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Article

Simvastatin and Captopril Combined Transdermal Delivery System for Controlling Blood Pressure and Fat: Design, Characterization, and In Vivo Pharmacokinetic Evaluation

by
Ya-Jing Ni
1,
Run-Jia Wang
1,
Zhao Liu
2,
Li-Hui Xiao
2 and
Yan-Qiang Liu
1,*
1
Department of Zoology and Development Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
2
Harvest Pharmaceutical Co., Ltd., Changsha 410006, China
*
Author to whom correspondence should be addressed.
Appl. Sci. 2024, 14(19), 9092; https://doi.org/10.3390/app14199092
Submission received: 29 August 2024 / Revised: 2 October 2024 / Accepted: 3 October 2024 / Published: 8 October 2024
(This article belongs to the Special Issue Advances in Research Related to Pharmacy and Food Technology)
Browse Figures
Versions Notes

Abstract

:
We developed a sustained-release transdermal drug delivery system (TDDS) containing simvastatin (SIM) and captopril (CAP) to treat hypertension and hyperlipidemia and overcome treatment drawbacks, including significant liver first-pass effects, low bioavailability, and the short half-life of SIM and CAP oral tablets. We used a transdermal diffusion meter to preselect the formula of the SIM-CAP TDDS. Based on in vitro permeation experiments, we optimized the formula of the SIM-CAP TDDS to include 24% SIM, 24% CAP, 34% polyvinyl alcohol (PVA), 16% oleic acid (OA)–azone, and 2% polyacrylic acid resin II. We evaluated the optimized SIM-CAP TDDS formula by its appearance, stability, stickiness, drug content, in vivo pharmacokinetics, and skin irritation tests. The results indicated that the patch had good stability and stickiness. The SIM and CAP contents were 5.02 ± 0.41 mg/cm2 in the 1 cm2 SIM-CAP TDDS. The pharmacokinetic results indicated that the system continuously released SIM and CAP for 24 h and significantly enhanced their bioavailability, with a higher area under the curve. The SIM-CAP TDDS exhibits a sustained-release effect with good characteristics and pharmacokinetics. And it is safe and has no irritating effects on the skin; therefore, it is an ideal formulation.

1. Introduction

Hypertension is affecting one billion people and is the most common modifiable risk factor for cardiovascular disease (CVD) [1,2]. Hyperlipidemia, characterized by abnormal blood lipid levels, is also recognized as one of the important risk factors of CVD [3,4]. Hypertension and hyperlipidemia frequently coexist and are associated with elevated cardiovascular adverse outcomes [5]. Globally, CVD is the primary cause of mortality [6]. It is estimated that 7.8 million people will die prematurely from CVD by 2025 [7]. Despite their increasing prevalence, the proportions of hypertension and hyperlipidemia awareness, treatment, and control are low [8,9]. The trial has demonstrated that lowering lipid levels and blood pressure decreases the incidence of major cardiovascular events more effectively than regulating hypertension or hypercholesterolemia separately [10]. Therefore, significant joint control of blood pressure and blood lipids is needed for reducing the mortality rate of CVD.
Captopril (CAP), an orally active angiotensin-converting enzyme inhibitor (ACEI), is considered the preferred drug for antihypertensive treatment due to its effectiveness and low toxicity. Simvastatin (SIM) is a hydroxymethyl glutarate coenzyme A (HMG-CoA) reductase inhibitor that reduces total cholesterol and low-density lipoprotein cholesterol, thereby reducing the risk of atherosclerosis and CVD [11]. CAP and SIM have profitable effects beyond blood pressure and lipid lowering, and when combined, they achieve greater improvements in outcomes than those associated with either monotherapies [12]. However, when administered orally, CAP undergoes first-pass hepatic metabolism [13,14], its bioavailability is reduced to 55% in the presence of food, and its half-life is less than 2 h [15]. SIM also has a significant liver first-pass effect, low bioavailability of only 5%, and a short half-life of 2 h [16]. So, oral SIM and CAP both have common shortcomings, including significant liver first-pass effects, low bioavailability, and a short half-life.
The transdermal drug delivery system (TDDS) is one of the systems under the controlled drug delivery category that aims to deliver drugs through the skin at a predetermined and controlled rate [17]. The TDDS has undergone the development of three generations [18]. The first generation includes ointments, creams, sprays, gels, or patches [18]. The second generation is involved in the use of different enhancements, including chemical enhancement, iontophoresis, and non-cavitational ultrasound [19,20]. The third generation correlates with novel chemical enhancers, electroporation, microdermabrasion, thermal ablation, cavitational ultrasound, and microneedle-based delivery [20,21]. Based on the above statements, the three generations of the TDDS all apply transdermal enhancer technology, known as physical enhancers or chemical enhancers. However, most physical enhancers rely on relatively costly, reusable devices [20], and some physical enhancers, such as microneedles, have physical invasiveness, which raises additional safety and sterility concerns [20]. Various chemical enhancers can be integrated into small, inexpensive patches that patients find convenient [20]. Thus, chemical enhancers may have some advantage in the transdermal drug delivery system.
In 1979, the US Food and Drug Administration (FDA) approved the first transdermal patch (scopolamine transdermal patch) to prevent motion sickness [22,23]. Since then, many transdermal patches have been approved for the market, including Estradiol; Testosterone; Clonidine; Fentanyl; Nitroglycerin; Nicotine transdermal patches; and so on [23]. The clonidine TDDS is used for the treatment of hypertension [24]; it can improve compliance and patient acceptance in antihypertensive treatment, which may enhance the clinical treatment advantages [25]. The nitroglycerin transdermal patch is used clinically to treat angina pectoris [24,26], and a 10 mg nitroglycerin transdermal patch has a significant therapeutic effect and can last for 24 h [27]. Transdermal administration provides a leading advantage over injection and oral routes by improving patient compliance, avoiding first-pass metabolism, avoiding gastrointestinal irritation, and achieving sustained release of the drug [17,28]. Thus, preparing SIM and CAP TDDSs may solve the problems caused by the oral administration of SIM and CAP.
More than 64% of hypertensive patients also have dyslipidemia, and approximately 47% of patients with dyslipidemia suffer from hypertension [29]. The frequent coexistence of hypertension and hyperlipidemia increases in cardiovascular disease events [29]. Thus, simultaneous control of blood pressure and blood lipids is of great significance for reducing cardiovascular disease events. CAP and SIM are antihypertensive drugs and lipid-lowering drugs, respectively. However, when they are orally administered, they often show some drawbacks, whereas compared with oral administration, transdermal administration shows many advantages. So, the objective of our study is to develop an SIM and CAP combined transdermal delivery system. It has important significance for simultaneously controlling blood pressure and blood lipids, as well as reducing the risk of cardiovascular disease.

