Preparation of a Pseudolatex-Membrane for Ketoprofen Transdermal

Oct 14, 2013 - Ethyl cellulose (EC) and deproteinized natural rubber latex (DNRL) were used to prepare a pseudolatex-base as a matrix membrane for ...
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Preparation of a Pseudolatex-Membrane for Ketoprofen Transdermal Drug Delivery Systems Jirapornchai Suksaeree,*,†,‡ Laksana Charoenchai,†,‡ Chaowalit Monton,†,‡ Tun Chusut,†,‡ Apirak Sakunpak,†,‡ Wiwat Pichayakorn,§ and Prapaporn Boonme§ †

Faculty of Pharmacy, Rangsit University, Pathum Thani 12000, Thailand Sino-Thai Traditional Medicine Research Center (Cooperation between Rangsit University, Harbin Institute of Technology, and Heilongjiang University of Chinese Medicine), Rangsit University, Pathum Thani 12000, Thailand § Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla 90112, Thailand ‡

ABSTRACT: Ethyl cellulose (EC) and deproteinized natural rubber latex (DNRL) were used to prepare a pseudolatex-base as a matrix membrane for ketoprofen patches. The pseudolatex-base was prepared using a homogenization and solvent removal method. Either polyvinyl alcohol or polysorbate 80 was used as surfactant and emulsifier. Polyvinyl pyrrolidone, glycerine, isopropyl palmitate, and dibutyl phthalate were used as a channeling agent, skin humectant, enhancer, and plasticizer, respectively. Ketoprofen was incorporated into the pseudolatex-base. All pseudolatex formulations were homogeneous and smooth in texture and elegant in appearance. The pH of pseudolatex formulations was 5−7, and the particle size was 487−787 nm. The viscosity and spreadability test showed the good characteristics of membrane. Stable colloidal dispersion was formed with a zeta potential of −35.18 to −51.55 mV. All pseudolatex formulations were formed into in situ membranes by solvent evaporation in a hot air oven at 70 ± 2 °C. The mechanical test and moisture uptake were characterized, which significantly depended on ingredient. The in vitro release and skin permeation of ketoprofen from the pseudolatex-membrane were evaluated. The suitable pseudolatex-membrane was produced from a EC:DNRL ratio of 1:1 and provided a controlled release and suitable permeation patterns of the ketoprofen. Thus, these systems are essentially based on a matrix membrane made from polymeric pseudolatex systems. polymer liquid, followed by solvent evaporation to form a film. The rate of drug release from the matrix and pseudolatex may be altered by varying the polymer matrix material and the drug concentration in the base. The physicochemical properties of the drug molecule, and differences in the condition of the skin, region, age, and sex, will also play important roles in the permeation of the drug through the skin.7 However, this approach has many clear advantages over other methods such as polyisobutylene, silicone, and acrylics. (1) The organic solvents are accepted for pharmaceutically product. (2) The solvent may possibly reuse. (3) It may be adaptable to several generally pharmaceutical polymers, e.g., Eudragit, cellulose derivatives. (4) It is a simple implementation, easy scaling up, and high reproducibility. Ketoprofen has low water solubility and is a potent nonsteroidal anti-inflammatory drug (NSAIDs) commonly used for the treatment of musculoskeletal disorders such as osteoarthritis and rheumatoid arthritis as well as for symptoms of trauma. Ketoprofen is easily absorbed from the gastrointestinal tract,8 where a high concentration often generates side effects.9 However, it has low bioavailability, with a plasma half-life of approximately 0.5−4 h;8 therefore, it must be frequently administered orally. Transdermal delivery system of the ketoprofen drug, such as nanoemulsion, gel formulation, or

