Preparation and Characterization of Aceclofenac-Loaded Amphiphilogels for Transdermal Drug Delivery

 

Himani Bajaj^1*, Vinod Singh ², Ranjit Singh ³, Tirath Kumar¹

¹Department of Pharmaceutical Sciences, Bhimtal Campus, Kumaun University, Nainital.

²Department of Pharmaceutical Sciences, Gurukul Kangri Vishwavidyalaya, Haridwar.

³AVIPS, Shobhit University, Gangoh, Saharanpur.

 

ABSTRACT:

The surfactant-based amphiphilogels were prepared using different surfactant combinations, such as Span 60, Tween 80 and Tween 20. Different concentrations of gelator (Span 60) within the fluid phase (Tween 20 and Tween 80) was investigated to optimize the correct combination which can result in amphiphilogels. Various test formulations were prepared and evaluated for various physicochemical properties, such as physical appearance, homogeneity, percentage gelation and formulation pH. Optimized formulations were further evaluated for spreadability, rheology, drug content and in-vitro drug permeation. The formulations were also evaluated for their stability studies. The pH of the test formulations was found within the acceptable range for transdermal application. The ex-vivo skin permeation studies showed that all the formulation have good skin permeation property due to the presence of surfactant as a main structural framework. The formulation 19% w/w (F2) in span 60- tween 20 and 29% w/w (A3) span 60 -tween 80 showed greater rate of skin permeation among all formulations. The developed amphiphilogels could be a potential drug delivery system for hydrolytic drugs and it provides a good platform for the management of arthritis.

 

 

 

INTRODUCTION:

The transdermal drug delivery systems gained popularity due to their ability to overcome the limitations associated with the conventional oral routes, such as first-pass effects, gastrointestinal irritation, and metabolic degradation¹. To date, various gel formulations have been prepared for enhanced transdermal drug delivery². The gel formulations have their own advantages, such as ease of formulation development, both hydrophobic and hydrophilic drug can be delivered, ease of application and removal, and can be used for the sustained drug release with some modification³. However, effective permeation of the drug through the transdermal barrier is still a challenge in front of a formulation scientist.

 

In order to full fill the unmet need, an advanced transdermal drug delivery system is of prompt requirement.

 

The gel is termed as hydrogel when the liquid component of the system is aqueous. When the liquid component of the system is replaced by an organic medium it is termed as an organogel. The amphiphilogels are the system where the liquid component of the system is replaced by a surfactant (Amphiphilic nature), it is termed as amphiphilogels⁴. In amphiphilogels, one surfactant acts as a gelator which causes gelation of another surfactant. Hence, sometimes the system also termed as surfactant-in-surfactant gels⁵. Amphiphilogels are an excellent carrier for poorly water-soluble drugs. Studies have shown that the amphiphilogels increase the solubility and the bioavailability of the poorly water-soluble drug, such as Cyclosporine through oral administration⁶ Amphiphilogels were also effectively used for the transdermal drug delivery application2. In-vivo studies of non-ionic surfactants based amphiphilogels in rat and human have shown enhanced transdermal/transdermal permeation of the drug with no significant irritation⁷.

 

To date, a few studies have been conducted on the transdermal application of amphiphilogels. Therefore, in the present investigation, an attempt has been made to develop a non-ionic surfactant based amphiphilogels for transdermal delivery of Aceclofenac. Surfactant-based amphiphilogels were prepared using different combinations of surfactants, such as Span 60 combined with Tween 80 and Span 60 combined with Tween 20. The developed formulations were evaluated for various physicochemical properties, such as physical appearance, homogeneity, percentage gelation, formulation pH, spreadibility, rheology, drug content and in-vitro drug release. The skin permeation study was evaluated using rat skin and Franz-diffusion cell.

 

MATERIAL AND METHOD:

Materials:

Aceclofenac was gifted from Shiva Biogenetic pharmaceuticals Pvt. Ltd., Solan, India. Span-60 (sorbitan monostearate), Tween 80 (Polysorbate 80) and Tween 20 (Polysorbate 20) were purchased from Loba Chemie, Mumbai, India. All other chemicals used in the study are of analytical grade.

 

Drug-polymer interaction:

The drug-excipients interactions were analyzed using FTIR spectroscopy. Potassium bromide (KBr) dispersion method was used to record the FTIR spectrum of ACF and polymers using AX-1 spectrophotometer (Perkin Elmer, USA). The gel samples were dried and crushed so as it can be easily combined with KBr (1:1) were recorded over the range of 400 to 4000 cm^-1 with the resolution of 4 cm^{-1 8}.