2. Materials and Methods

2.1. Materials

SIM (S129538) and EC (E809017, 18–22 mPa·s) were purchased from Shanghai Macklin Biochemical Technology Co., Ltd. (Shanghai, China). CAP (C837213) and carboxymethyl cellulose sodium (CMC-Na, S14016, 300–800 mPa·s), hydroxypropyl methylcellulose (HPMC, S14174, 4000–6500 mPa·s, HPMC K4m; 30,000 mPa·s, HPMC K30m; 100,000 mPa·s, HPMC K100m), polyacrylic acid resin II (S30569), and hydroxyethyl cellulose (HC, YY11927, 38,000–42,000 mPa·s) were purchased from Shanghai Yuan-ye Biotechnology Co., Ltd. (Shanghai, China). Azone, oleic acid (OA), polyvinylpyrrolidone (PVP K30, C20201, 3.4 mPa·s), and polyvinyl alcohol (PVA, D08019,44.0–54.0 mPa·s) were purchased from Tianjin Damao Chemical Reagent Co., Ltd. (Tianjin, China). Methanol and anhydrous ethanol were purchased from Tianjin Fengchuan Chemical Reagent Co., Ltd. (Tianjin, China). Acetonitrile was purchased from Tianjin Concord Technology Co., Ltd. (Tianjin, China). Phosphoric acid was purchased from Tianjin Huihang Chemical Technology Co., Ltd. (Tianjin, China). Acetonitrile and methanol were of high-performance liquid chromatography (HPLC) grade, while other reagents were of analytical grade.

2.2. Animals

Female Kunming mice (6 weeks old, weighing 16–18 g) and female Chinese rabbits (6 months old, weighing 2.0–2.5 kg) were purchased from Beijing SPF Biotechnology Co., Ltd. (Beijing, China). Kunming mice were kept in separate cages under standard laboratory conditions (12 h light/dark cycle, ~25 °C) and allowed to eat and drink freely. Chinese rabbits were kept in separate cages and fed a standard diet. Animal care and experimental protocols followed the institutional guidelines for the health and care of experimental animals. This research plan was approved by the Animal Experiment Ethics Committee of Nankai University in Tianjin, China.

