Preparation of Deproteinized Natural Rubber Latex and Properties of

Article pubs.acs.org/IECR

Preparation of Deproteinized Natural Rubber Latex and Properties of Films Formed by Itself and Several Adhesive Polymer Blends Wiwat Pichayakorn,*,† Jirapornchai Suksaeree,† Prapaporn Boonme,† Wirach Taweepreda,‡ and Garnpimol C. Ritthidej§ †

Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, and ‡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 ABSTRACT: This work aimed first to prepare deproteinized natural rubber latex (DNRL) and investigate the properties of films after it was blended with various adhesive polymers: hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), sodium carboxymethyl cellulose (SCMC), poly(vinyl alcohol) (PVA), poloxamer 407, and sodium alginate. The second aim was to identify the films that would be the best for medical and pharmaceutical applications. Dibutyl phthalate (DBP), diethyl phthalate, dibutyl sebacate, triethyl citrate, and glycerin (GLY) were used as plasticizers to improve the elasticity and adhesiveness of the novel materials. DNRL was prepared by proteolytic alcalase enzyme treatment, followed by centrifugation. The DNRL was virtually free of protein, produced no significant reaction in the rabbit skin irritation test, and formed a good elastic film, but it had low skin adhesive properties. Blending DNRL with several polymers produced better films with different elastic and adhesive properties. Moisture uptake and swelling tests indicated that its films provided increasing hydrophilicity when blended with several polymers. SEM showed homogeneous films, and water hydraulic permeability tests indicated some porosity in matrix films. Blending DNRL with HPMC or PVA and DBP or GLY produced films with the best potential for novel materials. FT-IR, DSC, and XRD studies indicated the compatibility of the blended ingredients. In conclusion, DNRL blends could be used suitably for medical and pharmaceutical applications.

1. INTRODUCTION Natural rubber latex (NRL), the colloidal cis-1,4-polyisoprene polymer obtained from Hevea brasiliensis, is a white or slight yellow milky liquid that undergoes acid coagulation to an elastic solid in 4−6 h at room temperature.1 Freshly tapped latex contains about 30% rubber fraction, 5% nonrubber, and other components which are dispersed in water, the serum component. The polymer from NRL has interesting physical properties such as high tensile strength, high elongation at break, outstanding resilience, impermeability to gases and liquids, and easiness of forming films.2 However, the surface of rubber particles is covered by a continuous monolayer of a negatively charged phospholipid−protein complex that provides colloidal stability.3 There are 14 NRL proteins (Hev b1−14) recognized by the International Union of Immunological Societies (IUIS) as causative agents of NRL allergies.4 Hev b1 and Hev b3 are two of the major allergenic proteins. Hev b1 is found mainly on large rubber particles, whereas Hev b3 is more abundant in smaller rubber particles.1 Deproteinized NRL (DNRL) prepared by treatment with proteolytic enzymes that removed the allergenic protein from fresh NRL has been reported elsewhere.5 However, there have been no reports about a specific DNRL preparation that can be used for medical and pharmaceutical skin applications, and for producing blends of DNRL with other substances for formation of nonallergenic films. Polymer patches are now effective alternative products for transdermal drug delivery systems to deliver small drug molecules into the systemic blood circulation. For the development of transdermal drug delivery systems, polymer selection and © 2012 American Chemical Society

product design are important since they directly affect the physicochemical properties, adhesion−cohesion balance, compatibility, and stability of the obtained products.6 Many types of polymers such as cellulose derivatives,7 poly(vinyl alcohol) (PVA),8 chitosan,9 and polyacrylate10 are being used as materials to apply to the skin as gelling agents, thickening agents, and film formers to control drug release.6 However, there are only a few reports about using NRL as a material for medical and pharmaceutical skin applications.11,12 Recently, applications of DNRL and its polymer blends in transdermal drug delivery have been developed by our groups;13−16 however, the details of DNRL preparations and characterization have not been given yet. This research is focused on the preparation of DNRL and the improvement of its properties by blending it with other bioadhesive polymers and plasticizers. Hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), sodium carboxymethyl cellulose (SCMC), PVA, poloxamer 407 (P407), or sodium alginate (SAG) was chosen to form blended polymers with DNRL. Dibutyl phthalate (DBP), diethyl phthalate (DEP), dibutyl sebacate (DBS), triethyl citrate (TEC), and glycerin (GLY) were used as plasticizers. The mechanical and physicochemical properties of these polymers were investigated. Moreover, the feasibility of using Received: Revised: Accepted: Published: 13393

July 25, 2012 September 16, 2012 September 20, 2012 September 20, 2012 dx.doi.org/10.1021/ie301985y | Ind. Eng. Chem. Res. 2012, 51, 13393−13404

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these novel polymer blends for medical and pharmaceutical skin applications was evaluated.

% DRC =

WDRC ·100 W0

(1)

For the TSC, 10 g of latex was accurately weighed (W0) into a Petri dish and dried at 60 ± 2 °C in a hot air oven overnight, without acid coagulation. The dry mass was then cooled in desiccators to room temperature and reweighed (WTSC). The percentage of TSC was calculated by eq 2. Ten replications were measured.

