Enhancing transdermal drug delivery: formulation and evaluation of simvastatin-loaded invasomes in carbopol gel for improved permeability and prolonged release

Abstract

The transdermal pathway serves as a significant route for achieving localized or systemic effects. Within this context, the stratum corneum is a crucial barrier limiting the permeation of many drugs. To surmount this barrier, carriers, and nanocarriers have been utilised, notably ‘invasome’ being one such example. In our study, we formulated invasomes loaded with simvastatin using the conventional thin-layer evaporation technique. This formulation involved the use of soy phosphatidylcholine, terpene (Limonene), chloroform, and ethanol. Simvastatin-loadedinvasomes were incorporated into a carbopol 934 solution to create a gel. We prepared and assessed different formulationsfor various parameters, including zeta potential, scanning electron microscopy, entrapment efficiency, viscosity, and drug content, and conducted in vitro studies. The entrapment efficiency was as high as 83.17±0.61%. The maximum in vitro drug permeation (45.44±0.4%) was found in the gel with 0.5% soy phosphatidylcholine and 0.25% terpene. Upon evaluating these parameters, our findings suggest that the simvastatin invasomal gel effectively enhances drug permeability across membranes and successfully achieves prolonged drug release.

Keywords:
Simvastatin; Invasome; Transdermal delivery; Permeability; Terpene; Carbopol

INTRODUCTION

To provide a controlled release of medication, controlled drug delivery systems (CDS) refer to technologies and formulations intended to deliver drugs in a preset way over an extended period (Park et al., 2014). With the least potential for adverse effects and increased patient compliance, these systems strive to optimize therapeutic efficacy. There are numerous varieties of controlled drug delivery systems, each designed to meet needs and address certain medical issues (Sharma, Bharti, Sharma, 2022). Among the various CDS options available, transdermal delivery offers distinct advantages compared to invasive methods and traditional oral routes (Pattnaik, Swain, Mallick, 2009; Swain et al., 2011; Pattnaik et al., 2011a; Pattnaik et al., 2011b; Swain et al., 2009). It promotes patient compliance, avoids the initial first-pass metabolism of drugs, and allows for the termination of drug action at any time. The primary obstacle in transdermal drug delivery lies in helping drug diffusion through the stratum corneum, which is composed of keratin-rich corneocytes held together by lipid layers (Sabbagh, Kim, 2022). Lipid lamella aids in barring diffusion. Several approaches like chemical (penetration enhances), mechanical (iontophoresis, microneedles), and vesicular drug carriers (liposomes, niosome, transfersomes, ethosomes, flexosomes, invasomes, polymerosomes) have been tried to improve the diffusion of drugs (Schafer et al., 2023; Chakraborty et al., 2023). Among all the vesicular systems, invasomes shown to provide better transdermal diffusion of drugs over the traditional liposomes (Babaie et al., 2020). Invasomes are composed of phospholipids, ethanol, and terpenes. Regular liposomes are not considered suitable for transdermal delivery due to their inability to diffuse through the deeper layer of skin and their action is limited to the superficial layers (Hasan et al., 2020). Recently developed elastic vesicles like transfersomes, ethosomes, and invasomes having penetration enhancers are better than the regular liposomes. Invasomes are created using phospholipids such as soy phosphatidylcholine, ethanol, and chloroform, along with one or a mixture of terpenes (Babaie et al., 2020). They enhance drug diffusion by disrupting the lipids within the stratum corneum, interacting with intracellular proteins, and improving drug partitioning into the stratum corneum. Ethanol plays a role in vesicle penetration through the stratum corneum and imparts a negative surface charge, preventing vesicle aggregation through electrostatic repulsion (Kumar et al., 2020). Terpenes, which are naturally occurring volatile oils, are recognized as generally safe substances and exhibit low irritancy at lower concentrations (1-5%). They have a reversible effect on the lipids of the stratum corneum and are considered acceptable penetration enhancers in clinical applications (Swain et al., 2011). The combination of terpenes and ethanol has a synergistic effect on the absorption of drugs through the skin.

