Formulation and Evaluation of Nanosponge-based Drug Delivery System of Aceclofenac for Topical application

 

Manishkumar Gupta¹, Birendra Shrivastava², Aditya Ghuge^2,3*, Neha Dand³

¹Department of Pharmacy, Faculty of Pharmaceutical Science and Nursing,

Vivekananda Global University, Jaipur, Rajasthan, India.

²Department of Pharmaceutics, School of Pharmaceutical Sciences,

Jaipur National University, Jaipur, Rajasthan, India.

³Department of Pharmaceutics, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India.

 

ABSTRACT:

A transdermal drug delivery system using nanosponge and BCS class II drug, Aceclofenac (ACE) was achieved using xerogel as a final dosage form. Blank Beta Cyclodextrin based nanosponge (CDNS) were loaded with aceclofenac to formulate ACE loaded CDNS not only can be effectively treated for osteoarthritis but also successfully evaluated using ex vivo skin permeation studies. Methods used for formulation of ACE loaded CDNS were found out to be effective and accomplished 89.29±2.59% drug entrapment. The optimized formulation had % drug loading of 72.16±3.13%. The zeta potential of the ACE-loaded CDNS was found to be -27.3±1.1mV. A zeta potential value close to ±30mV indicates good physical stability of the micro particles on account of electrostatic repulsion. ACE-loaded CDNS released more than 90% drug in just 150mins (2.5hrs) whereas the marked formulation and ACE drug released more than 90% drug in 240mins (4hrs) and 330mins (5.5hrs) respectively. The conclusion of the current work can be drawn as ACE-loaded CDNS based gel has the potential to improve the transdermal bioavailability of aceclofenac against osteoarthritis with less adverse actions.

 

 

 

INTRODUCTION: 

Transdermal Drug Delivery System (TDDS) is widely used routes of drug administration in relieving pain and helping in treating a lot of diseases. It is one the most easy and simple route for administration of drug onto body via skin, rectum, vagina, eyes, ears, and nose. Skin serves as the primary channel of topical medication delivery since it is the easiest organ to access on the human body for topical administration. TDDS has varied advantages like bypassing first pass metabolism, avoiding painful intravenous route and of the different anatomical and pathological pathways.

 

The biggest challenge with topical drug delivery is effective transfer of drugs across skin, Increasing efficiency and effectiveness of existing drugs by engineering into a novel system and formulating into topical formulations.^1-5

 

The major problems encountered by the conventional drug delivery system are the bioavailability and solubility. Targeting of drugs for spatial and temporal control is the obvious solution to overcome this problem for which various novel drug delivery systems such as solid dispersions, microemulsions, nanosponges, nanosuspensions, lipid-based nanospheres, nanocrystals, liposomes, proliposomes, niosomes, liquid crystalline systems, quantum dots, polymer-based delivery systems etc. have been explored to increase the solubility and bioavailability. The onset of nanoparticles has become a important step toward overcoming existing                 problems.

 

 

Nanoparticles, these are in the colloidal form with particle size ranging from 10nm to 1000nm. However, nanosponges (NS) took the lead among the current nanoparticle-based dosage forms because they effectively solubilize poorly water-soluble medications and simultaneously provide delayed release.^6-8

 

Nanosponge (NS) is a novel drug delivery system which comprises small particles with a narrow cavity of a few millimetres, which can carry both hydrophilic and lipophilic drugs. Nanosponge because of their minute size and spherical shape can release the drug at a specific site, increases the solubility of poorly water-soluble drugs, enhances stability, offers a wide pH range of 1-11, temperature range up to 130⁰C, improves dissolution, offers extended release of drug with fewer side effects, reduced drug dosing, non-irritant, non-mutagenic and cost-effective which increases the patient compliance. If we talk about the disadvantages there are only a few: dose dumping and loading are possible only for drugs which have small sizes.^9-11

 

The World Health Organization defines osteoarthritis (OA) as degeneration of cartilage in joints that is accompanied by bone hypertrophy and additional layering of the joint capsule. Middle-aged and elderly patients are most likely to suffer from the disease, with an estimated global percentage of 9.6% for men and 18.0% for women over 60 years old, although younger people can suffer from the disease as a result of injury or overuse.⁷ As part of the OA process, patients experience joint pain, stiffness and local inflammation. Joints in the hands and knees are the most commonly affected, which usually results in a decrease in mobility and physical activity, which negatively impacts a patient's quality of life and daily activities.^12-15