2. MATERIALS AND METHODS 2.1. Materials. DNRL was prepared in-house as described in section 2.2. HPMC E5 was obtained from Onimax (Thailand). MC 4000 and SCMC 1500 were supplied from Srichand United Dispensary (Thailand). P407 (Lutrol F127) was a gift from BASF (Germany). PVA 67K (Mowiol 8-88) was from Aldrich (Germany). SAG was from Sigma (USA). DBP and DBS were from Fluka (USA). DEP and TEC were from Aldrich (USA). GLY, sodium dodecyl sulfate (SDS), and sodium hydroxide were supplied from P.C. Drug Center (Thailand). Alcalase enzyme was from Calbiochem (Germany). The combination of methylparaben, ethylparaben, propylparaben, isobutylparaben, and butylparaben that is normally used in cosmetic applications was produced by Induchem (Switzerland) under the Uniphen P-23 trademark. All chemicals were of analytical grade and used as received. 2.2. Preparation of DNRL. DNRL was prepared from fresh NRL collected from H. brasiliensis (RRIM 600 clone) by the combination of enzyme treatment and centrifugation methods as shown in Figure 1. The 1% v/v SDS solution was used as a

% TSC =

WTSC ·100 W0

(2)

The pH was measured by a SevenEasy S-20 pH meter (Mettler Toledo, Switzerland) at room temperature. The viscosity was measured by a Brookfield DV-III ULTRA programmable rheometer (Brookfield Engineering Laboratories, USA) at 25 ± 2 °C using spindle no. SC4-31 and various speeds of 50−250 rpm. These parameters were measured in triplicate. The particle size, size distribution, and surface charge on the rubber particles were obtained by ZetaPALS (Brookhaven, Germany) at 25 ± 2 °C, and presented as the effective diameter, polydispersity index (PI), and zeta potential (ζ), respectively. The sample was diluted with distilled water to an appropriate concentration prior to measurements. Ten sub-runs were recorded for each measurement. The protein content was determined from the nitrogen content (% N) using the Kjeldahl method as described in ASTM D3533.18 Briefly, the sample was digested in strong sulfuric acid solution with Kjelblet, K2SO4:CuSO4·5H2O = 9:1, as a catalyst which converted the amine nitrogen to ammonium ions. The ammonium ions were then converted into ammonia gas by heating and distillation, and entrapped in an acid solution. Finally, the amount of the trapped ammonia that correlated to the nitrogen content was determined by titration with 0.1 N sodium hydroxide. The protein content was calculated by multiplying the % N with a Kjeldahl factor of 6.25 as follows in eq 3. % protein = 6.25(% N)

(3)

The DNRL skin irritation test was carried out by the Thailand Institute of Scientific and Technology Research (TISTR) following the OECD guidelines for testing of chemicals (TG 404).19 It was tested in three healthy adult albino rabbits of the New Zealand white hybrid strain, each weighing 2−3 kg. The animals were obtained from the Department of Animal Science, Faculty of Agriculture, Kasetsart University (Thailand). The animals were kept in the laboratory environment for 1 week. One day before the experimental test, each rabbit was clipped free of skin hairs on the dorso-lumbar region of 10 cm × 10 cm, and two areas of the shaven skin of approximately 2.5 cm × 2.5 cm were selected. Then 0.5 mL of DNRL was introduced onto a 2.5 cm × 2.5 cm gauze patch, and 0.5 mL of distilled water was also introduced on another patch as a control. They were applied to the selected skin sites on each rabbit. The sample was secured by Transpore adhesive tape. The entire trunk of the rabbit was wrapped with an elastic cloth to avoid dislocation for 4 h. Finally, they were removed and the treated skin was gently wiped with moistened cotton wool to remove any residual test materials. The animals were assessed for the degree of erythema and edema evidence on each site at 1, 24, 48, and 72 h after the removal of the sample. Further observation was made as necessary, to establish the time for reversibility of any irritation sign(s) that still existed,

Figure 1. DNRL preparation process by enzyme treatment and centrifugation methods.

stabilizer to prevent the agglomeration of droplets, 2% v/v Uniphen P-23 was used as a preservative, and alcalase enzyme in the concentration of 0.2 parts per hundred of dried rubber (phr) was chosen as proteolytic enzyme and acted in pH 7−8. 2.3. Characterization of NRL and DNRL. The dry rubber contents (DRC) and total solid contents (TSC) of NRL and DNRL were measured as described in ASTM D1076.17 For the DRC, 10 g of latex was accurately weighed (W0) into a Petri dish and diluted with 20 mL of distilled water. Then 2% v/v glacial acetic acid was added, stirred, and placed on a steam bath for 30 min to coagulate the rubber until coagulation was complete. The coagulum was washed with distilled water, made into a 0.2 mm thin rubber sheet by roller pressing, and dried at 60 ± 2 °C in a hot air oven overnight. Finally, the dry sheet was cooled in desiccators to room temperature and reweighed (WDRC). The percentage of DRC was calculated by eq 1. Ten replications were determined. 13394

dx.doi.org/10.1021/ie301985y | Ind. Eng. Chem. Res. 2012, 51, 13393−13404

Industrial & Engineering Chemistry Research 10 − − 10 − − 10 − − 10 − − 10 − − 10 − − − − 10 − − − − −

