Formulation, Optimization, and Evaluation of Transdermal Patches of Clotrimazole and Betamethasone Dipropionate for Candidiasis

 

Shivani A. Wable1, Prashant L. Pingale1*, Dattatray M. Shinkar1, Sahebrao S. Boraste1,

Sunil V. Amrutkar2

1Department of Pharmaceutics, Gokhale Education Society’s Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research, Nashik - 422009, Maharashtra, India.

2Department of Pharmaceutical Chemistry, Gokhale Education Society’s Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research, Nashik - 422009, Maharashtra, India.

*Corresponding Author E-mail: prashantlpingale@gmail.com  

 

ABSTRACT:

The most effective way to minimize the undesirable side effects of an overdose and to maximize both therapeutic benefits and patient compliance is through TDDS. Due to first-pass metabolism, clotrimazole possesses antifungal action and a half-life of two hours. It has to be dosed frequently. Betamethasone Dipropionate gives anti-inflammatory effect to reduce symptoms of candidiasis. To prolong the release, increase the drug's bioavailability, and increase patient compliance, a transdermal patch containing Clotrimazole and Betamethasone Dipropionate was developed. By adjusting the polymer concentrations through the solvent casting process, various formulations were created. The generated formulations conducted evaluations for several factors, including drug excipient compatibility, drug content, thickness, weight variation, folding durability, moisture uptake, moisture loss, and in vitro drug release. A 32 complete factorial design was used to examine the impact of various polymer concentrations on the reactions of clotrimazole and betamethasone dipropionate, including moisture uptake and percentage of medication released in 12 hours. To determine the kinetics of drug release, in vitro release data were fitted to various models. Batch F5 was considered optimum batch which contained HPMC K4M and Eudragit L-100 in concentrations of 350 and 250 mg respectively. For clotrimazole and betamethasone dipropionate, formulation F5 was shown to have the maximum drug release 75.91% and 67.09%, respectively. The created F5 had the highest drug content, with clotrimazole and betamethasone dipropionate concentrations of 98.78% and 98.82%, respectively.

 

KEYWORDS: Clotrimazole, TDDS, Betamethasone Dipropionate, Sustained Release, Kinetics, Candidiasis, Drug release.

 

 

INTRODUCTION: 

Transdermal drug delivery systems (TDDSs) are self-contained unique dosage forms that administer the medication through transdermal patch via the epidermis of the skin at a predictable and sustained rate with a short biological half-life. Through enhanced bioavailability and decreased dose frequency, it allows for systemic drug administration1,2,3.

 

The broad-spectrum antifungal drug clotrimazole prevents the formation of ergosterol by impairing the permeability and functionality of the fungal cell membrane. Clotrimazole is used to treat a variety of skin infections and has antimycotic activity against several types of candida. However, taking clotrimazole by mouth has several undesirable side effects, including nausea, vomiting, mouth discomfort, and gastrointestinal irritation. Transdermal administration of clotrimazole can reduce systemic side effects, provide longer therapy with a single application, enhance bioavailability, therapeutic efficacy, and increase patient compliance by delivering the drug through the skin4.

 

 

Betamethasone dipropionate binds to specific intracellular glucocorticoid receptors before it binds to DNA in order to alter the expression of genes.  Fungal infections cause the synthesis of some anti-inflammatory proteins to be stimulated while inhibiting the synthesis of other inflammatory mediators. Interleukin-10 and other anti-inflammatory genes are enhanced by betamethasone dipropionate5.

 

The skin has many advantages over other routes of administration when used for drug delivery, including greater acceptance by patients, the capacity to prevent irritation to the stomach, no liver first-pass metabolism which improves the bioavailability, reduce the risk of adverse reactions in the body through decreasing blood levels in comparison to oral therapy, give a sustained release of drug at the site of application, and fast withdrawal of treatment by removal of patch6.

 

Only once weekly administrations are necessary for transdermally administered medications. By preventing issues with presystemic metabolism, gastrointestinal discomfort, the generation of toxic metabolites, limited absorption, and other issues related to various medications, transdermal patches increased therapeutic effects of numerous drugs7. For the treatment of numerous illnesses, including antifungal disease, Parkinson's disease, anxiety, and Alzheimer's disease, transdermal administration systems are already available8.