 

Formulation of drug-loaded amphiphilogel:

Surfactant-based amphiphilogels of Aceclofenac (ACF) were fabricated as per the method described in the literature^9,10. Briefly, as a solid component of the system, Span 60 (S60) is used as the gelator and Tween 20 (T20) and Tween 80 (T80) were used as a fluid phase of the system.  The drug was dissolved in the liquid phase of the system using a glass vial. The vial was then placed in a water bath at 60⁰C for 10 min with occasional vortexing. After continuous heating along with occasional vortexing, a solution (sol phase) was developed. Then, Span 60 was added with continuous stirring and the final solution was allowed to cool at room temperature and kept overnight for sol to gel transformation. Butylated hydroxy toulene (BHT) was added as a preservative.

 

Preparation of test formulations:

Different concentration of gelator (Span 60) were investigated to optimize the correct amount of surfactants that can be used to develop drug-loaded amphiphilogels. In amphiphilogel having Tween 20 and Span 60, different concentration of gelator (Span 60, 5-25 % w/w) were tested with liquid phase (Tween 20, Quantity sufficient). Similarly, amphiphilogel having Tween 80 and Span 60 as a main structural components, different concentration of gelator (Span 60, 5-30%) were tested with liquid phase (Tween 80, Quantity sufficient). All the tested concentrations of gelators for the development of drug-loaded amphiphilogel are mentioned in table 1 (b) and 2 (b).

 

Table-1:

(a)    Minimum gelation concentration of gel with span 60 and tween 20

 

(b)   Test formulations using Tween 20 and Span 60

 

Table-2:

(a)    Minimum gelatin concentration of span 60 with tween 80

 

(b)   Test formulations using Tween 80 and Span 60

 

Evaluation of test preparations:

The test preparations which showed the gel formation F1, F2, F3 and A1, A2, A3, A4 were selected and evaluated for various physicochemical properties, such as physical appearance, percentage gelation, pH, drug content, homogeneity, spreadability and viscosity.

 

Physical appearance:

The physical appearance of the test gel preparations were studied using the method as described in the literature¹¹. The glass vial having sol form of the test preparations F1, F2, F3 and A1, A2, A3, A4 were kept on standing overnight at room temperature for cooling. Following a cooling period, the glass vial was inverted to confirm the formation of the gel. The appearance was inspected via visual inspection.

 

Percentage gelation:

To determine the percentage gelation, required amount of the test gel preparations F1, F2, F3 and A1, A2, A3, A4 in the sol phase were weighed and kept in a glass container overnight for gelling. After 24 hr, the gel portion of the test preparations were carefully taken out from the glass container with the help of the spatula and weighed¹².  The percentage gelation was calculated using the following formula,

 

                      Weight of developed amphiphilogels

% gelation= ––––––––––––––––––––––––––––––– ×100

                     (Initial weight of the gelling solution)

 

pH measurement:

Depending upon the physicochemical properties, such as appearance and percentage gelation, formulations F1, F2, F3 and A1, A2, A3, A4 were selected for further studies. The pH measurement of the optimized gel formulations (F1, F2, F3 and A1, A2, A3, A4) was carried out using a digital pH meter. About 1gm of the gel was dissolved in 100ml freshly prepared distilled water and stored for two hours. The measurement was carried out in triplicate (n=3)¹³.

 

Drug content of the gel:

The optimized formulations of 1gm were taken in a volumetric flask filled with 100ml of PBS (pH 5.5). The volumetric flask filled with drug-loaded gel along with PBS stirred for 2 hr using a mechanical stirrer in order to dissolve the drug from the gel into the solvent. The solution was filtered through Whatman filter paper. The absorbance was recorded by UV Vis spectrophotometer at 275nm after suitable dilutions. Drug content was determined using the slope of the standard curve previously plotted¹⁴.

 

Homogeneity:

The optimized formulations F1, F2, F3 and A1, A2, A3, A4 were placed on the petri dish and allowed to set into it. These formulations were evaluated for their appearance and any possible aggregates via visual inspection¹⁵.