1. INTRODUCTION Transdermal drug delivery systems can be categorized as either i) drug in matrix or ii) drug in reservoir systems. In the matrix membrane, the drug is dispersed or dissolved in a polymer. It is attached to an adhesive layer that is connected to the skin. Some matrix membranes can act as an adhesive layer by itself. Matrix membrane layers and/or the added adhesive layer acts as a control on the rate of delivery.1,2 Although there have been significant advances in transdermal drug delivery systems which can control drug release into the systemic blood circulation to the target organ, the concept of providing systemic therapy via the skin is not a recent innovation. Over several centuries, attempts have been made to treat both local and systemic aliments by the application of drugs to the skin.2 Pseudolatex systems should possess suitable characteristics to form a film after solvent evaporation.3 They must be colloidal aqueous dispersions that are water-based systems. Particle size is the key to pseudolatex stability or resistance to settling and sedimentation. Their particle size is the most important specification, which typically should fall between 10 and 1000 nm.3 They must be useful in mediating drug release4−6 and should be fluid, comprised of polymer concentrations at 20− 30%. Pseudolatex can be prepared by the emulsification− evaporation technique, by dissolving the polymer in a suitable solvent system and introducing the organic phase into water in order to form an emulsion by employing surfactant as stabilizers. After homogenization, the solvent is removed by vacuum evaporation.4 Drug delivery systems can control drugs released by the matrix. Pseudolatex-bases dispense drugs in © 2013 American Chemical Society

Received: Revised: Accepted: Published: 15847

July 22, 2013 September 21, 2013 October 14, 2013 October 14, 2013 dx.doi.org/10.1021/ie402345a | Ind. Eng. Chem. Res. 2013, 52, 15847−15854

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Table 1. Pseudolatex-Base System Formulations formulas

EC (%w/w)

DNRL (%w/w)

glycerine (%w/w)

PVA (%w/w)

polysorbate 80 (%w/w)

PVP (%w/w)

dibutyl phthalate (%w/w)

IPP (%w/w)

P1 P2 P3 P4 P5 P6 P7 P8 P9 P10

20 15 10 5 0 20 15 10 5 0

0 5 10 15 20 0 5 10 15 20

6 6 6 6 6 6 6 6 6 6

14 14 14 14 14 0 0 0 0 0

0 0 0 0 0 14 14 14 14 14

4 4 4 4 4 4 4 4 4 4

6 6 6 6 6 6 6 6 6 6

0 0 0, 5, 10, 15 0 0 0 0 0, 5 0 0

formulations had the ketoprofen content about 20 mg/mL in each pseudolatex system. The pH of the pseudolatex systems was measured by a S220 SevenCompact pH/Ion pH meter (Mettler Toledo, Switzerland) at room temperature. The pH meter was calibrated by using pH 4.0, 7.0, and 10.0 standard buffers. The viscosity was measured by a Brook field viscometer (Brookfield Engineering Laboratories Inc., USA) at 25 ± 2 °C. The particle size, size distribution, and surface charge on the particles were measured by a ZetaPALS (Brookhaven, Germany) at 25 ± 2 °C and presented as the effective diameter, polydispersity index (PI), and zeta potential (ζ), respectively. The spreadability values (g cm2/s) were measured by pouring each of the formulations onto the glass plate. Then, each was pressed with another glass plate to expel air and form a complete membrane between the two plates. The film diameter during each interval was given as the area of complete membrane which indicated the spreadability property. It was further calculated by eq 1

patch system has previously been used for topical treatments to minimize side effects associated with the use of oral antiinflammatories.8,10−12 Therefore, ketoprofen was selected as the transdermal formulation for a controlled-release dosage form. The main objective of this work was to prepare pseudolatexbase systems from ethyl cellulose (EC) and deproteinized natural rubber latex (DNRL). Polyvinyl alcohol (PVA) or polysorbate 80 was used as the surfactant and stabilizer of the pseudolatex systems. Glycerine was used as a skin humectant, dibutyl phthalate as a plasticizer, and polyvinyl pyrrolidone as the channeling agent. The ketoprofen was incorporated into these pseudolatex-base systems. They were homogenized to form the colloidal emulsion, and vacuum evaporation was used to remove the organic solvent. Then, the matrix membrane for ketoprofen transdermal patches was produced by solvent evaporation using a hot oven. The physical appearances, chemical, and mechanical properties of pseudolatex systems and in situ membranes were characterized. Consequently, the in vitro release of ketoprofen and the skin permeation were also studied.

