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The COVID-19 pandemic brought unprecedented challenges to higher education. The extraordinary challenges created by the pandemic required equally extraordinary efforts from faculty and other stakeholders to rapidly convert face-to-face classes to online/hybrid instruction. This rapid change was facilitated by use of a robust framework for not only making changes in short order but also sustaining the changes to reshape healthcare education for a post-pandemic future. To this end, the chapter discusses the effective use of Kotter's 8-step framework to successfully implement change in healthcare education at a college of pharmacy and allied health professions. This chapter discusses each step of Kotter's 8-step process to create, implement, and sustain change in pharmacy and allied health education. The model integrated people, processes, and effective strategies to create changes amid the pandemic (crisis). Lessons learned and implications for the future in a post-pandemic educational environment are presented.

The COVID-19 pandemic has resulted in changes in the way we teach at all levels of education globally. This chapter specifically focusses on the impact of COVID-19 pandemic on MS and PhD programs in pharmaceutical sciences in schools/colleges of pharmacy in the United States. Potential expectations to bring the pandemic in control by rolling out the vaccine gives us hope, but there is an unmet need of medicines to treat patients affected by the disease. The impact of the pandemic on pharmaceutical sciences education has been on the pedagogy of teaching, research, mentoring, writing, and enrollment. This has also affected the progression of students in their programs as well as their stress levels and well-being. The role of administrators and accreditation agencies is critical in supporting graduate education by providing leadership and directions for the successful outcomes of these programs. Challenges and opportunities for these graduate programs are discussed in this chapter.

The goal of this study was to develop bioadhesive food protein nanoparticles using zein (Z), a hydrophobic corn protein, as the core and whey protein (WP) as the shell for oral pediatric drug delivery applications. Lopinavir (LPV), an antiretroviral drug, and fenretinide, an investigational anticancer agent, were used as model drugs in the study. The particle size of ZWP nanoparticles was in the range of 200-250 nm, and the drug encapsulation efficiency was >70%. The nanoparticles showed sustained drug release in simulated gastrointestinal fluids. ZWP nanoparticles enhanced the permeability of LPV and fenretinide across Caco-2 cell monolayers. In both ex vivo and in vivo studies, ZWP nanoparticles were found to be strongly bioadhesive. ZWP nanoparticles enhanced the oral bioavailability of LPV and fenretinide by 4 and 7-fold, respectively. ZWP nanoparticles also significantly increased the half-life of both drugs. The nanoparticles did not show any immunogenicity in mice. Overall, the study demonstrates the feasibility of developing safe and effective food protein-based nanoparticles for pediatric oral drug delivery.

Almost all breast cancers originate from epithelial cells lining the milk ducts in the breast. To this end, the study investigated the feasibility of localized transdermal delivery of α-santalol, a natural chemopreventive agent to the breast. Different α-santalol formulations (cream, solution and microemulsion) were developed and the in vitro permeability was studied using excised animal (porcine and rat) and human breast skin/mammary papilla (nipple). The in vivo biodistribution and efficacy studies were conducted in female rats. A chemical carcinogenesis model of breast cancer was used for the efficacy studies. Phospholipid based α-santalol microemulsion showed the highest penetration through the nipple and breast skin. Delivery of α-santalol through the entire breast (breast skin and nipple) in vivo in rats resulted in significantly higher concentration in the mammary gland compared to transdermal delivery through the breast skin or nipple. There was no measurable α-santalol concentration in the blood. Transdermal delivery of α-santalol reduced the tumor incidence and tumor multiplicity. Furthermore, the tumor size was significantly reduced with α-santalol treatment. The findings from this study demonstrate the feasibility of localized transdermal delivery of α-santalol for chemoprevention of breast cancer.