Simvastatin is a lipophilic drug that reduces hepaticsynthesis by inhibiting 3-hydroxy3-methyl-glutaryl-CoA reductase, the enzyme responsible for the rate-limiting step in cholesterol biosynthesis via the mevalonic acid pathway (Li et al., 2020). Simvastatin is prescribed for the treatment of atherosclerosis to prevent heart attacks. It faces challenges with poor oral bioavailability (only 5%), significant first-pass metabolism, and a short plasma half-life of 2 hours (Zhang et al., 2021). Maintaining a consistent plasma drug concentration is crucial for achieving the desired therapeutic response and improving patient adherence to treatment. While earlier research has recognized simvastatin as a potential candidate for transdermal drug delivery, no reports were found regarding its formulation as invasomes (Manjula, Gupta, Sekhar, 2022; El-Say et al., 2015; Zidan et al., 2016). Therefore, the current study aims to develop and characterize a simvastatin-loadedinvasome gel formulation to achieve transdermal delivery with controlled release.

MATERIAL AND METHODS

Material

Simvastatin was obtained as a gift sample from Cadila Pharmaceutical Ltd. India. Soy phosphatidylcholine was bought from Hi-media Laboratories, India.Limonene and Carbopol 934 werebought from LobaChemie Pvt Ltd, India. All other chemicals and materials were of analytical grade.

Formulation optimization and preparation of simvastatin-loadedInvasomes

The principles of design of experiments have recently been widely used in the development of pharmaceutical drug products (Hota, Pattnaik, Mallick, 2020; Pattnaik et al., 2015). For the formulation optimization, a factorial design was used. A total of 9 invasome formulations were developed using soyphosphatidylcholine and limonene as two independent factors with three concentration levels (low, medium, and high), whereas other components such as simvastatin (50 mg), ethanol (4 ml), and chloroform (6 ml) were fixed. The study focused on several dependent variables, namely entrapment efficiency, permeation flux, and particle size. To develop the simvastatin invasome formulations (Table I), varying proportions of soy phosphatidylcholine and limonene were prepared using the conventional thin-layer evaporation technique. The process involved taking simvastatin, soy phosphatidylcholine, and limonene in a clean, dry, round-bottom flask and dissolving them in a mixture of chloroform and ethanol in a 2:1 (v/v) ratio. The organic solvent was then removed using a rotary evaporator, and any remaining traces of solvent were eliminated by subjecting the flask to vacuum conditions overnight. The resulting lipid film was hydrated by introducing it to saline phosphate buffer (pH 7.4) while rotating at 60 rpm for 1 hour at room temperature. Subsequently, the vesicles formed were allowed to swell for 2 hours at room temperature, resulting in the formation of large multi-lamellar vesicles. These vesicles were then subjected to probe sonication at 4°C with an output frequency of 40% (40 W) to produce smaller vesicles (Prasanthi, Lakshmi, 2013).

TABLE I
Formulations of Simvastatin loaded invasomes with three levels of soyaphosphatidylcholine and terpene

Formulations	Independent factors
	Soyaphosphatidylcholine (a)	Terpene (b)
F1	L	L
F2	L	M
F3	L	H
F4	M	L
F5	M	M
F6	M	H
F7	H	L
F8	H	M
F9	H	H

• Low (L)=0.25%, Medium (M)=0.5%, High (H)=0.75%

Entrapment efficiency

A 10ml aliquot of the invasome formulation was subjected to ultracentrifugation at 3000 rpm for 30 minutes (Kaltschmidt et al., 2020). After centrifugation, the supernatant was separated and diluted appropriately with methanol. The concentration of the drug was then measured at 238 nm using a UV spectrophotometer. The entrapment efficiency was calculated using the formula:

$\%Entrapment=\left(Totalamountofdrug-Freedrug\right)\times 100/Totalamountofdrug$

Zeta potential, particle size, and poly dispersion index

The simvastatin-loaded invasomes were characterized using a Malvern Zetasizer. The formulation was properly diluted with deionized water before going ahead with the analysis. The samples were placed in folded capillary cells after cleaning cuvettes with methanol and rinsing them with the sample to be measured. The results, including particle size, poly dispersion index (PDI), and zeta potential, were recorded. The results are expressed as the mean of three determinations.

