Deproteinized Natural Rubber Latex ... - ACS Publications

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Deproteinized Natural Rubber Latex/Hydroxypropylmethyl Cellulose Blending Polymers for Nicotine Matrix Films Wiwat Pichayakorn,*,† Jirapornchai Suksaeree,† Prapaporn Boonme,† Thanaporn Amnuaikit,† Wirach Taweepreda,‡ and Garnpimol C. Ritthidej§ †

Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla 90112, Thailand ‡ Department of Materials Science and Technology, Faculty of Science, Prince of Songkla University, Songkhla 90112, Thailand § Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand S Supporting Information *

ABSTRACT: Nicotine matrix films were prepared using DNRL/HPMC blends for transdermal delivery. Several plasticizers were also mixed. The mechanical and physicochemical properties, moisture uptake, and swelling ratio of films depended on HPMC and plasticizers. The compatibility of each ingredient in the blended films was confirmed by FT-IR, XRD, and DSC. The in vitro release of nicotine showed a monophasic slow release pattern. The polymer and plasticizer blends produced a faster release rate. The kinetics of nicotine release from the films fitted the diffusion type. Surprisingly, the permeation of the nicotine into the skin occurred by zero-order kinetics. It was concluded that nicotine matrix films could be produced that could provide a controlled release of the drug and suitable permeation patterns. Moreover, they were safe to apply to the skin as they did not cause irritation.

1. INTRODUCTION Transdermal drug delivery systems (TDDSs), known as medicated adhesives or patches, were designed to deliver therapeutic drugs across the skin into the systemic blood circulation. However, only small molecular therapeutic drugs can penetrate the skin from TDDSs because the skin is a very effective barrier.1,2 Generally, TDDSs in patch dosage forms are polymer films directly applied to the skin. They can be categorized as either (i) drug in matrix or (ii) drug in reservoir systems. For the matrix system, the drug is dispersed or dissolved in a polymer matrix and attached to an adhesive layer that contacts the skin. In some cases, the polymer matrix can act as the adhesive layer by itself. Polymer matrix layers and/or the added adhesive layer act as a control on the rate of delivery.3−6 Nicotine (NCT) is a pyridine alkaloid derived from the tobacco plant. It is volatile, highly soluble in hydrophobic solvents, and lipid in nature, but it is also miscible in both water and hydrophobic solvents. It is initially colorless but becomes yellow or brown when exposed to air or light through autooxidation. It is easily absorbed and readily permeates through the skin when applied topically and can even cross the blood− brain barrier.7 However, administration of NCT orally exhibits a low bioavailability because of its first pass metabolism in the liver. Therefore, development of NCT delivery systems, such as in chewing gum,8 or buccal,9 transdermal,10 and sublingual methods,11 has been carried out to cope with this problem. Nowadays, NCT transdermal patches are widely and easily used to facilitate cessation of smoking. A number of NCT patches have been designed and marketed to deliver NCT of 7, 14, and 21 mg over a period of 24 h. These films have been © 2012 American Chemical Society

approved by the U.S. FDA. They provide a therapeutic effect by releasing a controlled amount of NCT through the skin into the bloodstream.12 Many classes of polymers, such as cellulose derivatives, polyvinyl alcohol, chitosan, and polyacrylates, could be normally used for TDDSs because they have good physicochemical properties and adhesion-cohesion balance, and are stable and compatible with other ingredients as well as with the skin.13 Natural rubber latex (NRL) obtained from Hevea brasiliensis is composed of a cis-1,4-polyisoprene polymer that has low adhesiveness in the form of a film. NRL presents interesting physical properties such as high tensile strength, high elongation at break, outstanding resilience, impermeability of gases and liquids, and easy film-forming.14−16 There are many reports claiming to have developed NRL blended polymers with better properties than NRL itself.17 However, there have been several reports of latex allergies from 14 NRL proteins (Hev b1−14) that have been confirmed by the International Union of Immunological Societies (IUIS).18 NRL allergy refers to any immune-mediated reaction to latex associated with clinical symptoms, which include type I mediated hypersensitivity reactions to the latex protein itself and type IV mediated hypersensitivity. Another reaction associated with NRL is irritant contact dermatitis. 19−21 Deproteinized processes to remove these protein allergens from NRL have Received: Revised: Accepted: Published: 8442

March 8, 2012 May 24, 2012 June 1, 2012 June 1, 2012 dx.doi.org/10.1021/ie300608j | Ind. Eng. Chem. Res. 2012, 51, 8442−8452

Industrial & Engineering Chemistry Research

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also been reported.22 High safety deproteinized NRL (DNRL) for pharmaceutical applications has been developed by our research group.23,24 Moreover, it was reported to be a suitable matrix for drug delivery systems which could release NCT and could be used with different types of backing layers.23 The main objective of this study was to demonstrate the use of DNRL as a polymer matrix for NCT transdermal delivery. A blend of the DNRL with hydroxypropylmethyl cellulose (HPMC), a polymer normally used as a suspending, filmforming and thickening agent, and is mucoadhesive in topical formulations and a matrix former in patches, was chosen to improve the adhesive property of DNRL. In addition, several types of plasticizers, i.e., glycerin (GLY), dibutylphthalate (DBP), diethylphthalate (DEP), dibutylsebacate (DBS), and triethylcitrate (TEC), were added to produce films that were ideal for transdermal applications. The properties of the blended films were characterized including their physical appearances, mechanical properties, physicochemical properties, moisture uptake, swelling ratio, and compatibilities. Consequently, the in vitro release of NCT and the skin permeation were also studied for comparison with normal commercial NCT films.

