Investigation on factors affecting drug delivery using polymers and phospholipids 5

CHAPTER Effect of Polymer Transition Temperature on the Topical Delivery of Levothyroxine 7.1 Introduction Polymeric microspheres are being widely used in drug delivery systems. Biodegradable polymers can be designed to control and prolong drug release by adjusting the degradation rate of the polymer. Ethyl cellulose (EC), a non-toxic, inexpensive and biodegradable polymer, has been used in a variety of applications in pharmaceutical dosage forms such as sustained release and controlled delivery of drugs (Kang et al., 2006; Duarte et al., 2006; Crowley et al., 2004). Due to its hydrophilic structure it can help increase the bioavailability of poorly water-soluble compounds by forming an inclusion (Duarte et al., 2006). Smart polymers can release the drug by external stimuli such as change in temperature, pH or ionic composition (Singh et al., 2007; Schmaljohann 2006). Thermosensitive polymers, such as Poly-N-isopropylacrylamide (PNIPAM), exhibit a temperature-dependent shrinking at temperatures below the low critical solution temperature (LCST). These changes corresponding to swelling or de-swelling of the polymer can be controlled to release the encapsulated drugs in response to external temperature changes (Dimitrov et al., 2007; Makino et al., 2001; Gutowska et al., 1992; Zhang et al., 2002; Guo et al., 2008). 104 PNIPAM microgels have been studied as transdermal carriers, however results did not show penetration enhancement across human epidermis (Lopez et al., 2005). PLGA microparticles were able to increase drug retention in the epidermis and decrease the drug permeation through the skin (Ga de Jalón et al., 2001a and b; Rolland et al., 1993; Tsujimoto et al., 2007). Several studies have shown sustained and controlled release of drugs from transdermal patches which contained EC (Mutalik and Udupa 2005; Mukherjee et al., 2005; Rama Rao et al., 2006; Rama Rao 2003; Mayorga et al., 1997 and 1996; Rama Rao and Diwan 1998; Amnuaikit et al., 2005). These polymers have been studied individually as transdermal carriers in previous works. Variation on the effect of partition coefficient and skin permeability was studied using PNIPAM microgels (Lopez et al., 2005). Formulation variation of PLGA microparticles was also investigated (Santoyo et al., 2002; Tsujimoto et al., 2007). Formulation strategies have also been studied using EC polymer as a transdermal vehicle ((Mutalik and Udupa 2005; Mukherjee et al. 2005; Rama Rao et al. 2006). Here we wanted to compare and see the effect of polymer hydrophobicity, polymer transition temperature on the skin permeation. The aim of this work is to determine if topical application of T4 can produce systemic effects. Four types of polymers of different molecular weights and different hydrophobicities were used to encapsulate T4. The microspheres were characterized for drug entrapment efficiency, storage stability, in vitro drug release and skin penetration. 105 7.2 Materials and Methods 7.2.1 Materials L-levothyroxine, poly vinyl alcohol (MW 31,000), poly (N-isopropylacrylamide) (MW 20,000-25,000), ethyl cellulose and phosphate buffer saline tablets were purchased from Sigma, Singapore. PLA (R 203H) and PLGA 48/52 (RG 503H) were gifts from Boehringer Ingelheim (Germany). The density of PLA and PLGA were 0.34 dl/g and 0.52 dl/g respectively. 7.2.2 Preparation of Microparticles Levothyroxine-loaded microparticles were prepared by emulsification-solvent evaporation technique. The organic phase consisted of 50 mg of polymer dissolved in ml of dicloromethane which was then emulsified in a PVA aqueous solution (5 ml, 5% w/v PVA, mg/ml T4). The system was stirred continuously at 700 rpm for hours to allow the evaporation of the organic solvent. 7.2.3 Encapsulation Efficacy and Stability Studies The drug-loaded microparticles were centrifuged at 17 000 rpm for 45 at 20oC. The free levothyroxine in the supernatant was determined by HPLC method and the encapsulation efficacy (EE %) was calculated using Eq. 2-3. Encapsulation efficacy was investigated after 14-week storage at room temperature (20oC) and in the fridge (4oC). 