−

−

−

−

TEC

GLY

−

−

− − − − − − − − − − − − − − − − − − − − − 10 − − − −

−

− DBS

−

−

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

10 −

10 −

− −

− −

−

− DEP

−

− − DBP

−

−

− 10 − − 10 − − 10 − − 10 − − 10 − − 30 20 10 − − − − − 30 20

−

− −

10

− − − − − − − − − − − − − − − − − − − − − − − − −

10

SAG

−

−

10 10

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

−

− − P407

−

− − PVA

−

−

− −

− −

− 15

− −

15 15

− −

10 10

− −

10 −

15 15

− −

15 10

− −

10 10

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

− −

−

−

−

−

− SCMC

100

−

MC

−

100 100

− −

100 100

− −

100 100

− −

100 100

− −

100 100

− −

100 100

− −

100 100

− 15

100 100

15 15

100 100

15 15

100 100

10 10

100 100

10 10

100 100

10 10

100 100

10

100

HPMC

10

H6 H5 H4

DNRL

100

V2 V1 C6 C5 C4 C3 C2 C1 M6 M5 M4 M3 M2 M1 H13 H12 H11 H10 H9 13395

H7

H8

where F is the breaking load (N), A is the cross-section area of the specimen (width × thickness, mm2), L0 is the original length of the specimen (mm), and LS is the length at the breaking point of the specimen (mm). The peel strength is the force to peel away the adhesive tapes from a surface of substrate. It is greatly influenced by the experimental parameters such as dwell time, substrate (e.g., stainless steel, skin, high density polyethylene, and poly(vinyl chloride)), peel angle, and peel speed. In this study, it was

H3

(6)

H2

Ls − L0 ·100 L0

H1

% elongation at break =

(5)

R

F A

(4)

formula (phr)

UTS =

stress strain

Table 1. DNRL/Polymer Blends as Film Formulations

Young’s modulus =

V3

but not after 14 days of application. In addition to the observation of irritation, any lesions and other toxic effects were recorded. The skin irritation effects were graded according to the scale originally proposed by Draize et al.: (1) erythema and eschar formation with a score of 0, 1, 2, 3, and 4 with no erythema, very slight erythema, well-defined erythema, moderate to severe erythema, and severe erythema and slight eschar formation, respectively; and (2) edema formation with a score of 0, 1, 2, 3, and 4 with no edema, very slight edema, slight edema, moderate edema, and severe edema, respectively.20 2.4. Preparation of Film Formulations. For improving the mechanical and adhesive properties of DNRL films, several types of pharmaceutical-grade bioadhesive polymers and plasticizers were chosen to blend with DNRL. DNRL and 5, 10, or 15 phr blended polymer (prepared as an aqueous solution of 10% HPMC, 2.5% SCMC, 2.5% MC, 20% P407, 10% PVA, or 10% SAG) without or with 10, 20, or 30 phr plasticizer were mixed homogeneously and stored at 4 °C to decrease air bubbles until a clear viscous fluid was formed. The films were then constructed by pouring the mixtures into a Petri dish and drying in a hot air oven at 70 ± 2 °C for 4 h. Subsequently, the dry films were peeled from the Petri dish and kept in desiccators. The compositions of some appropriate blended films are shown in Table 1. 2.5. Evaluation of Film Formulations. 2.5.1. Mechanical Properties. The film specimens were cut into rectangular shapes of a suitable size, and their mechanical properties were determined using the Instron testing machine (Model 5569; Instron Corp., USA) with a 500 N loaded cell. The mechanical parameters of the studied films included measurements of (1) tensile strength in terms of Young’s modulus, ultimate tensile strength (UTS), and elongation at break, and (2) adhesiveness in terms of peel strength and tack adhesion. The tensile strength determinations were modified from ASTM D412.21 The size of a film specimen was 10 mm × 30 mm in which the gauge length of the tested area was 10 mm. The cross-head speed was controlled at 10 mm/min. Young’s modulus, the manifestation of material stiffness, was calculated from the initial slope of the stress−strain plot within the stretching elastic limit range. The UTS was defined as either a maximum distinct or a region of strong curvature approaching a zero slope in the stress−strain curve. The elongation at break was determined by measuring the distance between the gauge marks of the fractured specimen.22 The tensile strength values were calculated by eqs 4−6.

−

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pressure of 500−2000 kPa.27 Distilled water was transported though the void space in the films continuously until a steadystate flux was obtained. The flow rate of the permeated water was recorded. The water flux value was determined by eq 11.

measured by a T-peel method that was modified from ASTM D187623 using a cleaned poly(vinyl chloride) transparent sheet as substrate. The size of the film specimen was 10 mm × 60 mm. The cross-head speed was controlled at 300 mm/min dwell time. Tack adhesion, the “stickiness” of the adhesive polymers, is the force required to separate the adhesive tapes from the contact surface.10 It was measured by the loop tack method that was modified from ASTM D619524 using stainless steel as substrate. The film specimen of 25 mm × 60 mm was formed into a loop, pushed down on the substrate with a specific force, and pulled off by a tensile tester and vertical jaw with a separation rate of 300 mm/min dwell time. 2.5.2. Moisture Uptake, Swelling Ratio, and Erosion Studies. The moisture uptake was studied using 10 mm × 10 mm film specimens. These films were kept in desiccators with silica gel beads for 24 h, and weighed (W0). Then, they were moved to desiccators containing saturated sodium chloride that provides a 75% relative humidity environment. They were taken out and weighed every week until their weight was constant (Wu). The percentage of moisture uptake was calculated by eq 7. % moisture uptake =

Wu − W0 ·100 W0

water flux (Jw ) =

% erosion =

Ws − W0 ·100 W0

W0 − Wd ·100 W0

(7)