Scanning electron microscopy (SEM)

Scanning electron microscopy was used to visualize the invasomes. To prepare samples for SEM analysis, a monolayer of the invasome dispersion was applied to one side of a double adhesive stub. These stubs were then platinum coated with an auto fine coater. Afield emission scanning electron microscope (FESEM) was used to obtain scanning electron microphotographs of the invasomes.

Formulation and characterization of gels

Carbopol 934 was used as a base in the gel formulation development procedure. Carbopol 934 was precisely weighed and dispersed in a beaker with 80ml of double-distilled water. This solution was stirred continuously at 800 rpm for 1 hour, and then 10 ml of propylene glycol was added. The slightly acidic solution obtained was neutralized by the gradual addition of 0.05 N sodium hydroxide solution until the gel became transparent. Simvastatin-loaded invasomes were incorporated into the base with constant stirring, and the final volume was adjusted to 100 ml. The mixture was then sonicated for 10 minutes using a bath sonicator to eliminate air bubbles, and the final pH of the gels was adjusted to 6.5.

Measurement of pH, viscosity, spreadability, and drug content

The pH of the optimized gel formulations was determined using a calibrated digital pH meter.The viscosity of the prepared topical invasome-based gel was measured using a Brookfield viscometer with spindle no. 63 at an optimum speed of 10rpm.Spreadability was determined by placing 1g of gel between two glass slides, and a weight of 150g was applied to the slides for 5 minutes to compress the sample to a uniform thickness. The time taken to separate the two slides was recorded and used to calculate spreadability using the formula:

$S=ML/T,$

where “S” is spreadability, “M” is the weight attached to the upper slide, “L” is the length moved on the glass slide, and “T” is the time taken to separate the slides.

Drug content was determined bydissolving 10 mg of gel in phosphate buffer pH 6.8, and the volume was adjusted to 50 ml in a volumetric flask. The mixture was then filtered through Whatman filter paper no. 41, and the simvastatin content was quantified using a UV/visible spectrophotometer by measuring the absorbance at 238nm against a blank.

In vitro skin permeation study

An in vitro drug diffusion study was conducted using a Franz diffusion cell with goat skin as the semi-permeable membrane. The receptor medium (50 ml) was phosphate buffer pH 7.4, continuously stirred with a magnetic stirrer, and maintained at 37±0.5°C on a thermostatic hot plate. The donor side of the membrane is applied with the gel sample (equivalent to 10 mg of simvastatin). Samples from the receptor compartment were withdrawn at 60-minute intervals and replaced with an equal volume of fresh buffer to maintain the sink condition. The samples were analyzed using a UV spectrophotometer at 238 nm. Permeation kinetics were evaluated using zero-order, first-order, Higuchi, and Korsemeyer-Peppas models, and the regression coefficients were determined.

Stability studies

Stability studies were conducted for drug-loaded invasomes at two different temperatures: refrigeration temperature (4.0±0.2°C) and room temperature (25±0.2°C) for 3 months. The formulations were stored in borosilicate glass containers to prevent interaction between the formulation and the container. The formulations were examined for any physical changes (pH and viscosity) and drug content during the stability study period.One-way analysis of variance was used to assess the significance of the data (p<0.05) using a statistical software package (SigmaStat version 3.5).

RESULTS AND DISCUSSIONS

Entrapment efficiency

The percentage of drug entrapment of invasome is given in Table II. Drug entrapment varied when the terpene and soy phosphatidylcholine proportion varied. It was observed that 75% to 83% of drugs were entrapped. The formulation F4shows the highest entrapment efficiency at 83.17±0.61%. The entrapment efficiency of the invasome formulation is affected due to the amount of soy phosphatidylcholine. The increased amount ofsoy phosphatidylcholine enhanced the entrapment efficiency of the invasome (Table II). The composition of invasome formulations, particularly the amount of soy phosphatidylcholine, plays a crucial role in drug entrapment. Increased levels of soy phosphatidylcholine were observed to enhance the entrapment efficiency of invasomes.