106 7.2.4 Microparticle Characterization The surface morphology and appearance of microparticles were examined using FESEM mentioned in section 4.2.3. 7.2.5 HPLC Analysis T4 concentration was analyzed using the method mentioned in section 6.2.6. 7.2.6 In vitro Drug Release Studies In vitro drug release from the drug-loaded beads was studied in phosphate buffer saline (PBS; pH 7.4) at 37oC in a horizontal shaker. At specific intervals, 1-ml samples were taken and the microparticulate dispersions were centrifuged to remove impurities before being assayed for drug content by HPLC method. An equal volume of fresh PBS was immediately added to the receptor cell after each sampling. 7.2.7 In vitro Skin Permeation Studies Permeation studies of drug-loaded microparticles were performed using a flowthrough diffusion cell apparatus (described in section 2.2.8.). The donor compartment was filled with ml of aqueous polymeric microparticle solution and the receptor compartment was phosphate buffer saline pH 7.4. Samples from the receptor compartment were collected at predetermined time points over a 24-h period, and the amount of T4 permeated was analyzed by HPLC. 107 7.2.8 FTIR of Skin Sample FTIR spectra of the skin samples treated with polymeric particles were obtained with Perkin Elmer Spectrum 100 (USA). After treating the epidermis with each formulation for 24 h, the samples were washed times with PBS and vacuum-dried at room temperature. Samples were then subjected to FTIR measurements. Details are mentioned in section 4.2.4. 7.2.9 Confocal Studies of the Treated Skin To study the effect of polymeric microparticles on the extent of skin penetration, confocal study was carried out. Skin samples were treated with polymeric microparticles and then aquous solution of 0.03% w/v fluorescein dye was applied and its skin penetration was viewed using a CLSM described in section 2.2.9. 7.3 Results and Discussion 7.3.1 FESEM Characterization of Microparticles FESEM images of the microparticles are shown in Fig. 7.1. It can be seen that the appearance of the microparticles clearly varied with the polymer type. Ethyl cellulose microspheres had a uniform microporous and sponge-like structure. No considerable difference was observed between the microstructures of PLA and PLGA microparticles. Cracks in the surface of PLGA microparticles were probably artifacts due to the high energy of the electron beam at high magnifications. PLGA has a low glass transition temperature (Tg), therefore the polymer transforms from a glassy to a 108 rubbery state which is more susceptible to the vacuum pressure of FESEM (Wischke et al., 2006). PNIPAM microcapsules were fragmented but not deformed. The rate of solvent evaporation, polymer precipitation and stability of the inner aqueous phase play a major role in microcapsule morphology (Crotts and Park 1995). Surface tension of the solution greatly affects the microparticle structure. Reduction in surface tension of the solution will lead to fast and rapid solvent evaporation which will result in fewer pores on the particle surface (Niwa et al., 1993). In our study, parameters such as compositions of solvent system and aqueous phase were kept constant, therefore any difference in the morphology or structure of the particles is likely to be related to the intrinsic properties of the polymers. 109 (a) (c) (b) (d) Fig. 7.1 FESEM images of T4-loaded (a) PLA, (b) PLGA, (c) EC and (d) PNIPAM microparticles. 7.3.2 Determination of Encapsulation Efficacy The encapsulation efficiencies of T4-loaded microparticles consisting of different polymers and their physical stability over a 14-week period are displayed in Fig. 7.2. It was found that ethyl cellulose microparticles exhibited the highest drug encapsulation of 85.98 ± 8.84%. PLA and PLGA resulted in similar encapsulation efficacy of 75.54 ± 12.11% and 76.47 ± 17.88%, respectively. PNIPAM had the lowest T4 encapsulation of 67.59 ± 1.81%. 