(8)

(9)

2.5.3. Microscopic and Porosity Determinations. The film surfaces were first observed using a CK2 inverted microscope (Olympus, Japan) at 100× magnification. The morphology of the film formulations was then examined by scanning electron microscopy (SEM). Film samples were coated with gold in a sputter coater. Their surface and cross-section morphologies were photographed with a JSM-5800 LV SEM (JEOL, Japan) at an appropriate magnification. After the film was equilibrated in water, the volume occupied by the water and the volume of film in the wet state were determined. The film porosity was obtained by eq 10. % porosity =

W1 − W2 100 d water wlt

(11)

where V, A, and t are the volume of water permeation (L), the effective area of the test film (m2), and the operating time (hours), respectively.26 2.5.4. Compatibility Study. The compatibility of the various components was confirmed by Fourier transform infrared (FT-IR) spectroscopy. The prepared transparent thin films were examined using the attenuated total reflection FT-IR (ATR-FTIR) technique. In the case of raw materials, the powder sample was mixed with dry potassium bromide and ground into a fine powder using an agate mortar before being compressed into a potassium bromide disk sample, while the liquid sample was directly pasted onto the potassium bromide disk sample. They were scanned at a resolution of 4 cm−1 with 16 scans over a wavenumber region of 400−4000 cm−1 using the FT-IR spectrophotometer (Model Spectrum One, PerkinElmer, USA). The characteristic peaks of the IR transmission spectra were recorded. A differential scanning calorimeter (DSC) was used to investigate the endothermic transition of the substances that also confirmed the compatibility of each ingredient. A 5−10 mg sample of film was transferred into the DSC pan that was then hermetically sealed and run in the DSC instrument (Model DSC7, Perkin-Elmer, USA) from −100 to 180 °C at a heating rate of 10 °C/min under a liquid nitrogen atmosphere. The DSC thermogram was reported, and the endothermic transition was investigated. X-ray diffractometry (XRD) (Model WI-RES-XRD-001, Philips Analytical, The Netherlands) was also employed to study the compatibility of the DNRL and blended films. The generator operating voltage and current of the X-ray source were 40 kV and 45 mA, respectively, with an angle of 5−40° (2θ) and a stepped angle of 0.02 deg(2θ)/s. 2.6. Statistical Analysis. The average value for each experiment was subsequently calculated and presented as a mean ± standard deviation. All results were statistically evaluated with a p-value of less than 0.05 using either the Student’s t-test for comparison of the difference between two data sets or one-way analysis of variance followed by post hoc analysis for comparison of the significant differences between multiple data sets.

For the swelling ratio and erosion study, the 10 mm × 10 mm film specimens were weighed (W0) and immersed in 5 mL of distilled water at room temperature for 48 h. After removal of excess water, the hydrated films were reweighed (Ws), then dried at 60 ± 2 °C overnight, and weighed again (Wd). The swelling ratio and erosion were calculated by eqs 8 and 9, respectively.25 % swelling ratio =

V At

3. RESULTS AND DISCUSSION 3.1. NRL and DNRL Characteristics. Normally, the production of commercial NRL on an industrial scale has used toxic chemicals such as high concentrations of ammonia as a stabilizer that causes a strong irritation of the skin. This would be totally inappropriate for skin preparations.28 In this study, fresh NRL was chosen as the raw material for preparing DNRL. By the enzyme treatment and centrifugation methods, DNRL was successfully produced. As shown in Table 2, the physical properties of DNRL were not significantly different from those of fresh NRL. The pH of the DNRL was higher than that of NRL, which was close to the pH adjustment required for the proteolytic enzyme activity. However, this pH value was safe for medical and pharmaceutical skin applications. The viscosity of DNRL was slightly less than that of NRL. Both NRL and DNRL produced low viscosity values and showed Newtonian

(10)

where W1 and W2 are the weights of film in the wet and dry states (g), respectively, dwater is the density of pure water at 20 °C, and w, l, and t are the width (cm), length (cm), and thickness (cm) of the film in the wet state, respectively.26 Estimation of the film porosity was also made by a modified reverse osmosis technique. The films were cut in a circular shape with an area of 10.76 cm2, placed into the cross-flow membrane modules, and compacted with distilled water as the feeding solution. The experiments were carried out using a laboratory-scale system at room temperature using an operating 13396



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Table 2. NRL and DNRL Properties NRL DNRL

pH

viscosity (cP)

DRC (%)

TSC (%)

protein content (%)

effective size (nm)

PI

ζ (mV)

6.68 ± 0.19 7.47 ± 0.01

7.03 ± 0.01 6.90 ± 0.03

38.43 ± 3.01 39.55 ± 2.42

− 40.72 ± 2.22

1.61 ± 0.11 0.17 ± 0.15

294.70 ± 50.52 485.88 ± 38.75

0.24 ± 0.04 0.22 ± 0.07

−37.00 ± 5.70 −40.34 ± 6.03

Figure 2. Mechanical properties of HPMC blended DNRL films without plasticizer, with 10 phr, 20 phr, 30 phr DBP, 10 phr DEP, DBS, TEC, and GLY (n = 6).