Young’s modulus, which is the manifestation of stiffness of a material, was calculated from the initial slope of the stress− strain plot within the range of the elastic limit of stretching. The UTS is defined as either a distinct maximum or as the region of strong curvature approaching a zero-slope in the stress−strain curve. The elongation at break was determined by removing the fractured specimen from the grips, fitting the broken ends together and measuring the distance between the gauge marks. Peel strength measures the force required to peel away an adhesive material from its attached surface. It was measured by a T-peel method modified from the ASTM D187626 using a transparent polyvinyl chloride sheet as substrate that had been previously cleaned with distilled water and dried. The size of the film specimen was 10 × 60 mm2. The cross-head speed was controlled at 300 mm/min dwell time. Tack adhesion is the force to separate the adhesive from the surface of another material at their interface shortly after they have been brought into contact under a load equal only to the weight of the pressure-sensitive article on the contact area by means of a loop tack method. In other words, it is a definition of the “stickiness” of the adhesive.27 Tack adhesion measurements were modified from the ASTM D6195.28 The loop tack of the adhesive was determined using a stainless steel surface as substrate. The size of the film specimen was 25 × 60 mm2. A tensile tester and vertical jaw had a separation rate of 300 mm/ min dwell time. 2.3.2. Compatibility Study. The raw materials were identified by Fourier transform infrared (FT-IR) spectroscopy. The HPMC powder was mixed with dry potassium bromide (KBr). Then, the mixture was ground into a fine powder using an agate mortar before being compressed into a KBr disk sample. The liquid samples, i.e., NCT, DBP, GLY, were applied directly onto the KBr disk sample. Moreover, the transparent blended films were analyzed using the attenuated total reflection FT-IR (ATR-FTIR) technique. They were scanned at a resolution of 4 cm−1 with 16 scans over the wavenumber region 400−4000 cm−1 using the FT-IR spectrophotometer (model Spectrum One, Perkin-Elmer). The characteristic peaks of the IR transmission spectra were recorded. Samples of about 5−10 mg of DNRL film, HPMC, NCT, and blended films were weighed and transferred to the DSC pan which was then hermetically sealed, and examined in the DSC instrument (model DSC7, Perkin-Elmer). The temperature scanning was from −100 to 180 °C at a heating rate of 10 °C/min in a liquid nitrogen atmosphere. The X-ray diffractometry (XRD) (model WI-RES-XRD-001, Philips analytical, The Netherlands) was also employed to study the DNRL and blended films. The X-ray source had a 40 kV operating voltage, 45 mA current, 5−40° angular (2θ), and a stepped angle of 0.02° (2θ)/s. 2.3.3. Moisture Uptake, Swelling Ratio, and Erosion Studies. The moisture uptake was studied using 10 × 10 mm2 film specimens. The test specimens were kept in desiccators with silica gel beads for 24 h, and weighed for their initial value (W0). Then, the films were moved to desiccators containing a saturated sodium chloride environment which produces a 75% relative humidity. The specimens were removed and weighed every week until constant (Wu). The percentage of moisture uptake was calculated as the increased weight (Wu − W0) compared to the initial weight (W0). The swelling ratio and erosion study were also determined by drying the 10 × 10 mm2 films at 60 ± 2 °C overnight. Then, the films were weighed (W0) and immersed in 5 mL of distilled

2. MATERIALS AND METHODS 2.1. Materials. The DNRL was prepared in-house from fresh NRL collected from Hevea brasiliensis (RRIM 600 clone) and purified by enzyme deproteinization followed by centrifugation.23 (−)-Nicotine (>99%) was from Merck (Germany). HPMC (grade E5) was supplied by Onimax (Thailand). GLY was obtained from the P.C. drug center (Thailand). DBP and DBS were from Fluka. DEP and TEC were from Aldrich. Polyacrylic ester (Voncoat AN868-S: a special self-cross-linked type of acrylic ester copolymer emulsion) used as the adhesive layer (AL) was a gift from the Siam chemical industry (Thailand). The other chemicals were of analytical grade. 2.2. Preparation of DNRL Blended Films. A 10%w/v HPMC E5 solution in distilled water was mixed homogeneously into DNRL either with or without 10 phr plasticizer, and stored at 5 °C overnight to allow for a decrease of air bubbles. The amount of HPMC was varied: 5, 10, and 15 phr. Then, the blended films were constructed by pouring the mixtures into a Petri dish and dried in a hot air oven at 70 ± 2 °C for 4 h. Subsequently, the dry films were peeled-off and kept in desiccators before evaluation. In the case of the NCT loaded films, the drug was mixed into the DNRL blended mixtures before construction of the film. The NCT content in the formulations was modulated to produce final concentrations of 1.75, 2.5, and 3.5 mg/cm2 in the dry films. In some preparations, the adhesive layer was coated by pouring the 80% w/w polyacrylic ester solution onto the NCT matrix films, and then drying them in a hot air oven at 70 ± 2 °C for 30 min. 2.3. Evaluation of DNRL Blended Films. 2.3.1. Mechanical Properties. The mechanical properties of the films were obtained as the tensile strength in terms of Young’s modulus, ultimate tensile strength (UTS), elongation at break, and the adhesion properties in terms of peel strength and tack adhesion. They were determined using an Instron testing machine (model 5569, Instron Corporation) with a 500 N loaded cell. Tensile strength was determined following the method, slightly modified from the ASTM D412.25 The size of each sample was of 10 × 30 mm2, and the gauge length test was 10 mm. The cross-head speed was controlled at 10 mm/min. The 8443

dx.doi.org/10.1021/ie300608j | Ind. Eng. Chem. Res. 2012, 51, 8442−8452


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sample were performed in triplicate. The kinetics of release of the NCT was investigated. 2.6. In Vitro Skin Permeation Study. The in vitro skin permeation of the NCT from the patches was also carried out using a modified Franz-type diffusion cell,32 and pig skin with hair removed was applied as the partitioning membrane.33,34 The newborn pigs of 1.4−1.8 kg weight that had died by natural causes shortly after birth were freshly purchased from a local pig farm in Songkhla Province, that is regulated by the Department of Livestock Development, Thailand. The full thickness of flank pig skin was excised, hair was surgically removed, and the subcutaneous fat and other extraneous tissues were trimmed with a scalpel, cleaned with PBS pH 7.4, blotted dry, wrapped with aluminum foil, and stored frozen. Before permeation experiments, this isolated skin was soaked overnight in PBS pH 7.4, and mounted on the Franz diffusion cells with the stratum corneum facing upward on the donor compartment. The NCT patch was laid onto the isolated skin in the same way as for the release study. The receptor compartment was 12 mL of PBS pH 7.4 and stirred constantly at 600 rpm by a magnetic stirrer, at a constant temperature of 37 ± 0.5 °C.31,35,36 A 1 mL sample of the receptor solution was withdrawn at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h time intervals, and an equal volume of fresh PBS pH 7.4 was immediately replaced. The NCT concentrations in these samples were determined by the HPLC method. For each sample, the measurements were done in triplicate. The permeation flux at steady state (Jss, mg/ cm2 h) which was the amount of drug passing through the skin per unit of time at a steady-state ((dQ/dt)ss, mg/h) per unit area (A, cm2) was calculated from the slope of the linear portion of the plot. The following eq 3 was used to calculate the permeability coefficient (Kp, cm2/h)

