Article pubs.acs.org/IECR
Physicochemical and Drug Release Characterization of LidocaineLoaded Transdermal Patches Prepared from STR-5L Block Rubber Wiwat Pichayakorn,† Hasleena Boontawee,† Wirach Taweepreda,‡ Jirapornchai Suksaeree,§,⊥ and Prapaporn Boonme*,† †
Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand ‡ Department of Materials Science and Technology, Faculty of Science, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand § Department of Pharmaceutical Analysis, Faculty of Pharmacy, Rangsit University, Pathum Thani 12000, Thailand ⊥ Sino-Thai Traditional Medicine Research Center (Cooperation between Rangsit University, Harbin Institute of Technology, and Heilongjiang University of Chinese Medicine), Rangsit University, Pathum Thani 12000, Thailand ABSTRACT: The aims of this study were to formulate 5% lidocaine-loaded transdermal patches using STR-5L block rubber as a main component of the patch base and to investigate their physicochemical characteristics, in vitro drug release, and stability. The results suggested that STR-5L block rubber could be feasibly used as a main component of the base of pharmaceutical transdermal patches with acceptable physicochemical properties. STR-5L block rubber patches containing lidocaine exhibited lower moisture absorption when compared with the blank counterparts because the drug molecules inserted between the polymer chains. Lidocaine still showed its own crystallinity characteristics after crushing and mixing in STR-5L block rubber patches. Additionally, no chemical interaction between the drug and polymer base was found. The drug-loaded patches could provide drug release with the best fitted to Higuchi square root of time. They had good stability during the studied period of 3 months when kept at 4 °C.
1. INTRODUCTION
in lower required storage area and higher stability compared with the latex. According to Standard Thai Rubber (STR), there are eight grades of block rubber traded in Thailand, i.e., STR-XL, STR5L, STR-5, STR-5CV, STR-10, STR-10CV, STR-20, and STR20CV.7 Among these, STR-5L has great potential to be used in pharmaceutical formulations because it is prepared from quality latex by converting rubber into crumbs and drying at 100 °C, resulting in very low impurity. Therefore, STR-5L was selected to be studied for its feasibility in transdermal patch formulation instead of synthetic polymers and natural rubber latex. This study aimed to formulate lidocaine-loaded transdermal patches using STR-5L block rubber as main component of the patch base and to investigate their physicochemical characteristics, in vitro drug release, and stability.
A transdermal patch, either matrix or reservoir systems, is one of novel alternative dosage forms because it can deliver a small molecular drug to achieve a systemic activity by skin application. It can provide several benefits over conventional dosage forms such as to avoid gastrointestinal absorption difficulties and first pass metabolism. Moreover, it is easy to be used and terminated, leading to good patient compliance.1 A matrix patch is also easy to be prepared by simple dispersing or dissolving a drug with the appropriate polymers, casting into a patch or a film, and finally attaching to an adhesive layer to adhere the skin. Nevertheless, the polymer matrix itself can perform as the adhesive layer in some cases.2,3 Natural rubber latex tapped from the bark of Hevea brasiliensis contains colloidal cis-1,4-polyisoprene polymer with remarkable physical characteristics such as high tensile strength, high elongation at break, excellent resilience, impermeability to gases as well as liquids, and ease of patch formation.4 Recently, lidocaine, a local anesthetic drug used for pain relieve by disturbing the conduction of sensory nerve impulses,5 was reported that it could be prepared as transdermal patches using natural rubber latex as major component of the patch base.6 Natural rubber latex is composed of around 30−40% rubber particles and other components, which are dispersed in aqueous serum.4 Therefore, it might be difficult in storage due to its bulk volume and risk of microbial contamination. Block rubber is an interesting material for using in transdermal patch formulation instead of natural rubber latex because it is solid form, resulting © 2014 American Chemical Society
2. MATERIALS AND METHODS 2.1. Materials. Lidocaine was purchased from SigmaAldrich (USA). STR-5L block rubber containing 100% dry rubber content (DRC) was kindly gifted from Chalong Latex Industry Co., Ltd. (Thailand). All other chemicals were from local distributors in Thailand, pharmaceutical or analytical grade, and used as received without further purification. Isotonic phosphate buffer pH 7.4 solution (PBS) was prepared Received: Revised: Accepted: Published: 1672
October 19, 2013 December 31, 2013 January 10, 2014 January 10, 2014 dx.doi.org/10.1021/ie403529f | Ind. Eng. Chem. Res. 2014, 53, 1672−1677
Industrial & Engineering Chemistry Research
Article
USA). The characteristic peaks of IR transmission spectra were recorded. 2.4. Determination of Entrapped Drug in LidocaineLoaded Patches. The drug was extracted from three different points with an accurate area of each lidocaine-loaded patch with an accurate volume of ethanol under sonication for 3 h and adjusted to the determined volume. Its concentration was then determined by a high performance liquid chromatography (HPLC) assay. The amounts of actual lidocaine content were calculated by comparing the peak area values with those in the standard curve. The determination was performed in triplicate. Afterward, the entrapment efficacy (EE) of each patch was calculated according to eq 1.