 

MATERIALS AND METHODS:

Materials:

Clotrimazole and Betamethasone Dipropionate were received as a gift sample from Glenmark Pharmaceuticals, Nashik, India. HPMC K4M, Eudragit L-100, Propylene Glycol and Dichloromethane were procured from Modern Industries. Methanol was purchased from Fine Chem Laboratories.

 

Methods:

Preformulation studies of drug:

Organoleptic Properties:

Visual inspection was used to examine the organoleptic characteristics of both medications. Colour, odour, appearance, and other organoleptic characteristics are measured.

 

Determination of Melting Point:

The Thiele's Tube Method was used to calculate the melting point9.

 

Determination of UV absorption maxima:

Drug identification was carried out using a UV spectrophotometric technique. The spectra provide the λmax of Clotrimazole and Betamethasone Dipropionate was found at 262 nm and 240 nm respectively.

Calibration of Clotrimazole and Betamethasone Dipropionate:

10 mg each of Clotrimazole and Betamethasone Dipropionate were dissolved in a volumetric flask with (70:30) methanol: phosphate buffer (pH 7.4) to create a stock solution. The desired concentration was made in an aliquot. The λmax of Clotrimazole and Betamethasone Dipropionate was found at 262 nm and 240nm respectively.

 

Fourier transform infrared analysis:

Compound identification was done on the sample using FTIR analysis (Bruker Alpha-II FTIR). The drug was scanned between 400 and 4000 cm-1.

 

Differential Scanning Calorimetry analysis:

DSC (Shimadzu DSC 60-Plus) was used to analyse the purity and suitability of drugs and polymers. The drugs and polymers were analysed on DSC.

 

Determination of solubility:

The solubility study for drugs were carried out by determining the solubility in various solvents, such as water, dichloromethane, DMSO, ethanol, and others.

 

Drug- excipients compatibility studies:

Utilizing FTIR and Differential Scanning Calorimetry, research on the compatibility between the excipients and the medicine were conducted. Both the physical combination and the individual drugs (HPMC K4M and Eudragit L-100) were tested.

 

Formulation of Transdermal Matrix Patch:

The preliminary batches of transdermal patches were formulated using “Solvent Casting Method”

 

Trial Batches:

Trial batches were made where different polymers like HPMC, Ethyl cellulose and Eudragit L -100 with different penetration enhancers like Propylene Glycol and Polyethylene Glycol 400 at different concentrations were taken in different trial batches. The solvents like Methanol and Dichloromethane were taken. But the batches were failed due to compatibility and may be due to climatic conditions as the patches done in trial batches were not dried properly and some became turbid. Then when HPMC 200 mg and Eudragit L- 100 100mg were taken then patches became clear and dried properly.

 

Method of Preparation:

The solutions of both the polymers HPMC K4M and Eudragit L- 100 were prepared by blending HPMC K4M in 10 ml of Methanol and Eudragit L- 100 in 10ml of Dichloromethane. Mix mixture of dichloromethane solution of Eudragit L- 100 in methanolic solution of HPMC K4M by the side of the beaker. Put the solution stable to remove the bubbles for 30 min. After, add weighed quantity of Clotrimazole and Betamethasone Dipropionate in that mixture and blend properly to solubilize drugs. Again, put solution stable to remove bubbles for 20min. Then add propylene glycol in it and stable it for 10min. In order to allow the solvent to evaporate, the petri plate had the solution, which was then dried for 24 hours at room temperature. One may regulate how much solvent evaporates by inverting the glass funnel over the petri dish. Later, patches were scraped off, allowed to dry for two to four days, and then cut into circles. These patches were put in desiccator and wrapped in aluminium foil10. The factorial design optimization concentrations were shown in Table 1.

 

Evaluation Parameters:

Physical Appearance: Visual assessments were made of each prepared patch for physical appearance11.