water at room temperature for 48 h. After removal of excess water, the hydrated films were weighed (Ws). They were then dried again at 60 ± 2 °C overnight, and weighed again (Wd). The percentage of swelling ratio was calculated as the increased weight (Ws − W0), and the percentage of erosion was calculated as the loss in weight (W0 − Wd) compared to the initial film weight (W0). 2.3.4. Estimation of Film Porosity. Estimation of the blended films porosity was modified from the reverse osmosis technique by using a laboratory-scale system29 at room temperature with various pressures from 500 to 2000 kPa. The blended films with a circular shape area of 10.76 cm2 were placed into the cross-flow membrane modules. The observed permeated water flow rate was measured as the volume of the water permeation (V, L) per the operating time (t, h). The water flux value (JW) was calculated from the permeated water flow rate per effective membrane area (A, m2) by eq 1. water flux (JW ) =

V A×t

(1)

2.3.5. Porosity Determination. After the membrane was equilibrated in water, the volume occupied by the water and the volume of the membrane in the wet state were determined. The membrane porosity was obtained by eq 2. % porosity =

(W1 − W2) 100 × d water w×l×t

(2)

Here, W1 and W2 are the weights of the membranes in the wet and dry states (g), respectively; dwater is the density of pure water at 20 °C; and w, l, t are the width (cm), length (cm), and thickness (cm) of the membrane in the wet state, respectively.30 2.3.6. Microscopic Morphology. The surface and cross section morphologies of the film formulations were examined by scanning electron microscopy (SEM). Film samples were coated with gold in a sputter coater. Their surface and cross section morphology were photographed with JSM-5800 LV SEM (JEOL, Japan) at an appropriate magnification. 2.4. Determination of the NCT Content. A known weight of the NCT matrix films was extracted in 5 mL of distilled water by sonication for 30 min, filtered appropriately, and diluted with distilled water. The NCT content in each formulation was determined by a spectrophotometric measurement at 260 nm (Spectronic Genests 5 spectrophotometer, Milton Roy). The amount of NCT in each sample was determined by comparison with a validated calibration curve. Triplicate observations of each sample were measured. 2.5. In Vitro NCT Release Study. The in vitro release of NCT from the DNRL blended patches and a commercial NCT patch (Nicotinell TTS-20; 1.75 mg/cm2) was investigated using a modified Franz-type diffusion cell (Hanson 57−6M, Hanson Research Corporation) with an effective diffusion area of 1.77 cm2. The receptor medium was 12 mL of isotonic phosphate buffer solution (PBS) pH 7.4, thermoregulated with a water jacket at 37 ± 0.5 °C, and stirred constantly at 100 rpm with a magnetic stirrer.31 The film preparations were cut in a circular shape and directly placed as a membrane between the donor and receptor cells. The 1 mL of receptor solution was withdrawn at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h time intervals, and immediately replaced with an equal volume of fresh PBS pH 7.4. The NCT concentration in these samples was determined by a HPLC method. The experiments for each

Kp =

Jss C0

(3)

where C0 represents the drug donor concentration data (mg/ cm3). The description of the in vitro NCT release and its permeation time profile were determined using different kinetics, i.e., zero-order, first-order, and Higuchi’s square-root model as the following eqs 4−6. Q t = Q 0 + K 0t

(4)

log Q t = log Q 0 + K1t

(5)

Qt Q0

= KH t

(6)

Here, Qt is the amount of NCT released or permeation (mg) in time, t (h), and Q0 is the initial amount of NCT (mg) in the formulation. K0 is the zero constant rate (mg/h), K1 is the first constant rate (log mg/h), and KH is the Higuchi’s constant rate (mg/√h).37 2.7. HPLC Condition for NCT Analysis. The solutions collected from the receptor of the Franz diffusion cell were filtered through a cellulose acetate membrane (0.22 μm pore size). The NCT analysis was carried out using an HPLC system (Agilent 1100 series, Thermo electron corporation) with a column (BDS HYPERSIL C18, 150 mm × 4.6 mm diameter, 5 μm particle size, Thermo scientific). The mobile phase consisted of 0.05 M sodium acetate/methanol = 9/1 v/v containing 1.3% triethanolamine, and the pH was adjusted to 8444



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Table 1. Mechanical Properties of DNRL and DNRL/HPMC Blended Films (n = 6) formula DNRL DNRL/HPMC(5) DNRL/HPMC(10) DNRL/HPMC(15) DNRL/HPMC(5)/DBP DNRL/HPMC(10)/DBP DNRL/HPMC(15)/DBP DNRL/HPMC(10)/DEP DNRL/HPMC(10)/DBS DNRL/HPMC(10)/TEC DNRL/HPMC(10)/GLY DNRL/HPMC(15)/GLY

modulus (MPa) 0.56 0.89 1.46 2.80 0.59 1.18 1.45 0.76 0.90 0.23 1.13 1.37

± ± ± ± ± ± ± ± ± ± ± ±

0.12 0.09 0.38 0.28 0.17 0.29 0.30 0.17 0.16 0.10 0.38 0.28

UTS (MPa) 0.23 0.28 1.32 1.41 0.17 0.30 0.23 0.19 0.24 0.14 0.27 0.29

± ± ± ± ± ± ± ± ± ± ± ±

0.04 0.08 0.30 0.31 0.04 0.11 0.03 0.06 0.05 0.08 0.09 0.02

elongation at break (%) 604.46 369.72 506.68 551.21 305.28 517.22 604.72 403.13 291.11 495.83 595.41 616.84