TABLE II
Vesicle size, entrapment efficiency (EE), polydispersibility index and zeta potential of invasomes

Formulations	Vesicles size (nm) (YI)	FLUX (µg/cm2/h) (Y2)	%EE (Y3)	Polydispersibility Index (PDI)	Zeta potential (mv)
F1	38.8±0.24	241.6±3.4	75.79±0.32	0.72	-33.8±0.8
F2	42.8±0.12	225±2.88	78.17±0.61	0.64	-42.01±1.1
F3	43.2±0.31	233.3±4.20	80.59±0.58	0.65	-37.7±0.5
F4	35.95±0.26	375±3.28	83.57±0.75	0.51	-48.8±0.7
F5	37.8±0.33	266.6±4.19	77.66±0.38	0.59	-38.4±0.7
F6	39.9±0.21	237.5±2.47	81.73±0.51	0.62	-17.9±0.8
F7	31.9±0.42	291.6±2.91	67±0.34	0.74	-21.6±0.8
F8	41.6±0.33	316.6±3.44	58.58±0.52	0.71	-19.8±0.8
F9	44.5±0.09	308.3±4.27	53.68±0.45	0.69	-22.8±0.8

This outcome aligns with earlier research on lipid-based drug delivery systems, where the composition of lipids significantly influences drug encapsulation (Berthelsen et al., 2019). The high entrapment efficiency of F4 makes it a promising candidate for further development and application in drug delivery.

Particle size and Zeta potential

F4 was considered for the analysis of particle size because of its high entrapment efficiency and stability. The particle size was found to be 35.95±0.26 nm (Figure 1), the polydispersity index 0.51 and the mean charge was -48.8±0.7 mV (Table II). The negative charge is due to the presence of ethanol. The small particle size of F4 indicates its potential for enhanced drug delivery, as smaller particles often exhibit improved tissue penetration and cellular uptake (Lundqvist et al., 2008). The negative zeta potential suggests the stability of the formulation, which is critical for long-term storage and drug release (Fuentes et al., 2021).

FIGURE 1
Zeta potential and particle sizedistribution.

Scanning electron microscopy (SEM)

Scanning electron microscopy images of the invasomes under lower 764 magnification shows that the particles are not agglomerated existing separately without any physical forces (Figure 2). Here invasomes were formed with size in the micron range below 100 nm. The higher magnification of SEM shows that the invasomes have an irregular surface, the shape is not spherical. Irregularities in particle shape can influence drug release kinetics, and understanding these characteristics is crucial for tailoring drug delivery systems to specific therapeutic applications (Varde, Pack, 2004).

FIGURE 2
SEM image at 764 magnification.

pH, viscosity, spreadability, and drug content

The pH of the gel formulation was measured by a digital pH meter and found to be in the range of 6.4 to 7.4, which lies in the normal pH range of the skin. All the invasome gel formulations show pH nearer to the skin pH (Table III). Much variation was not observed in the viscosity of different formulationsmay be due to the same base with much difference in their concentration. The viscosity in the range of 3000 cp provides good spreadability and ease in topical application (Table III).

TABLE III
pH and viscosity, spreadability, and drug content of the gel

Formulation	pH	Viscosity (cp)	Spreadability (g.cm/sec)	Drug content (%)
F1	6.57±0.28	3289±0.18	51.57±0.12	94.3±0.23%
F2	6.89±0.25	3345±0.23	63..61±0.22	96.7±0.12%
F3	6.76±0.32	3146±0.16	45.78±0.17	91.2±0.34%
F4	6.66±0.27	3347±0.13	64.29±0.16	95.1±0.24%
F5	6.52±0.21	3344±0.16	55.28±0.22	92.2±0.14%
F6	6.57±0.26	3326±0.21	59.24±0.15	94.2±0.32%
F7	6.71±0.22	3243±0.22	48.26±0.12	90.8±0.31%
F8	6.62±0.26	3332±0.19	49.22±0.16	93.5±0.24%
F9	6.66±0.29	3349±0.24	55.18±0.16	93.1±0.24%
Plain Gel	6.71±0.28	3361±0.31	57.34±0.15	95.2±0.14%

• Mean±SD, n=3

The spreadability (g.cm/sec) of the invasome gel formulation F3 was found to be the lowest (45.78±0.17) and formulation F4 has the highest (64.29±0.16). All the prepared gel formulationsare easily spreadable. Spreadability depends on the viscosity and gelling properties of the polymers used in the formulation (Table III). The drug content of all gel for formulations was above 90% (Table III). The maximum drug content was found in formulation F2 (96.7±0.12%) and lowest in formulation F7 (90.8±0.31%).