within 24 h. Moreover, the three treated rabbits showed no edema reaction with score of 0 at any time of the investigations. Hence, this indicated that DNRL caused only a slight irritation on the skin, so it could be safely used for skin applications. Thus, the deproteinization process in this research successfully produced DNRL with low protein content and good properties. This process was highly reproducible. The obtained DNRL dispersion might be used for several applications including medical and pharmaceutical skin products which were then further studied. 3.2. DNRL Film Formulations. Several polymers and plasticizers were blended with DNRL for screening the best film formulations for medical and pharmaceutical skin products. DNRL and its blends readily formed transparent thin films. The amount of DNRL in the formulations directly affected the filmforming time, the film appearance, and the peeling from the Petri dish. The appropriate amount of each formulation was optimized as shown in Table 1. 3.2.1. Mechanical Properties. The mechanical properties of each film formulation are shown in Figures 2 and 3. It was found that DNRL could form a good elastic film with a high percentage elongation at break, but low adhesive properties such as low peel strength and tack adhesion. Blending DNRL with different types and amounts of polymer and plasticizer formed satisfactory films with different mechanical properties, as shown by the following results.

behavior, so they could be easily applied to the skin or formulated in any preparations. In addition, this deproteinization process did not significantly affect the DRC and TSC of DNRL, which could be approximately adjusted. The protein in NRL is hydrolyzed by the alcalase enzyme and solubilized with SDS, so it could be separated from the rubber by centrifugation. The efficacy of protein reduction to produce DNRL was more than 89.21 ± 9.45%. The particle size of DNRL was larger than that of the raw NRL due to the aggregation of some latex particles during the centrifugation process. Furthermore, both NRL and DNRL had a low PI, indicating a relatively narrow size distribution of the particles. The ζ-potential analysis, which is the electric potential at the plane of shear, is a useful tool for predicting the physical storage stability of colloidal systems. If colloidal systems have good physical stability, the ζ-potential values are higher than ±30 mV. When the colloidal systems are approximately optimized at ±60 mV, they exhibit very good physical stability during the shelf life.29 As a result in Table 2, the surface charge of DNRL dispersion had a more negative value, which indicated moderate stability. However, the steric hindrance from the SDS stabilizer would have the additional effect of increasing the particle stability. Thus, DNRL showed a stable dispersion when stored in the refrigerator for more than 4 months. In the acute skin irritation test in healthy rabbits, three treated rabbits exhibited a very slight erythema with score of 1 of skin at 1 h. However, this adverse skin reaction recovered 13397



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Figure 3. Mechanical properties of polymer blended DNRL films with 10 phr and 15 phr HPMC, MC, SCMC, PVA without plasticizer and with 10 phr DBP and GLY (n = 6).

3.2.1.1. Effects of Amount of HPMC. Blending DNRL with 10−15 phr HPMC provided films with improved mechanical properties over the DNRL film alone (Figure 2). However, the 5 phr HPMC blends showed only slight increases in these values; thus they were not further investigated (data not shown). The same trends were observed both without and with 10 phr DBP as plasticizer. The Young’s modulus and elasticity values increased with increasing amounts of HPMC. Moreover, the elasticity of the HPMC blended film was lower than that of the pure DNRL film due to the continuity of the polymer network. DNRL and HPMC blends were miscible, but the homogeneity of the polymer chain was lower than that of DNRL alone. The elasticity increased with increasing HPMC blends, which was directly related to the concentration of the methoxy groups in HPMC molecule.30 A more flexible and viscous film was produced. This indicated that the mechanical improvement to a hard and strong film was obtained by blending HPMC into the DNRL polymer due to the bulkiness of anhydroglucose in the HPMC structure. However, the tensile strengths were not significantly different in these blends. Only DNRL/HPMC blends without DBP showed high UTS values which were due to the properties of HMPC, but these values significantly decreased in DBP blended films. This indicated the strong effect of plasticizer on the tensile values of blended films. In addition, the adhesive properties in terms of the peel strength and tack adhesion slightly increased with increasing amounts of HPMC due to adhesive properties of HPMC.30 These indicated the improvement of mechanical properties of DNRL by HPMC blending. 3.2.1.2. Effects of Amount of DBP. Plasticizers were mixed into the polymer mixtures in order to enhance the flexibility and/ or reduce the brittleness. In contrast to the effects of the amount

of HPMC, there was a decrease of the Young’s modulus, UTS, and adhesive properties, and an increase of the elasticity when the amount of DBP was increased for both the 10 and 15 phr HPMC blending ratios (Figure 2). A significant difference of the modulus and UTS properties and the slight difference of the elongation and adhesive properties were observed between the HPMC blends without and with different DBP amounts. These differences increased when the amount of DBP increased. The plasticizer could interpose in the intermolecular forces between the polymer chains by extending and softening the films, and basically causing a decrease in the tensile strength and glass transition temperature of the films.31,32 However, a slippery and soft surface film with poor adhesiveness was observed when ≥20 phr DBP was used and it was difficult to prepare a completely dry film. Thus, the polymer with 10 phr plasticizer was chosen for further studies. 3.2.1.3. Effects of Type of Plasticizer. The films with various 10 phr plasticizer types were all more flexible than the unplasticized films. They were also easily removed from the Petri dish. Their mechanical properties are also shown in Figure 2. The addition of plasticizers significantly decreased the Young’s modulus and UTS, which indicated a softer film. The elasticity property was also different with any type of plasticizer. The blended film using DBS provided the lowest modulus and UTS, and indicated that this was the softest. The use of TEC provided the lowest percentage of elongation at the break to indicate that it was the most brittle film. The inclusion of TEC and GLY provided a slightly hazy film. The blended films composed of DBP or GLY had higher adhesive properties than the unplasticized films, while DEP, DBS, and TEC showed the opposite results. Thus, DBP and GLY were the most suitable plasticizers to provide good mechanical films for application to 13398