Drug delivery by direct intraductal administration can achieve high local drug concentration in the breast and minimize systemic levels. However, the clinical application of this approach for breast cancer treatment is limited by the rapid clearance of the drug from the ducts. With the goal of developing strategies to prolong drug retention in the breast, this study was focused on understanding the influence of particle size and formulation on breast duct and lymph node retention. Fluorescent-labeled polystyrene (PS) particles ranging in size from 100 to 1000 nm were used to study the influence of particle size. Polylactic acid-co-glycolic acid (PLGA) was used to develop and test formulations for intraductal delivery. Cy 5.5, a near-IR dye, was encapsulated in PLGA microparticles, nanoparticles, and the in situ gel to study the biodistribution in rats using an in vivo imager. PS microparticles (1 μm) showed longer retention in the duct compared to 100 and 500 nm nanoparticles. The ductal retention half-life was 5-fold higher for PS microparticles compared to the nanoparticles. On the other hand, the free dye was cleared from the breast within 6 h. PLGA nanoparticles sustained the release of Cy 5.5 for >4 days. Microparticles and gel showed a much slower release than nanoparticles. PLGA in situ gel and microparticles were retained in the breast for up to 4 days, while the nanoparticles were retained in the breast for 2 days. PLGA nanoparticles and microparticles drained to the axillary lymph node and were retained for up to 24 and 48 h, respectively, while the in situ gel and the free dye did not show any detectable fluorescence in the lymph nodes. Taken together, the results demonstrate the feasibility of prolonged retention in the breast duct and lymph node by optimal formulation design. The findings can serve as a framework to design formulations for localized treatment of breast cancer.

The study was aimed at systematically investigating the influence of shell composition on the particle size, stability, release, cell uptake, permeability, and in vivo gastrointestinal distribution of food protein based nanocarriers for oral delivery applications. Three different core-shell nanocarriers were prepared using food-grade biopolymers including zein-casein (ZC) nanoparticles, zein-lactoferrin (ZLF), nanoparticles and zein-PEG (ZPEG) micelles. Nile red was used as a model hydrophobic dye for in vitro studies. The nanocarriers had negative, positive, and neutral charge, respectively. All three nanocarriers had a particle size of less than 200 nm and a low polydispersity index. The nanoparticles were stable at gastrointestinal pH (2-9) and ionic strength (10-200 mM). The nanocarriers sustained the release of Nile red in simulated gastric and intestinal fluids. ZC nanoparticles showed the slowest release followed by ZLF nanoparticles and ZPEG micelles. The nanocarriers were taken up by endocytosis in Caco-2 cells. ZPEG micelles showed the highest cell uptake and transepithelial permeability followed by ZLF and ZC nanoparticles. ZPEG micelles also showed P-gp inhibitory activity. All three nanocarriers showed bioadhesive properties. Cy 5.5, a near IR dye, was used to study the in vivo biodistribution of the nanocarriers. The nanocarriers showed longer retention in the rat gastrointestinal tract compared to the free dye. Among the three formulations, ZC nanoparticles was retained the longest in the rat gastrointestinal tract (≥24 h). Overall, the outcomes from this study demonstrate the structure-function relationship of core-shell protein nanocarriers. The findings from this study can be used to develop food protein based oral drug delivery systems with specific functional attributes.

Glutathione disulfide (GSSG) is the oxidized form of glutathione (GSH). GSH is a tripeptide present in the biological system in mM concentration and is the major antioxidant in the body. An increase in GSSG reflects an increase in intracellular oxidative stress and is associated with disease sates. The increase has also been demonstrated to lead to an increase in protein S-glutathionylation that can affect the structure and function of proteins. Protein S-glutathionylation serves as a regulatory mechanism during cellular oxidative stress. Though GSSG is commercially available, its roles in various GSSG-associated normal/abnormal physiological functions have not been fully delineated due to the reason that GSSG is not cell membrane permeable and a lack of method to specifically increase GSSG in cells. We have developed cationic liposomes that can effectively deliver GSSG into cells. Various concentrations of GSSG liposomes can be conveniently prepared. At 1 mg/mL, the GSSG liposomes effectively increased intracellular GSSG by 27.1±6.9 folds (n=3) in 4 h and led to a significant increase in protein S-glutathionylation confirming that the increased GSSG is functionally effective. The Trypan blue assay demonstrated that GSSG liposomes were not cytotoxic; the cell viability was greater than 95% after cells were treated with the GSSG liposomes for 4 h. A stability study showed that the dry form of the GSSG liposomes were stable for at least 70 days when stored at −80 °C. Our data demonstrate that the GSSG liposomes can be a valuable tool in studying GSSG-associated physiological/pathological functions., Highlights • Glutathione disulfide (GSSG) liposomes were developed to deliver GSSG into cells. • The GSSG liposomes effectively increased intracellular GSSG by 27.1±6.9 folds. • The delivered GSSG is confirmed to be functionally effective through protein S-glutathionylation.