S=

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 by W. Pichayakorn laboratory.13−15 Ketoprofen (98% purity, Mw = 254.28 g/mol), polyoxyethylene-20 oleyl ether, EC, polyvinyl pyrrolidone, glycerine, isopropyl palmitate (IPP), PVA (Mw = 31,000 g/mol), polysorbate 80, and dibutyl phthalate were obtained from Sigma-Aldrich (USA). The other chemicals were of analytical grade. 2.2. Preparation and Characterization of Pseudolatex Systems. As shown in Table 1, for the oil phase, EC and dry DNRL were dissolved in 500 mL of dichloromethane by using a magnetic stirrer until it was a clear solution. After that, the dibutyl phthalate, and 2 g of ketoprofen were mixed together into polymeric pseudolatex-base systems. In some cases, the IPP was mixed in this solution used as an enhancer. For the water phase, surfactant and channeling agent were dissolved in 100 mL of water and stirred until completely soluble. Then, glycerine was mixed into this solution. The two phases were mixed together by pouring water phase into the oil phase, and then the homogenization method was used for 30 min until an emulsion-like system occurred. This was then poured into a round-bottom flask where the dichloromethane was removed by rotary evaporator with a controlling temperature of 40 ± 2 °C and a vacuum condition for 5 h. Finally, these pseudolatex systems were adjusted to 100 mL with water. Thus, the

W×A T

(1)

where S is the spreadability (g cm2/s), W is the weight of the sample (g), A is the area of the sample spread on the glass plate (cm2), and T is the time taken to spread completely on the glass plate from each formula (s).16,17 2.2. Preparation and Characterization of Ketoprofen Pseudolatex-Membranes. To determine the properties of in situ membranes, the 15 mL of pseudolatex systems preparation was poured into a Petri-dish. This was dried in a hot air oven at 70 ± 2 °C until a complete membrane having 4 mg/cm2 of ketoprofen content was formed. Subsequently, the dry and complete membranes were peeled from the Petri-dish and kept in desiccators. Then, the mechanical properties for their tensile strength (ultimate tensile strength [UTS] and elongation at break), and the adhesion properties (T-peel strength and loop tack adhesion), were tested using the Universal Testing Machine Model QC-508E (Cometech, Taiwan) with a 500 N loaded cell. These methods and sample preparations were described by Pichayakorn et al.13,14 The percentage of moisture uptake was tested using 1 cm × 1 cm membrane specimens kept in desiccators with silica gel beads for 24 h. The initially weight (W0) was reported, and specimens were then moved to desiccators with a 75% relative humidity environment from a saturated sodium chloride solution. Every month for three months, the membrane specimens were removed and weighed until constant values were obtained (Wu). The percentage of 15848

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Table 2. Physicochemical Properties of the Pseudolatex System for Initial Preparation (Mean ± SD, n = 3) initial preparation formulas P1 P2 P3 P4 P5 P6 P7 P8 P9 P10

pH 6.04 6.12 6.08 6.19 6.17 6.08 6.11 6.19 6.22 6.18

± ± ± ± ± ± ± ± ± ±

viscosity (cps) 0.10 0.21 0.18 0.23 0.12 0.12 0.10 0.17 0.20 0.17

351.65 372.88 387.32 391.62 406.46 339.28 352.81 364.79 365.03 385.33

± ± ± ± ± ± ± ± ± ±

19.66 25.64 21.78 29.21 13.45 26.84 17.92 27.22 29.12 19.27

effective diameter (nm)