2.3. Calibration Curve of SIM-CAP Compound

We used a CoM 6000 HPLC system (Albany, New York, NY, USA) with a Comatex C18-AB column (250 × 4.6 mm, 5 µm; 115 Corp, Plainfield, IL, USA) to measure the CAP and SIM concentrations in the samples. The wavelength was 230 nm. The mobile phase consisted of acetonitrile, water, and phosphoric acid (v/v/v, 300:100:0.1) at a 1.0 mL/min flow rate at 35 °C. All mobile phases were degassed; the sample volume was maintained at 20 µL. The SIM-CAP complex stock solution was prepared with five concentration gradients of 50, 100, 200, 300, and 500 µg/mL. The peak area values corresponding to different concentrations were determined according to the chromatographic conditions mentioned earlier. Linear analysis was performed with concentration as the x-axis (X) and peak area values as the y-axis (Y) to obtain a standard curve.
Figure 1 shows high-performance liquid chromatograms of simvastatin and captopril with injecting 200 µg/mL under the chromatographic conditions shown in Section 2.3. The retention times of CAP and SIM are 2.6 min and 11.8 min.
Table 1 shows the peak areas corresponding to different concentrations of SIM-CAP compound. The standard curve was obtained with concentration as the x-axis (X) and peak area values as the y-axis (Y). The standard curve equation for SIM-CAP compound is Y = 45,307X − 1,695,273, with a correlation coefficient R2 = 0.9956 (Figure 2). This indicates a good linear relationship between the concentration of SIM-CAP compound and peak area within the concentration range of 50–500 µg/mL.

2.4. Preparation of Mice Abdominal Skin

After experimented Kunming mice were anesthetized, they were euthanized using the cervical dislocation method. First, we removed their abdominal hair with hair removal cream. Then, we cut off approximately 2 × 2 cm of abdominal skin with scissors and checked the integrity of the skin. After repeatedly rinsing the skin with physiological saline, we placed it flat in a culture dish moistened with physiological saline and stored it at −20 °C for later use. We thawed the material naturally at 25 °C before the formal experiments began.

2.5. Optimization of Transdermal Systems

Preliminary screening of the matrix composition of the SIM-CAP TDDS used the L25 (55) orthogonal experimental table. The experiment used the primary skeleton material, secondary skeleton material, and enhancer as the three factors of the orthogonal experiment, with five different types of the three factors at the level of the orthogonal experiment (Table 2). A Franz TP-6 transdermal diffusion instrument (Tianjin Jingtuo Instrument Technology Co., Ltd., Tianjin, China) was used to measure the drug release rate and determine the preliminary formula. Then, we used in vitro permeation experiments to screen different proportions of penetration enhancers and polyacrylic acid resin II (Table 3) to determine the optimal formulation.

2.6. In Vitro Release Studies

We used the TP-6 transdermal diffusion meter to conduct drug release studies. Six TP-6 transdermal diffusion cells can be placed in the Franz transdermal diffusion meter. The effective diffusion area of TP-6 transdermal diffusion cells is 3.14 cm2. The excised skin of Kunming mice was firmly fixed between the donor and receptor compartments. Each receptor chamber was filled with 15 mL of saline solution, maintained at a temperature of 37 ± 0.5 °C, and stirred with a rotor to ensure uniform distribution. Sample aliquots (0.5 mL) were extracted from the receptor compartment at different time intervals (4, 8, 10, and 24 h) and replaced with an equal volume of saline solution. The samples were first filtered using a 0.22 µm pinhole filter (Scienhome Scientific Technology Development Co., Ltd., Tianjin, China) and then injected into HPLC instrument.

2.7. Preparation of TDDS

Figure 3 shows the preparation flowchart of the SIM-CAP combined transdermal drug delivery system. We used a solvent evaporation technique to prepare drug-containing transdermal systems according to the optimized formulation. PVA was dissolved in water, while the remaining components were dissolved in anhydrous ethanol. SIM and CAP are dissolved to form the drug-containing solution. OA and azone are dissolved to form the permeation-promoting solution. PVA and polyacrylic acid resin II are dissolved to form the pressure-sensitive liquid. They were mixed and magnetically stirred (60 °C, 30× g) for 2 h to obtain the medicated gel solution. The evenly mixed solution was degassed via the use of ultrasound at room temperature for 30 min. Then, the mixed solution was dropped onto an anti-adhesion layer and dried at 60 °C for 120 min. After drying, release paper was attached to obtain transdermal patches. The prepared patches were placed in a sealed environment at 25 °C for the convenience of subsequent experimental research.

2.8. Scanning Electron Microscopy Analysis

A scanning electron microscope (QUANTA 200, FEI Company, Hillsboro, OR, USA) was used to analyze the external morphology of the TDDS.

2.9. Stability of the Prepared TDDS

For the high-temperature, cold resistance, and freeze–thaw experiment, the SIM-CAP TDDSs were placed at 50 ± 5 °C for seven days, 2–8 °C for seven days, and alternately in a freezer at −20 °C and in an oven at 37 ± 0.5 °C for eight days. The patches’ appearances and ductility were examined. Each process was repeated three times.

2.10. Stickiness of the Prepared TDDS

The methods for evaluating the adhesion of the SIM-CAP TDDS include peel strength testing; shear strength testing; and hand adhesion experiment. We referred to the previous experimental procedure in our laboratory for evaluating peel strength, shear strength, and hand adhesion [30]. The time to completely peel off the SIM-CAP TDDS represented the peel strength. The time for the complete detachment of the TDDS was the shear strength. The displacement of stainless steel after contact with the patch indicated hand adhesion.