4.2 with acetic acid. The flow rate was 0.7 mL/min, and the injection volume was 10 μL. The absorbance was detected by the UV detector at the wavelength of 260 nm. The NCT amount was calculated by comparison with a validated calibration curve. 2.8. Stability Study. The selected DNRL blending films were stored in well closed container, and kept in 3 different conditions: 4 °C, ambient temperature, and 45 °C. At appropriate time intervals, the preparations were withdrawn, and the NCT contents were analyzed by the validated UV method. 2.9. Skin Irritation Test. The selected DNRL blended films were further studied in an acute dermal irritation/corrosion test in rabbit approved by the Thailand Institute of Scientific and Technology Research (TISTR) with the Animal Ethics Committee approval number TS-54001 (16/09/2010). This test was conducted according to the OECD guidelines for testing of chemicals (TG 404). Briefly, three healthy adult albino rabbits of the New Zealand white hybrid strain were purchased from the Department of Animal Science, Faculty of Agriculture, Kasetsart University, Thailand. Their body weight range was 2−3 kg. One day before experimentation, an area of skin approximately 10 × 10 cm2 on the dorso-lumbar region of each rabbit was clipped free of hair. Two areas of the shaven skin approximately 2.5 × 2.5 cm2 were selected. The DNRL matrix film (0.5 g) was introduced onto a 2.5 × 2.5 cm2 gauze patch, to serve as the treated patch while 0.5 mL of distilled water on another patch served as a control patch. Both patches were applied to the selected skin sites on each rabbit. The patches were then secured to the skin by Transpore adhesive tape. The entire trunk of the rabbit was wrapped with an elastic cloth to avoid dislocation of the patches for 4 h. At the end of the exposure period, all patches were removed, and the treated skin was gently wiped with moistened cotton wool to remove any residual test materials. The test areas were assessed for the degree of erythema and edema at each site at 1, 24, 48, and 72 h after removal of the patches. If further observations were needed, when necessary to establish the reversibility of the signs of irritation, these times did not exceed 14 days after application. In addition to the observation of irritation, any lesions and other toxic effects were recorded. The skin reactions were independently scored by two inspectors using the numerical scoring system as shown in Supporting Information data. 2.10. Statistical Analysis. The average value for each experiment was subsequently calculated and presented as a mean ± a standard deviation value. All results were statistically

± ± ± ± ± ± ± ± ± ± ± ±

95.38 81.40 73.47 94.92 116.88 51.05 37.17 47.25 32.02 62.52 92.32 79.15

peel strength (N/cm2) 0.10 0.11 0.16 0.19 0.15 0.16 0.20 0.07 0.04 0.08 0.19 0.20

± ± ± ± ± ± ± ± ± ± ± ±

0.01 0.02 0.02 0.01 0.04 0.02 0.01 0.01 0.02 0.01 0.04 0.04

tack adhesion (N/cm2) 1.51 1.97 2.24 2.93 2.18 2.57 3.02 0.65 0.57 1.37 2.61 2.95

± ± ± ± ± ± ± ± ± ± ± ±

0.51 0.12 0.21 0.76 0.13 0.41 0.51 0.08 0.05 0.37 0.18 0.34

evaluated using one-way analysis of variance followed by post hoc analysis (for comparison of the differences between multiple data sets) that showed a significance at p < 0.05.

3. RESULTS AND DISCUSSION The DNRL was developed from our previous study of alcalase treatment that reduced the protein content of NRL by more than 89.21% when compared with its initial protein content.23 It might avoid the protein allergy. Thus, the NCT patches made from DNRL might be a very low potential for causing sensitization. Nevertheless, this work did not test for protein allergy. Therefore, the DNRL raw material and NCT patches might be further tested for the protein allergy to confirm the safety of their skin applications. In addition, the technique of DNRL preparation might be further developed for more effective deproteinization process. The pure DNRL films had high tensile strength and high elongation at break, and were easily film-forming. Nevertheless, they had low adhesiveness for contact to the skin. Blending the films of DNRL with HPMC and different types of plasticizers could improve their effectiveness as shown in Table 1. Hard and strong films were obtained when HPMC was blended, both with and without DBP, because they had a higher modulus, higher UTS, and moderate elongation.38 Higher amounts of HPMC increased all their mechanical parameters, especially the adhesiveness properties. Addition of DBP to the DNRL/ HPMC blends produced softer and weaker films with the lowest modulus, lowest UTS, and moderate elongation. However, addition of DBP did not affect the adhesiveness of the blended films. In a preliminary study, an increment of DBP higher than 20 phr produced a slippery and soft surface that was poorly adhesive (raw data not shown). The types of plasticizer used also affected the blended films. All studied plasticizers produced softer films as shown by their lower modulus and UTS values. The DBS blended film showed the lowest modulus and UTS values to indicate that these were the softest film, while the TEC blended film showed the lowest elongation values to indicate that it was the most brittle film. Furthermore, the TEC or GLY blends produced slightly hazy films. However, only the addition of DBP or GLY to the DNRL/HPMC blended films produced a higher adhesiveness than the unplasticized films. Thus, DNRL/HPMC/DBP or GLY was chosen for further studies in preparing NCT films. Compatibility of the DNRL with a blending polymer and plasticizers was also confirmed by their FT-IR spectra, DSC thermograms, and XRD diffractograms (Figures 1−3). For the FT-IR study, the major peaks of DNRL, HPMC, DBP, GLY, 8445



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Figure 3. XRD diffractograms of DNRL, HPMC, and their blended films.