110 Encapsulation Efficiency % 100 Day 80 Week (20ºC) 60 Week (4ºC) Week (20ºC) 40 Week (4ºC) Week 14 (20ºC) 20 Week 14 (4ºC) EC PLA PLGA PNIM Fig. 7.2 Stability of lipid suspensions: Encapsulation efficacy of the vesicles over time at room temperature (20oC) and fridge temperature (4oC), n=3. The in vitro degradation behavior of polymeric microparticles was investigated at 20oC and 4oC (Fig. 7.2). It was found that irrespective of the storage temperature, ethyl cellulose microparticles remained stable during the 14-week storage period without significant drug leakage (p > 0.05). The degradation rate of PNIPAM microparticles was faster than PLA and PLGA microparticles. PLGA microparticles stored at 4oC did not show any significant drug loss over the study period (p > 0.05) however, storage at 20oC resulted in significant drug leakage (p < 0.05). After 14 weeks at 20oC and 4oC, the T4 contents of PLA and PNIPAM microparticles were significantly lower than the original (p < 0.05). 7.3.3 In vitro Release of Levothyroxine The release rate of T4 from microspheres of EC, PLA, PLGA and PNIPAM are shown in Fig. 7.3. The profiles show the influence of polymer type on the in vitro release of T4. It was found that T4 exhibited a burst release from all formulations 111 irrespective of polymer type. The drug release from microparticles seems to occur in two phases: an initial rapid release followed by a slow release. The initial burst effect is probably due to the adsorption of the drug onto the wall of the microparticles which would be immediately released. After which, the drug release profile displayed a delayed release that may be attributed to diffusion of the drug entrapped within the core of the microparticles. 100 T4 released (%) 80 60 40 EC PLA PLGA PNIPAM 20 0 60 120 180 240 300 360 420 480 540 Time (min) Fig. 7.3 In vitro release profile of T4 from microparticles in phosphate buffer (pH 7.4) at the body temperature (37oC), n = 3. 7.3.4 In vitro Skin Permeation Studies In vitro skin permeation studies were performed to evaluate the skin absorption of T4 from these preparations. Fig. 7.4 depicts the permeation profile of T4 from the polymeric particles. The systems with PLA, PLGA and PNIPAM did not provide any T4 penetration, however EC microparticles showed some drug penetration across the 112 skin. This work showed that the use of the T4-loaded PLA, PLGA and PNIPAM microparticles increased drug retention in the epidermis and decreased drug permeation through the skin. Consequently, these polymeric microparticles represent a good delivery system to retard the release rate of drugs into the skin and improve topical therapy. Cumulative T4 (μg/cm ) 150 Control EC 120 PLGA, PLA, PNIPAM 90 60 30 0 12 16 20 24 Time (h) Fig. 7.4 Permeation profile of T4 across human epidermis (n=6-8). Amorphous polymers exhibit glass transition temperature (Tg). Below this temperature, polymer is in a glass-like state. Above this temperature, the polymer passes from a glassy to a rubber-like state which may cause coalescence and precipitation of the polymer network on the surface (Wischke et al., 2006; Kangarlou et al., 2008; Middleton and Tipton 2000). Tg may be lowered by loading polymers with other molecules. This could be critical with respect to storage stability and drug release profile (Wischke et al., 2006). 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Pharm., 358 (2008) 151-158. 166 [...]... encapsulation efficacy was not calculated for this formulation A PBS solution of diclofenac was used as control All formulations contained a total of 5 mg/ml diclofenac sodium 123 Table 8.1 Composition of lipid suspensions Formulation Conventional liposome Ethosome Proniosome Niosome Transferosome PEG-PPG-PEG niosome PBS 65 65 20.3 63 64 63 Ethanol 30 30 31.6 30 30 30 Lecithin 5 5 22.8 5 5 - Composition (%... skin permeation (Boinpally et al., 2003; Cevc et al., 1998; Cevc and Blume 2001; Jain et al., 20 05; Honeywell-Nguyen et al., 2002 and 2003; El Maghraby et al., 1999; 2001) 2 Cumulative drug amount (μg/ml ) 250 Transferosome Ethosome Niosome 200 