In vitro skin permeation study

The in vitro permeation study was carried out to compare the permeation of the drug from the plain gel and invasomegel inthe Franz diffusion cell using goat skin as the barrier. The calculated skin permeation rate of plain gel and invasome gel is given in Table IV and Figure 3. The result obtained from skin permeability studies indicates that the maximum percentage of drug permeation was found fromgel F4 (45.44±0.4%) at the end of six hours. The maximum skin permeation of the invasome gel was due to the presence of terpene and ethanol in the formulation. Most of our formulations fit into zero and 1st order kinetic models.Formulations F2 and F5-F9 also fit the Higuchi kinetic model. The ‘n’ values for the Korsemeyer-peppas model were found to be less than 0.5 for all formulations indicating the permeation is governed by diffusion (Table V). The presence of terpene and ethanol in the formulation likely contributed to this enhanced skin permeation. The results suggest that invasome gel formulations can effectively facilitate drug penetration through the skin barrier. The kinetic models applied to the data indicated that most formulations followed zero and first-order kinetics, with “n” values for the Korsemeyer-Peppas model indicating that drug permeation was governed by diffusion. This information is essential for understanding the release mechanism and designing controlled-release formulations (Costa, Sousa Lobo, 2001).

FIGURE 3
In-vitro skin permeation study.

TABLE IV
In-vitro drug permeation study

Time (hrs)	%Permeation
	Plain gel	F1	F2	F3	F4	F5	F6	F7	F8	F9
1	2.67±0.21	3.48±0.15	3.26±0.32	3.57±0.6	5.56±0.32	4.56±0.32	3.26±0.32	4.61±0.32	5.06±0.32	6.26±0.32
2	4.21±0.32	7.51±0.23	7.31±0.23	8.31±0.11	10.31±0.2	8.33±0.2	6.31±0.2	8.33±0.2	9.31±0.2	9.61±0.23
3	9.11±0.23	11.25±0.2	9.45±0.34	12.45±0.4	16.45±0.3	10.44±0.3	9.42±0.3	9.47±0.3	12.42±0.3	13.44±0.34
4	12.56±0.12	14.58±0.2	11.38±0.20	14.38±0.1	23.38±0.2	13.38±0.1	11.38±0.2	12.38±0.2	13.38±0.2	16.48±0.20
5	18.98±0.45	22.24±0.1	16.14±0.26	24.14±0.4	33.14±0.2	15.12±0.3	12.14±0.2	13.11±0.2	14.84±0.2	23.34±0.26
6	25.36±0.26	29.34±0.2	18.44±0.40	32.44±0.3	45.44±0.4	17.41±0.2	15.45±0.4	15.74±0.4	16.42±0.4	25.88±0.40

• Mean±SD, n=3

TABLE V
Regression Coefficient (r²) obtained from different kinetic models

Model		Plain gel	F1	F2	F3	F4	F5	F6	F7	F8	F9
Zero order		0.95	0.97	0.99	0.95	0.96	0.97	0.97	0.95	0.91	0.98
1st order		0.94	0.95	0.98	0.93	0.93	0.98	0.98	0.96	0.93	0.98
Higuchi		0.78	0.82	0.91	0.8	0.81	0.97	0.95	0.98	0.98	0.92
Korsmeyer-peppas	n	0.18	0.16	-0.04	0.19	0.28	-0.15	-0.13	-0.22	-0.2	-0.02
	r2	0.94	0.92	0.95	0.95	0.89	0.93	0.97	0.94	0.91	0.95

Factorial analysis of the formulations

Regression equations were developed using Minitab© (Version 19). The maineffect of fitted means on entrapment efficiency shows that it increases with increased concentration of terpene, while it increases till the 0.5% concentration of soy phosphatidylcholine but decreases at 1%. The interaction plot shows that terpene and soy phosphatidylcholineat 5% concentration has a maximum combined effect on the entrapment efficiency (Figure 4).