in-house by dissolving appropriate amounts of sodium dihydrogen orthophosphate, disodium hydrogen phosphate, and sodium chloride in water. Distilled water was used throughout the experiments. 2.2. Preparation of Blank and Lidocaine-Loaded Patches. For each blank patch, 5 g of STR-5L block rubber was crushed with a mixing roll machine (191-TM, Yasuda Seiki Seisakusho, Japan) at ambient temperature for 15 min. The gap between two mixing rolls was set at 0.5 mm. Each obtained rubber patch was kept between an elastic fabric as a backing and a grease paper as a liner. For each lidocaine-loaded patch, 5 g of STR-5L block rubber was crushed with a mixing roll machine (191-TM, Yasuda Seiki Seisakusho, Japan) with the gap of 0.5 mm for 15 min, and afterward 0.25, 0.50, or 0.75 g of lidocaine powder, which was equalized to 5, 10, or 15% w/w of DRC, respectively, was added and crushed to combine with STR-5L block rubber for 15 min. Finally, each resulted patch was kept like the blank patch. The 5% w/w lidocaine-loaded patches, which contained the identical drug concentration to a commercial product (Lidoderm),8 were further characterized for physical properties, drug release, and stability. The 10 and 15% w/w lidocaineloaded patches were further used in only X-ray diffractometry. 2.3. Physical Characterization of the Patches. Blank and lidocaine-loaded patches were observed for their visual appearances such as color and homogeneity. Each patch was measured for thickness at three different points with a dial thickness gauge (Teclock Corporation, Japan). The morphological surface was performed using a scanning electron microscope (JSM-5800LV SEM, JEOL, Japan). The blank patch samples were cut into rectangular shapes of 25 × 100 mm. Their peel strength or the force to peel away the adhesive tapes from a surface of substrate of the prepared patches was determined using a tension testing machine (LLOYD Instruments Ltd., U.K.). The measurement was followed a T-peel method that was modified from ASTM D18769 using a cleaned aluminum sheet as substrate and crosshead speed of 254 mm/min dwell time. The peel strength of a blank block rubber patch was compared with that of an available commercial adhesive patch (Capsicum Plaster Patch, Dersan Pharmaceutical Co., Ltd., Taiwan). The experiment was performed in triplicate. Moisture absorption of the patches was studied under the condition of 75% relative humidity at 45 °C by storing the samples in desiccators containing saturated sodium chloride solution, which were in a controlled-temperature oven. The samples were taken and weighed every week until constant. The percentage of moisture uptake was calculated as the percentage of the increased weight compared to the initial weight. The experiment was carried out in triplicate. X-ray diffractometer (XRD, WI-RES-XRD-001, Philips analytical, The Netherlands) was used to evaluated the crystallinity of the samples. The X-ray source generated a 40 kV operating voltage, 45 mA current, 0−90° angular (2θ), and 0.02° (2θ)/s stepped angle. Lidocaine was characterized by Fourier transform infrared (FTIR) spectroscopy. The drug was mixed with dry potassium bromide (KBr) and compressed into a KBr disc sample using an agate mortar. The patches were examined for compatibility using the attenuated total reflection FTIR (ATR-FTIR) technique. Samples were scanned at a resolution of 4 cm−1 over the wavenumber regions of 400−4000 cm−1 by FTIR spectrophotometer (model Spectrum One, Perkin-Elmer,
EE(%) = (analyzed lidocaine content in patch /theoretical lidocaine content) × 100
(1)