PI

± ± ± ± ± ± ± ± ± ±

0.11 0.12 0.15 0.17 0.14 0.19 0.20 0.16 0.17 0.16

542.33 655.38 698.53 742.94 787.54 487.32 492.54 522.93 554.73 589.62

38.22 41.15 37.29 29.83 25.88 32.49 38.22 27.18 32.81 19.82

ζ (mV) −51.55 −47.29 −40.32 −38.22 −35.18 −50.38 −48.29 −42.39 −35.39 −35.63

± ± ± ± ± ± ± ± ± ±

2.14 1.33 1.82 2.83 1.82 1.44 1.78 1.82 2.73 2.43

spreadability values (g cm2/s) 1.34 1.42 1.48 1.50 1.57 1.54 1.66 1.68 1.82 2.08

± ± ± ± ± ± ± ± ± ±

0.12 0.21 0.26 0.20 0.18 0.25 0.17 0.15 0.28 0.24

Table 3. Physicochemical Properties of the Pseudolatex System after Storage at 4 °C for 3 Months (Mean ± SD, n = 3) 3 months formulas P1 P2 P3 P4 P5 P6 P7 P8 P9 P10

pH 6.12 6.16 6.18 6.04 6.22 6.19 6.08 6.28 6.17 6.16

± ± ± ± ± ± ± ± ± ±

viscosity (cps) 0.17 0.11 0.08 0.18 0.24 0.17 0.18 0.29 0.18 0.21

400.18 401.37 412.98 444.71 467.23 352.48 368.17 372.22 392.43 419.33

± ± ± ± ± ± ± ± ± ±

14.62 10.23 11.82 16.32 19.43 18.43 15.33 23.82 24.54 29.16

effective diameter (nm)

PI

± ± ± ± ± ± ± ± ± ±

0.12 0.15 0.13 0.20 0.19 0.17 0.17 0.17 0.13 0.19

559.02 703.84 743.19 783.29 832.59 492.18 539.29 592.37 648.29 675.49

43.83 32.38 39.17 29.36 29.17 41.92 38.64 42.18 36.73 29.54

moisture uptake was calculated as the increased weight (WuW0) compared to the initial weight (W0).18 2.3. The Determination of Ketoprofen Content. The ketoprofen content in pseudolatex-base and pseudolatexmembrane were extracted with 0.5 w/v of polyoxyethylene-20 oleyl ether in isotonic phosphate buffer solution pH 7.4. They were immersed for 30 min and sonicated for 1 h. They were filtered by using a 0.45 μm cellulose membrane. The ketoprofen content in each sample was determined by the HPLC method. 2.4. The in Vitro Studies. The in vitro study of ketoprofen was performed using a modified Franz-type diffusion cell with a diffusion area of 1.77 cm2. The pseudolatex-membranes were cut into 4 cm2 having 16 mg of ketoprofen (4 mg/cm2). The receptor compartment was filled with 12 mL of 0.5 w/v of polyoxyethylene-20 oleyl ether in isotonic phosphate buffer solution (pH 7.4), controlled with a water jacket at 37 ± 0.5 °C, and constantly stirred at 300 rpm with a magnetic stirrer. A 1 mL sample of isotonic phosphate buffer solution was withdrawn at 0.5, 1, 2, 4, 6, 8, and 12 h time intervals, and an equal volume of fresh isotonic phosphate buffer solution was then added as a replacement.19 For the in vitro release, the pure ketoprofen was applied to cellulose membrane (Mw cutoff 3,500 g/mol). The ketoprofen patches were directly applied to the donor compartment. The in vitro permeation of ketoprofen was determined using pig skin. The method for pig skin preparation was d by Songkro et al.20 The pig skin was placed on the top of the receptor compartment with the stratum corneum facing upward to the donor compartment. The pseudolatexmembranes were directly applied to the pig skin. The samples collected from the in vitro study were analyzed by the HPLC system (Agilent 1260 series, USA) with an Agilent C18 analytical column 4.6 mm × 150 mm. The mobile