The study was aimed at investigating the feasibility of using a poly (amidoamine) (PAMAM) dendrimer as a carrier for topical iontophoretic delivery of an antisense oligonucleotide (ASO). Bcl-2, an anti-apoptotic protein implicated in skin cancer, was used as the model target protein to demonstrate the topical gene silencing approach. Confocal laser scanning microscopy studies demonstrated that the iontophoretically delivered ASO-dendrimer complex can reach the viable epidermis in porcine skin. In contrast, passively delivered free or dendrimer complexed ASO was mainly localized to the stratum corneum. The cell uptake of ASO was significantly enhanced by the dendrimer complex and the complex suppressed Bcl-2 levels in the cell. In the skin cancer mouse model, the iontophoretically delivered ASO-dendrimer complex reduced the tumor volume by 45% and was consistent with the reduction in Bcl-2 protein levels. The iontophoretically delivered ASO-dendrimer complex caused significant apoptosis in skin tumor. Overall, the findings from this study demonstrate that dendrimers are promising nanocarriers for developing topical gene silencing approaches for skin diseases.

The main objective of this study was to investigate the potential of calcium phosphate (CAP) nanoparticles for transcutaneous vaccine delivery. CAP nanoparticles were prepared by nanoprecipitation method followed by sequential adsorption of sugars and ovalbumin. Nanoparticles were characterized using dynamic light scattering, XRD, ATR-FTIR, and microscopy methods. In-vitro release of ovalbumin from nanoparticles was studied in phosphate buffer (pH 7.4). In-vivo immunization studies were carried out in Balb/C mice. The size and zeta potential of ovalbumin-sugar adsorbed CAP nanoparticles was 350 +/- 22.5 nm and -12.93 +/- 1.02 mV respectively. Around 60% ovalbumin was released from nanoparticles within 24 hrs. To test the feasibility for transcutaneous vaccine delivery, the nanoparticles were applied in mice after removing the stratum corneum by tape-stripping. In the positive control group, the nanoparticles were administered by intradermal injection. Ovalbumin-sugar coated CAP nanoparticles showed significantly higher antibody titers (Total IgG and IgG1) compared to ovalbumin alone. IgG2a antibodies were only seen with intradermal injection. Both topical and intradermal treatment groups showed splenocyte proliferation when re-stimulated with ovalbumin. The results from this study demonstrate the potential of using CAP nanoparticles for transcutaneous vaccine delivery.

Majority of breast cancers originate from epithelial cells in the duct and lobules in the breast. Current systemic treatments for breast cancer are associated with significant systemic side effects, thus warranting localized drug delivery approaches. The aim of this study was to investigate the influence of hydroalcoholic vehicle on topical delivery of 4-hydroxy tamoxifen (4-HT) through the mammary papilla (nipple). The in vitro permeability of 4-HT through porcine mammary papilla was studied using different hydroalcoholic vehicles (0, 33.33, and 66.66% alcohol). Nile red was used as a model lipophilic dye to characterize the drug transport pathway in the mammary papilla. The penetration of 4-HT through the mammary papilla increased with increase in alcohol concentration in the vehicle. The solubility of 4-HT was enhanced by increasing alcohol concentration in the vehicle. On the other hand, the epidermis/vehicle partition coefficient decreased with increase in alcohol concentration. The mammary papilla served as a depot and slowly released 4-HT into the receptor medium. Highest drug penetration was observed with saturated drug solution in 66.66% alcohol, and 4-HT levels were comparable to IC50 value of 4-HT. Results from this study demonstrate the possibility of using mammary papilla as a potential route for direct delivery of 4-HT to the breast.