PEG-PPG-PEG niosome Conventional liposome Proniosome Cerosome 150 100 Control 50 0 0 5 10 15 20 25 30 35 40 45 Time (h) Fig 8.3 Cumulative concentrations of diclofenac... permeation of the drug and RM β-CD could be due to the surface active effect of this CD derivative At higher concentrations with the formation of CD micellar aggregates, drug permeation decreased Ionization and CDdrug complexation (at concentrations below the CMC values of RM β-CD) can synergistically increase drug solubility and skin permeation Decrease in the contact angle of the drug carrier with the... 2 955 to 2 958 cm-1 Carbonyl (C=O) stretching at wave number 1740 cm-1 corresponds to the esterified ester lipids This peak became negligible after skin treatment with vesicles which indicates fusion of the vesicles with the epidermal layer and alteration of SC protein conformation (Babita et al., 2006; Goates and Knutson 1994; Narishetty and Panchagnula 20 05; Tanojo et al., 1997) Protein secondary conformation... vesicles from nonionic surfactants, were thought to be an improvement over the conventional liposomes (Hofland et al., 1991; Hao et al., 2002) Alternatively, polyethyleneglycol (PEG) containing niosomes (Liu et al., 2007; Hua and Liu et al., 2007) and other formulations such as proniosomes, containing cholesterol and non-ionic surfactants, were developed (Alsarra et al., 20 05; Fang et al., 2001; Hu and Rhodes... PEG-PPG-PEG niosome Proniosome Conventional Liposome Fig 8.1 Stability of lipid formulations: Mean diameter of vesicle formulations (nm) with time, (n=3) 127 8.3.2 Determination of Encapsulation Efficiency Fig 8.2 represents the encapsulation efficiency of the vesicles There was no significant difference in the amount of drug encapsulated in all formulations (p > 0. 05) Proniosomes and conventional liposomes... hydrophilic drugs and transdermal delivery of hydrophobic molecules 1 35 CHAPTER 9 Conclusion The stratum corneum is the main barrier against skin permeation of drug molecules and compounds In order for a drug molecule to penetrate the skin, the carrier has to adhere to the skin surface then release the drug from the carrier and diffuse to allow the drug through the skin Therefore both drug and carrier... ionic and non-ionic types In Chapter 3, RM β-CD and HP β-CD, were examined for their separate influence on the aqueous solubility of haloperidol Solutions of RM β-CD 0.3M in pH 5 resulted in a 128-fold increase in the intrinsic solubility of the drug The effect of RM β-CD concentration on the skin permeation was studied It was found that the parabolic effect observed between the permeation of the drug. .. formulations and can help achieve therapeutic concentrations of the drug in the plasma 119 CHAPTER 8 Effect of Skin Lipid Fluidization and Drug Encapsulation on the Transdermal Delivery of Diclofenac 8.1 Introduction Diclofenac sodium is a widely used non-steroid-type anti-inflammatory agent Its administration is associated with adverse gastro-intestinal effects It is extensively metabolized in the liver and. .. increased the skin retention of the drug molecule Surfactants used alone were found to be more effective in increasing the skin permeation, however surfactant mixtures were able to decrease the skin permeation of haloperidol This finding can help in the development and production of penetration enhancers and penetration retardants using non-ionic surfactants While this work involved only two types of surfactants, . in transdermal formulations and can help achieve therapeutic concentrations of the drug in the plasma 120 CHAPTER 8 Effect of Skin Lipid Fluidization and Drug Encapsulation on the Transdermal Delivery of. Characterization The surface morphology and appearance of microparticles were examined using FESEM mentioned in section 4.2.3. 7.2 .5 HPLC Analysis T 4 concentration was analyzed using the method mentioned. topical and transdermal drug delivery. However, it is generally agreed that conventional liposomes have little or no effect on the penetration of drugs through the skin and are chemically and physically