2.11. Drug Content in the Prepared TDDS

In total, 1 cm2 of SIM-CAP transdermal patches was dissolved in 10 mL of ethanol, treated with ultrasound for 8 h, centrifuged at 12,000 rpm for 10 min, filtered, and analyzed by HPLC (the method is shown in Section 2.3). This process was repeated six times.

2.12. In Vivo Pharmacokinetic Studies

The rabbits were divided into three groups: group A received blank patches, group B received oral gavage, and group C received the optimized SIM-CAP TDDS. The abdominal hair of the rabbits in groups A and C was shaved off using an electric hair removal device, and the skin was washed with physiological saline. The optimized TDDS was applied to the abdomen of group C rabbits, and the blank patch was applied to the abdomen of group A rabbits. The oral gavage (group B) process includes fixing the rabbits, placing a specially designed mouth expander into its mouth, and securing it to its mouth with a rope. We inserted an elastic rubber catheter through the small circular hole on the expander and entered the esophagus along the posterior pharyngeal wall. Then, a solution was added with the same concentration as the TDDS. After gastric perfusion, first the catheter was removed and then the mouth opener was removed. We collected 1 mL aliquots of blood from the ear vein of rabbits of different groups at different time intervals (1, 2, 4, 7, 12, and 24 h), placed them in heparinized tubes, and centrifuged them at 1500× g for 10 min. The blood serum was obtained and stored at −70 °C. We mixed 600 µL of blood serum with 900 µL of acetonitrile in a 1.5 mL polyethylene centrifuge tube, centrifuged it at 2500× g for 10 min, and then filtered it through a 0.22 µm membrane to obtain the sample for subsequent HPLC analysis.

2.13. Skin Irritation Studies

After 48 h, we removed the patches from the abdomen of rabbits in groups A and C and observed skin irritation condition, including erythema and edema. The scoring criteria for skin irritation referred to Literature 24 and are presented in Table 4.

2.14. Data Analysis

Pharmacokinetic parameters include Cmax (observed maximum plasma drug concentration), Tmax (time required to reach maximum drug concentration), AUC(0–t) (area under the plasma concentration time curve from time 0 to t), and MRT (average time the drug molecule stays in the body).
We used the DAS 2.0 procedure based on statistical moment theory to analyze the pharmacokinetic parameters of group A and group C. AUC(0–t) was calculated using the trapezoidal rule. F-value (calculated relative bioavailability) referred to the ratio of AUC(0–t) of the TDDS to AUC(0–t) of oral administration. A bilateral t-test was performed for Cmax and AUC(0-t) analysis, and a non-parametric test was performed for Tmax analysis.
All results are represented as the mean ± standard deviation (Mean ± SD). One-way analysis of variance (ANOVA) and Student’s t-test were used to compare different groups. The statistical significance was set at p < 0.05.

3. Results

3.1. Preselection of Transdermal Systems

The results of the orthogonal experiments are presented in Table 5. We found that the final cumulative release percentage of SIM-CAP was decided by the different components of the TDDS. When polyvinyl alcohol (PVA) was used as the primary and secondary skeleton material and oleic acid (OA)/azone (1:1) was used as the enhancer, the cumulative release rates of SIM and CAP were the highest within 24 h, reaching 66.3%. It was preliminarily determined that PVA could be used as the SIM-CAP TDDS skeleton material and OA/azone (1:1) as the enhancer.

3.2. The Effect of Penetration Enhancer Concentration on the Transdermal System

We selected six concentrations of OA/azone (1:1) to determine the optimal concentration of the penetration enhancer in the transdermal system (A1–A6; Table 2). The effect of different concentrations of OA/azone (1:1) as a penetration enhancer on the release of SIM-CAP is presented in Figure 4. When the concentration of the penetration enhancer was 0–16%, the cumulative drug release increased significantly with increasing the penetration enhancer concentration. When the concentration of the enhancer was 20%, the cumulative drug release began to decrease. The cumulative drug release of 16% concentration of OA/azone (1:1) was 465.49 ± 17.41 μg/cm2, significantly higher than the other groups. Therefore, 16% OA/azone (A5) was chosen as the concentration of penetration enhancer in the transdermal system.

3.3. Effects of Polyacrylic Acid Resin II on the Transdermal Systems

We selected five different concentrations of polyacrylic acid resin II to determine its optimal content for use as a pressure-sensitive adhesive (PSA) in the transdermal system (B1–B5; Table 2).
The effect of polyacrylic acid resin II concentration on in vitro release of SIM and CAP compounds from the transdermal drug delivery system is presented in Figure 5. When the concentration of polyacrylic acid resin II is 1%, 3%, and 4%, their cumulative release of the transdermal patch was less than 0% polyacrylic acid resin II. The cumulative release of the transdermal patch with 2% polyacrylic acid resin II was the highest, reaching 503.46 ± 24.91 μg/cm2. Therefore, 2% polyacrylic acid resin II (B3) was used in this transdermal system.

