Electronic Theses and Dissertations

Date of Award

1-1-2019

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

S. Narasimha Murthy

Second Advisor

Seongbong Jo

Third Advisor

Micheal A. Repka

School

University of Mississippi

Relational Format

dissertation/thesis

Abstract

Silymarin is an extract of Milk Thistle, major constituents are taxifolin, silychristin, silydianin, silybin A, silybin B, isosilybin A and isosilybin B. The in vitro, preclinical and clinical studies have demonstrated silymarin possesses hepatoprotective, anticancer, hypocholesterolemic, cardioprotective effect and dermatological beneficial effect (treatment of UV induced erythema, melanoma, non-melanoma skin cancer, rosacea, melasma, vitiligo and psoriasis) both individually and collectively. Solubility enhancement of silymarin constituent is utmost important to increase bioavailability and to improve drug developability property. The solubility of silymarin in water was enhanced by SBE-β-CD by conventional and heating method, heating method was found to be more efficient with less time consuming. The oral bioavailability and tissue exposure of silymarin constituents were increased on oral administration of SBE-β-CD–silymarin complex compared to silymarin suspension. To treat dermal ailments SBE-β-CD–silymarin cream was developed and optimized to stabilize the cream and increase the skin penetration and permeation of all silymarin constituents across the skin. Progesterone is a female sex hormone, and it is crucial to maintain a basal level of 10-20 ng/mL to treat luteal phase deficiency or estrogen dominance and to maintain normal physiological functions of progesterone. The clinical trials of available oral progesterone products have shown high interpatient and intrapatient variability, attributed to progesterone’s low aqueous solubility and resulting in sub-optimal or excessive plasma levels. The solubility of progesterone in water was enhanced by SBE-β-CD, progesterone in 100 mM SBE-β-CD was ~2000-fold more soluble than its intrinsic solubility. The optimized SBE-β-CD formulation increased ex-vivo rat intestinal permeation of progesterone and rat oral bioavailability of progesterone in SD rats compared to progesterone API. In drug discovery, demand for drug candidates with increased potency has led to synthesis of lipophilic molecules to enhance their binding to target. This has resulted in approvals of large number of drugs having poor biopharmaceutical properties. Aqueous solubility of drugs can be increased by various techniques, the simple and most commonly employed technique is by preparation of inclusion complex using cyclodextrins. The Sulfobutyl ether β-cyclodextrin (SBE-β-CD) was used to enhance the aqueous solubility of progesterone and silymarin.

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