DiscussionFormulation optimization

The experiment's design called for 15 runs for the set of variables. All the runs recommended by the DOE were developed and tested for responses like folding endurance and drug release. Table 5 displays the design of experimental runs along with their responses.

Table 5 Design of experiment and the responsesFolding endurance

Folding endurance is the ability of any patch to withstand pressure applied in the form of folding at the same spot without breaking. This is an important need for patches since activity causes the skin at the application site to stretch and contract repeatedly, and the patch needs to have the best folding endurance during those times. The folding endurance equation is represented by Eq. 1, and the ANOVA table is represented as Table 6.

$$}\;} = \, 9.2375 \, + \, 97.5 \, * \, A \, + \, 0.833333 \, * \, B \, + \, 1.63125 \, * \, C$$

(4)

Table 6 ANOVA of Linear model of folding endurance

The Model F-value of 3.24 indicates that there is a 6.43% possibility that noise may result in an F-value this significant. Lack of fit is not significant when compared to pure error, as indicated by the F-value of 0.48 for the lack of fit. A negligible lack of fit is advantageous for the model.

For model terms to be deemed significant, the P-value needs to be less than 0.05. In cases where the value exceeds 0.1, model terms are not meaningful. Folding endurance was significantly impacted by Factor A, or HPMC K-100 concentration (p-value 0.0151). According to Eq. 1, Factor A has the highest coefficient and is preceded by a positive sign, indicating that Folding endurance improved with increasing HPMC concentration. This means that patches with greater HPMC K100 percentages tend to have higher folding endurance. Although increasing the concentration of PEG and ERL100 has a effect on folding endurance, there is a slight increase in folding endurance due to this effect. Therefore, there is a correlation between higher polymer concentration and increased folding endurance. Figure 1 displays the 3D response surface diagram of folding endurance.

Fig. 1

3D response surface diagram of folding endurance

In-vitro drug release

The formulation of various drug batches and their related in-vitro release percentages are displayed in Table 5. The formulation's key ingredients are HPMC K100, ERL 100, and PEG, which are altered to produce various release profiles. The amount of medication released from the formulation during a specific time under simulated physiological conditions is measured by the in-vitro release percentage. To achieve the appropriate release profile for the medicine, the formulation can be optimized using the data. Table 7 displays a summary of the model fitting. The linear model for in-vitro drug release was anticipated by the software. Based on its Model F-value of 4.76, the model is deemed significant. Only 2.30 percent of the time is there a probability that noise may result in an F-value this large. The F-value of 1.0 for the lack of fit indicates that it is not significant when compared to the pure error. A non-significant lack of fit is advantageous for the model.

Table 7 Model fit summary of in-vitro drug release

The in-vitro drug release ANOVA table is shown in Table 8. The in-vitro drug release model's p-value of 0.0230, which is less than 0.05, shows that it is significant.

Table 8 ANOVA table of in-vitro drug release

The in-vitro drug release model's ANOVA table reveals that factor C, or PEG400 concentration, is the only scenario where the p-value is less than 0.05. PEG400 was used as a permeation enhancer in this optimization design. The increased PEG400 concentration will result in increased in-vitro drug release. Equation 2 represented in terms of coded factors allows one to predict the results for specific values of each variable. The relative importance of the variables can be determined by comparing the factor coefficients using the coded equation. Factors A and B are preceded by a negative sign in the equation, and factor C is preceded by a positive sign. An increase in the value of factor C leads to an increase in the release of drugs in vitro, which is what the positive sign denotes as a synergistic effect. The fact that C has a higher coefficient value means that it has a greater influence on the release of medicines.

$$}\;}\;} = \,49.0267 \, - 1.87125 \, * \, A \, - 1.13 \, * \, B \, + \, 4.87875 \, * \, C$$

(5)

The optimized value for factors and their response were predicted by software and shown in Table 9. Based on criteria, the software predicted that the optimized patch's levels of factors A, B, and C would be 1.80, 0.1, and 50, respectively, and that its responses to folding endurance and in-vitro drug release would be 266.36 and 53.17, respectively. An optimized patch of the specified level of factors was constructed, and its performance was assessed.

Table 9 Factors level predicted by software for designThickness and physical appearance

Table 9 displays the thicknesses of all formulations. The resulting patches were homogenous, opaque, pliable, and smooth at varying polymer concentrations. The thickness of the films ranged from 0.52 ± 0.76 to 0.625 ± 0.85 mm.

