Author : Biji Palliyil
Publisher :
ISBN 13 :
Total Pages : 258 pages
Book Rating : 4.:/5 (128 download)
Book Synopsis The Preformulation and Formulation Development for Transungual Delivery of Antifungal Drug Ciclopirox Olamine by : Biji Palliyil
Download or read book The Preformulation and Formulation Development for Transungual Delivery of Antifungal Drug Ciclopirox Olamine written by Biji Palliyil and published by . This book was released on 2013 with total page 258 pages. Available in PDF, EPUB and Kindle. Book excerpt: Onychomycosis also known as dermatophytic onychomycosis is the fungal infection of the toenails and fingernails, characterized by discoloration and thickening of the nail and involves the nail plate, nail bed and nail folds. The disease is more than a cosmetic problem, as it severely impacts the patient's quality of life. Onychomycosis is an opportunistic infection in special subpopulations of patients suffering from diabetes, psoriasis, HIV/AIDS etc. The current treatment strategies involve systemic delivery of oral antifungal agents including azoles (e.g. itraconazole) and allylamines (e.g. terbinafine hydrochloride) which are delivered to the nail plate from the nail bed. More recently, topical delivery of drugs including amorolfine and bifonazole/urea (available outside the United States) and Penlac® nail lacquer (ciclopirox) topical solution, 8%, available in the US are an alternative treatment option to the oral antifungal agents. Topical delivery of antifungal agents through the human nail offer several advantages over oral therapy including lower incidence of adverse events and lower potential for drug-drug interaction with drugs used to treat diabetes, HIV/AIDS and psoriasis. The objectives of this project were to: 1) To determine the critical factors affecting the delivery of ciclopirox olamine across the human nail, 2) To screen and select penetration enhancer(s) specific for ciclopirox olamine delivery into the target tissue(s) and 3) To develop a novel transungual formulation containing ciclopirox olamine (CPO) and penetration enhancer(s) for transungual delivery. Ciclopirox olamine, the salt form of the free acid of ciclopirox was used in the study to develop a novel transungual patch formulation and skin and nail permeation from the patch formulation was compared to Penlac® nail lacquer. Various factors such as drug partitioning into the healthy and infected toenail, drug-keratin binding, lateral diffusion, drug-epidermal binding and the formulation components, all play a role in achieving optimum drug penetration and permeation through the nail. Understanding the interplay of these factors helped in the development of an effective topical formulation which was observed to be superior to Penlac® nail lacquer in the in vitro studies. Most cases of onychomycosis show infection and inflammation of the nail folds (skin surrounding the nails). Therefore for an efficient treatment of OM, the antifungal drugs must be delivered to two target tissues - human nail and the nail folds. The major challenges in developing a topical formulation for treatment on OM are: a) Achieving antifungal drug minimum inhibitory concentration (MIC) in the epidermis of the nail folds. b) Enhancing penetration and permeation of the antifungal drug across the human nail to reach the nail bed and achieve the necessary MIC (tissue underneath the nail). Twelve chemical penetration enhancers (PEs) were screened for their ability to enhance ciclopirox olamine accumulation into the nail folds and permeation through the nail. Propylene glycol (PG) enhanced the levels of the drug in the epidermis of the skin while limiting its permeation across the skin. Thiourea (TU) was selected as the best enhancer to increase ciclopirox olamine penetration into the nail. The diffusion of the antifungal drug across the human nail was studied in vitro using human cadaver toenails mounted in Franz diffusion cells. Pressure sensitive adhesives (PSA) belonging to the polyisobutylene, polysiloxane and polyacrylate classes of adhesives were screened to develop a monolithic drug-in-adhesive-type nail patch. The in vitro release of CPO from the PSA patches were limited and did not improve in presence of hydrophilic plasticizer (propylene glycol) and hydrophobic plasticizers (triacetin and triethyl citrate). Increasing the concentration of TU from 1 % to 10 %, lead to its crystallization in the dry patches. Therefore a change in the patch design was recommended. Other hydrophilic polymers including Polyoxyethylene (POLYOX®) and hydroxyl propyl methyl cellulose (HPMC) were also screened to develop a modified drug-in-hydrophilic matrix patch design. The patch was designed to incorporate CPO, PG and TU in the polymer matrix overlaid on a non-occlusive backing membrane cast with polyacrylate PSA. The HPMC films showed the best drug release profile with 80 % release in 2 to 4 hours using a USP apparatus 5. These patches were characterized for drug penetration into the skin and nail permeation. Penlac® nail lacquer was used as the comparator control product. The prototype HPMC K15M patch containing 10 %w/w each of the drug and TU and 150 % w/w of PG showed 2.8 fold increase in CPO accumulation in epidermis compared to Penlac® nail lacquer in 24 hours. The skin permeation was found to be similar to that of Penlac®. The HPMC K15M patch formulation showed 2.7 fold increase in CPO concentration within the nail and 4.2 fold increase in transungual flux compared to Penlac®. The patch delivered higher levels of ciclopirox olamine into the target tissues with a lower permeation lag-time. The novel nail patch delivery system had the following properties: a) Ease of application, b) Contact with the nail surface, c) Increased concentration of drug in dissolved form within the patch, d) Presence of enhancers. The novel nail patch formulation has shown increased efficiency in topical and transungual drug delivery for treatment of OM, when compared to the commercial formulation, Penlac® nail lacquer in the in vitro studies. The physical characterization of the patch using Scanning Electron Microscopy, Polarized Light Microscopy, Optical Light Microscopy, Differential Scanning Calorimetry, X-Ray Diffractometer and Fourier Transform Infrared Spectroscopy show that ciclopirox olamine exists at a sub-saturation level in a non-crystalline form in the patch without any significant drug-polymer interaction. In conclusion, all the objectives of the study were met by successfully selecting penetration enhancers for CPO delivery into the nail folds and across the nail plate, evaluating the interaction between CPO and target tissues, developing a transungual patch system and characterizing the novel transungual patch.
