selective inhibition of the enzyme Cyclooxygenase 2 (COX-2)23,16,17,18,19,24,25. Orally administrated Celecoxib undergoes significant first hepatic metabolism, thus its bioavailability is low (22-40%) 17, and has several gastrointestinal and cardiac side effects due to long-term use14,15,16,17,18,19. Therefore, administration of Celecoxib systemically via the patch will reduce the side effects that appear after prolonged oral use due to the use of lower doses15,17. The administration of Celecoxib via patches can also be used for topical dermatological uses such as relieving the pain of sunburn, preventing the development of UV-induced cutaneous papillomas, and also reducing the formation of scars after wounds26,27.
Celecoxib has several properties that make it a candidate for formulation in a transdermal patch. It is insoluble in water, has a suitable partition coefficient (log P=3.68), and has a low molecular weight (381.4 daltons)14,19,28.
The importance of this research is to develop an extended-release formulation through the skin using patches, which contributes to reducing the undesirable side effects, and the object is to prepare prolonged-release Celecoxib transdermal patches and to characterize their properties.
MATERIALS AND METHODS:
Materials:
Dichloromethane DCM (Surchem products LTD, England), Tween 40 (Road/Rail KeinGefahrgut), Sodium hydroxide (Surechem products LTD, England), anhydrous monosodium phosphate (Scharlau, the European Union). Other materials like Celecoxib, ethylcellulose (EC), Oleic acid, Poly ethylene glycol 400 (PEG 400), Span 60, and Silicon oil, were of analytical degree.
Methods:
1. Preparation of a phosphate buffer (pH = 7.4):
Phosphate buffer was prepared according to the United States Pharmacopeia 29. Breifly 24 gr of anhydrous monosodium phosphate NaH2PO4 were dissolved in distilled water and the volume was made up to 1 liter (Solution A). 8 gr of Sodium hydroxide NaOH were dissolved in distilled water and the volume was made up to 1liter (Solution B). 50ml of solution A and 39ml of solution B were taken and mixed and the pH was adjusted by NaOH using a pH meter (Jenway 3510 pH meter, UK) to get a pH= 7.4, then the volume was made up to 200ml using distilled water.
2. Celecoxib maximum absorption wavelength determination (λ max):
Celecoxib was dissolved in 1% Tween 40 in water and 1% Tween 40 in Phosphate buffer (pH=7.4). A scan of absorbance in the UV domain was run and the wavelength of maximum absorbance was noted as shown in figure (1). λ max for Celecoxib was 261.5nm in both solutions.
Figure (1). λmax of Celecoxib in 1% Tween 40 solution in phosphate buffer (pH = 7.4)
3. Study the solubility of Celecoxib in a solution of 1% Tween 40 in water and a solution of 1% Tween 40 in a phosphate buffer (pH= 7.4) 30
Three samples were prepared by adding 100mg Celecoxib to 50ml of 1% Tween 40 in water, the samples were placed on a Shaker device (HeidolphUnimax 2010, Germany) for 48 hours (the sufficient period for reaching the solubility of Celecoxib). After 24 and 48 hours, the absorbance of Celecoxib was measured in the three solutions using a UV spectrophotometer (Jasco-V-530-UV/Vis spectrophotometer, Japan) at 261.5nm after filtering the solution by a micronized filter. The same previous experiment was repeated but with the use of 1% Tween 40 in phosphate buffer (pH= 7.4) instead of 1% Tween 40 in water. After that, the dissolved amount of Celecoxib in three samples (after 48 hours) were calculated by applying the equation y = 42.782 x + 0.0242 (R2 = 0.9991) for samples of Tween 40 solution in water, or the equation y = 46.132 x + 0.0089 (R2 = 0.9994) for samples of Tween 40 solution in phosphate buffer (pH = 7.4).
The solubilities of Celecoxib in 1% Tween 40 solution in water and in 1% Tween 40 solution in phosphate buffer (pH = 7.4) were 0.52mg/ml and 0.29mg/ml, respectively.
4. Preparation of transdermal patches:
The transdermal patches were prepared as matrix system (ie, the active ingredient Celecoxib is mixed with the release-modifying polymer, Ethyl cellulose EC). These films were prepared using different concentrations of EC with different plasticizers such as Oleic acid, Silicon oil, Span 60, and PEG 400 (the concentration of the plasticizer was changed in proportion to the weight of the dry polymer).