3.4. Preparation of SIM-CAP Transdermal Patches

After optimizing the concentration of penetration enhancers and polyacrylic acid resin II, it was determined that the transdermal patch contained 16% OA/azone (1:1) and 2% polyacrylic acid resin II to achieve maximum SIM-CAP administration. Based on the recommended clinical dosage, the percentage of SIM and CAP that should be added to transdermal patches has been determined. The SIM-CAP TDDS optimized formulation is shown in Table 6. According to the operating procedure shown in Section 2.7, the SIM-CAP transdermal patches were prepared. Figure 6 shows SIM-CAP transdermal patches. It shows that the prepared patch had a white appearance, a smooth surface, and no graininess.

3.5. Scanning Electron Microscopy of SIM-CAP Transdermal Patches

Figure 7 shows a scanning electron microscopy (SEM) image of the SIM-CAP composite transdermal delivery system, showing that the patch was smooth without obvious drug particles or cracks, and the drugs were evenly distributed in the polymer. This indicates that the SIM-CAP transdermal patches meet the appearance characteristics required by the TDDS.

3.6. Stability of SIM-CAP Transdermal Patches

There was no flow, wrinkling, or embrittlement on the surface of the patch at 50 ± 5 °C for seven days or at 2–8 °C for seven days, or at −20 °C and in an oven at 37 ± 0.5 °C for eight days. Moreover, no oil leakage or delamination was observed. This indicates that the appearance structure of the SIM-CAP transdermal patches had not undergone any changes under high-temperature, low-temperature, and freeze–thaw conditions, and the stability of the SIM-CAP TDDS was good.

3.7. Stickiness of SIM-CAP Transdermal Patches

The complete peel time; the complete detachment time; and stainless-steel displacement were 920 ± 21 s, 1107 ± 85 s, and 5.03 ± 0.25 cm, respectively. This indicated that the SIM-CAP composite transdermal patches had suitable peel strength, shear strength, and tactile viscosity. Thus, the patches had good adhesive qualities.

3.8. Drug Content of SIM-CAP Transdermal Patches

The results showed that the SIM and CAP contents in the SIM-CAP transdermal patches were 5.02 ± 0.41 mg/cm2 (n = 6).

3.9. In Vivo Pharmacokinetic Studies of SIM-CAP Transdermal Patches

The pharmacokinetic performance of the optimized SIM-CAP TDDS in rabbits was compared with oral SIM-CAP. The plasma concentration–time profiles are shown in Figure 8; the relevant pharmacokinetic parameters are summarized in Table 7. Compared with oral administration, the maximum blood drug concentration (Cmax) of the SIM-CAP TDDS is lower, but the patches’ time to reach the maximum blood drug concentration (Tmax) is extended to 4 h. The AUC(0-t) and mean residence time (MRT) of the SIM-CAP transdermal patches were extremely increased, reaching 110,192.83 ± 7103.89 ng·h−1·mL−1 and 9.29 ± 0.59 h, respectively. This indicates that this developed SIM-CAP TDDS stayed in the body for a longer period of time, maintaining a stable blood drug concentration and achieving sustained release. The F-value is 235.16%, indicating that the SIM-CAP TDDS had a higher bioavailability compared to oral administration.

3.10. Skin Irritation Tests

Table 8 shows the erythema and edema stimulation scores of blank patches and SIM-CAP transdermal patches at 0 and 48 h. The results showed that the stimulus split was less than 0.5, indicating no significant stimulation. Thus, SIM-CAP transdermal patches were safe and had no irritating effects on the skin.