 

Spread ability:

The spreadability of the optimized formulations F1, F2, F3 and A1, A2, A3, A4 is studied as per the method described in the literature¹⁶.The spreading capacity of the gel was measured 48 h after formulations have been developed. Briefly, two glass slides of standard dimensions were taken and the developed gel formulation (2g) was placed over one of the slides. The other slide was placed over the gel in such a manner that the gel was sandwiched in between the two slides uniformly to form a thin layer in an area occupied by a distance of 7.5cm along the slides. The slides were fixed to a stand in such a manner that only upper slide will slip off freely by the force of weight tied on it. A 20g weight was tied to the upper slide carefully and the time taken for the upper slide to travel the distance of 7.5 cm and separated away from the lower slide under the influence of the weight was noted. The experiment was repeated for three times (n=3). Spreadability was calculated by using the following formula,

 

S = L / T

 

Where, S-Spreadability, M-weight tied to upper slides, L- length of the glass slide (7.5cm) and T- time taken in sec.

 

Rheological Studies:

The viscosity and the torque of the optimized gel formulations were measured using a digital Brookfield viscometer LVDV II+ model with S 64 spindle¹⁷. The measurement was performed at a controlled temperature of 30 ± 2°C. About 0.5gm of the optimized formulations were used for the measurements. The viscosity and torque were determined at 20, 50 and 100rpm. The experiment was carried out in triplicate (n=3).

 

Ex-vivo skin permeation study of gel:

Ex-vivo skin permeation study was carried out as per the method described in the literature¹⁹. The experimental procedures and protocols were reviewed and approved by the Institutional Animal Ethical Committee (IAEC) [CPCSEA/IAEC/SBS/2017-18/009]. A section of the young rat skin (3 × 3mm) from the abdominal region of the rat was carefully excised after animal sacrifice. The hairs on the skin were removed with the help of scissors and any undesirable matter was wiped-out with the help of cotton. The cleaned skin was then washed with saline before the experiment. Ex-vivo skin permeation of ACF-loaded amphiphilogels F1, F2, F3 and A1, A2, A3, A4 was investigated at predetermined time points 0, 15, 30, 60, 90 and 120 min using Franz-diffusion cell. The abdominal skin was washed with PBS (pH 5.5) and mounted over the diffusion cell. About 1gm of the gel was placed on the donor compartment and covered with aluminium foil to prevent drying out of the gel. The temperature of the cell was maintained at 37 ± 5⁰C and the medium was by magnetic stirrer at 100 rpm.

 

Sample (2ml) were collected from the receptor compartment at a predetermined time intervals and then immediately analyzed spectrophotometrically at 275nm against a blank prepared with the permeated formulation without the drug. At each sampling time point, the medium of receptor compartment was replaced by the equal volume of fresh medium. The experiment was carried out in triplicate (n=3). Cartesian plots with the cumulative amount of drug present in receptor compartment versus time were plotted.

 

Stability studies:

The optimized formulations were prepared and stored in glass vials and kept at room temperature for 3 months. The stability of the formulations was analyzed for colour, odour, drug content, pH, and phase separation²⁰.

 

RESULTS:

Drug-polymer interaction:

The drug-polymer interaction may affect the physicochemical properties of the formulation, such as drug stability, drug-encapsulation efficiency and drug release²². Therefore, evaluation of the drug-polymer interaction is of great interest to develop stable formulation. FTIR spectrum of the drug ACF and its physical mixture with other excipients were recorded over the range of 400 to 4000 cm^-1with the resolution of 4 cm^-1(Figure 1).

 

Figure 1: FTIR spectrum of (A) Aceclofenac, (B) Aceclofenac + Tween 20, (C) Aceclofenac + Tween 80 and (D) Aceclofenac + Span 60.

 

The FTIR spectrum of ACF showed various characteristic peaks which were used to investigate any possible interaction. The peak-1 (3318 cm^-1) represents N-H Stretching related to broad secondary amine and carboxylic acid (hydroxyl) band in ACF. Peak-2 (1771.5 cm^-1) represents –C=O Stretching of ketone band. Peak-3 (1716.8 cm^-1) represents -C=O Stretching of ketone band. Peak-4 (1589.5 cm^-1) represents the C=C bending of the aromatic group. Peak-5 (1500 cm^-1) represents C-C bending of the aromatic group. Peak-6 (1480.61 cm^-1) represents the C=C bending of the aromatic group.  Peak-7 (1178.86 cm^-1) represents C-O stretching of carboxylic acid in ACF (Figure 1 A). The FTIR spectrum of the drug-surfactants also showed the characteristic peaks of ACF which indicate the compatibility and their suitability for the formulation development (Figure 1 (B-D)).