Celecoxib (50 mg), EC (3, 1 or 0.5%) and plasticizer: Oleic acid (35, 25 or 15%) or PEG 400 (25%) were dissolved in 5 ml Dichloromethane (DCM). The mixture was poured in a glass Petri dish and the dishes were left uncovered at room temperature for DCM evaporation.
Blank patches corresponding to each formulation were prepared as these films contain EC with plasticizer without Celecoxib.
Table (1) shows the formulations prepared using EC.
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
Celecoxib (mg) |
50 |
50 |
50 |
50 |
50 |
50 |
EC (%) |
3 |
1 |
0.5 |
0.5 |
0.5 |
0.5 |
Oleic acid (%)* |
25 |
25 |
15 |
25 |
35 |
- |
PEG 400 (%)* |
- |
- |
- |
- |
- |
25 |
*Oleic acid and PEG 400 percentage is in proportion to the weight of dry polymer
5. Content uniformity test:
The test was carried out by taking three samples of the prepared patches and a sample of the blank patch (the sample area is 1cm2). Each sample was placed in a Becher, then 5ml of DCM was added to dissolve EC. The Becher was placed on magnetic stirrer (Variomag Electronicrührer, Germany) until complete dissolution, then 150ml of 1% Tween 40 solution were added to each Becher and stirring was continued for an hour, leaving the Becher exposed until DCM evaporation. After that, the Bechers were placed on a Shaker device (HeidolphUnimax 2010, Germany) for 24 hours to ensure the dissolution of Celecoxib.
The absorbance of Celecoxib was measured in the resulting solutions at a wavelength of 261.5nm versus the blank solution. The concentration of Celecoxib was calculated by applying the equation y = 42.782 x + 0.0242 (R2 = 0.9991).
The samples pass content uniformity test if the percentage of their Celecoxib content is within the range 90 – 110% permitted by the European pharmacopoeia 31.
6. Weight uniformity test:
Three prepared patches (each patch area is 1 cm2) were taken and weighed individually. The results were expressed as mean±standard deviation. This test was conducted to ensure the homogeneity of weight of the samples taken because they were manually cut32,33,34,35,36.
7. Folding endurance test:
The test was conducted by folding the film at the same place several times until it broke or cracked. The value of folding endurance test is equal to number of times the film was folded before it breaks or cracks2,6, this test expresses the extent of the film's flexibility and indicates that the patches would not break and they would maintain their integrity with natural skin folding when administration32,37,38,39,40,41,42.
8. In vitro drug release test:
The test was performed after simulating USP apparatus V (Paddle over disc) by replacing the disc with a small-sized watch glass29,43. Three prepared patches and one blank patch (each patch was 1 cm2) were taken and placed on a watch glass and covered with a sieve to fix the film on the watch glass, then the watch glass was placed in the dissolution apparatus flask with 600ml of 1 % Tween 40 in phosphate buffer solution (pH = 7.4) 17,44,45 and the apparatus was equilibrated to 320C. The paddle was then set at a distance of 2.5cm from the watch glass and operated at speed of 50rpm17.
Samples (5ml aliquots) were withdrawn at appropriate time intervals (10min, 20min, 30min, 1 h, 1.5h, 2h, 3h up to 10h, 24h), they were filtered by a micronized filter, and replaced with fresh dissolution medium.
The samples were analyzed by UV spectrophotometer (Jasco-V-530-UV/Vis spectrophotometer, Japan) at 261.5nm wavelength against a suitable blank at each interval. Celecoxib concentration was calculated by applying the equation y = 46.132 x + 0.0089 (R2 = 0.9994). Then, the percentage released at each time interval was calculated and release plots were drawn.
9. In vitro drug release kinetics study:
The results of Celecoxib release from the prepared patches were analyzed according to Zero-order: (Q = Ko . t), First order: (Ln Q = -K t + Ln Qo), Higuchi model: (Q = Kh . √t), and Korsmeyer-Peppas model: (Log Qm/Qo = n Log t + Log K).n value in Kormeyer-Peppas equation is used to describe the release according to the following: when n ≤ 0.5 the drug is released according to the diffusion mechanism, while when 0.5 < n < 1.0 the drug is released by the diffusion mechanism and by relaxation of the polymer chains, when n = 1 the release is according to Zero-order, while when n > 1 the mechanism that leads todrug release is mainly due to the relaxation of polymeric chains23.
RESULTS AND DISCUSSION:
After a series of primary experiments in which polymer and plasticizer type and concentration were changed, appropriate quantities were determined and the formulas were carried out as shown in table1.