ζ (mV) −49.34 −45.28 −39.79 −36.72 −31.29 −47.92 −44.39 −38.43 −33.28 −30.38

± ± ± ± ± ± ± ± ± ±

1.08 2.01 3.29 3.42 2.93 3.92 3.19 2.99 3.42 3.12

spreadability values (g cm2/s) 1.29 1.36 1.38 1.42 1.47 1.48 1.50 1.54 1.70 1.88

± ± ± ± ± ± ± ± ± ±

0.11 0.18 0.17 0.29 0.24 0.12 0.19 0.18 0.24 0.21

phases used were 0.025% v/v trifluoroacetic acid in water (solvent A) and acetonitrile (solvent B), and they were run at a gradient of 70:30 for 5 min and then 10:90 for 8 min followed by 0:100 (solvent A:B, respectively) with a flow rate of 1 mL/ min. Ketoprofen content in the samples was determined at 255 nm. The ketoprofen content was calculated comparing with the validated calibration curve. The HPLC method provided good accuracy (97.28−102.17%), precision (0.62−1.17), and linearity in the required concentration range of 10−50 μg/mL of pure ketoprofen in 0.5 w/v of polyoxyethylene-20 oleyl ether in isotonic phosphate buffer solution. 2.5. Statistical Analysis. The average value was calculated as a mean ± standard deviation value. All results were statistically analyzed by one-way analysis of variance followed by post hoc analysis. A p-value of less than 0.05 was considered to be statistically significant.

3. RESULTS AND DISCUSSION 3.1. Characteristics of Pseudolatex Systems. The latex is harvested using the tapping process from the Para rubber tree. It is very stretchy and flexible and extremely waterproof.21,22 However, it is comprised various types of proteins (Hev 1−14) which can cause allergic reactions to patients.23,24 Thus, the latex used in this study had the protein content reduced, as performed by Pichakorn et al.14 This low protein content latex is called DNRL. DNRL solution was safe enough to apply to the skin of New Zealand white rabbits, as shown by the Thailand Institute of Scientific and Technology Research.13,14 Therefore, the DNRL solution was deemed to be a suitably safe polymer to use in this work. The polymeric pseudolatex dispersion as a new topical system was prepared by using a solvent removal method first reported by Büyükyaylaci et al.25 The preparation of each 15849

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Figure 1. The (a) UTS, (b) elongation at break, (c) T-peel strength, and (d) tack adhesion values of ketoprofen pseudolatex-membrane, with different surfactant of PVA (red line) and polysorbate 80 (blue line) (mean ± SD, n = 5).

ketoprofen transdermal patch from a pseudolatex-base had different of concentrations of EC and DNRL and different types of surfactant. They could be easily prepared by homogenization. The ketoprofen solid forms could be completely dissolved in mixed solvents comprised of EC and DNRL polymers before adding any other ingredients, and all finished polymeric pseudolatexs exhibited equally sticky properties. The physicochemical properties of the polymeric pseudolatexs are summarized in Table 2. They were all yellowish mixtures due to the color of ketoprofen, with good homogeneity and were smooth in texture by visual observation. They also showed good drying times for forming membranes and performed well in the in situ membrane integrity tests. The pH, viscosity, effective diameter, ζ, and spreadability values of the pseudolatex systems are presented in Tables 2 and 3, for both initial preparation (Table 2) and after storage at 4 °C for 3 months (Table 3). They had pH values between 6.04 and 6.28. As this was close to neutrality, the pH of all

formulations were safe for use on the skin and they produced no irritation.26 In addition, the pH was not significantly changed from initial preparation after storage for 3 months, and various ingredients were not significantly in their formulation. When ketoprofen-pseudolatex systems used PVA as a surfactant and emulsifier, significantly higher viscosity values were found than when using polysorbate 80. This is because the PVA is a pharmaceutical excipient used as a viscosity increasing agent.27 However, an increase in the DNRL concentration slightly increased the viscosity values of pseudolatex systems with narrow PI values. This was confirmed by ζ values that were between −60 and −30 mV. Moreover, the ketoprofenpseudolatex systems with high viscosity values will take more time to spread onto a glass plate and will have high spreadability values.16 The spreadability values of the ketoprofen-pseudolatex systems was increased after the DNRL concentrations were increased. This result was related to increasing viscosity and effective diameter values of their 15850