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Figure 4. Moisture uptake, swelling ratio, and erosion of DNRL blended films with various types and amounts of (A) plasticizer and (B) polymer blends; without plasticizer, with 10 phr, 20 phr, 30 phr DBP, 10 phr DEP, DBS, TEC, and GLY (n = 3).

the skin. They had the effect of making the films softer and more elastic.33 3.2.1.4. Effects of Amount and Type of Polymer. In a way similar to that of the DNRL/HPMC blended films, blending

with MC, SCMC, PVA, P407, or SAG with/without DBP or GLY as plasticizer showed significant increase of the modulus, UTS, elasticity, and adhesive properties when the amount of the blended polymer was increased (Figure 3, and data of P407 13399



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Figure 5. SEM micrographs of (A) blended film surfaces and (B) cross sections.

different plasticizers blended into DNRL films. The water swelling indicated that some hydrophilic parts could be dissolved and eroded from the matrix film, to increase the number of porous channels. The moisture uptake, swelling, and erosion behaviors of the polymeric films play important roles during the early stages of film degradation.37 The increasing moisture uptake, swelling ratio, and erosion were also revealed when various polymers were blended into DNRL films. The moisture uptake and swelling ratio values were affected by the polymer types. The effects could be ranged in the order MC > SCMC > P407 > PVA >HPMC > SAG in both the 10 and 15 phr polymer blends (data of P407 and SAG not shown). In addition, these values significantly increased when DBP was used as the plasticizer. However, the polymer types did not have significantly different effects on erosion values. The latter effects could be ranged in the order MC > SCMC > HPMC > SAG > PVA > P407 in both the 10 and 15 phr polymer blends. These changes could be due to the increasing hydrophilic properties of DNRL/various polymer/ plasticizer blends. These blended materials were dissolved and eroded when water molecules penetrated into their films due to individual hydrophilicity properties.38,39 This indicated the possibility of hydrophilic adjustment of DNRL films by blending with different polymer and plasticizer types. 3.2.3. Microscopic Morphology and Film Porosity. The optical microscope photographs of NRL, DNRL, and DNRL/ polymer blended preparations all showed films with smooth surfaces. There were some air bubbles in the MC, SCMC, and P407 blended DNRL films. However, the overall image was good for each film formulation (data not shown). SEM was used to confirm the high resolution morphology in each film. The DNRL films all had a smooth surface (Figure 5). After the HPMC and DBP were mixed with the DNRL, no obvious change was observed, indicating the polymer miscibility at microscopic scale. In contrast, DNRL blended with HPMC and GLY showed some minimal cracking on the surface which might be due to the water being lost rapidly through surface evaporation.40 In addition, DNRL blended with PVA and DBP or GLY produced smooth surface films. From these results, it was concluded that the film made from PVA had a smoother surface than that from HPMC, and the films made from DBP had smoother surfaces than that from GLY. Moreover, the cross-section morphology of these films showed dense films without poring, cracking, or cavities. However, the blended

and SAG not shown). The DNRL/MC blends exhibited the highest tensile properties, and DNRL/P407 blends showed the lowest tensile properties due to the properties of blended polymers. In addition, all polymer blended DNRL films had slightly increased adhesive properties. Their adhesiveness could be ranged in the order of DNRL/PVA, HPMC, MC, SCMC, SAG, and P407, respectively. In these results, HPMC, MC, SCMC, and PVA were the most suitable polymers for forming DNRL blended films with appropriate tensile and adhesive properties. P407 and SAG had unuseful properties and so were not chosen because of low tensile and adhesive improvements. However, the high viscosity MC and SCMC mixed polymers had many air bubbles that were difficult to eliminate. Moreover, polymer blends of 15 phr PVA produced such sticky films that they were difficult to peel from the Petri dish as complete films so were not further investigated. Only the 10−15 phr HPMC and 10 phr PVA mixed DNRL polymers were the most appropriate DNRL blended film preparations because they were easy to prepare in solution and were easily dispersed in the DNRL without air bubbles to form the appropriate films. Blending of NR with several types of polymer was a useful technique for preparing and developing materials with properties superior to those of individual constituents.34,35 It was important to provide the different properties depending on the type of polymer blends with individual properties of each polymer. 3.2.2. Moisture Uptake, Swelling Ratio, and Erosion Studies. The moisture uptake, swelling ratio, and erosion of DNRL films containing various types and amounts of polymer and plasticizer are presented in Figure 4. These parameters increased when DNRL was mixed with HPMC in blends that were similar to those found in previous works,30,33,35 and increased further when various plasticizers were added. It can be seen that these values depended directly on the amounts of HPMC and DBP. Increasing amounts of HPMC and DBP slightly increased the moisture uptake, swelling ratio, and erosion. These changes could be due to the greater hydrophilicities of the films when the amounts of HPMC and DBP increased.36 Moreover, these values were also affected by the types of plasticizers. The increase caused by the change of plasticizer could be ranged in the order GLY > TEC > DBP > DBS > DEP due to their hydrophilicity properties that were reported in a previous work.33 Furthermore, high moisture uptakes and swelling ratios were observed, and the erosion of the blended films were significantly increased by HPMC and 13400



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films of GLY showed a few cavities on the cross-section morphology. The estimation of film porosity in the hydrate stage by reverse osmosis techniques had been predicted for a number of films to be related to the water flux value. The films with the highest water flux values had high porosities, while the films with low water flux values had low porosities.26 The water fluxes in the DNRL blended films with various polymers were higher than that in the DNRL-alone film. These water fluxes were significantly affected by the polymer types. The water fluxes could be ranged in the order MC > SCMC > PVA >HPMC, respectively. Furthermore, any increase of the amount of HPMC increased the water flux. GLY generated a higher water flux than DBP. In addition, these water flux results were correlated to the percentage of porosity as shown in Figure 6; that

Figure 7. FT-IR spectra of NRL and DNRL.