HPMC/DBP matrix film was also found.23 In addition, there was a large broader peak at 3338 cm−1 (OH stretching) and at 1650 cm−1 (CO stretching) of GLY in the DNRL/ HPMC/GLY matrix film. Moreover, both the NCT/DNRL/ HPMC/DBP and NCT/DNRL/HPMC/GLY matrix film also showed a shift of the aromatic ring bending band at 714 cm−1 of NCT. However, the spectra of DNRL/HPMC, DNRL/ HPMC/DBP, and NCT/DNRL/HPMC/DBP had been previously published by our research group.23 There were also no marked spectrum changes observed to indicate that there was no incompatibility of any ingredients in the blended NCT/DNRL/HPMC/GLY films (Figure 1). This compatibility was also confirmed by the DSC thermograms that showed no glass transition temperature (Tg) in the range 0−180 °C. The DSC chromatogram in the range −100 to 0 °C where the major temperature transition appeared had its glass transition temperature (Tg) at around −64.794 °C for the DNRL film and the HPMC was found not to change over this range, while that of DNRL/HPMC blends occurred at −64.785 °C. The DBP and GLY blends slightly changed the Tg of DNRL/HPMC/ DBP and DNRL/HPMC/GLY blends to −67.752 and −63.730 °C, respectively. Furthermore, in the DSC thermogram of NCT, an endothermic peak at −88.206 °C appeared that was due to the melting point of NCT. A similar observation was made for the thermograms of NCT/DNRL/HPMC/DBP and NCT/DNRL/HPMC/GLY blended films with the Tg slightly reduced to −69.777 and −65.948 °C, respectively. There was no disguised signal in the DSC thermograms. This again indicated the compatibility of each ingredient in the blended films that showed no significant shift of Tg in these ranges (Figure 2).39 Moreover, the XRD patterns of the blended films showed only the broad halo spectrum that was the same as for DNRL alone. The HPMC diffractogram disappeared from the spectrum, due to its lower amount in the blended film. This result demonstrated a larger domain of the amorphous phase of the DNRL blended films. Moreover, the addition of NCT to the blended films showed the same XRD pattern as for the blank films again indicating the compatibility of all ingredients and showed no crystalline stage of the drug (Figure 3). The moisture uptake, swelling ratio and erosion of the matrix films were significantly increased when DNRL was blended with HPMC due to the hydrophilic property of HPMC (Table 2). This result was similar to a previous study of HPMC blends.40 These values were also slightly increased when the various plasticizers were added because the hydrophobic structure of the DNRL films was significantly changed by inserting the plasticizer molecules into the polymer network.

Figure 1. FT-IR spectra of DNRL, HPMC, NCT, GLY, and their blended films.

Figure 2. DSC thermograms of DNRL, HPMC, NCT, and their blended films.

and NCT were also found in the DNRL/HPMC blended film. Isoprene functional groups were assigned at 2856−2963 cm−1 (CH stretching), 1664 cm−1 (CC stretching), 1376−1449 cm−1 (CH bending), and 830 cm−1 (CCH wagging). The stretching vibration in the hydroxyl group of HPMC had a broad spectrum at 3446 cm−1. A slightly broader peak at 1738 cm−1 that could be a CO stretching of DBP in the DNRL/ 8446



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Table 2. Moisture Uptake, Swelling Ratio, and Erosion of DNRL and DNRL/HPMC Blended Films (n = 3) non-NCT loaded formula DNRL DNRL/HPMC(5) DNRL/HPMC(10) DNRL/HPMC(15) DNRL/HPMC(5)/DBP DNRL/HPMC(10)/DBP DNRL/HPMC(15)/DBP DNRL/HPMC(10)/DEP DNRL/HPMC(10)/DBS DNRL/HPMC(10)/TEC DNRL/HPMC(10)/GLY DNRL/HPMC(15)/GLY

moisture uptake (%) 0.21 1.12 2.08 2.63 3.03 4.92 5.53 4.32 4.66 5.35 5.63 6.34

± ± ± ± ± ± ± ± ± ± ± ±

0.17 0.11 0.31 0.47 0.87 0.93 1.19 0.73 1.20 1.31 0.60 0.52

swelling ratio (%) 7.32 12.13 18.14 30.89 16.18 27.40 34.33 24.33 26.67 30.19 35.52 41.22

± ± ± ± ± ± ± ± ± ± ± ±

0.26 1.05 5.16 8.82 1.86 1.30 4.80 2.52 10.69 3.47 6.42 5.32

NCT loaded erosion (%) 0 1.18 1.50 1.58 1.44 1.58 1.79 1.40 1.48 1.41 1.65 1.79

These values were directly dependent on the amounts of HPMC and type of plasticizer. Furthermore, the erosion of the blended film increased remarkably when different plasticizers were added to the HPMC and became comparable with the DNRL film. When the film had a high moisture uptake and swelling ratio, the hydrated film would be highly porous with a high erosion of the film. The water swelling resulted in the dissolution and erosion of some hydrophilic substances from the matrix film, and increased the porous channels for release of the drug.41,42 The NCT was hygroscopic, and this also increased the moisture uptake and swelling ratio when compared to the blank films. Moreover, the NCT was dissolved by water penetrating through the films. It increased the erosion of films when compared with their blank films (Table 2). The moisture uptake, swelling, and erosion behaviors of the polymeric film would play an important role during the early stages of the drug release from the films.43 Thus, a film with a higher water uptake, swelling, and erosion seemed to provide a higher drug release and skin permeation rate. Estimation of the porosity of blank films using the reverse osmosis techniques had been predicted from the number of pores in the film structure as this provided the water flux value. The films with a high water flux value provided high porosity, while the films with a low water flux value provided a low porosity.44 The blending of various polymers and plasticizers into the DNRL film increased the water flux value (Figure 4) compared to the NCT/DNRL alone films. These water flux values were significantly affected by the polymer types. The NCT/DNRL film itself showed a 2.62 ± 0.99% porosity. This percentage porosity of the blended films was significantly increased by blending with HPMC and different plasticizer. The porosity ranged from 17.88 ± 3.03, 17.87 ± 4.54, 16.48 ± 2.45, 16.38 ± 2.15, and 10.80 ± 2.15%, for NCT/HPMC(15)/ GLY > NCT/HPMC(15)/DBP > NCT/HPMC(10)/GLY > NCT/HPMC(10)/DBP > NCT/HPMC(10), respectively. These results correlated with the swelling ratio and water flux of the blended films. The SEM photographs (Figure 5) were used to confirm the high resolution microscopic morphology in each film. The DNRL film had a smooth surface. When HPMC and DBP were mixed in DNRL, no obvious change was observed. In contrast, DNRL blended with HPMC and GLY showed minimal cracking on the surface due to the rapid evaporation in the preparation process.45 From these results, it could be concluded that the film made from DBP had a smoother surface than that from GLY as the plasticizer. In addition, when the film was