FIGURE 4
Main effects on entrapment efficiency and interaction fitted means.

Entrapment efficiency Y3=72.97-1.504 a1+3.466a2-1.961a3-2.161b-0.9411b2+3.102b3+8.861a1b1-11.95a1b2+3.088a1b3+6.311a2b1+6.231a2b2-12.54a2b3-15.17a3b1+5.718a3b2+9.454a3b3

The maineffect of fitted means on vesicle size decreases with increased concentration of terpene, whereas it decreases till the 0.5% concentration of soy phosphatidylcholine but increases again at 1%. The interaction plot shows that terpene and soy phosphatidylcholine at all concentrations do not interact with each other’s effect on the vesicle size (Figure 5).

FIGURE 5
Main effects on vesicle size and interaction fitted means.

Vesicle Size Y1=39.6+1.133a1-1.267a2+0.1333a3+3.9b1+0.5b2-4.4b3-1.833a1b1+0.3667a1b2+1.467a1b3+0.9667a2b1+1.067a2b2-2.033a2b3+0.8667a3b1-1.433a3b2+0.5667a3b3

Main effects of fitted means on flux show that, it increases with increased concentration of terpene, whereas it decreases till the 0.5% concentration of soy phosphatidylcholine but decreases at 1%. The interaction plot shows that terpene and soy phosphatidylcholine interact affecting the flux (Figure 6).

FIGURE 6
Main effects of flux and interaction fitted means.

Flux Y2=277.3-43.98a1+15.76a2+28.22a3+25.46b1-7.878b2-17.58b3-17.16a1b1-0.4222a1b2+17.58a1b3+56.51a1b2-18.56a2b2-37.96a2b3-39.36a3b1+18.98a3b2+20.38a3b3

Factorial analysis revealed that the concentration of terpene and soy phosphatidylcholine significantly influenced entrapment efficiency, vesicle size, and flux. Terpene concentration positively correlated with entrapment efficiency and flux (Aqil et al., 2007), while soyphosphatidylcholine concentration had a more complex effect like the earlier reports (Berrocal et al., 2000). This analysis offers valuable insights into the optimization of invasome formulations.

Stability study

The stability study was performed for invasome gel formulation F4 for three months at different storage conditions. At different time points, sampleswere withdrawn and examined for various parameters such as pH, viscosity, and drug content. The results of the stability study are presented in Table VI.

The results showed a slight decrease in drug content and a slight increase in viscosity at room temperature. However, the studied parameters were almost unchanged (p<0.05) when the gel was refrigerated indicating its stability.

CONCLUSION

In conclusion, the study demonstrates the potential of invasome gel formulations, particularly formulation F4 with the highest entrapment efficiency, for efficient drug delivery through the skin. The results highlight the importance of formulation composition in controlling drug entrapment and release and the stability of the formulation under different storage conditions. All the invasome formulations have negative zeta potential. The prepared invasome gels were found to have suitable pH, viscosity, and spreadability for topical application. The invasome gel formulation shows good skin permeation as compared to the plain gel formulation. The formulation was found to be stable for three months of study without any significant changes. Further studies and clinical trials are warranted to validate the suitability of these invasome gels for specific drug delivery applications.