Swelling index

The formulation and related swelling index of various samples are shown in Table 10 (F1–F15). The swelling index calculates how much the samples swell in a certain solvent. Sample F12 had the highest swelling index of 62.38 ± 0.69%, while sample F2 had the lowest swelling index of 43.45 ± 0.86%. The research indicates that different formulations may cause varying levels of edema and emphasizes the significance of formulating products that are best suited for a given application.

Table 10 Different parameters of simvastatin transdermal patchMoisture content

Each formulation had a different moisture content ranging from 5.1 ± 0.43% to 8.9 ± 0.51%. All formulas had a mean moisture content of 6.6%, with a standard deviation of 1.27%. Because of the hydrophilic characteristic of HPMC, it was found that high concentrations of HPMC had higher % moisture contents.

Moisture uptake

With a standard deviation of 0.49–0.72, each formulation has a distinct moisture uptake value that spans from 6.2 to 11.6 percent. Patches with high HPMC content exhibited high moisture absorption.

Drug content

The percentages of drugs present in each formulation, designated as F1 through F15, are shown in the Table 9. These percentages show how many active medication components there are in each formulation (measured in mass). The F4 and F14 contain the lowest percentages of drug content, while the F11 and F12 have the highest amounts. The medication concentration in the other formulations is between 90.76 and 98.75%. Pharmaceutical companies employ formulations to enhance the efficacy and delivery of their products (Figs. 2, 3).

Fig. 2

3D response surface diagram of in-vitro drug release

Fig. 3

Overlay plot of the design predicting the values of individual factors and their response based on input criteria

In-vitro drug release

The in vitro release profile is a vital tool for predicting how drugs will behave in vivo. Release analyzes are necessary to forecast the repeatability of the rate and duration of pharmaceutical activity. Figure 4 displays the optimized transdermal patch's percentage medication release over the course of 24 h. Over time, the cumulative proportion of medication release gradually rises, reaching its peak at 24 h (55.3%). The variation in drug release characteristics among all patch formulations could perhaps be attributed to the presence of polymeric chain cross-linking networks. Different polymeric mixtures used to make transdermal patches have different diffusion pathways, which affect the delivery and intensity of the dispersion.

Fig. 4

In-vitro drug release of optimized simvastatin patch

In-vivo study

Albino adult male and female in good health Wistar rats weighing between 110 and 240 g were used. Figure 5 depicts the impact of the simvastatin patch that has been optimized on total cholesterol levels. Rats were effectively exposed to Triton to cause hyperlipidemia, which was visible in the disease-control group. In comparison to normal controlled animals, disease-control animals have higher cholesterol and triglyceride levels (173.200.12 mg/dl and 189.02.68 mg/dl, respectively). The cholesterol level was seen to slightly decline in the test formulation. The levels of cholesterol and triglycerides are shown in the Fig. 5. The NC group has the lowest levels of both cholesterol and triglycerides, with average levels of 89.03 ± 0.89 mg/dL and 79.80 ± 0.28 mg/dL, respectively. The DC group rats treated with triton has the highest levels, with average levels of 173.20 ± 0.12 mg/dL for cholesterol and 189.02 ± 0.68 mg/dL for triglycerides, indicating the induction of hyperlipidemia and a higher risk for cardiovascular disease. In the standard treatment (simvastatin oral) groups, there is a decrease in the cholesterol (132.76 ± 0.35) and triglyceride level (139.80 ± 76) whereas, in the test formulation group or test group, there was also a decrease in cholesterol (169.65 ± 0.21 mg/dL) and triglyceride level of (151.20 ± 31 mg/dL) level. The triglyceride level in the standard treatment group and test group were comparable.

Fig. 5

Effect of simvastatin patch on A Triglyceride B Cholesterol in triton-induced hyperlipidemia in rats

Scanning electron microscopy study

Any material's morphological or surface changes can be evaluated using scanning electron microscopy. Various magnifications of the SEM images of the optimized patches before and after drug release were displayed in Fig. 6. Prior to medication release, the optimized simvastatin patch may seem uniformly smooth in SEM pictures. At 10 µm magnification, the patch's surface exhibits a matrix structure with uniformly dispersed drug particles; nevertheless, at 50 µm magnification, the patch surface seems to be nearly smooth. To regulate the medication's release rate, thin film coatings might also be present on top of the drug matrix.

Fig. 6

SEM images of optimized simvastatin patch before drug release (A, B) and after drug release (C, D)

The improved simvastatin patch's SEM pictures after drug release might reveal a rougher surface with fewer drug particles. Contrary to the previous photograph, the drug particles that were remaining on the surface were distributed unevenly. Drug elution may cause wear and tear on the patches, and drug release is confirmed by some porous forms on the surface of the patches, which demonstrate that the medication was gone out of the patches.