 

A common treatment for OA is nonsteroidal anti-inflammatory drugs (NSAIDs). In health professionals and among patients, NSAIDs are considered popular "over the counter" medicines because of their effectiveness compared to placebo. When compared with other NSAIDs, including diclofenac, ACE showed relatively better gastric tolerance. Economic benefits are also expected from ACE due to its better tolerability and significant efficacy. The use of ACE has been reported to be well tolerated.^16-20

 

In fact, formulation scientists frequently propose this route of delivery as a means of avoiding the gastric side effects. Furthermore, topical administration of ACE will minimize the possibility of drug-drug interactions. As a result, topical therapy is both safe and effective as well as economically viable too.

 

Cyclodextrin-based nanosponges could prove to be effective in the transdermal delivery of aceclofenac. Owing to their porous natures, they would have higher drug loading capacity as compared to other nanocarriers. Their small size and biocompatible nature would aid in the improved permeability of the drug via the stratum corneum.

 

MATERIALS AND METHODS:

Materials:

Aceclofenac (ACE) was received as a Gift sample from Umedica Labs., Mumbai. Rest of chemicals and excipients of analytical grade were purchased from local suppliers.

 

Synthesis of Blank Cyclodextrin Based Nanosponges (CDNS):

CDNS can be synthesized using both common traditional heating techniques, like melt and solvent evaporation methods, as well as newer heating techniques, like microwave and ultrasonic wave-assisted methods. Conventional methods, melt as well as solvent evaporation were used in this case to produce CDNS. Amongst these synthetic processes a method which was found to be most effective in terms of simplicity in processing parameters and quality of the product formed was further optimized.²¹

 

In melt method CDNS were fabricated by changing ratios βCD (beta Cyclodextrin), polymer and DPC (Diphenyl Carbonate), Crosslinker (1:2 to 1:10). For synthesis, DPC was kept in 100ml flask and it was heated to approx. 100°C. DPC has a melting point of 89 °C, thus an operating temperature above its melting point was chosen to ensure complete and rapid cross-linking of the cyclodextrins to form nanosponges. After it has melted anhydrous βCD is added and the reaction mixture is heated for 5h under magnetic stirring at 500 rpm. Numerous needle-shaped crystals of phenols formed at the top of flask, which were removed carefully. After reaction mixture reached at room temperature, resultant product washed using distilled water to remove phenol by product, the washing water was tested for phenol after every wash by adding 1ml of acidified ferric chloride solution 1% w/v. In order to remove the unreacted βCD and DPC, the product was further washed with acetone. The amount of distilled water and acetone needed for the washings was determined by repetitive washings and scanning the filtrate obtained after each washing for the presence of impurities i.e., phenol and unreacted DPC at their λ max 446 and 260nm respectively. The prepared NS were dried in an oven overnight at 60°C and finally powdered. Final product was stored at 25°C in a desiccator for further studies.²²

 

 

Optimization of blank CDNS:

The variables that are crucial for formula development were found and the data were analysed using Statease® Design-Expert v13 Software. Using a systematic approach known as formulation by design, which is based on the ideas of DoE and QbD, it is feasible to find the optimal formulation with the least amount of time, expense, and effort. Box-Behnken Design (BBD) of a three-centric, three-factor, two-level yielding 15 runs was employed for optimization of blank CDNS. This design includes an appropriate method for determining the effects of formulation components and variables (independent factors) and their corresponding impact on the response variables (dependent factors).

 

The formulation variables (independent factors) in this study were the molar concentrations of βCD (A), DPC (B), and reaction time (C) at two levels. These variables, which could affect the extent of polymerization by quantifying the percent yield and extent of bond formation, were chosen as response variables (dependent factors). Studying the effect of different independent variables on the responses under study response surface analysis was carried out.²³

 

Characterization of CDNS:

The optimized CDNS were evaluated for the responses such as yield (%) and particle size. For the determination of yield (%), washed and dried NS weighed and determined by formula (1) for each of the 15 runs.

 

Percent yield =

(Practical yield) / (Theoretical yield) X 100 …………. (1)

Where, practical yield = the weight of the product obtained,

 

Theoretical yield = weight of CD taken corresponding to moles for the reaction+weight of the cross linker corresponding to the moles taken for the reaction.