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formulations. This might be due to a slight agglomeration of the latex particle that was confirmed by research elsewhere.14,28−30 Thus, the ketoprofen-pseudolatex systems exhibited a very good physical stability during their shelf life, as there were no significant changes to their physicochemical properties from the initial preparation to after storage for 3 months. 3.2. Characteristics of Ketoprofen Pseudolatex-Membranes. EC is a derivative of cellulose, having some of the hydroxyl groups on the repeating glucose units converted into ethyl ether groups. It is relatively weaker and more brittle than cellulose. However, it can be made into many versatile products, such as thermoplastic polymers. In pharmaceutical applications, they can be used to mask the taste of bitter actives, enhance the strength and appearance of tablets or capsules, and enable controlled release of drugs in formulations. It can form a membrane after solvent is evaporated.27,31−33 Thus, the pseudolatex membranes are brittle membranes which have high UTS values and a low percentage of elongation at break (Figure 1 a,b). These membranes had significantly increased softness and flexibility, caused by a decrease in tensile strength and increased percentage of elongation at the break when the DNRL was mixed into their formulation. The elasticity increased with increasing DNRL concentration, which was directly related to the individual properties of DNRL (Figure 1 a,b). DNRL is very stretchy and flexible;21,22 therefore, more flexible and viscous membranes were produced. In addition, the DNRL is a sticky polymer with improved adhesion properties that increased the T-peel and tack adhesion values (Figure 1 c,d). Moreover, when the PVA was used as a surfactant, it made the membrane more brittle and hard compared with using polysorbate 80. This was due to the brittle property of PVA polymer.34 Thus, their blended membranes exhibited high UTS values and a low percentage of elongation at the break (Figure 1 a,b), but they are sticky polymers that have increasing viscosity which enhances adhesion.13,27 The membranes made using PVA showed significantly higher adhesive properties, i.e., T-peel strength and tack adhesion of the in situ membranes, than polysorbate 80 (Figure 1 c,d). Therefore, the DNRL concentration and surfactant type directly affected the mechanical and adhesion properties of the ketoprofen pseudolatex-membranes. The percentage moisture uptakes of the ketoprofen pseudolatex-membranes are presented in Figure 2. The percentage moisture uptakes of the ketoprofen pseudolatexmembranes were affected by the storage time, surfactant type, and DNRL concentration. The increased storage time produced higher percentage moisture uptakes of the ketoprofen pseudolatex-membranes using either PVA or polysorbate 80 as surfactant. These surfactants are widely used to make hydrophilic polymers that could dissolve in water over a wide range of temperatures. Moreover, compared with PVA, the percentage moisture uptakes of ketoprofen pseudolatexmembranes made from polysorbate 80 were higher. This could be attributed to the higher solubility in water of polysorbate 80, as compared with PVA. Thereby, these ketoprofen pseudolatex-membranes have a high affinity for water and induce higher moisture uptake as the polysorbate 80 in the ketoprofen pseudolatex-membranes increased. Although DNRL has low hydrophilicity,14 the percentage moisture uptakes of the ketoprofen pseudolatex-membranes were also found to increase with decreasing DNRL concentration.

Figure 2. The moisture uptake values of ketoprofen pseudolatexmembrane, with different surfactants of PVA (red line) and polysorbate 80 (blue line) (mean ± SD, n = 5).