All patches were transparent, visually homogeneous, and had weight uniformity and content uniformity whereas all content percentages were within constitutional range (90 - 110%) as shown in table2.
Table (2) physiochemical evaluation of Celecoxib patches
Weight uniformity (g) (M±SD) |
Content uniformity (%) (M±SD) |
Folding endurance value (M±SD) |
% drug release after 24 h |
|
F1 |
0.0186±0.0005 |
98.43 ±1.51 |
196±1.15 |
8 |
F2 |
0.0179±0.0018 |
101.5±0.548 |
240±0.57 |
25.6 |
F3 |
0.0172±0.0022 |
94.04±1.62 |
259±1.15 |
56.5 |
F4 |
0.0118±0.0008 |
106.81±2.16 |
315±1.52 |
70.5 |
F5 |
0.0156±0.0016 |
106.09±1.422 |
352±1.52 |
59 |
F6 |
0.0119±0.0005 |
100.71±0.271 |
500±1.52 |
89.8 |
From the results shown in table (2), it is noted that when the EC concentration was decreased from 3% to 1% and then to 0.5% in the formulas F1, F2, and F3, respectively, the flexibility of the patches increased as the folding endurance value increased from 196 to 240 and then to 259 folds respectively (Table 2), and also the released percentage of Celecoxib increased from 8% to 25% and then to 56.5%, respectively, as shown in figure (2).
These results agreed with the results of the study of M.I.Alam et al. in 2009, in which celecoxib patches were prepared using a mixture of EC and polyvinyl pyrrolidone (PVP) with PEG 400 as a plasticizer. They observed that when EC concentration decreased and PVP concentration increased, the amount of released Celecoxib from the patches was increased17.
Figure (2). Effect of EC concentration on the released percentage of Celecoxib from patches prepared according to formulas F1, F2, and F3.
Also, the results of the formulas (F1, F2, and F3) are consistent with the results of S.Jayaprakashet al. in 2010, in which Meloxicam patches were prepared using different polymers (Hydroxy propyl methyl cellulose HPMC, EC or PVP) with propylene glycol as a plasticizer. In their study it was observed that with the decrease of EC concentration to 1%, the folding endurance value increased to 272 ± 2 folds, and for the in vitro drug release test using Franz cell it was also observed that the released percentage of drug from the patches increased to 89.45±1.5% (46).
When 0.5% EC concentration was used, and the percentage of Oleic acid increased from 15% to 25% in the formulas F3 and F4, the flexibility of the patches increased as the folding endurance value increased from 259 to 315 folds (P-value<0.05), respectively, as shown in table (2), and also the released percentage of Celecoxib increased from 56.5% to 70.5% (P-value < 0.05) as shown in figure (3). This may be explained bythe separation of EC chains from each other and reduction of their entanglement due to the contribution of Oleic acid. This is in agreement with the study of O.G.Quinoneset al. in 2013, where a gel containing Celecoxib was prepared and Oleic acid was used as a penetration enhancer. It was observed that when Oleic acid concentration was increased from 5% to 10%, the amount of Celecoxib permeated through pigskin increased47.
But increasing the percentage of Oleic acid up to 35% while remaining 0.5% EC in formula F5 did not increase the released percentage of Celecoxib (59%) as shown in figure (3). This means that 25% of oleic acid used in F4 may be the upper limit of plasticizing, and above this ratio, EC chains will not separate further from each other, and therefore no greater amount of Celecoxib will be released, but a smaller amount was released, this may be due to the increased hydrophobicity that occurs with the increase in Oleic acid concentration.
Figure (3). Effect of Oleic acid concentration on the released percentage of celecoxib from patches prepared according to formulas F3, F4, and F5.
When the plasticizer Oleic acid (F4) was replaced with PEG 400 (F6) with the same concentration 25%, while EC was still 0.5%, the flexibility of the patches increased as the folding endurance value increased from 315 to 500 folds (P-value < 0.05) (table 2), and also the released percentage of Celecoxib increased from 70.5% to 89.8% (P-value < 0.05)as shown in figure (4). This is due to the adding of hydrophilic plasticizer (PEG 400) that allowed the released medium to permeate more than the presence of Oleic acid and thus increased the released percentage of Celecoxib.These rasults agree with the results of the study of R.V. Kulkarni et al. in 2002, in which blank films were prepared using Eudragit RS100 and they study the effect of adding different plastictzers sush as Dibutylphthalate DBP (hydrophobic plasticizer) or Poly ethylene glycol 400 (PEG 400) (hydrophilic plasticizer), it was observed that films plasticized with PEG 400 have higher permeability coefficients compared to DBP films48.