 

Particle size of the nanosponges, photon correlation spectroscopy was determined using a Zetasizer Nano ZS 90 (Malvern® Instruments Limited, Worcestershire, UK).²⁴

 

Drug loading:

300mg of optimized CDNS were suspended in 20ml distilled water 20ml. Then, a 20mg quantity of the ACE was dispersed in suspension and the resulting mixture kept for sonication for 10minutes. This preparation was mixed for 24hours employing a magnetic stirrer at 200 rpm. After 24h, centrifugation at 3000rpm for 10min was doen for the suspension to separate the un-complexed ACE as a residue below the colloidal supernatant. The colloidal supernatants were lyophilized for about 48hours to yield dried ACE loaded CDNS.²⁵

 

TEM study:

To study the surface morphology of the particles, TEM studies for blank CDNS and ACE loaded CDNS were carried out using TECNAI 12 G2–Transmission Electron Microscope (Field Electron and Ion Company, FEI). Samples were prepared by dispersing the appropriate amounts of nanosponge powders into the distilled water. Acceleration voltage of 120kV and 0.49 nm resolution were used to take the scans at 11000x and 46000x resolutions.

 

Entrapment efficiency:

For determining %entrapment efficiency (EE) accurately weighed 5mg of prepared drug-loaded nanosponges from each batch were taken in 10ml methanol. The suspension was shaken gently and allowed to stand for 5 min and centrifuge at 2000rpm for 10mins to separate residue and supernatant. The supernatant was analyzed UV spectroscopically at 220nm by appropriate dilutions for the estimation of ACE which could have been adsorbed on the surface of the NS.

 

The residue obtained was resuspended in the 10ml methanol which was then sonicated for 30mins followed by centrifugation and UV analysis of the obtained supernatant. The %EE of ACE-loaded NS was calculated by equation 2.

 

EE (%) = (Initial amount of drug - Amount in the supernatant)/(Initial amount of drug) X 100 --------- (2)

 

Characterization of ACE loaded CDNS:

a) Fourier transform infrared spectroscopy (FTIR):

For optimized final ACE loaded CDNS, FTIR-ATR spectra were measured using IRSpirit FTIR, Shimadzu over a range of 4000-400cm-1.  Each spectrum was captured with a resolution of 4 cm-1 in a dry atmosphere to identify the new peaks or disappearance of peaks in drug loaded FTIR-ATR spectra as compared to the one obtained with blank CDNS.

 

b) Determination of Particle size, Polydispersity index and Zeta potential:

For the determination of average particle size and polydispersity index of the nanosponges, photon correlation spectroscopy using Using a Zetasizer Nano ZS 90 (Malvern® Instruments Limited, Worcestershire, UK), the average size, polydispersity index (PDI), and zeta potential were measured for drug loaded and blank CDNS to study the differences. Each test sample was diluted 10-times with deionized water and measurements were taken three times at a fixed scattering angle of 90° and a temperature of 25°C respectively.

 

c) Powder X-ray diffraction (PXRD) studies:

In order to comprehend the behavior of differential crystallinity of βCD, ACE, blank CDNS and ACE loaded CDNS, PXRD studies were carried out using EMPYREAN, (PANalytical, The Netherlands) diffractometer. Samples were scanned using an X-Ray tube with copper line as a radiation source at a scanning rate of 4° min-1 over a 2θ range between 5-100° angle at a 45 kV voltage and 40 mA current.^26-30

 

RESULT AND DISCUSSION:

Functionalization of CDNSs and drug loading:

Initially prepare blank CDNSs and ACE loaded CDNS was used for analytical characterization.

 

IR spectroscopy:

The pure CDNS has no obvious characteristic absorption peaks. The spectra of ACE loaded CDNS indicated intensive bands at ideal wavelengths shown in (figure 1).

 

Optimization of blank CDNS:

Blank CDNS were optimized using a two level three factor three centric Box Behnken design (Table 3) for the systemic study of the joint influence of the effect of independent variables Molar Concentration of βCD (A), Molar Concentration of DPC (B) and Reaction time (C) on the dependent variables Percent yield (Y1) and particle size (Y2) with the help of Design Expert® software version 13 (Stat-Ease®, Minneapolis, MN). The list of independent and the dependent variables selected for the study are given in Tables 1 and 2 respectively.