 

Weight Variation:

A defined patch area should be divided into multiple parts, each of which must be separately weighed on a digital scale. The individual weights should be used to calculate the average weight12.

 

Folding Endurance:

A strip of a particular area was evenly cut, folded repeatedly at the exact position, and then broken. The folding durability of the film was determined by counting the number of folds that it could endure without cracking13.

 

Thickness:

The thickness was determined with a digital micrometre screw gauge (Vernier Caliper), and the average value was computed14.

 

Drug Content:

A patch of 1x1 cm2 was totally dissolved in 10ml of phosphate buffer solution (pH 7.4) to assess the amount of medication it contained. By putting the patch with the solution on a shaker for roughly 24 hours, total breakdown was achieved. The solution was filtrated after a suitable dilution, and the number of drugs was determined spectrophotometrically at 262 and 240        nm15, 16.

 

Surface pH:

Using a pH meter, the surface pH of the produced transdermal patch was determined. With the aid of water, Patch became a little moist. By placing the electrode against the patch's surface, the pH was determined17,18.

 

Percentage Moisture Absorption:

The patches were placed within a desiccator with a saturated solution of aluminium chloride. The films were taken off three days later and weighed to assess how much moisture they absorbed19,20,21.

 

                                     Final weight – Initial weight

Percentage Moisture = -------------------------------- × 100

Absorb (%)                             Initial weight

                                                      

Percentage Moisture Loss:

The created patches were weighed separately and desiccated with fused calcium chloride for 24 hours at room temperature. The patches were reweighed after 24 hours, and the approach below was used to calculate the percentage of moisture loss22,23.

 

                                     Initial weight – Final weight

Percentage Moisture Loss (%) = --------------------- × 100

                                                       Initial weight

 

Swellability:

The 1 cm2 of film-weighed patches were immersed in distilled water for 0.5, 1, 2, 4, 8 and 24 hours. Films that had been soaked were removed from the medium at the proper time, washed to eliminate extra liquid, and weighed right away. The weight rises in the method calculated as given below was used to calculate the swelling index24,25.

 

                                Final weight – Initial weight

Swellability (%) = ------------------------------------- × 100

                                           Initial weight

 

 

 

Table 1: Optimization batches developed by 32 factorial designs

Ingredient

Formulation Code

F1

F2

F3

F4

F5

F6

F7

F8

F9

Clotrimazole (mg)

20

20

20

20

20

20

20

20

20

Betamethasone Dipropionate (mg)

1.28

1.28

1.28

1.28

1.28

1.28

1.28

1.28

1.28

Hydroxypropyl methylcellulose (mg)

400

400

400

350

350

350

300

300

300

Eudragit L -100 (mg)

300

250

200

300

250

200

300

250

200

Methanol (ml)

10

10

10

10

10

10

10

10

10

Dichloromethane (ml)

10

10

10

10

10

10

10

10

10

Propylene Glycol (ml)

5

5

5

5

5

5

5

5

5

 

In-Vitro Drug Release Study:

The 20 ml Franz diffusion cell was utilized for in vitro drug diffusion investigations, using an egg membrane as the skin. A magnetic stirrer and pH 7.4 phosphate buffer were placed inside the receptor compartment. At intervals of 1, 2, 3, 4, 6, 8, and 12 hours, samples were taken and replaced, and a UV-visible spectrophotometer was used to determine how much medication had permeated, the absorbance is measured at λmax 262 nm and 240 nm, the number of drugs that penetration was calculated. Further by using mathematical models the drug release mechanism and kinetics of release rate were determined26,27,28.

 

Steady state flux:

Steady state flux (Jss) is equal to Q/ (A.t), where A is the membrane's exposed area in cm2 and Q is the amount of substance that was carried across the membrane in time t. A steady state flow is measured in quantity/(cm2.hr)29, 30, 31.

 

RESULT:

Organoleptic properties:

Both the drug's white, crystalline, and odorless organoleptic qualities were confirmed to be within acceptable limits32, 33.

 

Melting point:

The melting points of Clotrimazole and Betamethasone Dipropionate were found to be 146±2℃ and 176±1℃ respectively, which are like the reported melting point values indicate that samples were pure.