After 3 months, the high percentage moisture uptakes of the ketoprofen pseudolatex-membranes slightly increased the mechanical properties in term of UTS and elongation at break35 (Figure 1 a,b). This is due to the sorption of water molecules in these membranes, which typically causes an anisotropic volume expansion, and results in increased mechanical properties. Conversely, the high percentage moisture uptakes were also found to decrease their adhesion properties (Figure 1 c,d); therefore, the water molecules might make the membranes more slippery. Statistical analysis shows the effect of the ratio of EC and DNRL concentration. Different types of surfactant were significantly related to UTS values, percentage of elongation at break, T-peel strength, tack adhesion, and percentage moisture uptakes of the ketoprofen pseudolatex-membranes. 3.3. Determination of Ketoprofen Content. All prepared ketoprofen-pseudolatex formulations were yellowish due to the color of the drug and could adhere by their polymer matrix that acts as a pressure sensitive adhesive. The percent content of the various formulations are shown in Table 4. The initial preparation of all formulations found the ketoprofen Table 4. Ketoprofen Content of the Pseudolatex System (Mean ± SD, n = 5) initial preparation

formulas P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 15851

pseudolatexbase (mg/mL) 19.83 21.34 20.33 20.88 19.83 19.79 20.38 20.37 19.87 20.88

± ± ± ± ± ± ± ± ± ±

2.17 2.09 2.31 2.19 2.17 2.77 2.91 3.03 2.97 2.17

3 months

pseudolatexmembrane (mg/cm2) 4.03 4.12 3.97 3.94 4.08 4.02 3.92 4.09 3.92 4.03

± ± ± ± ± ± ± ± ± ±

0.83 0.65 0.59 0.49 0.53 0.93 0.49 0.54 0.94 0.73

pseudolatexbase (mg/mL) 19.73 20.87 20.38 19.83 20.31 19.69 19.78 20.02 19.78 20.13

± ± ± ± ± ± ± ± ± ±

2.03 2.39 3.12 2.93 2.89 2.38 2.39 2.38 2.43 2.39

pseudolatexmembrane (mg/cm2) 3.98 4.02 4.01 3.94 3.92 3.87 3.82 3.91 3.88 3.92

± ± ± ± ± ± ± ± ± ±

0.38 0.84 0.39 0.77 0.42 0.55 0.68 0.54 0.66 0.83

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Figure 3. The release of ketoprofen pseudolatex-membrane, with different surfactants of (a) PVA and (b) polysorbate 80 (mean ± SD, n = 3).

Figure 4. The permeation of ketoprofen pseudolatex-membrane, with different surfactants of (a) PVA and (b) polysorbate 80 (mean ± SD, n = 3).

release profile, compared with pure drug. Ketoprofen has low solubility in water and has dissolution problems.36 Therefore, the pseudolatex could enhance the aqueous solubility of this poor water-soluble drug. When the pseudolatex systems were made into the ketoprofen pseudolatex-membranes, they provided faster ketoprofen from their formulations, compared with pure drug. However, the polysorbate 80 is more highly solubility than PVA. It acts as a good surfactant, which increases the solubility of ketoprofen in formulations more so than PVA. This was confirmed by the solubility of ketoprofen in polysorbate 80 and PVA that are 63.05 ± 4.87 and 14.05 ± 1.04 mg/mL, respectively. Thus, the ketoprofen pseudolatexmembranes made from polysorbate 80 as surfactant significantly increased the ketoprofen release profile more so than PVA. In addition, Figure 3 a,b shows the decreasing ketoprofen release profile when DNRL concentration was increased in their formulations. This was due to fact that DNRL is a hydrophobic polymer. Therefore, increasing DNRL concen-

content in the range of 19.79−21.34 mg/mL and 3.92−4.12 mg/cm2 when extracted from pseudolatex-base and pseudolatex-membrane, respectively. After all preparations were kept at 4 °C for 3 months, the ketoprofen content was found to be in the range of 19.69−20.87 mg/mL and 3.82−4.02 mg/cm2 from pseudolatex-base and pseudolatex-membrane, respectively. The ketoprofen contents extracted from all formulations were not significantly different from initial preparation. From these results, its might be assumed that pseudolatex formulations entrap ketoprofen very well. 3.4. The in Vitro Studies. The ketoprofen pseudolatexmembranes were made from the mixture of drug dissolved into a pseudolatex base that comprised of different ratios of EC and DNRL and different types of surfactant, either PVA or polysorbate 80. It was found that these different compositions affected the in vitro release of ketoprofen, compared with pure drug. The in vitro release of ketoprofen from pseudolatexmembrane consisting of PVA (Figure 3 a) and polysorbate 80 (Figure 3 b) as surfactant showed an increasing ketoprofen 15852