4. Discussion

Transdermal drug delivery is a method for local or systemic treatment through the skin [32]. Transdermal drug delivery systems (TDDSs) include the reservoir system, matrix system, and microreservoir systems [17]. Matrix-type TDDSs are the most commonly used due to their simple design, ease of manufacturing, and good wear performance [33]. Matrix-type TDDSs have a low risk of accidental overdose and a low likelihood of drug abuse, making it the preferred choice for patients [34]. The SIM-CAP TDDS prepared in this study was designed as a matrix-type TDDS.
Matrix materials are important for TDDSs. Hydroxypropyl methyl cellulose (HPMC) is considered the most important hydrophilic carrier material for the preparation of controlled drug delivery systems [35]. One of its most important features is high expansibility, which has a significant impact on the release kinetics of incorporated drugs [36]. HPMC is widely used due to its advantages such as wide availability, ease of use, good biocompatibility, strong film-forming ability, and good biodegradability [24]. Ethyl cellulose (EC) is a non-allergic and nontoxic polymer with excellent properties for the formation of tough films [37]. Carboxyl methyl cellulose (CMC-Na) is an anionic derivative of carboxymethyl cellulose that exhibits good biocompatibility and stable water solubility [38]. It has swelling properties and uniform viscosity and has been widely used in local drug formulations to achieve controlled and sustained targeted drug delivery [39,40]. Polyvinylpyrrolidone (PVP) is a non-ionic water-soluble linear polymer widely used in cosmetics and pharmaceuticals because of its good solubility, excellent affinity for resins and polymers, biodegradability, nontoxicity, and compatibility [41]. Polyvinyl alcohol (PVA) has been widely used in biomedical and pharmaceutical applications due to its good biocompatibility, nontoxicity, hydrophilicity, and ability to form nanofibers and hydrogels [42,43]. In this study, we used an orthogonal experimental table to verify the cumulative release of the two-polymer combinations. The results showed that when both the main and secondary matrix skeleton materials were made of PVA, the cumulative drug release was higher. Therefore, PVA was selected as the matrix skeleton material for the SIM-CAP transdermal patches.
The skin, particularly the cuticle, forms an effective barrier to drug penetration, making it difficult to deliver drugs from the patches across the skin. The most widely used method for enhancing drug penetration through the cuticle employs chemical enhancers [44]. We used two chemical penetration enhancers: OA and azone. The ability of OA to enhance skin penetration has been widely recognized in various in vitro studies [45]. It disrupts highly stacked intercellular domain lipids in the cuticle [46]. Azone was the first compound specifically designed as a skin penetration enhancer, and its penetration-enhancing properties reflected the molecule’s ability to reduce skin diffusion resistance [47,48]. Due to the limited enhancement effect of a single chemical enhancer on skin permeability, the combined use of chemical enhancers may achieve more satisfactory therapeutic effects and safety owing to their synergistic effects [49]. This study evaluated the permeability of SIM-CAP transdermal patches using oleic acid and azone alone and in combination. The results showed that at the 16% concentration of OA/azone (1:1), the cumulative drug release was the highest and was selected as the enhancer for the SIM-CAP transdermal patches.
Pressure-sensitive adhesives (PSAs) are viscoelastic materials that can adhere to various solid surfaces under slight pressure quickly [50]. They have the advantages of convenient use, good stability, simple manufacturing, and good appearance [51]. Polyacrylic acid resin II is a type of polyacrylic acid resin pressure-sensitive adhesive that can adhere to biological tissues and shows excellent sustained release effects in the skin [52]. We investigated the effect of different concentrations of polyacrylic acid resin II in SIM-CAP transdermal patches on drug release. The results showed that 2% polyacrylic acid resin II maintained the developed patch’s moderate adhesive qualities and optimized the cumulative release of SIM-CAP from the sustained-release TDDS.
The optimal formula for the SIM-CAP composite transdermal patch was determined by screening the skeletal material, penetration enhancer, and pressure-sensitive adhesive. The quality of the optimal formula was then evaluated, including quality indicators such as integrity, stability, and viscosity. SEM was used to inspect the integrity of the patch; the results showed that the surface of the prepared SIM-CAP composite transdermal patches was relatively smooth and uniform without solid particles or cracks. The SIM-CAP composite transdermal patches exhibited no significant changes in appearance and good stability under high-temperature, severe cold, and freeze–thaw conditions. The patches were also evaluated for their initial adhesion, adhesion retention, and peel strength. The results indicated that the SIM-CAP composite transdermal patch exhibited good adhesion.
We conducted pharmacokinetic analysis of oral administration and the SIM-CAP TDDS using rabbits. Compared with oral medication, the maximum concentration of the SIM-CAP TDDS was reduced, which avoids the side effects caused by peak oral administration. The Tmax of the SIM-CAP TDDS was prolonged to 4 h, showing that the speed at which drugs are absorbed into the body slows down. The extension of MRT from 5.34 h to 9.29 h indicated an increase in the duration of drug retention in the body. Compared with oral administration, the AUC(0–t) value of the SIM-CAP TDDS increased significantly, indicating that the patches had a longer duration of action and a more stable blood drug concentration. The AUC(0–t) ratio of the SIM-CAP TDDS and oral administration was compared. We found that the SIM-CAP TDDS gained a significant increase in relative bioavailability, reaching 235.16%. In summary, this pharmacokinetic parameter indicated that the SIM-CAP TDDS had a better absorption effect in vivo, longer action time, higher bioavailability, and more stable blood drug concentration and overcomes the first-pass effect of oral administration.
However, skin reactions may still occur with transdermal medications [53]. The most common skin irritation of transdermal administration is redness erythema (redness) or edema (swelling) at the site of application [54]. If the transdermal patch causes any skin irritation reaction, it will affect the patient’s use of the transdermal patch. Thus, evaluating skin irritation for transdermal patches is of great significance. So, we finally tested whether the transdermal patch would cause skin inflammation. The transdermal patch was applied to the abdominal skin of rabbits, and after removing the patch, redness and edema were observed. Then, we scored the redness and swelling on the skin. The results showed that the scores for erythema and edema were both less than 0.5, indicating that there were no obvious erythema and edema on the skin of the rabbits. This indicated that the SIM-CAP TDDS did not cause skin irritation.
Our study has established an SIM-CAP TDDS for simultaneously controlling blood pressure and blood lipids. Hypertension and hyperlipidemia are both recognized as important risk factors of CVD [1,2,3,4]. The coexistence of the two risk factors has more than an additive adverse impact on the vascular endothelium, which results in enhanced atherosclerosis, leading to CVD [55]. CVD is currently the leading cause of death, accounting for one-third of deaths worldwide [7,56]. The SIM-CAP TDDS can slowly and continuously release SIM and CAP, increase the bioavailability of SIM and CAP, efficiently control blood pressure and blood lipids, and has great significance in reducing CVD incidence and improving human health.