REFERENCES

• Aqil M, Ahad A, Sultana Y, Ali A. Status of terpenes as skin penetration enhancers. Drug Discov Today. 2007; 12(23-24): 1061-1067. doi: 10.1016/j.drudis.2007.09.001.
  » https://doi.org/10.1016/j.drudis.2007.09.001
• Babaie S, Del Bakhshayesh AR, Ha JW, Hamishehkar H, Kim KH. Invasome: A novel nanocarrier for transdermal drug delivery. Nanomaterials. 2020; 10(2): 341. doi: 10.3390/nano10020341.
  » https://doi.org/10.3390/nano10020341
• Berrocal MC, Buján J, García-Honduvilla N, Abeger A. Comparison of the effects of dimyristoyl and soya phosphatidylcholine liposomes on human fibroblasts. Drug Deliv. 2000; 7(1): 37-44. doi: 10.1080/107175400266777.
  » https://doi.org/10.1080/107175400266777
• Berthelsen R, Klitgaard M, Rades T, Müllertz A. In vitro digestion models to evaluate lipid based drug delivery systems; present status and current trends. Adv Drug Deliv Rev. 2019; 142: 35-49. doi: 10.1016/j.addr.2019.06.010.
  » https://doi.org/10.1016/j.addr.2019.06.010
• Chakraborty S, Dhibar M, Das A, Swain K, Pattnaik S. A Critical Appraisal of Lipid Nanoparticles Deployed in Cancer Pharmacotherapy. Recent Adv Drug Deliv Formul. 2023. doi: 10.2174/2667387817666230726140745.
  » https://doi.org/10.2174/2667387817666230726140745
• Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001; 13(2): 123-133. doi: 10.1016/s0928-0987(01)00095-1.
  » https://doi.org/10.1016/s0928-0987(01)00095-1
• El-Say KM, Ahmed TA, Badr-Eldin SM, Fahmy U, Aldawsari H, Ahmed OAA. Enhanced permeation parameters of optimized nanostructured simvastatin transdermal films: Ex Vivo and In Vivo evaluation. Pharm Dev Technol. 2015; 20(8): 919-926. doi: 10.3109/10837450.2014.938859.
  » https://doi.org/10.3109/10837450.2014.938859
• Fuentes K, Matamala C, Martínez N, Zúñiga RN, Troncoso E. Comparative study of physicochemical properties of nanoemulsions fabricated with natural and synthetic surfactants. Processes. 2021; 9(11): 2002. https://doi.org/10.3390/pr9112002
  » https://doi.org/10.3390/pr9112002
• Hasan M, Khatun A, Fukuta T, Kogure K. Noninvasive transdermal delivery of liposomes by weak electric current. Adv Drug Deliv Rev. 2020; 154-155: 227-235. doi: 10.1016/j.addr.2020.06.016.
  » https://doi.org/10.1016/j.addr.2020.06.016
• Hota SS, Pattnaik S, Mallick S. Formulation and evaluation of multidose propofol nanoemulsion using statistically designed experiments. Acta Chim Slov. 2020; 67: 179-188.
• Kaltschmidt BP, Ennen I, Greiner JFW, Dietsch R, Patel A, Kaltschmidt B, Kaltschmidt C and Hutten A. Preparation of terpenoid-invasomes with selective activity against s. aureus and characterization by cryo transmission electron microscopy. Biomedicines. 2020; 8(5): 105.
• Kumar B, Pandey M, Aggarwal R, Sahoo PK. A comprehensive review on invasomal carriers incorporating natural terpenes for augmented transdermal delivery. Futur J Pharm Sci. 2022; 8: 50. https://doi.org/10.1186/s43094-022-00440-6
  » https://doi.org/10.1186/s43094-022-00440-6
• Li H, Rabearivony A, Zhang W, Chen S, An X, Liu C. Chronopharmacology of simvastatin on hyperlipidaemia in high-fat diet-fed obese mice. J Cell Mol Med. 2020; 24(18): 11024-11029. doi: 10.1111/jcmm.15709.
  » https://doi.org/10.1111/jcmm.15709
• Lundqvist M, Stigler J, Elia G, Lynch I, Cedervall T, Dawson KA. Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Natl Acad Sci USA. 2008; 105(38): 14265-70. doi: 10.1073/pnas.0805135105.
  » https://doi.org/10.1073/pnas.0805135105