INTRODUCTION Skin is the largest organ in the human body and functions as a protective barrier. The large surface area (1.8 m2) and easy accessibility of skin make it one of the attractive routes for drug delivery. However, the unique bioarchitecture of skin limits the transport of molecules through it (1). The skin is primarily divided into epidermis, dermis, and subcutaneous tissue. Epidermis is again subdivided into stratum corneum (SC), stratum lucidum, stratum granulosum, stratum germinativum, and stratum basale [Fig. 1(A)]. Stratum basale is the germinal layer which continuously divides to produce new keratinocytes that move to outer layers finally to form a horny layer of dead cells in the SC. It takes 2 to 3 weeks for the migration of keratinocytes from the basal layer to finally shed off from the SC. The skin also has appendages such as hair follicles and sweat pores, which constitute 0.1% of the total skin surface area. The hair follicles originate from the dermis and terminate at the surface of the skin. Although the SC is only 10 to 20 m thick, it forms a formidable barrier for the exchange of solutes and moisture. It is made up of stacks of keratin-filled corneocytes interdispersed by tightly arranged lipid bilayers (2). The intercellular lipids mainly consist of free fatty acids, ceramides, and cholesterol (2). Molecules can penetrate the skin by three main routes: (i) intracellular (across the corneocytes), (ii) intercellular lipids, and (iii) appendageal [Fig. 1(B)]. The intercellular lipids are the major transport pathways for most drugs, in which the molecule has to pass through successive hydrophilic and hydrophobic domains in the lipid bilayers. On the other hand, the skin appendages serve as a shunt pathway for drug molecules. Since the appendages occupy only a fraction of the skin surface, they contribute very little to the drug transport. However, the appendages constitute a significant pathway for the iontophoretic transport of charged molecules and the penetration of particulate systems (3,4). Once the molecule crosses the SC and subsequently the viable epidermis, it is absorbed through the blood vessels in the dermis [Fig. 1(A)].

Novel biodegradable micelles were synthesized by conjugating methoxy poly(ethylene glycol) (mPEG) to zein, a biodegradable hydrophobic plant protein. The mPEG-zein micelles were in the size range of 95-125 nm with a low CMC (5.5 × 10(-2) g/L). The micelles were nonimmunogenic and were stable upon dilution with buffer as well as 10% serum. Curcumin, an anticancer agent with multiple delivery challenges, was encapsulated in mPEG-zein micelles. The micelles significantly enhanced the aqueous solubility (by 1000-2000-fold) and stability (by 6-fold) of curcumin. PEG-zein micelles sustained the release of curcumin up to 24 h in vitro. Curcumin-loaded mPEG-zein micelles showed significantly higher cell uptake than free curcumin in drug-resistant NCI/ADR-RES cancer cells in vitro. Micellar curcumin formulation was more potent than free curcumin in NCI/ADR-RES cancer cells, as evidenced from the 3-fold reduction in IC(50) value of curcumin. Overall, this study for the first time reports a natural protein core based polymeric micelle and demonstrates its application for the delivery of hydrophobic anticancer drugs such as curcumin.

The main objective of the present study was to investigate the influence of various formulation parameters on the preparation of zein nanoparticles. 6,7-dihydroxycoumarin (DHC) was used as a model hydrophobic compound. The influence of pH of the aqueous phase, buffer type, ionic strength, surfactant, and zein concentration on particle size, polydispersity index, and zeta potential of DHC-loaded zein nanoparticles were studied. Smaller nanoparticles were formed when the pH was close to the isoelectric point of zein. DHC-loaded zein nanoparticles prepared using citrate buffer (pH 7.4) was better than phosphate buffer in preventing particle aggregation during lyophilization. The ionic strength did not have a significant influence on the particle size of DHC-loaded zein nanoparticles. A combination of Pluronic F68 and lecithin in 2:1 ratio stabilized the zein nanoparticles. An increase in zein concentration led to increase in particle size of DHC-loaded zein nanoparticles. The use of optimal conditions produced DHC-loaded nanoparticles of 256 ± 30 nm and an encapsulation efficiency of 78 ± 7%. Overall, the study demonstrated the optimal conditions to prepare zein nanoparticles for drug encapsulation.