 

Evaluation of test preparations:

To optimize the ratio of the gelator (Span 60) and the fluid phases (Tween 20 and Tween 80), various test preparations were developed (Table-1 and 2). Depending upon the variable compositions, different test formulations F1, F2, F3 and A1, A2, A3, A4 have been prepared. These optimized formulations were further evaluated for physical appearance, percentage gelation, pH, drug content, homogeneity, spreadability and viscosity.

 

Physical appearance:

The developed test formulations F1, F2, F3 and A1, A2, A3, A4 in a sol form with varying compositions were stored overnight for sol-gel transformation. Formulation with different concentrations of gelator (S60), were evaluated for their appearance and physical form. Results showed that at a lower concentration, the sol form failed to convert into gel form. However, with an increase in the concentration of S60, the sol form converts into the gel form (Figure 2).  The test formulations F1, F2, F3 and A1, A2, A3, A4 showed proper gel formation. The developed formulations were slightly yellow in colour.

 

Figure 2: Amphiphilogels. (A) Formulation T (20/60) and (B) Formulation T (80/60).

 

Percentage gelation:

The concentration of the gelators has a huge impact on the transformation of the sol form into the gel form which can also be observed from the appearance of the gels²³. As per the previous report and the results obtained in the present investigation, increase in the concentration of the gelator increases the percentage gelation. At the low gelator concentration, the sol form failed to transform into a proper gel state. However, it remains as liquid state. The study showed that in formulation of Span60 with Tween 20 the percentage gelation increases from 0 to 96.32±0.32%. In the similar fashion, the formulations of Span 60 with twen 80, showed an increase in the percentage gelation from 0 to 98.81±0.21 %.

 

pH measurement:

According to USP the pH of the gels for transdermal applications should lie within the limits of normal skin pH of 4.5-6.5¹⁸. The pH range deviated from this range may cause immunological responses like redness, burning and itching of the skin. The prepared test gel formulations F1, F2, F3 and A1, A2, A3, A4 have a pH range of 5.4±0.18 to 6.3±0.08 which is within the pH range desired for the skin.

 

Drug content:

Formulations F1, F2 and F3 showed a drug content of 96.11±0.26%, 97.02±0.15%, and 98.32±0.17%. Whereas, formulation A1, A2, A3 and A4 showed a drug content of 95.41±0.16 %, 96.25±0.11%, 97.65±0.22 %, and 98.72±0.33%.

 

Spreadability:

The selected formulations F1, F2, F3, and A1, A2, A3, A4 were evaluated for the homogeneity and results shown a good homogeneity. In terms of spreadability, formulations F1, F2 and F3 showed a spreadability of 34.13±0.38, 32.11±0.25, 31.23±0.50mg.cms^-1. Formulations A1, A2, A3 and A4 showed a spreadability of 36.23±0.27, 34.22±0.45, 33.29±0.60, 32.11±0.15 mg.cm s^-1.

 

Viscosity:

The viscosity (cps) and torque (%) of the selected formulations F1, F2, F3, and A1, A2, A3, A4 were evaluated at 20, 50 and 100rpm using digital Brookfield viscometer LVDV II+ model with S 64 spindle (Table-3)^19,20. There was a decrease in viscosity with an increase of RPM which represents the resistive force offered by the gel to the rotation of the spindle. The viscosities of the selected formulations increases with the concentration of the gelator (Span 60).

 

Table-3: The viscosity of the amphiphilogel systems (Mean ± SD)

Formulation code	RPM 20	VISCOSITY (cps)	RPM 50	VISCOSITY (cps)	RPM 100	VISCOSITY (cps)
	% Torque		% Torque		% Torque
F1	32.2	7789	39.8	5476	53.6	2854
F2	34.7	9642	41.5	7723	58.3	5476
F3	35.9	9925	42.6	8438	61.2	6563
A1	31.5	6792	37.8	4361	46.3	2341
A2	33.3	10121	40.5	8641	48.5	6341
A3	34.2	13462	42.6	11023	51.2	9976
A4	36.4	15276	44.5	14323	54.3	13176

 

Ex-vivo skin permeation study of gel:

For in-vitro drug release, Franz-diffusion cell with a rat skin membrane (Electro Lab, India) filled with PBS (pH 5.5) was used^21-23. The drug release from the selected formulations i.e F1, F2, F3, and A1, A2, A3, A4 at the predetermined time intervals were shown in Figure 3 and Figure 4. All the selected formulations F1, F2, F3, and A1, A2, A3, A4 showed an initial burst release of the drug which is a common limitation with the gel formulations²⁴. This initial burst release state was followed via the complete release of the drug up to 120 min. Formulation F2 and F3 showed a more restriction or control over the drug release over the time compared to the F1. There is no significant difference between F2 and F3 release. Similarly, formulation A2, A3, A4 showed a more restriction or control over the drug release over the time compared to the A1. There is no significant difference between A2, A3, and A4 release.