 

Table 1: List of independent variables selected to optimise the blank CDNS

Name of the independent variable	Unit	Code	Levels
			Low	High
Molar Concentration of βCD	Moles	A	1	10
Molar Concentration of DPC	Moles	B	1	15
Reaction Time	Hours	C	1	6

 

Table 2. List of dependent variables selected to optimize the blank CDNS

Name of the dependent variable	Unit	Goal
Percent Yield	%	Maximum
Particle size	nm	Minimum

 

Figure 1: IR spectroscopy of (A) pure CDNS and (B) ACE loaded CDNS.

Table 3: Box-Behnken experimental design with the measured responses.

Std.	Batch number	Runs	Polymer concentration (mol) A	Crosslinker concentration (mol) B	Reaction time (hr) C	Response 1: Yield (%)	Response 2: Mean Particle Size (nm)
11	AN 1	1	5.5	1	6	33.3	100
1	AN 2	2	1	1	3.5	55	165
15	AN 3	3	5.5	8	3.5	50	150
5	AN 4	4	1	8	1	91.7	275
2	AN 5	5	10	1	3.5	51.3	154
9	AN 6	6	5.5	1	1	75	225
7	AN 7	7	1	8	6	80	240
3	AN 8	8	1	15	3.5	75	225
8	AN 9	9	10	8	6	49.3	148
14	AN 10	10	5.5	8	3.5	50.7	152
10	AN 11	11	5.5	15	1	71.7	215
6	AN 12	12	10	8	1	83.3	250
12	AN 13	13	5.5	15	6	59.7	179
13	AN 14	14	5.5	8	3.5	49	147
4	AN 15	15	10	15	3.5	53.3	160

 

    

Figure 2: Pertubation plot and Response surface plot presenting the interactions between the Molar Concentration of βCD (A), Molar Concentration of DPC (B), and Reaction time (C) on Percent yield (Y1)

 

   

Figure 3: Pertubation plot and Response surface plot presenting the interactions between the Molar Concentration of βCD (A), Molar Concentration of DPC (B), and Reaction time (C) on particle size (Y2)

 

The final batch was obtained with molar concentration of βCD as 6.77 moles, Molar concentration of DPC as 15 moles and reaction time of 1.07 hours. This predicted the formation of a batch of blank CDNS has percent yield of 53.95 % and particle size of 161.83 (Figure 4)

 

Figure 4. Overlay plot showing the final selected batch

 

Determination of Particle size, Polydispersity index (PDI) and Zeta potential:

The z-average particle size of optimized ACE-loaded CDNS was 169.57±1.5nm with PDI of 0.279±0.005. The z-average particle size of re-dispersed ACE-loaded CDNS was 166.2±1.5nm with PDI 0.252±0.035 (Figure 5). The identical particle size of the blank and drug-loaded CDNS shows that drug loading does not have any significant effect on the particle size of CDNS. The zeta potential of the ACE-loaded CDNS was found to be -27.3±1.1mV. A zeta potential value close to ± 30 mV indicates good physical stability of the microparticles on account of electrostatic repulsion.

 

 

Figure 5: DLS graph with z-average particle size for ACE-loaded CDNS

 

TEM study:

A definite crystalline geometry for ACE loaded CDNS can be found out by TEM. As (Figure 6) shows a CDNS particle with spherical shape wherein the cavities as visible. Whereas Figure 6 B shows the porous surface of the CDNS at increased magnification. The TEM scans for ACE-loaded CDNS shows the encapsulation of ACE inside the nanocavities as the cavities can be seen filled with the drug molecules. The loaded CDNS were found to be retaining the spherical morphology after the loading indicating the freeze drying did not affect the morphological characteristics of CDNS in any manner (Figure 7).

 

 

Figure 6. TEM scans for blank CDNS (A) 11000X (B) 46000X.

 

 

Figure 7: TEM scans for ACE loaded CDNS (A) 11000X (B) 46000X.

 

Powder X-ray diffraction (PXRD) studies:

The Powder X-ray diffraction pattern of βCD confirms its crystalline form as shown in Figure 8. The PXRD pattern of blank CDNS (Figure 9) showed changes in peaks and a slightly diffused pattern intimating the crystalline/para-crystalline nature of the formed NS.

 

Figure 8. PXRD diffractogram of ACE.

 

 

Figure 9. PXRD diffractogram of ACE-loaded CDNS.

 

Entrapment efficiency and percent drug loading:

Percent drug loading of 72.16±3.13% and drug entrapment efficiency of 89.29±2.59% was selected for further characterization

 

Drug content:

The drug content for ACE-loaded CDNS was found to be 99.37±0.41%.