To investigate skin penetration of poly (amidoamine) (PAMAM) dendrimers as a function of surface charge and molecular weight in presence and absence of iontophoresis. Dendrimers were labeled with fluoroisothiocynate (FITC); skin penetration of dendrimers was studied using excised porcine skin in-vitro. Skin penetration of FITC-labeled dendrimers was quantified using confocal laser scanning microscope (CLSM). G2-G6 NH2, G3.5-COOH and G4-OH dendrimers were used. Cationic dendrimers showed higher skin penetration than neutral and anionic dendrimers. Skin penetration of cationic dendrimer increased linearly with increase in treatment time. Iontophoresis enhanced skin penetration of cationic and neutral dendrimers. Increase in current strength and current duration increased skin transport of dendrimers. Passive and iontophoretic skin penetration of cationic dendrimers was inversely related to their molecular weight. Dendrimer penetrated the skin through intercellular lipids and hair follicles. With iontophoresis, dendrimer was also found in localized skin regions. The study demonstrates that the physicochemical properties of dendrimers influence their skin transport. Findings can be used to design dendrimer-based nanocarriers for drug delivery to skin.

The aim of present study is to investigate the effect of poly(amidoamine) (PAMAM) dendrimer on skin permeation of 5-fluorouracil (5FU). Permeation studies were performed using excised porcine skin in a Franz diffusion cell and 14C labeled 5FU samples were analyzed using liquid scintillation counter. Three different vehicles were used, including phosphate buffer (PB), mineral oil (MO) and isopropyl myristate (IPM). The studies were carried out by simultaneously applying the drug and dendrimer together or by pre-treating the skin with dendrimer before drug application. Simultaneous application of drug and dendrimer increased the flux of 5FU in IPM and MO, while there was no change in PB. The increased skin partitioning of dendrimer from lipophilic vehicles increased the drug solubility in skin. Pre-treatment with dendrimer increased permeability coefficient of 5FU by 4-fold in MO and 2.5-fold in IPM, while it decreased by half in PB. Skin partitioning of 5FU increased after dendrimer treatment from lipophilic vehicles. The flux increased linearly with increase in pre-treatment time. Dendrimer pre-treatment increased transepidermal water loss and decreased skin resistance. The decrease in skin resistance directly correlated to the enhancement in skin permeation of 5FU (r2 = 0.99). Overall, the study showed that dendrimer increases the skin permeation of 5FU from lipophilic vehicles mainly by altering the skin barrier.

Worldwide, breast cancer remains as one of the most common cancer diagnosis and cause of cancer related death among women. Fortunately, nanomedicine has brought forth new potential and hope in breast cancer research. The extremely small size of nanoparticles makes it advantageous and potentially superior to use in tumor detection and imaging. One of the more extensively studied particles is quantum dots, semiconductor crystals which are capable of enhanced labeling and imaging of cancer cells. In addition, due to serious toxicity of chemotherapeutic agents, nano-formulations of breast cancer chemotherapy are under investigation and development. This may provide easier administering route and reduced frequency of drugs. With the use of nanoparticles, drug delivery can be carried out in a minimally invasive fashion and treatment regimens can be made much more targeted and specific for each patient. In this review article, we provide an overview on the role nanomedicine has played in breast cancer and mention some of the latest diagnostic and treatment modalities researched to date.

Dendrimers are highly branched polymers with tunable surface topology. This polymer has spherical core-shell nanoarchitecture with a high density of surface functional groups. It is available in a number of different generations and size making it a diverse nanocarrier for biomedical applications. Drugs can be loaded in multiple ways including complexation and/or conjugation to surface functional groups and/or encapsulation inside the core of the dendrimers. Dendrimers have been explored as drug delivery vehicles by various routes of drug administration and for other biomedical applications. The chapter provides an overview of physicochemical properties of dendrimers and its various biomedical applications.