2.5. In Vitro Release Study of Lidocaine-Loaded Patches. In vitro drug release studies were performed using modified Franz diffusion cells (Hanson Research Corporation, USA). The diffusion cells were connected with a circulating water bath and the temperature was controlled at 37 °C. PBS was used as a receptor fluid with a receptor compartment volume of 12 mL and stirred by an externally driven Tefloncoated magnetic bar at 200 rpm. Due to liquid impermeability of STR-5L block rubber, each lidocaine patch was directly placed on each cell with the diffusion area of 1.77 cm2. At suitable time intervals (0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 h), an accurate amount of each sample (1.5 mL) was withdrawn from the center of the receptor compartment using a syringe connected with a needle. An equal volume of fresh PBS (37 °C) was immediately replenished. The amount of lidocaine in the in vitro released samples was assayed by the HPLC. The experiment was performed in triplicate. The cumulative drug release (Qt) was calculated according to eq 2. t−1
Q t = VrCt +
∑ VsCi i=0
(2)
where Ct is the drug concentration in the receptor fluid at each sampling time, Ci is the drug concentration of the ith sample, and Vr and Vs are the volumes of the receptor fluid and the sample, respectively. Two possible mathematical equations were employed to fit with the release profiles, i.e., zero order and Higuchi square root of time equations as shown in eq 3, and 4, respectively.
Q = Q 0 − k 0t
(3)
Q = kHt 1/2
(4)
where Q is the cumulative amount of active compound released in time t; Q0 is initial amount of active compound in the lidocaine-loaded patch; k0 and kH are constants in zero order and Higuchi square root of time equations, respectively. 2.6. Stability Study of Lidocaine-Loaded Patches. Lidocaine-loaded patches were kept for 3 months at 3 various temperatures, i.e., 4 ± 1 °C, ambient temperature (≈28 ± 4 °C), and 45 ± 1 °C. They were then evaluated for the possibility of a change in appearances, drug contents, and drug release profiles by the previously described methods. 2.7. Analytical Method. The concentrations of lidocaine were quantitatively analyzed by HPLC as described in the previous study.6,10 The HPLC system (Shimadzu, Japan) 1673
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Figure 1. SEM of blank and lidocaine-loaded patches.
Figure 2. XRD patterns of lidocaine, various concentrations lidocaine-loaded and blank patches.
were identically flexible and translucent brownish. Their thickness was 0.54 ± 0.04 mm and 0.53 ± 0.02 mm, respectively. They also had identically smooth surfaces (Figure 1). No separation could be observed even if under SEM. Thus, it could be seen that the preparation method could provide low variation in thickness of the obtained patches and good incorporation of the drug into the rubber sheet. The moisture absorption values of blank and lidocaineloaded patches were 0.73 ± 0.28% w/w and 0.36 ± 0.17% w/w, respectively. Lidocaine-loaded patches provided much lower average moisture absorption than their blank counterparts. The possible reason was that lidocaine molecules inserted between molecular chain of the rubber, resulting in higher density and lower moisture absorption of the matrix. This phenomenon was also found when natural rubber latex was used as main component of the patch base,6 due to intrinsic property of the identical cis-1,4-polyisoprene in both natural rubber latex and STR-5L.
connected with a HPLC column (Thermo Hypersil-Keystone, Canada). A mixture of 50 mM ammonium acetate and methanol (60:40 v/v) mixed with 0.6% v/v acetic acid and 0.1% v/v triethylamine was used as a mobile phase. The samples were detected at 254 nm and integrated with the RF 10A (version 1.1) LC software program. The calibration curve was constructed by running standard solutions for every series of samples. Validation of the method was performed to ensure that the calibration curve between 5 and 150 μg/mL of lidocaine solutions and peak areas was in the linearity range (r2 > 0.999) and coefficients of variation were less than 2% for both intraday and interday. The blank patch was analyzed by the identical method to ensure that no interference from the components of the patch affecting the assay results was found.