± ± ± ± ± ± ± ± ± ± ±

0.13 0.15 0.57 0.14 0.25 0.19 0.12 0.29 0.27 0.21 0.39

moisture uptake (%)

swelling ratio (%)

erosion (%)

0.84 ± 0.21

8.01 ± 1.31

0.40 ± 0.08

3.69 ± 1.33

18.96 ± 0.53

1.97 ± 0.16

6.44 ± 0.75 6.67 ± 1.80

28.86 ± 8.32 34.89 ± 3.98

2.07 ± 0.11 2.23 ± 0.18

7.38 ± 1.13 8.01 ± 0.97

35.98 ± 2.51 36.12 ± 2.22

2.10 ± 0.12 2.21 ± 0.15

Figure 4. Water flux of three blended films (n = 3).

coated with an adhesive layer, the morphology became rugged and a few small pores were observed on its surface that are presented in another publication by our research group.23 In addition, the cross section morphology of all blended films showed a dense matrix without pores or cavities. From the above results, the blending of a DNRL polymer and 10−15 phr HPMC without or with 10 phr DBP or GLY was further chosen for preparations that delivered NCT and were compared with DNRL/NCT alone. After the dried NCT matrix films were constructed, the entrapment efficiency of NCT in DNRL films decreased to 65.68 ± 5.96%. This was due to the volatility of NCT in the drying process of forming the film. The blended matrix films had lower entrapment efficiency in the same range (55.93−57.25%) because they required a longer drying time. Thus, the drying process should be further developed to increase the drug entrapment efficiency in matrix patches. In this study, the NCT added to preparations must be modulated to get the required concentration for the next experiments. The r2 of different three kinetics from both in vitro release and skin permeation of NCT was calculated and is presented in the Supporting Information, and Table 3 shows only their best fitted mechanisms. The in vitro release of NCT showed a monophasic slow release pattern from the DNRL matrix films (Figure 6). The DNRL films without plasticizer and polymer 8447



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Figure 5. SEM micrographs of (A) DNRL, (B) DNRL/HPMC/DBP, and (C) DNRL/HPMC/GLY films (-a-, surface of films; -b- and -c-, cross section of -a- before and after the release study, respectively).

Table 3. NCT Entrapment Efficiency, in Vitro Release, and Skin Permeation Kinetics of DNRL/HPMC Blended Films release kinetics formulas

NCT (mg/cm2)

Nicotinell TTS-20 NCT/DNRL NCT/DNRL/HPMC(10) NCT/DNRL/HPMC(10)/GLY NCT/DNRL/HPMC(15)/GLY NCT/DNRL/HPMC(10)/DBP NCT/DNRL/HPMC(15)/DBP NCT/DNRL/HPMC(15)/DBP NCT/DNRL/HPMC(15)/DBP NCT/DNRL/HPMC(15)/DBP/ALc

1.75 2.5 2.5 2.5 2.5 2.5 1.75 2.5 3.5 2.5

a

entrapment efficiency (%)

r2a

± ± ± ± ± ± ± ± ±

0.936 0.843 0.779 0.771 0.928 0.812 0.809 0.900 0.922 0.977

65.68 56.10 56.63 57.25 55.93 49.97 57.03 58.34 55.34

5.96 0.80 4.02 1.63 0.60 4.67 2.40 1.93 2.67

Ka 0.022 0.027 0.032 0.070 0.079 0.036 0.037 0.048 0.096 0.031

± ± ± ± ± ± ± ± ± ±

permeation kinetics r2b

0.003 0.002 0.004 0.005 0.012 0.006 0.007 0.005 0.007 0.002

0.999 0.993 0.993 0.997 0.990 0.993 0.998 0.996 0.996 0.999

Jssb (mg/cm2 h) 0.032 0.018 0.028 0.039 0.043 0.030 0.027 0.043 0.070 0.035

± ± ± ± ± ± ± ± ± ±

0.002 0.006 0.015 0.005 0.004 0.010 0.004 0.005 0.022 0.001

Kpb (×10−3) (cm/h) 3.686 1.766 2.839 4.894 6.529 3.956 3.939 4.456 5.095 3.528

± ± ± ± ± ± ± ± ± ±

0.201 0.567 0.469 0.640 0.484 0.276 0.606 0.555 0.577 0.080

Calculated from first-order. bCalculated from zero-order. cAL = adhesive layer.

release study, the blended films showed pores and cavities, and the films became rough. The pores and roughness might be attributed to the diffusion of NCT molecules and some erosion of the hydrophilic polymer from the matrix films. The film containing GLY showed more pores than films containing DBP; thus, a faster release rate was obtained. However, these release profiles were much higher than those of commercial NCT films (Nicotinell TTS-20). Furthermore, after the DNRL blended films were coated with the adhesive layer of Voncoat AN868-S, the NCT release significantly decreased since the drug had to diffuse throughout the added layer. This profile was close to that of the commercial Nicotinell TTS-20. However, the kinetics of the NCT release from the DNRL film and blended films had a lower hydrophilicity that controlled the diffusion and produced a depleted release from the surface of the patch. Thus, the dissolution or erosion of the patch was not the only parameter that influenced the NCT release. This led to diffusion release kinetics, i.e., the Higuchi’s model. Furthermore, the increased

blends provided the lowest release amount, while the addition of HPMC produced a faster release. In addition, the higher amount of polymer blends also provided a higher amount of drug release. The presence of the plasticizer increased the release of NCT from the blended. These results could be explained by their increased hydrophilicity. The blending of plasticizer and hydrophilic polymer resulted in a higher hydrophilicity of the blended films, which correlated to their moisture uptake, swelling ratio, and erosion data (Table 2) and resulted in a faster release rate. The NCT could dissolve more readily in distilled water from the more porous films when compared to the DNRL alone films. Blending of HPMC with the DNRL film provided an improvement of the water flux value compared with the DNRL alone films. Therefore, this behavior was apparently related to the swellability and solubility of HPMC,46 and the solubility of the plasticizer47 and also of the NCT. Thus, porosity was an important factor in controlling the rate of drug release and permeation. These parameters also correlated with the SEM photographs (Figure 5). After the 8448