The main goal of this study is to overcome docetaxel (DTX) resistance in prostate cancer cells by combined delivery of eIF4E siRNA and DTX using dendrimer as a nanocarrier. To this end the objective of this study is to prepare, characterize and test the feasability of the combination delivery approach in-vitro in DTX sensitive and resistant prostate cancer cells. During the last evaluation period we prepared and characterized the dendrimer-DTX conjugate and dendrimer-siRNA complex. During this evaluation period our goal was to optimize the delivery system, develop the DTX resistant prostate cancer cells and test the in-vitro efficacy of the multifunctional delivery system. The DTX resistant prostate cancer cells were developed by treating PC3 cells with sub-therapeutic concentration of DTX for 9 months and it was found to overexpress eIF4E. The multifunctional therapeutic system was able to overcome the resistance in PC3 cells and lowered the IC50 value in drug resistant PC3 cells. The siRNA reduced the levels of eIF4E and Myc in PC3 cells. Overall the outcomes from this study demonstrate the feasibility of developing a therapeutic strategy for drug resistant prostate cancer. Our future studies will focus on further optimizing the delivery system and testing the efficacy in-vivo in prostate cancer mouse model.

Skin is an important site for local or systemic application of drugs. However, a majority of drugs have poor permeability through the skin's topmost layer, stratum corneum (SC). The aim of this study was to identify safe and smaller peptides that could enhance the skin penetration of drug molecules. By screening phage display peptide library, we have identified a T2 peptide (LVGVFH), which enhanced the penetration of bacteriophages (~800 nm long bacterial viruses) across porcine and mouse skin. Pretreating the skin with synthetic T2 peptide at pH 4.5 resulted in significant penetration enhancement of hydrophilic drug 5-fluorouracil (5-FU) across skin. FTIR spectroscopy showed that the T2 peptide interacted with skin lipids to enhance the skin penetration. Pretreating the skin with T2 peptide enhanced the partitioning of small molecules with different lipophilicities (5-FU, fluorescein isothiocyanate, and rhodamine 123 hydrochloride) into skin. Fluorescence studies showed that T2 peptide enhanced the diffusion of these molecules into intercellular lipids of SC and thus enhanced the penetration into the skin. Histidine at the c-terminus of T2 peptide was identified to be critical for the skin penetration enhancement. T2 peptide interacted with skin lipids to cause skin penetration enhancement. The study identified a novel, safe, and noninvasive peptide to improve the skin penetration of drugs without chemical conjugation.

Zein is a hydrophobic water insoluble plant protein and the main goal of the present study was to prepare zein nanoparticles using pH controlled nanoprecipitation method. Nanoparticle characteristics such as size, polydispersity index (PI), zeta potential, and encapsulation efficiency were studied using 6, 7-dihydroxycoumarin, as a model hydrophobic compound. Lecithin and pluronic F68 were used as stabilizers. The blank zein nanoparticles had a mean particle size of 460 nm; while coumarin loaded zein nanoparticles had a mean particle size of 365 nm. The encapsulation efficiency of coumarin loaded zein nanoparticles was 62%. The release of coumarin from zein nanoparticles was sustained in phosphate buffer (pH 7.4) for upto 9 days. Overall the results from this study demonstrate a new method for preparing drug loaded zein nanoparticles.

Preformulation testing has a significant role in a drug discovery and development program, as it provides valuable feedback to the various discovery and development teams in enabling druggability during lead identification and optimization. In a generic setting, preformulation studies are mainly focused on developing a formulation that is bioequivalent to the innovator's product with the main objective of filing an abbreviated new drug application (ANDA). This article focuses on preformulation testing for oral solid dosage forms in a drug discovery setting. Keywords: preformulation testing; abbreviated new drug application (ANDA); drug discovery; oral solid dosage forms