 

UV absorption maxima:

The maximum wavelength of Clotrimazole and Betamethasone Dipropionate in 7.4 Phosphate buffer was found to be at λ max 262 nm and 240 nm. The figure 1 and figure 2 shows the λmax of drugs and calibration curves of both the drugs.

 

Drug Excipient Compatibility:

Fourier transform infrared spectroscopy:

From the FTIR of Clotrimazole and Betamethasone Dipropionate we could conclude that FTIR gives prominent peaks of both the drugs as shown in figure 2. So, the drugs were pure and determined as the same. The FTIR spectra of the mixture show the presence of all the important functional group peaks of both the drugs which indicates that there is no shift in any peak of drugs.  This implies that the mixture of drugs and polymers was found to be stable, compatible, and safe to use.

 

Differential Scanning Calorimetry analysis:

The endothermic plot in the DSC thermograms of Clotrimazole and Betamethasone Dipropionate pure APIs was found to be at 147.68°C and 181.76°C, respectively as shown in figure 2. This demonstrates the purity and crystal structures of these drugs.

 

Figure 1. 𝝺max of both the drugs (A) Clotrimazole (B) Betamethasone Dipropionate (C) Simultaneous estimation of both drugs

 

Figure 2. 1. FTIR of (A) Clotrimazole; (B) Betamethasone Dipropionate; (C) Physical Mixture of both the drugs (D) Physical Mixture of drugs and excipients ; 2. DSC of (A) Clotrimazole; (B) Betamethasone Dipropionate; (C) Mixture of drugs and excipients

 

Solubility:

According to the solubility investigation, Clotrimazole and Betamethasone Dipropionate were slightly soluble in ethanol but easily soluble in methanol and dichloromethane. Both medications were insoluble in phosphate buffer and water.

 

Evaluation Parameters:

Physical Appearance:

The physical appearance of all 9 batches of transdermal patches was found to be transparent, clear, flexible, smooth, and non-sticky.

 

Physical Characteristics:

The manufactured transdermal patches' weights for various combinations varied from 0.635 to 1.49 gm.  The findings showed that patches of batches F6, F8 and F9 shows folding endurance less than 200. Each film's thickness was determined to be consistent across all formulations. The thickness of the patches ranged from 0.40 mm to 0.72 mm. It can be used on skin as it is not too acidic or alkaline as it did not irritate skin. The pH was found to be in between 6.48- 7.31 as shown in Table 2.

 

Table 2: Physical characteristics of transdermal patches

Formulation

Code

Thickness

(mm)

Folding

Endurance

Surface

pH

Weight

(gm)

F1

0.52

252

6.79

1.023

F2

0.71

235

6.56

1.284

F3

0.40

222

6.48

0.881

F4

0.45

211

6.56

1.031

F5

0.72

233

7.31

1.398

F6

0.63

167

6.92

1.393

F7

0.36

212

6.49

0.635

F8

0.63

153

6.50

1.49

F9

0.43

136

7.20

1.07

 

Drug Content:

The drug content of clotrimazole was found in between 88.12- 98.78% and betamethasone dipropionate was found in between 89.91- 98.82%.

 

Physicochemical characteristics:

The percentage moisture uptake was found to be in the range of 1.32% to 4.79 %. The hydrophilic polymer enhanced surface wettability, which led to better water absorption into the matrix and the considerable swelling. The swelling index was found in between 43.6% to 87.47% as shown in Table 3.

 

Table 3: Physicochemical characteristics of transdermal patches

Formulation

Code

Moisture

Uptake (%)

Moisture

Loss (%)

Swelling Index (%)

F1

4.794

3.967

87.51

F2

4.086

2.288

78.54

F3

3.710

2.201

61.11

F4

3.176

3.177

55.82

F5

2.821

1.326

52.24

F6

1.810

1.843

48.18

F7

1.724

4.509

45.91

F8

1.534

2.734

43.60

F9

1.229

1.347

40.17

 

In-Vitro Drug Release Study:

Transdermal patch batches' diffusion profiles demonstrate that Eudragit L-100's hydrophobic polymer is to blame for this. For 12 hours, the medication release from the patch is controlled. According to Tables 8 and 9, the cumulative %drug release for all formulations ranged from 35.38% to 75.91% in 12hours for clotrimazole and from 37.86% to 67.09% in 12hours for betamethasone dipropionate. The graphs of cumulative drug release of clotrimazole and betamethasone dipropionate were given in figure 3.