5. Conclusions

The formulation of transdermal patches was optimized using in vitro penetration tests, and transdermal patches were prepared and tested in vivo. This optimized formula of the SIM-CAP TDDS included SIM, CAP, PVA, OA/azone (1:1), and polyacrylic acid resin II. The SIM and CAP contents in the 1 cm2 SIM-CAP transdermal patches were 5.02 ± 0.41 mg/cm2. The prepared patches have good integrity, stability, and adhesion and can continuously and slowly release the drug without causing skin irritation. However, clinical studies are required to evaluate its actual efficacy.

Author Contributions

Conceptualization, Y.-Q.L.; methodology, Y.-J.N.; validation, Y.-J.N., R.-J.W., Z.L. and L.-H.X.; investigation, Y.-J.N.; resources, Z.L. and L.-H.X.; data curation, Y.-J.N. and R.-J.W.; writing—original draft, Y.-J.N.; writing—review and editing and visualization, Y.-J.N. and Y.-Q.L.; supervision, Z.L., L.-H.X. and Y.-Q.L.; project administration, Y.-Q.L.; funding acquisition, Y.-Q.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Natural Science Foundation of Tianjin City (grant 20JCYBJC01370); Fundamental Research Funds for the Central Universities of Nankai University (grant BE123081); and the University–Enterprise Cooperation Project (grant F1023741).

Institutional Review Board Statement

This study protocol was approved by the Committee for Ethics of Animal Experiments at Nankai University, Tianjin, China (NKEAE20211230).

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

Authors Zhao Liu and Li-Hui Xiao were employed by the Harvest Pharmaceutical Co., Ltd. The remaining authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