3. RESULTS AND DISCUSSION 3.1. Physical Characteristics of Blank and LidocaineLoaded Patches. Both blank and lidocaine-loaded patches 1674
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Figure 3. FTIR and ATR-FTIR spectra of lidocaine, blank and lidocaine-loaded patches.
The maximum peeling load and T-peel strength of the blank block rubber patch were 19.64 ± 0.40 N and 7.85 ± 0.16 N/ cm, respectively, whereas those of the commercial adhesive patch were 10.74 ± 1.64 N and 4.30 ± 0.66 N/cm, respectively. Therefore, the block rubber patch itself had high tendency to perform as the self-adhesive patch. Lidocaine provided many sharp peaks with the highest peaks at 2θ of 10° and 12.5° whereas blank patch exhibited only the broad halo spectrum (Figure 2). No crystallinity was observed in the 5% lidocaine-loaded patch. However, when higher concentrations (10 and 15%) of the drug were loaded in the patches, small peaks at 2θ of 10° and 12.5° could be found. Thus, the peak height in 5% w/w lidocaine-loaded patch might be too small to be seen. This result suggested that incorporation of lidocaine in STR-5L block rubber by crushing did not affect the crystallinity of the drug, an intrinsic property,
implying to no effect on drug activity when lidocaine was incorporated into STR-5L block rubber patches. The FTIR spectrum of lidocaine and ATR-FTIR spectra of blank and lidocaine-loaded patches (Figure 3) showed that lidocaine had peaks at 3500−3100, 1666−1663, 1500, and 1165−1162 cm−1 for NH stretching (secondary amines), CO stretching, NH bending, and CN stretching, respectively. No change in characteristic peaks of lidocaineloaded patch was observed when compared to spectra of lidocaine and blank patch, implying no chemical interaction between the drug and polymer base. 3.2. Drug Entrapment in Lidocaine-Loaded Patches. The drug content and efficiency of drug entrapment of lidocaine-loaded patches were 2.03 ± 0.14 mg/cm2 and 86.29 ± 5.77%, respectively. The ideal or theoretical amount of drug content in the patch or 100% efficiency of drug entrapment was calculated as 2.35 mg/cm2. The partial drug might be entrapped 1675
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Figure 4. In vitro release profiles of lidocaine from lidocaine-loaded patches after preparation and stability test in various conditions with different mathematical models, i.e., zero order and Higuchi root of time.
Figure 5. Drug contents of lidocaine-loaded patches kept at various conditions.
matrix of a block rubber patch into the receptor fluid. The cumulative drug release was also high when compared with analyzed drug content. In the other words, it was possible to use the STR-5L block rubber as the base of transdermal patches because it could provide drug release, implying treatment efficacy. 3.4. Stability of Lidocaine-Loaded Patches. The appearance of the patches at initial preparation and after storage at 4 °C and at ambient temperature for 3 months was quite similar. The color of the patches after storage for 3 months at 45 °C was obviously darkened. Temperature could discolor STR-5L block rubber patches due to oxidation.11 Discoloration was also found when rubber latex was used as the base of lidocaine-loaded transdermal patches.6 Although the drug contents of the patches after stability test in all conditions were not significantly different from the initial one, those kept at 4 °C seemed to be slowest and least changed compared with those stored at ambient temperature and 45 °C,
in matrix of the patches and could not be completely extracted out. This was supported by that lidocaine-loaded patches had much lower moisture absorption than their blank counterparts as previously explained. However, the results exhibited that the drug could thoroughly distributed in the rubber patches because the drug contents obtained from different three points of each patch were not significantly different (P > 0.05). Hence, crushing method was feasible to obtain transdermal patches of STR-5L block rubber with uniformity of the loaded drug. 3.3. In Vitro Drug Release from Lidocaine-Loaded Patches. According to the results of moisture absorption, it could be seen that both blank and lidocaine-loaded patches could absorb very little moisture content (