 

Figure 3. Percent cumulative drug release of F1 to F9 batches of (A) Clotrimazole (B) Betamethasone Dipropionate

 

Figure 4. Kinetic study graphs (A) Zero order (B) First order (C) Higuchi (D) Korsmeyer Peppas

 

Kinetic study:

The data was subsequently fitted into Zero order equation to corroborate the diffusion mechanism. As the peppas equation shows n value 0.169 for both drugs, it follows fickian diffusion.

 

Optimization data analysis:

In this design, 32 factorial design was used following the linear model. 2 factors were taken which are observed as independent variables such as HPMC K4M and Eudragit L-100 and as dependent variables 3 responses were taken such as %Drug release of clotrimazole, %Drug released of betamethasone dipropionate and %Moisture uptake.

 

Steady state flux:

The F5 batch shows highest steady state flux which was 2.590 µg/cm2 12hr and 2.922 µg/cm212hr for both clotrimazole and betamethasone dipropionate. 

 

 

Stability Study:

The optimised transdermal patch (F5) completed three months of stability testing, and it was found that there had been no significant alterations to the drug content, in vitro drug release, or steady state flux and F5 was steady.

 

Antifungal Study:

The antifungal study of the formulation has been done and the patch shows antifungal activity up to 30mm as compared to nystatin. The antifungal activities of drugs were shown in figure 9.

 

Figure 5. Zone of Inhibition of Clotrimazole and Standard Sample (Nystatin)

 

DISCUSSION:

The objective of this study was to develop a transdermal patch that releases medications gradually, clotrimazole and betamethasone dipropionate using solvent casting and a variety of polymers, including HPMC K4M, Eudragit L-100, and ethyl cellulose, as well as plasticizers, including PEG-400 and propylene glycol, as penetration enhancers. It took several test batches to find the ideal polymer combination. Hydrophilic and hydrophobic polymers were properly combined. The ideal pairing of HPMC K4M, a hydrophilic polymer, and Eudragit L-100, a hydrophobic polymer, was discovered after several combinations. Transdermal patches showed outstanding swelling and maintained the crucial formulation integrity when the weight gain or water absorption of the patches caused by the polymer's presence was evaluated. The amount of moisture transfer across a patch's unit area was measured in order to ascertain the permeation qualities. A minimum water vapor transfer rate means a stronger stability, even in humid environments. The patches are kept constant and kept from becoming brittle by the low water loss and absorption percentages, which also shield them from microbial growth. Clotrimazole and Betamethasone Dipropionate loaded with polymers HPMC K4M - Eudragit L-100 with propylene glycol as a plasticizer were found to be the best formulation, with drug release of 75.91% and 67.09%, respectively, of both medications, according to in-vitro drug studies. The physicochemical and drug release characteristics of the patches containing Clotrimazole and Betamethasone Dipropionate remained largely unchanged after three months. It was discovered that the quantity of HPMC K4M had an effect on water uptake, i.e., when its quantity was enhanced, water absorption also was enhanced, demonstrating that determining the interplay of formulation factors was facilitated through optimization. Additionally, it was discovered that increasing both the polymer concentration and the drug quantity reduces drug release. To look at the drug release kinetics, the zero-order and Korsmeyer-Peppas models were compared. Zero order kinetics for drug release were produced by the formulation of TDDS patches. When the release data was evaluated using Peppa's equation, TDDS patches confirmed fickian diffusion as the release mechanism. These transdermal patches of Clotrimazole and Betamethasone Dipropionate may provide sustained release transdermal distribution for prolonged periods of time in the treatment of candidiasis, which may be a good strategy to prevent significant hepatic first-pass biotransformation, according to the findings of this study. The results of the investigation showed that it is feasible to create transdermal patches of betamethasone and clotrimazole that are controlled in rate. More in-vivo research is required to match in-vitro permeability trials in order to develop a suitable transdermal system for Clotrimazole and Betamethasone Dipropionate.