 

 

Figure 3: Ex Vivo drug permeation of selected formulations of Tween 20-span 60.

 

 

Figure 4: Ex-vivo drug permeation of selected formulations of Tween 80-span 60

 

DISCUSSION:

In the current study, ACF-loaded amphiphilogels were developed using different combinations of surfactants, such as Tween 20, Tween 80 and Span 60. In order to optimize the surfactant concentration for the gel formation, different test formulations using span 60 with tween 20 and span 60 with tween 80 were prepared. Different concentrations of gelator (Span 60) were added within the fluid phase (Tween 20 and Tween 80) (Table- 1 and 2). As soon as the temperature of the formulation was lowered down simultaneously, the gelator starts precipitating the solvent system due to the formation of gelator crystals. These crystals are grown in size progressively as a fiber which interacts with each other to form three-dimensional networked gel structure^25,26. Increasing concentration of the surfactants in the above developed formulations (Table-1 and 2) results into the thick gel formulation with grittiness which may be due to the excessive formation of gelator crystals.  This may cause irritation when applied to the skin.

 

The drug and surfactants were found compatible with each other with no sign of interaction (Figure 1). The developed gel formulations were evaluated for various physicochemical properties, such as physical appearance, percentage gelation, pH. The test formulations which showed gel formation were selected for further characterization, such as drug content, homogeneity, spreadability and viscosity. The study showed that in the formulations of Span 60 with Tween 20 the percentage gelation increases from 0 to 96.32± 0.32%. In the similar fashion, the formulations of Span 60 with tween 80, showed an increase in the percentage gelation from 0 to 98.81±0.21%. The developed test gel formulations showed acceptable pH thus avoids any possible irritation at the site of application.

 

The spreadability is one of the most important properties of the semisolid transdermal formulation which ensures correct dose administration at the target site and overall therapeutic efficacy of the transdermal formulation. Therefore, it must be taken into consideration carefully during the development of the transdermal semisolid formulations^{27, 28}. The rate of spreading depends upon the viscosity of the formulation. In the selected optimized gel formulations, it has been found that the spreadability decreases with increase in gelator concentration which ultimately increases the formulation viscosity. The concentration of excipients and the rate of evaporation of the solvent from the formulations have a huge impact on the viscosity and thus spreadibility²⁹.

 

Depending upon the different physicochemical properties, formulations F1, F2, F3 and A1, A2, A3, A4 were selected for further analysis. The in-vitro drug release studies of the formulations showed an initial burst release from the gel system. The gel systems are known to have high initial burst release as their major limitation. However, a slight slowdown in drug release profile can be seen after 30 min. This could be due to the formation of the solid skeleton fibre network of the gelator molecules within the gel which reduces the diffusion of the loaded drug from the gel (Figure 3 and 4)³⁰.

 

The ex-vivo skin permeation studies revealed that all the formulations have good skin permeation property due to the presence of surfactant as a main structural framework. The formulation F2 in span 60 tween 20 and A3 span 60 tween 80 showed greater rate of skin permeation than plain drug solution. In addition to the surfactant action, low viscosity and good spreadability of formulation also facilitate the skin permeation. Depending upon the physicochemical properties, stability and skin permeation, formulation F2 and A3 can be selected for further evaluation by in-vivo study.

 

CONCLUSION:

To date, few studies have been conducted to investigate the potential of the amphiphilogels for transdermal application. The present study is an attempt in order to explore a good transdermal drug delivery system of Aceclofenac. Study also showed significant results indicating amphiphilogels as a good candidate for transdermal drug delivery with enhanced drug permeation properties.

 

ACKNOWLEDGEMENT:

The author also gratefully acknowledges SBS PG Institute of Biomedical Sciences and Research, Dehradun, India for providing the animal facilities.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Accepted on 29.07.2020           © RJPT All right reserved

Research J. Pharm. and Tech 2021; 14(3):1298-1304.