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Figure 6. Effect of blending polymers and plasticizers on the release of NCT from DNRL matrix films compared to commercial Nicotinell TTS-20 (n = 3). Figure 7. Effect of blending polymers and plasticizers on the permeation of NCT from DNRL matrix films compared to commercial Nicotinell TTS-20 (n = 3).

hydrophilicity of the blended films showed an increased NCT dissolution that was confirmed by first-order kinetics (Table 3). These proposed mechanisms were related to the cross section morphology of DNRL/HPMC blended films that are presented in Figure 5. Although the release of NCT from the DNRL/HPMC blended films was much higher than that of the commercial Nicotinell TTS-20, the permeation of these preparations was further studied. The developed DNRL/HPMC matrix films did not contain enhancers or other components that could enhance the drug permeation; thus, the permeation patterns of these matrix films might be different from those of the commercial Nicotinell TTS-20. Thus, the addition of penetration enhancers, and hydrophilic polymers, such as starch, sodium polyacrylate, polyethylene oxide, and polyvinyl pyrrolidone blends, in transdermal patches might enhance the NCT permeation through the skin. The permeation of NCT into the skin from all DNRL/ HPMC matrix films was by zero-order kinetics which was similar to that of the commercial Nicotinell TTS-20 (Figure 7 and Table 3). The DNRL film showed the lowest NCT permeation. This was due to the hydrophobicity of DNRL that would tend to prevent the release of NCT from the film. It was a surprise that the DNRL/HPMC blends that released NCT produced a lower NCT permeation compared with Nicotinell TTS-20. This might be due to there being no enhancers in the DNRL/HPMC blends, but there might have been some enhancers or other factors that enhanced NCT absorption into the skin from the Nicotinell TTS-20. Films containing GLY still increased NCT permeation when compared with DBP. The higher amount of HPMC also produced a higher skin permeation of NCT. These results were similar to other results that had indicated that the major effect on drug release and permeation was their hydrophilic property.43 When coating the film with the adhesive layer of Voncoat AN868-S, the skin permeation of NCT slightly decreased due to the additional layer through which the drug had to diffuse.48 Figure 8 shows that there were some effects of drug loading on the release of NCT from the DNRL/HPMC blended films.

Figure 8. Effect of drug loading on the release of NCT from NCT/ DNRL/HPMC(15)/DBP matrix films compared to commercial Nicotinell TTS-20 (n = 3).

A higher drug loading in the patches produced a higher percentage of NCT release. This was due to the higher drug amount producing a higher concentration gradient in the film matrix. Thus, the diffusion was faster. The 1.75 mg/cm2 NCT loading patch showed that the release of NCT was controlled by diffusion and became depleted at the surface of the patch. Thus, the dissolution or erosion of the patch was not the parameter that influenced the release of NCT. This led to the diffusion release kinetics or Higuchi’s model (Table 3). Furthermore, patches loaded with more than 2.5 mg/cm2 NCT showed the dissolution mechanism with the release of NCT being proportional to the amount of NCT remaining in its patch.49 However, the 2.5 and 3.5 mg/cm2 NCT patches provided a similar release pattern. Moreover, NCT at a higher 8449



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shelf life values of NCT remained in different patches after storage for 3 months at 4 °C, ambient temperature, and 45 °C and are shown in Figure 11.

loading level became more dissolved in the polymer matrix than from a lower loading level, that gave a higher percentage of NCT release and an increase of the hydrophilicity of the patch because of the hygroscopic nature of NCT.50 However, it is also possible that the higher loaded patch might have a higher number of pores after the release of NCT. Therefore, the higher NCT loads produced a higher release rate. For the skin permeation study (Figure 9), the higher NCT loading produced the higher permeation of NCT.

Figure 11. Shelf life of NCT remaining in DNRL/HPMC matrix films after storage in different conditions: (A) 4 °C, (B) ambient temperature, and (C) 45 °C.

This DNRL/HPMC(15)/DBP matrix films loaded with 2.5 mg/cm2 NCT were also tested in the acute dermal irritation test. None of the three rabbits treated exhibited any dermal irritation. All the scores of the dermal reactions of the treated and control groups received a scaling of 0 during the whole time of the test meaning no any irritation. This indicated that it was safe to apply of the DNRL/HPMC matrix films for transdermal drug delivery.

Figure 9. Effect of drug loading on the permeation of NCT from NCT/DNRL/HPMC(15)/DBP matrix films into the skin compared to commercial Nicotinell TTS-20 (n = 3).