Figure (4). Effect of plasticizer type on the released percentage of Celecoxib from patches prepared according to formulas F4 and F5.
In vitro drug release kinetics study:
The plots of released amount of celecoxib according to equations of the four studied models: Zero-order, first-order, Higuchi models, and Korsmeyer-Peppas model, the values of R2 (the determination factor) were determined. Table (3) shows the values of R2 and figure (5) shows plots of the release kinetics of Celecoxib from formula F6 as an example.
Table (3) R2 values for Celecoxib release kinetics for the prepared patches
R20 |
R21 |
R2Higuchi |
R2Korsmeyer |
n |
|
F1 |
0.7031 |
0.5972 |
0.8994 |
0.8337 |
1.7737 |
F2 |
0.5594 |
0.2166 |
0.7147 |
0.6724 |
0.9805 |
F3 |
0.8908 |
0.6561 |
0.9629 |
0.9749 |
0.5876 |
F4 |
0.9618 |
0.7004 |
0.9862 |
0.9968 |
0.6648 |
F5 |
0.9758 |
0.8215 |
0.984 |
0.9366 |
0.4758 |
F6 |
0.8157 |
0.3362 |
0.9713 |
0.7874 |
0.8611 |
It is noted by studying the values of R2 in table (3) that the release of celecoxib in all formulas was closer to Higuchi model, because the values of R2 corresponding to this model is the largest, meaning that the diffusion of Celecoxib from EC chains is the main mechanism of release, and when the in vitro release data were applied to Korsmeyer-Peppas equation, the values of n corresponding to the formulas F2, F3, F4, and F6 were between 0.5 and 1.0, this means that the release of celecoxib from the patches follows anomalous transport (non-Fickian diffusion)i.e there is a partnership between the mechanism of drug diffusion and relaxation of the polymeric chains. For the formula F1, the mechanism of relaxation of the polymeric chains is dominant because n is greater than 1.0, and for the formula F5 the diffusion mechanism is dominant because n is less than 0.5.
The results are in agreement with the study of Y. Begum et al. in 2011. In this study, Celecoxib patches were prepared using a mixture of different polymers (HPMC, PVP, and methyl cellulose MC) with dibutyl phthalate as a plasticizer, and when studying the release Kinetics, it was found that they are closer to Higuchi model, and from the value of n, the release of Celecoxib from the patches was also shown to follow anomalous transport (non-Fickian diffusion)19.
In another study by S.Jayaprakashet al. in 2010, Celecoxib patches were prepared using different polymers (MC, HPMC, and PVP) with dibutyl phthalate as a plasticizer. When studying the release kinetics, it was found that they were closer to Higuchi model, and from n values, it was also shown that the release of Celecoxib from the patches follows anomalous transport (non-Fickian diffusion)15.
In the study of M. Amjadet al. in 2011, Atenolol patches were prepared using HPMC alone or a mixture of HPMC and EC49, and the study carried out by A.Madhulathaet al in 2013, in which Ibuprofen patches were prepared using Chitosan and HPMC (alone or in combination) with Glycerin as a plasticizer(50), they found that the release of active ingredient from patches followed anomalous transport (non-Fickian diffusion).
Figure (5). Plots of the release kinetics of Celecoxib from formula F6 according to Zero – order (a), First – order (b), Higuchi model (c), and Korsmeyer-Peppas model (d)
CONCLUSION:
Celecoxib patches have been prepared using Ethyl cellulose (EC) as a modified-release polymer. After several experiments, it was found that when EC concentration was decreased, the flexibility of the patches increased as the folding endurance value increased. And when EC concentration was fixed with increasing in Oleic acid percentage, the flexibility of the patches increased, but the released percentage of Celecoxib gradually increased with increase in Oleic acid percentage, and then began to decrease when reaching 35% of Oleic acid. Whereas, when the hydrophobic plasticizer (Oleic acid) was replaced with the hydrophilic plasticizer (PEG 400), better patches were obtained in terms of morphology and flexibility and the released percentage of Celecoxib increased, so a prolonged – release for 24 hours was obtained. Celecoxib release from the patches followed the Higuchi model.
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Received on 02.07.2022 Modified on 08.09.2022
Accepted on 11.11.2022 © RJPT All right reserved
Research J. Pharm. and Tech 2023; 16(4):1574-1580.