• Manjula B, Gupta VRM, Sekhar KBC. Comparative in vivo evaluation of simvastatin after oral and transdermal administration in rabbits. Curr Trends Biotechnol Pharm. 2022; 16(3s), 1-8.
• Park K. Controlled drug delivery systems: past forward and future back. J Control Release. 2014; 190: 3-8. doi: 10.1016/j.jconrel.2014.03.054
  » https://doi.org/10.1016/j.jconrel.2014.03.054
• Pattnaik S, Swain K, Bindhani A, Mallick S. Influence of chemical permeation enhancers on transdermal permeation of alfuzosin: An investigation using response surface modeling. Drug Dev Ind Pharm. 2011a; 37: 465-474.
• Pattnaik S, Swain K, Mallick S, Lin Z. Effect of casting solvent on crystallinity of ondansetron in transdermal films. Int J Pharm. 2011b; 406: 106-110.
• Pattnaik S, Swain K, Mallick S. Influence of Polymeric System and loading dose on drug release from alfuzosin hydrochloride transdermal films. Lat Am J Pharm. 2009; 28: 62-69.
• Pattnaik S, Swain K, Rao JV, Varun T, Mallick S. Temperature influencing permeation pattern of alfuzosin: An investigation using DoE. Medicina (B Aires). 2015; 51: 253-261.
• Prasanthi D, Lakshmi PK. Iontophoretic Transdermal delivery of finasteride in vesicular invasomal carriers. Pharm Nanotechnol. 2013; 1(2). https://dx.doi.org/10.2174/2211738511301020009
  » https://dx.doi.org/10.2174/2211738511301020009
• Sabbagh F, Kim BS. Recent advances in polymeric transdermal drug delivery systems. J Controlled Release. 2022; 341: 132-146. doi: 10.1016/j.jconrel.2021.11.025.
  » https://doi.org/10.1016/j.jconrel.2021.11.025
• Schafer N, Balwierz R, Biernat P, Ochędzan-Siodłak W, Lipok J. Natural ingredients of transdermal drug delivery systems as permeation enhancers of active substances through the stratum corneum. Mol Pharm. 2023; 20(7): 3278-3297. doi: 10.1021/acs.molpharmaceut.3c00126.
  » https://doi.org/10.1021/acs.molpharmaceut.3c00126
• Sharma B, Bharti R, Sharma R. Controlled drug delivery: “A review on the applications of smart hydrogel”. Mater Today Proc. 2022; 65.
• Swain K, Pattnaik S, Chandra SAHU S, Mallick S. Feasibility assessment of ondansetron hydrochloride transdermal systems: Physicochemical characterization and in vitro permeation studies. Lat Am J Pharm. 2009; 28: 706-720.
• Swain K, Pattnaik S, Yeasmin N, Mallick S. Preclinical evaluation of drug in adhesive type ondansetron loaded transdermal therapeutic systems. Eur J Drug Metab Pharmacokinet. 2011; 36: 237-241.
• Varde NK, Pack DW. Microspheres for controlled release drug delivery. Expert Opin Biol Ther. 2004; 4(1): 35-51. doi: 10.1517/14712598.4.1.35.
  » https://doi.org/10.1517/14712598.4.1.35
• Zhang J, Wang J, Qiao F, Liu Y, Zhou Y, Li M, et al. Polymeric non-spherical coarse microparticles fabricated by double emulsion-solvent evaporation for simvastatin delivery. Colloids Surf B Biointerfaces. 2021; 199: 111560. doi: 10.1016/j.colsurfb.2021.111560.
  » https://doi.org/10.1016/j.colsurfb.2021.111560
• Zidan AS, Hosny KM, Ahmed OAA, Fahmy UA. Assessment of simvastatin niosomes for pediatric transdermal drug delivery. Drug Deliv. 2016; 23(5): 1536-1549. doi: 10.3109/10717544.2014.980896.
  » https://doi.org/10.3109/10717544.2014.980896

• DATA AVAILABILITY
  Data will be provided as needed.

Edited by

• Associated Editor:
  Gabriel Araújo.

Data availability

Data will be provided as needed.

Publication Dates

• Publication in this collection
  20 Jan 2025
• Date of issue
  2025

History

• Received
  24 Dec 2023
• Accepted
  26 July 2024