 

Following many test batches, it was determined that the formulation is suitable for the HPMC K4M and Eudragit L- 100 combination. 9 formulations were created, a 32 full factorial design was taken into consideration, and its primary assessments were completed. According to an in-vitro drug release study, the F5 batch had the best release. The best batch among the others, demonstrating good stability parameters, was found to be F5, according to the stat easy design software. To confirm which kinetic model it complies with, kinetic investigations were also carried out.

 

CONCLUSION:

The goal of this study was to create a transdermal patch that would distribute clotrimazole and betamethasone dipropionate continuously. By using the solvent evaporation approach, transdermal patches of betamethasone dipropionate and clotrimazole have been produced successfully. Evaluation of the prepared patches reveals that the method used to produce the transdermal patches was repeatable, ensured outstanding quality, and had the least amount of variability in patch characteristics in terms of physical appearance, weight, thickness, surface pH, folding endurance, moisture absorption, moisture loss, swelling index, and uniformity of drug content. Additionally, investigations on the drug release in vitro and ex vivo showed that all formulations released the drug, and within 12 hours, 75.91% and 67.09% of the medication was released nearly completely, respectively. These findings demonstrate that transdermal delivery of clotrimazole and betamethasone dipropionate can potentially be used in therapeutic situations, offering benefits such as decreased dosing frequency, increased patient compliance, non-invasive nature, improved bioavailability, and simple therapy termination.

 

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

 

ACKNOWLEDGMENTS:

The authors would like to thank support staff of GES’s Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research, Nashik for their kind support during completion of this research work.

 

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28.   Gajbhiye K, Hakam N, Rathod G, Tawar M. Formulation and evaluation of transdermal patches of benidipine hydrochloride. Asian Journal of Pharmacy and Technology. 2021; 11(3): 207-12. doi.org/10.52711/2231-5713.2021.00034

29.   Latha AV, Kumar JN, Sojana N, Mounika N, Priyanka G, Venkatesh A. Design and Optimization of Clotrimazole Emulgel by using various Polymers. Asian Journal of Pharmacy and Technology. 2021; 11(1): 41-7. doi.org/10.5958/2231-5713.2021.00007.6

30.   Banu VT, Jaiswal VA, Ansari MS. Formulation and evaluation of transdermal patches of decongestant drug. Research Journal of Pharmaceutical Dosage Forms and Technology. 2022; 14(3): 195-8. doi.org/10.52711/0975-4377.2022.00031

31.   Alhaushey L, Ahmad RD. Formulation and Evaluation of Celecoxib Transdermal Patches. Research Journal of Pharmacy and Technology. 2023; 16(4): 1574-80. doi.org/10.52711/0974-360X.2023.00257

32.   Sejal Patel, Anita P. Patel. Formulation and Evaluation of Benidipine Nanosuspension. Research Journal of Pharmacy and Technology. 2021; 14(8): 4111-6. doi.org/10.52711/0974-360X.2021.00712.

33.   Singh RK, Garg R. Formulation and Evaluation of Erythromycin Estolate Loaded Drug Balls. Research Journal of Pharmacy and Technology. 2020; 13(1): 282-6. doi.org/10.5958/0974-360X.2020.00057.8

34.   Prasad KC, Pavani S, Sri SR. Formulation and Characterization of Transdermal Patches for Controlled Delivery of Cyproheptadine. Research Journal of Topical and Cosmetic Sciences. 2022; 13(2): 71-5. doi.org/10.52711/2321-5844.2022.00012

 

 

 

 

Received on 07.08.2023            Modified on 15.02.2024

Accepted on 22.06.2024           © RJPT All right reserved

Research J. Pharm. and Tech 2024; 17(9):4267-4274.

DOI: 10.52711/0974-360X.2024.00660