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Applsci 14 09092 g001
Figure 1. High-performance liquid chromatograms of simvastatin and captopril.
Figure 1. High-performance liquid chromatograms of simvastatin and captopril.
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Figure 2. Calibration curve of SIM-CAP compound (n = 3).
Figure 2. Calibration curve of SIM-CAP compound (n = 3).
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Figure 3. Preparation flowchart of SIM-CAP combined transdermal drug delivery system.
Figure 3. Preparation flowchart of SIM-CAP combined transdermal drug delivery system.
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Figure 4. Effect of different concentrations of OA/azone (1:1) on the release of the SIM and CAP compounds from the transdermal drug delivery system (mean ± SD, n = 3).
Figure 4. Effect of different concentrations of OA/azone (1:1) on the release of the SIM and CAP compounds from the transdermal drug delivery system (mean ± SD, n = 3).
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Figure 5. Effect of polyacrylic acid resin II concentration on in vitro release of SIM and CAP compounds from the transdermal drug delivery system (mean ± SD, n = 3).
Figure 5. Effect of polyacrylic acid resin II concentration on in vitro release of SIM and CAP compounds from the transdermal drug delivery system (mean ± SD, n = 3).
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Figure 6. SIM-CAP transdermal patches. Note: Three replicates of SIM-CAP transdermal patches are shown.
Figure 6. SIM-CAP transdermal patches. Note: Three replicates of SIM-CAP transdermal patches are shown.
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Figure 7. A SEM photograph of the SIM-CAP composite transdermal delivery system.
Figure 7. A SEM photograph of the SIM-CAP composite transdermal delivery system.
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Figure 8. Plasma drug concentration–time curve analysis in rabbits after SIM-CAP TDDS and oral application (mean ± SD, n = 6); * p < 0.05 vs. oral administration.
Figure 8. Plasma drug concentration–time curve analysis in rabbits after SIM-CAP TDDS and oral application (mean ± SD, n = 6); * p < 0.05 vs. oral administration.
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Table 1. Values of calibration points of SIM-CAP compound (n = 3).
Table 1. Values of calibration points of SIM-CAP compound (n = 3).
Concentration of SIM-CAP Compound (μg/mL)Peak Area (AU × min)
50507,182
1002,721,720
2008,110,334
30011,149,351
50021,137,980
Table 2. Orthogonal test table L25 (55).
Table 2. Orthogonal test table L25 (55).
OptionFactors
First Skeleton Materials (a)Second Skeleton Material (b)Penetration Enhancers (c)
Level1HPMC K4MHPMC K100MOA
2HPMC K30MCMC-Naazone
3HCECOA/azone = 1: 1
4PVP K30PVP K30OA/azone = 2: 1
5PVAPVAOA/azone = 1: 2
Table 3. Optimization of preliminary formula for SIM-CAP TDDS.
Table 3. Optimization of preliminary formula for SIM-CAP TDDS.
FormulationOA/Azone (1:1)
(%, v/v)		Polyacrylic Acid Resin II
(%, v/v)
A10
A24
A38
A412
A516
A620
B1 0
B2 1
B3 2
B4 3
B5 4
Table 4. Scoring criteria for skin irritation [31].
Table 4. Scoring criteria for skin irritation [31].
Experimental IndicatorsSkin ConditionEvaluation Score
erythemaNo erythema0
Very slight erythema1
Well-defined erythema2
Moderate to severe erythema3
Severe erythema (beef redness) to eschar formation preventing grading of erythema4
edemaNo edema0
Very slight edema1
Slight edema (edges of area well defined by definite raising)2
Moderate edema (raised approximately 1 mm)3
Severe edema (raised more than 1 mm and extending beyond area of exposure)4
Table 5. L25 (55) orthogonal experiments.
Table 5. L25 (55) orthogonal experiments.
First Skeleton MaterialsSecond Skeleton Materials Penetration EnhancersCumulative Release Rate (%)
111134.24
212211.60
31339.78
41448.46
51559.77
62125.77
72237.70
823411.74
924511.89
1025112.40
113139.80
1232411.00
1333510.80
1434121.47
153529.70
164148.76
1742512.70
184319.80
1944210.40
204539.80
215158.70
225218.30
2353212.65
2454420.22
2555366.30
K173.8567.2786.21
K249.5051.3050.03
K362.7754.77103.38
K451.4672.4460.18
K5113.17109.9753.86
R12.7411.3310.68
K1–K5 represent the sum of the indicators at each factor level, and R represents the range of the mean indicators at each factor level. The larger the range of a certain factor, the greater its impact on the experimental indicators, indicating that it plays a more important role in the experiment.
Table 6. SIM-CAP TDDS optimized formulation.
Table 6. SIM-CAP TDDS optimized formulation.
ComponentsUsage (%)
SIM24% (w/w)
CAP24% (w/w)
PVA34% (w/w)
OA/azone (1:1) 16% (v/v)
Polyacrylic acid resin II2% (w/w)
Table 7. Pharmacokinetic parameters (n = 6).
Table 7. Pharmacokinetic parameters (n = 6).
ParametersOral AdministrationSIM-CAP TDDS
Cmax (ng/mL)12,503.50 ± 952.1011,762 ± 535.87 *
Tmax (h)14 *
AUC(0–t) (ng·h−1·mL−1)46,858.18 ± 7563.52110,192.83 ± 7103.89 *
MRT (h)5.34 ± 1.029.29 ± 0.59 *
F (%)-235.16
Cmax: peak concentration; AUC: area under drug time curve; MRT: mean residence time; F (%): the calculated relative bioavailability is AUC(0-t) for the TDDS/AUC(0-t) for the oral administration; * p < 0.05, compared with oral administration.
Table 8. Skin irritation scores for blank patches and SIM-CAP transdermal patches (n = 6).
Table 8. Skin irritation scores for blank patches and SIM-CAP transdermal patches (n = 6).
AdministrationErythemaEdema
0 h48 h0 h48 h
Blank patch0.00 ± 0.000.24 ± 0.040.00 ± 0.000.14 ± 0.01
SIM-CAP TDDS0.00 ± 0.000.36 ± 0.080.00 ± 0.000.23 ± 0.05
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Ni, Y.-J.; Wang, R.-J.; Liu, Z.; Xiao, L.-H.; Liu, Y.-Q. Simvastatin and Captopril Combined Transdermal Delivery System for Controlling Blood Pressure and Fat: Design, Characterization, and In Vivo Pharmacokinetic Evaluation. Appl. Sci. 2024, 14, 9092. https://doi.org/10.3390/app14199092

AMA Style

Ni Y-J, Wang R-J, Liu Z, Xiao L-H, Liu Y-Q. Simvastatin and Captopril Combined Transdermal Delivery System for Controlling Blood Pressure and Fat: Design, Characterization, and In Vivo Pharmacokinetic Evaluation. Applied Sciences. 2024; 14(19):9092. https://doi.org/10.3390/app14199092

Chicago/Turabian Style

Ni, Ya-Jing, Run-Jia Wang, Zhao Liu, Li-Hui Xiao, and Yan-Qiang Liu. 2024. "Simvastatin and Captopril Combined Transdermal Delivery System for Controlling Blood Pressure and Fat: Design, Characterization, and In Vivo Pharmacokinetic Evaluation" Applied Sciences 14, no. 19: 9092. https://doi.org/10.3390/app14199092

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