(CO stretching), 1593 cm−1 (N−H bending), 1203 cm−1 (C−O), and 1029 cm−1 (−O−O−). After deproteinization, the principal peaks of the isoprene functional groups were shown more clearly, and the protein/phospholipids spectra disappeared from the DNRL film. This confirmed that the deproteinized process by enzyme treatment could completely reduce the amount of protein in NRL.3,41 In Figure 8A, the HPMC showed the broad spectra of the stretching vibration of O−H at 3446 cm−1 and the stretching of the C−O−C anhydroglucose ring at 1054 cm−1. In addition, the PVA spectra showed both O−H stretching and C−O stretching at 3449 and 1637 cm−1, respectively. The acquired spectra were similar to those reported for HPMC42,43 and PVA.44,45 DNRL/HPMC blends obtained spectra at 3423, 2856−2963, 1449, 1376, and 1054 cm−1 that were assigned to O−H stretching, C−H stretching, C−H bending of CH2, C−H bending of CH3, and C−O−C stretching, respectively. DNRL/PVA also showed the peaks at 3439, 2963−2856, 1449, and 1376 cm−1 that signified O−H stretching, C−H stretching, C−H bending of CH2, and C−H bending of CH3, respectively. Thus, the major peaks of DNRL and each polymer were also found in the DNRL/ polymer blended films. When DNRL/HPMC and DNRL/ PVA were blended with DBP or GLY as plasticizer, a s lightly broader peak of DBP was found at 1738 cm−1 (CO stretching) and those of GLY were found at 3337−3338 cm−1 (O−H stretching) and 1650−1663 cm−1(C−O stretching). Hence, new absorption bands were not observed in the polymer blends that had changed from those of the raw materials. These results clearly indicated no changes of each ingredient in the blended films.46 The DSC chromatograms of both raw materials and blended films were not changed in the range 0−180 °C. Thus, Figure 8B shows the DSC chromatograms only between −100 and 0 °C. Naskar and De47 have reported that the glass transition temperature (Tg) of cis-polyisoprene or natural rubber was −75 to −70 °C. In this study, however, the DSC thermograms of DNRL showed the Tg at −64.794 °C. Moreover, the DBP or GLY blends slightly changed the Tg's of DNRL/HPMC/ DBP, DNRL/HPMC/GLY, DNRL/PVA/DBP, and DNRL/ PVA/GLY blended films to −67.752, −63.730, −66.707, and −64.788 °C, respectively, due to the phenomenon of plasticization. These indicated some interactions between polymer chains and plasticizer to form the miscible polymer networks. This result related to their mechanical properties resulting in higher polymer flexibility or mobility that is described above.48

Figure 6. Water flux and percentage of porosity of DNRL/10 phr and 15 phr polymer blended films; without plasticizer, with 10 phr DBP and GLY (n = 3).

was also correlated to the moisture uptake, swelling ratio, and morphology of the blended films due to their hydrophilicities as described above. 3.2.4. Compatibility Study. In Figure 7, the principle FT-IR absorption peaks of the NRL spectrum were observed and corresponded to the isoprene functional groups at 3045 cm−1 (CH stretching), 2963 cm−1 (C−H stretching of CH3), 2929 cm−1 (C−H stretching of CH2), 2856 cm−1 (C−H stretching of CH2 and CH3), 1664 cm−1 (CC stretching), 1449 cm−1 (C−H bending of CH2), 1376 cm−1 (C−H bending of CH3), and 837 cm−1 (CCH wagging). In addition, the functional groups of the surface protein/phospholipids were also found at 3537 cm−1 (−OH stretching, N−H stretching), 1740 cm−1 13401



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Figure 8. (A) FT-IR spectra, (B) DSC thermograms, and (C) XRD patterns of (left) DNRL/HPMC and (right) DNRL/PVA blended films.

4. CONCLUSIONS

However, no disguised signal was observed in the DSC thermograms, which also indicated that all the ingredients in the blended films were compatible.47 The XRD patterns of the films between 5 and 40° (2θ) are shown in Figure 8C. The intensity results of pure HPMC at 7.95 and 20.13° and PVA at 19.69° represented their semicrystalline characters because of the strong intermolecular interaction between PVA or HPMC chains through intermolecular hydrogen bonding.49 In addition, these peaks were not found in the blended films which exhibited an amorphous phase similar to the DNRL pattern. These indicated the miscibility of polymer blends between DNRL and HPMC or PVA. Moreover, DBP or GLY also affected their DNRL/polymer blends so that the crystalline peaks of HPMC and PVA disappeared.