The study investigates the influence of surface charge, generation and concentration of poly(amidoamine) (PAMAM) dendrimers on skin permeation of a model hydrophilic drug, 5-fluorouracil (5FU). Permeation studies were performed using excised porcine skin in a Franz diffusion cell. Saturated concentration of 5FU in isopropyl myristate was applied on the skin after pretreatment with dendrimers and 14 C labeled 5FU was analyzed using a liquid scintillation counter. The influence of dendrimer surface charge (G4-NH 2 , G3.5-COOH, and G4-OH), generations (G2-G6-NH 2 ) and concentration (0.1–10 mM of G4-NH 2 ) on skin permeation of 5FU were studied. The enhancement in drug permeability coefficient ( K p ) was in the following decreasing order G4-NH 2 > G4-OH > G3.5-COOH. Dendrimer increased the skin permeation by increasing the skin partitioning of 5FU. Transepidermal water loss, skin resistance measurements and ATR-FTIR studies revealed that cationic dendrimers act by interacting with the skin lipid bilayers. Increase in G4-NH 2 concentration did not proportionally increase the skin permeation of 5FU. The 5FU K p was inversely related to the molecular weight of the dendrimer. G2-NH 2 dendrimer reduced skin resistance to a greater extent than higher generation dendrimers. Overall, the study showed that lower generation cationic dendrimer is more effective in enhancing the skin permeation of hydrophilic drugs. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association.

P-glycoprotein (P-gp) associated multi-drug resistance is one of the major challenges in the chemotherapy of various cancers. On the other hand, it is now widely recognized that P-gp influences drug transport across various biological membranes. To this end, there is an increasing trend to optimize pharmacokinetics and drug delivery right from the initial stages of drug discovery by exploring all the possible mechanisms involved in ‘deliverability’. Recent advances in molecular biology techniques and biochemical characterization methodologies have helped in identification of various transporters involved in absorption or secretion of drugs. P-gp, an efflux pump expressed along the gastrointestinal tract, limits the permeability of many drugs and thus affects their peroral absorption and bioavailability. A fundamental insight and thorough understanding of P-gp and its functional role in limiting drug absorption is critical to improve predictability of dynamic absorption models and aid in selection of new candidates for development, and also widen the scope of peroral delivery for ‘challenging’ molecules.

The study was aimed at investigating localized topical drug delivery to the breast via mammary papilla (nipple). 5-fluorouracil (5-FU) and estradiol (EST) were used as model hydrophilic and hydrophobic compounds respectively. Porcine and human nipple were used for in-vitro penetration studies. The removal of keratin plug enhanced the drug transport through the nipple. The drug penetration was significantly higher through the nipple compared to breast skin. The drug’s lipophilicity had a significant influence on drug penetration through nipple. The ducts in the nipple served as a major transport pathway to the underlying breast tissue. Results showed that porcine nipple could be a potential model for human nipple. The topical application of 5-FU on the rat nipple resulted in high drug concentration in the breast and minimal drug levels in plasma and other organs. Overall, the findings from this study demonstrate the feasibility of localized drug delivery to the breast through nipple.

Purpose: Honokiol, a plant lignan isolated and purified from Magonila Officinalis has been shown to have chemopreventive effects in chemically induced and UV-B induced skin tumor development in SKH-1 mice. However poor solubility of honokiol greatly limits its clinical application. The key objectives of the present investigation are to improve the solubility and stability of honokiol by encapsulating in nanostructured lipid nanoparticles. Methods: Honokiol was incorporated into nanostructured lipid nanoparticles and cream using hot homogenization method. Compritol 888 ATO, Precirol ATO 5, and miglyol 812 as lipid matrices and poloxamer 188 as emulsifier. Lipid nanoparticles were characterized for size, zeta potential, shape and morphology using photon correlation spectroscopy (PCS) and atomic force microscopy (AFM). Honokiol was quantified by isocratic HPLC method using mobile phase of 60:40 (%v/v, acetonitrile:water) at a flow rate of 1 ml/min at a wavelength of 254 nm. Permeation studies were carried out using porcine dermatome skin in Franz diffusion cell. Honokiol concentration corresponding to 0.5 mg/ml in sesame oil, cream and lipid nanoparticles was dispersed in PBS pH 7.4. Permeation studies were performed till 24hrs; the samples (200 µl) were withdrawn at regular time intervals and replaced with fresh medium. Amount of honokiol permeated across porcine skin was quantified using HPLC method. Stability of cream and lipid nanoparticle formulations was studied at 30° C and 65 % relative humidity in a stability chamber for one month. Results: The size of the optimized honokiol loaded lipid nanoparticles was 145±7 nm with a polydispersity index of 0.24±0.02. The zeta potential and encapsulation efficiency was 0.34±0.02 mV and 97±2 %. The particle size of lipid nanoparticles measured in AFM was very close to size measured by PCS. In case of precirol cream, particle size was more than 20 µm with drug content of 89±5 %. Honokiol loaded nanostructured lipid nanoparticles, and cream were stable for about 30 days without any significant changes in particle size, and drug content at 30° C and 65 % relative humidity. Skin treated with honokiol entrapped in nanoparticles and cream has shown more retention of honokiol in the skin compared to plain honokiol in sesame oil. Proposed lipid cream and nanoparticles formulation has shown effective skin penetration of honkiol. From the data it is evident that nanoparticles has shown higher amount of honokiol in skin compared to cream formulation. Conclusions: Preliminary results of this study have shown the potential of lipid based formulations for topical delivery of honokiol. Chemopreventive potential and efficacy of honokiol encapsulated in lipid based formulations will be evaluated in UV-B induced skin cancer model. Acknowledgements: Supported by Translational Cancer Research Center funded by the South Dakota Governor's Office of Economic Development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5709. doi:1538-7445.AM2012-5709