 

Formulation of ACE loaded xerogel:

ACE loaded CDNS were incorporated using 1% w/w sodium CMC as the gelling agent. Sodium CMC is known to be an adhesive polymer, and this would provide an added benefit, as this would allow for the formulation to retain on the skin for a longer time, to allow better permeation of the drug.

 

In vitro release study:

From the Figure 10 it was found that the optimised batches of ACE-loaded Xerogel formulation and ACE-loaded CDNS released more than 90% drug in just 150 mins (2.5 hrs) whereas the marked formulation and ACE drug released more than 90% drug in 240 mins (4 hrs) and 330 mins (5.5hrs) respectively. From the figure we can conclude the optimised batches of ACE-loaded Xerogel formulation and ACE-loaded CDNS provide faster drug release compared to the drug and marketed formulation, which will help in faster pain relief.

 

 

Figure 10: In vitro drug release study.

Table 4: Results of stability studies on ACE-loaded CDNS based gel.

Parameter	Zero day	30 ± 2 °C / 65 ± 5% RH			40 ± 2 °C / 75 ± 5% RH
		1 month	3 months	6 months	1 month	3 months	6 months
Appearance	Shiny, transparent gel	Shiny, transparent gel	Shiny, transparent gel	Shiny, transparent gel	Shiny, transparent gel	Shiny, transparent gel	Shiny, transparent gel
Drug content (%)	99.37 ± 0.41	99.24 ± 0.64	99.31 ± 0.35	98.17 ± 0.65	98.67 ± 0.51	98.11 ± 0.48	97.79 ± 0.74
pH	5.5 – 6	5.5 – 6	5.5 – 6	5.5 – 6	5.5 – 6	5.5 – 6	5.5 – 6

 

Stability study:

Physical as well as chemical stability studies of the ACE-loaded CDNS based gel stored at two conditions over 6 months were conducted to find out stability as per storage recommendations. The appearance, pH, and drug content (%) were calculated after formulation and for 6 months at different conditions as per (Table 4). No significant difference was observed in the parameters, confirming the stability of the formulation.

 

Ex vivo drug permeation:

The observations made during the percutaneous penetration study of the ACE-loaded CDNS based gel, marketed product, and the pure ACE suspension are depicted in Figure 11.

 

Figure 11: Cumulative quantity of drug permeated in μg/cm2 v/s time (hrs)

 

The flux at steady state (μg/cm2/hr) of pure ACE, marketed product, and ACE-loaded CDNS based gel was found to be 1.35, 1.19, and 2.18 respectively. The permeability coefficient of ACE-loaded CDNS based gel was found to be 3.11 X 10-5 cm/h as opposed to that of pure ACE and the marketed product which was deduced to be 1.93 X 10-5 and 1.71 X 10-5cm/h, showing a 1.6-times enhancement in the permeation of the drug as compared to the pure drug. This could be attributed to the smaller size of the nanocarriers and. surprisingly the aqueous portion of the gel can also wreak havoc in the stratum corneum in myriad ways. It can hydrate the skin increasing the interlamellar volume of the lipid bilayers and leading to their disruption. It may alternatively hydrate the corneocytes to which lipid chains in the stratum corneum are covalently attached which would also lead to a disordered structure. All of this could aid in the permeation of the drug into the deeper layers of the skin as could be observed from the results of the study.

 

CONCLUSION:

The ACE-loaded CDNS were formulated into a gel for the topical delivery. The ACE-loaded CDNS based gel was then characterized for physical appearance, in vitro drug release as well as in vitro drug permeation. The optimized batches of ACE-loaded xerogel and ACE-loaded CDNS released more than 90% drug in just 150 mins (2.5 hrs) with more than 80% of the drug getting permeated into the skin from the optimized batches of ACE-loaded CDNS based gel formulation. The ACE-loaded CDNS based gel samples were also kept for stability studies at 30±0.5°C/65±2% RH and 40± 0.5°C/75±2% RH for 6 months. They were analyzed for physical appearance, drug content, and surface pH, the samples remained unchanged at both conditions for the entire study period.

 

Thus, we can conclude beyond doubt that the aim envisaged at the start of the work could be accomplished and that ACE-loaded CDNS based gel has the potential to improve the transdermal bioavailability of aceclofenac.

 

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

 

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Accepted on 25.03.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(12):5713-5721.