4. CONCLUSIONS Blending DNRL with various amounts of HPMC as well as different types and amounts of plasticizers formed satisfactory films with different mechanical properties, moisture uptake, and swelling ratios. The DNRL/HPMC matrix films with DBP or GLY provided the best films for delivery of the drug to the skin. The compatibility of each ingredient in the blended films was confirmed by FT-IR spectra, DSC thermograms, and XRD diffractograms. Moreover, the in vitro release and skin permeation studies of NCT from the matrix films were affected by the amount of HPMC as well as the type of plasticizers

NCT degraded rapidly when exposed to air and other inappropriate conditions. It was easy to volatilize, and this resulted in a decrease of the NCT that remained in the preparations. Thus, these NCT preparations should be kept in a very tight container. The shelf life of NCT in patches remained more than 90% when stored at 4 °C and at ambient temperature; on the other hand, it became less than 90% when kept in 45 °C for 3 months (Figure 10). However, the

Figure 10. Percentage of NCT remaining in the DNRL/HPMC matrix films after storage in different conditions: (A) 4 °C, (B) ambient temperature, and (C) 45 °C (n = 6). 8450



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(12) Gore, A. V.; Chien, Y. W. The nicotine transdermal system. Clin. Dermatol. 1998, 16 (5), 599−615. (13) Kandavilli, S.; Nair, V.; Panchagnula, R. Polymers in transdermal drug delivery systems. Pharm. Technol. 2002, 62−80. (14) Zhang, W.; Gong, X.; Xuan, S.; Jiang, W. Temperaturedependent mechanical properties and model of magnetorheological elastomers. Ind. Eng. Chem. Res. 2011, 50 (11), 6704−6712. (15) Roberts, A. D. Natural Rubber Chemistry and Technology; Oxford University Press: Oxford, U.K., 1998; pp 10−150. (16) Hauser, E. A.; Dewey, B. Creaming of rubber latex. Ind. Eng. Chem. 1941, 33 (1), 127−130. (17) Ochigbo, S.; Luyt, A.; Focke, W. Latex derived blends of poly(vinyl acetate) and natural rubber: Thermal and mechanical properties. J. Mater. Sci. 2009, 44 (12), 3248−3254. (18) WHO/IUIS Allergen Standardization Committee Allergen Nomenclature; http://www.allergen.org/search.php?allergensource= latex (July 30, 2010). (19) Hepner, D. L.; Castells, M. C. Latex allergy: An update. Anesth. Analg. 2003, 96, 1219−1229. (20) Meade, B. J.; Weissman, D. N.; Beezhold, D. H. Latex allergy: past and present. Int. Immunopharmacol. 2002, 2 (2−3), 225−238. (21) Sussman, G. L.; Tarlo, S.; Dolovich, J. The spectrum of IgEmediated responses to latex. JAMA, J. Am. Med. Assoc. 1991, 265 (21), 2844−2847. (22) Perrella, F. W.; Gaspari, A. A. Natural rubber latex protein reduction with an emphasis on enzyme treatment. Methods 2002, 27 (1), 77−86. (23) Suksaeree, J.; Boonme, P.; Taweepreda, W.; Ritthidej, G. C.; Pichayakorn, W. Characterization, in vitro release and permeation studies of nicotine transdermal patches prepared from deproteinized natural rubber latex blends. Chem. Eng. Res. Des. 2012, 90 (7), 906− 914. (24) Pichayakorn, W.; Suksaeree, J.; Boonme, P.; Amnuaikit, T.; Taweepreda, W.; Ritthidej, G. C. Nicotine transdermal patches using polymeric natural rubber as the matrix controlling system: Effect of polymer and plasticizer blends. J. Membr. Sci. 2012, 411−412, 81−90. (25) ASTM. International Standard Test Methods for Vulcanized Rubber and Thermoplastic Elastomers-Tension D412; West Conshohocken, PA, 2003; Vol. 9. (26) ASTM. International Standard Test Method for Peel Resistance of Adhesives (T-Peel Test) D1876; West Conshohocken, PA, 2001; Vol. 15. (27) Minghetti, P.; Cilurzo, F.; Montanari, L. Evaluation of adhesive properties of patches based on acrylic matrices. Drug Dev. Ind. Pharm. 1999, 25 (1), 1−6. (28) ASTM. International Standard Test Methods for Loop Tack D6195; West Conshohocken, PA, 2003; Vol. 15. (29) Chinpa, W. Preparation and characterization of an asymmetric porous poly(vinyl chloride)/poly(methyl methacrylate-comethacrylic acid) membrane. ScienceAsia 2008, 34, 385−389. (30) Chen, Z.; Deng, M.; Chen, Y.; He, G.; Wu, M.; Wang, J. Preparation and performance of cellulose acetate/polyethyleneimine blend microfiltration membranes and their applications. J. Membr. Sci. 2004, 235 (1−2), 73−86. (31) Pongjanyakul, T.; Prakongpan, S.; Priprem, A. Acrylic matrix type nicotine transdermal patches: In vitro evaluations and batch-tobatch uniformity. Drug Dev. Ind. Pharm. 2003, 29 (8), 843−853. (32) Venter, J. P.; Müller, D. G.; du Plessis, J.; Goosen, C. A comparative study of an in situ adapted diffusion cell and an in vitro Franz diffusion cell method for transdermal absorption of doxylamine. Eur. J. Pharm. Sci. 2001, 13 (2), 169−177. (33) Meyer, W.; Schwarz, R.; Neurand, K. The skin of domestic mammals as a model for the human skin with special reference to the domestic pig. Curr. Probl. Dermatol. 1978, 7, 39−52. (34) Simon, G. A.; Maibach, H. I. The pig as an experimental animal model of percutaneous permeation inman: Qualitative and quantitative observationsAn overview. Skin Pharmacol. Appl. Skin Physiol. 2000, 13 (5), 229−234.

mainly by changes to their hydrophilicity. Furthermore, the addition of an adhesive layer also influenced the skin permeation. The skin irritation test confirmed that the use of DNRL/HPMC matrix films was safe as there was no irritation and edema observed in the skin tests. The results indicated that the film formulation composed of HPMC blended with DNRL was suitable for developing an NCT transdermal film.

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ASSOCIATED CONTENT

S Supporting Information *

Additional information of the scoring criteria for the acute dermal irritation test, and the r2 from three different kinetics of in vitro release and skin permeation of NCT. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*Tel.: +66-74-288842. Fax. +66-74-428148. E-mail: wiwat.p@ psu.ac.th. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to acknowledge the Prince of Songkla University (Grant PHA520078S), the Thailand Research Fund and the Office of Commission on Higher Education, Ministry of Education (Grant MRG5180243). for financial support. We also thank Dr. Brian Hodgson for assistance with English.

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REFERENCES

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