Skin cancer is the most prevalent of all cancers and its incidence is expected to increase substantially. UVB is major etiologic factor in the skin cancer development. Honokiol, a plant ligan isolated from bark and seed cones of Magnolia officinalis, has been shown to have chemopreventive effects on UVB-induced skin cancer development in our laboratory. The objectives of this investigation are to study chemopreventive effects of dose response of honokiol on UVB-induced skin tumor development in SKH-1mice and to prepare topical formulations of honokiol that deliver effective concentration of drug locally. Female SKH-1 mice were divided into 4 groups. Group 1 received acetone one hour before UVB treatment; Group 2, 3 and 4 received honokiol (0.2 ml of 30, 45 and 60 μg in acetone, topical) before each UVB treatment. Mice were treated with UVB dose of 30 mJ/cm2/day for 25 weeks. Tumor counts and group weights were taken weekly. Honokiol pretreated groups resulted in 36-78% reduction in tumor multiplicity compared to control. Honokiol pretreatment (60 μg) decreased tumor incidence by 40 %. Topical formulation of honokiol gel was prepared by using carbomer 940 as base and propylene glycol as penetration enhancer. Drug content and content uniformity were determined. Release studies and permeation studies were studied in detail. This study is supported by Translational Cancer Research Center funded as 2010 Research Initiative Center by the State of South Dakota Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4620. doi:10.1158/1538-7445.AM2011-4620

The purpose of this investigation is to characterize nevirapine from commercial samples and samples crystallized from different solvents under various conditions. The solid-state behavior of nevirapine samples was investigated using a variety of complementary techniques such as microscopy (optical, polarized, hot stage microscopy), differential scanning calorimeter, thermogravimetric analysis, Fourier transform infrared spectroscopy and powder X-ray diffractometry. The commercial samples of nevirapine had the same polymorphic crystalline form with an anhedral crystal habit. Intrinsic dissolution of nevirapine was similar for both the commercial batches. Powder dissolution showed pH dependency, with maximum dissolution in acidic pH and there was no significant effect of particle size. The samples recrystallized from different solvent systems with varying polarity yielded different crystal habits. Stirring and degrees of supersaturation influenced the size and shape of the crystals. The recrystallized samples did not produce any new polymorphic form, but weak solvates with varying crystal habit were produced. Recrystallized samples showed differences in the x-ray diffractograms. However, all the samples had the same internal crystal lattice as revealed from their similar melting points and heat of fusion. The intrinsic dissolution rate of recrystallized samples was lower than the commercial sample. It was found that the compression pressure resulted in desolvation and partial conversion of the crystal form. After compression, the recrystallized samples showed similar x-ray diffractograms to the commercial sample. Amorphous form showed slightly higher aqueous solubility than the commercial crystalline form.