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Figure 5. The permeation of ketoprofen pseudolatex-membrane with (a) P3 and P8 formulas using 5% w/w IPP as an enhancer and (b) P3 formulas with different concentrations of IPP (mean ± SD, n = 3).

that the high IPP loading level directly produced the higher skin permeation of ketoprofen from formulation.

tration significantly decreased the release of ketoprofen from the formulations. The in vitro skin permeation using the pig skin as a barrier between ketoprofen patches and the receptor medium was used due to the anatomical, physiological, and biochemical properties of the pig skin which resemble human skin.37,38 The ketoprofen pseudolatex-membrane significantly increased the in vitro skin permeation of ketoprofen (Figure 4 a,b). These results are related to the in vitro results, which depended on surfactant types and DNRL concentration. The polysorbate 80 (Figure 4 b) produced a significantly higher in vitro skin permeation of ketoprofen, more so than PVA (Figure 4 a). All ketoprofen pseudolatex-membrane formulations showed a zero order mechanism which was independent of time and concentration of drug. These results ensured that the drug concentrations remained within the therapeutic efficacy in maximizing the amount of time for 12 h delivery of drugs with a narrow therapeutic index. The use of polymer and ingredient combinations in these pseudolatex systems could be utilized to provide zero order ketoprofen permeation profiles and could control the release and permeation behavior of ketoprofen from the formulation. However, the optimum for this pseudolatex-membrane was the ratio of DNRL:EC = 1:1 that is selected for the next study by mixing with penetration enhancer. It was a higher permeation of ketoprofen that usage of 5% w/w IPP as penetration enhancer in P3 and P8 formulations (Figure 5 a). This was because IPP reversibly decreased the barrier resistance of the stratum corneum and allowed drugs to penetrate more readily to the viable tissues and the systemic circulation.39 The PVA acts as a lower surfactant in this system than polysorbate 80. The P3 formulation was selected to study the effect of IPP concentration on in vitro skin permeation of ketoprofen. It was found that increasing IPP concentration increased the skin permeation of ketoprofen (Figure 5 b), which provided a similar permeation pattern to the P3 formulation. It could be concluded that permeation of skin using IPP as a penetration enhancer directly increased skin permeation of ketoprofen and

4. CONCLUSIONS In conclusion, the present study prepared the ketoprofen pseudolatex-membranes from a pseudolatex-base made from the composition of EC and DNRL by using different surfactants, PVA or polysorbate 80. The satisfactory ketoprofen pseudolatex-membranes with different mechanical properties, adhesion properties, and moisture uptake depended on a ratio between EC and DNRL, surfactant types, and storage time. These properties were appropriately used to develop and produce the suitable membrane for ketoprofen pseudolatexmembranes. Moreover, in vitro study results showed that different patterns were produced from various ratios of EC and DNRL, surfactant types, and adding penetration enhancer. Thus, this work successfully used this system to increase solubility, in vitro release, and in vitro skin permeation of ketoprofen, making it suitable for developing ketoprofen patches.

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Corresponding Author

*Phone: +(66)-(2)-9972222 ext. 4911, 1502. Fax. +(66)-(2)9972222 ext. 1403, 1508. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to express their gratitude to KI Tull from Rangsit University for assistance with the English in this paper. The authors would like to acknowledge the Faculty of Pharmacy, Rangsit University for financial supports

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REFERENCES

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