DNRL could be prepared from fresh NRL using the alcalase enzyme for deproteinization and the centrifugation process to obtain DNRL that was safe for medical and pharmaceutical skin applications, together with paraben mixtures acting as a preservative and SDS acting as a stabilizer. Its physical properties were quite similar to those of fresh NRL. Many DNRL films could be prepared from DNRL blended with many adhesive polymers and plasticizers that showed their miscibility results. The mechanical and physicochemical properties of the blended films depended on the types and amounts of polymer and plasticizer added. DNRL blended with HPMC or PVA and DBP or GLY provided the best films for medical and pharmaceutical skin 13402



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(14) 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. (15) Pichayakorn, W.; Suksaeree, J.; Boonme, P.; Amnuaikit, T.; Taweepreda, W.; Ritthidej, G. C. Deproteinized natural rubber latex/ hydroxypropylmethyl cellulose blending polymers for nicotine matrix films. Ind. Eng. Chem. Res. 2012, 51 (7), 8442−8452. (16) Pichayakorn, W.; Suksaeree, J.; Boonme, P.; Amnuaikit, T.; Taweepreda, W.; Ritthidej, G. C. Deproteinized natural rubber film forming polymeric solutions for nicotine transdermal delivery. Pharm. Dev. Technol. 2012, DOI: 10.3109/10837450.2012.705297. (17) ASTM International. Standard Practice for Standard Specification for Rubber-Concentrated, Ammonia Preserved, Creamed, and Centrifuged Natural Latex D1076; ASTM: West Conshohocken, PA, USA, 2002; Vol. 9. (18) ASTM International. Standard Test Method for Rubber-Nitrogen Content D3533; ASTM: West Conshohocken, PA, USA, 2001; Vol. 9. (19) Organization for Economic Co-operation and Development (OECD). OECD Guidelines for Testing of Chemicals, Section 4: Health Effects, Test No. 404: Acute Dermal Irritation/Corrosion. OECD Publishing: Paris, France, 2002; Vol. 2, pp 1/13−13/13. (20) Draize, J. H.; Woodward, G.; Calvery, O. H. Method for the study of irritation and toxicity of substance applied topically to the skin and mucous membrane. J. Pharmacol. Exp. Ther. 1944, 82, 377−390. (21) ASTM International. Standard Test Methods for Vulcanized Rubber and Thermoplastic Elastomers-Tension D412. ASTM: West Conshohocken, PA, USA, 2003; Vol. 9. (22) Kundu, P. P.; Biswas, J.; Kim, H.; Choe, S. Influence of film preparation procedures on the crystallinity, morphology and mechanical properties of LLDPE films. Eur. Polym. J. 2003, 39 (8), 1585−1593. (23) ASTM International. Standard Test Method for Peel Resistance of Adhesives (T-Peel Test) D1876; ASTM: West Conshohocken, PA, USA, 2001; Vol. 15. (24) ASTM International. Standard Test Methods for Loop Tack D6195; ASTM: West Conshohocken, PA, USA, 2003; Vol. 15. (25) Pongjanyakul, T.; Puttipipatkhachorn, S. Alginate-magnesium aluminum silicate films: Effect of plasticizers on film properties, drug permeation and drug release from coated tablets. Int. J. Pharm. 2007, 333 (1−2), 34−44. (26) 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. (27) Chinpa, W. Preparation and characterization of an asymmetric porous poly(vinyl chloride)/poly(methyl methacrylate-comethacrylic acid) membrane. ScienceAsia 2008, 34, 385−389. (28) Nielsen, G. D.; Wolkoff, P.; Alarie, Y. Sensory irritation: Risk assessment approaches. Regul. Toxicol. Pharmacol. 2007, 48 (1), 6−18. (29) Riddick, T. M. Control of colloid stability through zeta potential. http://customers.hbci.com/∼wenonah/riddick/index.html (accessed June 14, 2012). (30) Kwok, T. S. H.; Sunderland, B. V.; Heng, P. W. S. An investigation on the influence of a vinyl pyrrolidone/vinyl acetate copolymer on the moisture permeation, mechanical and adhesive properties of aqueous-based hydroxypropyl ethylcellulose film coatings. Chem. Pharm. Bull. 2004, 52 (7), 790−796. (31) Lin, S.-Y.; Lee, C.-J.; Lin, Y.-Y. Drug-polymer interaction affecting the mechanical properties, adhesion strength and release kinetics of piroxicam-loaded Eudragit E films plasticized with different plasticizers. J. Controlled Release 1995, 33 (3), 375−381. (32) Tarvainen, M.; Sutinen, R.; Peltonen, S.; Mikkonen, H.; Maunus, J.; Vähä-Heikkilä, K.; Lehto, V.-P.; Paronen, P. Enhanced film-forming properties for ethyl cellulose and starch acetate using nalkenyl succinic anhydrides as novel plasticizers. Eur. J. Pharm. Sci. 2003, 19 (5), 363−371. (33) Ye, Z.-W.; Rombout, P.; Remon, J. P.; Vervaet, C.; Mooter, G. V. D. Correlation between the permeability of metoprolol tartrate

applications. These results have provided clear evidence for the feasibility of using DNRL blended films for applications as novel materials for medical and pharmaceutical skin applications including drug delivery film formulations. Further research has involved the preparation and evaluation of some drug delivery systems derived from these blended films.

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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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Preparation of Deproteinized Natural Rubber Latex and Properties of

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