PLAN OF WORK

Osmotic drug delivery remains an area of interest for its potential in answering many formulation related problems. However it suffers from a number of drawbacks which made it difficult to fully unleash this concept. With the advent of new technologies like asymmetric membrane capsules (AMCs); new doors have got opened in this field. Asymmetric membrane capsules are based on the concept of osmotic pressure but are much simpler to manufacture. Further, they can be suitably optimized by varying the parameters like concentration of pore former, polymer, osmotic agents and solubility enhancers to cater the specific needs of a particular formulation.

I concluded from my M. Pharm dissertation work that AMCs can successfully deliver poorly water soluble, anti-infective drugs like Ciprofloxacin in a controlled manner. However, the system would not be able to deliver relatively water soluble drugs and hence would be unsuccessful in delivering the combination of a poorly and highly water soluble anti-infective drugs. Semipermeable, dense membrane coatings provide controlled delivery of relatively soluble drugs, but a delivery port is needed to deliver the drug at required rate which makes the process cumbersome and costly. In lieu of the above, I wish to develop and formulate an osmotically regulated multi-drug asymmetric capsular delivery system which can simultaneously deliver both poorly and relatively water soluble anti-infective drugs in a controlled manner.

Ciprofloxacin, a poorly water soluble, broad spectrum, class II flouroquinolone antibiotic has a reduced activity against anaerobic pathogens. Therefore a combination with an antimicrobial agent which is active against anaerobes such as Metronidazole, a relatively water soluble antiprotozoal agent, seems to be interesting for the treatment of mixed aerobic/anaerobic infections. The combination has a wide applicability in the treatment of mixed systemic infections. Moreover, it is more potent than the individual agents, in the treatment of IBD.

However, both the drugs have a short half life and require more than once daily administration which reduces their patient compliance and increases incidence of resistance development. Frequent administration of these drugs produces fluctuations in plasma level that either exceed

safe therapeutic concentration or quickly fall below the MEC. All these factors greatly contribute to the failure of anti-infective therapy of the combination. These problems strongly demands a controlled delivery of the FDC which release the drugs typically by zero order thus maintaining plasma levels within safe and effective range. The concept of AMCs is a novel prospect in osmotic drug delivery. In lieu of this I wish to develop modified AMCs as a means to simultaneously deliver combination of poorly water soluble and relatively soluble anti-infective drugs such as an FDC of Ciprofloxacin and Metronidazole, in a controlled manner.

Project Title: Osmotically controlled simultaneous oral delivery of fixed dose combination of antimicrobials through modified asymmetric membrane capsules
Objective: To develop and evaluate modified asymmetric membrane capsular system (MAS) for simultaneous oral delivery of FDC of poorly water soluble and highly water soluble antimicrobials, in a controlled manner. Plan of Work: My whole project work will be carried out in following chronological order:

I: Literature Search II: Preformulation Studies 1. Drug characterization 2. Method development for simultaneous determination of Ciprofloxacin and Metronidazole in Dissolution fluids (Drug Analysis) 3. Drug-polymer-excipient interaction studies III: Preparation of AMCs 1. Preparation of Capsule shell: Various AMCs by trying different polymers in different concentration/combination with a varying concentration of pore former 2. Filling and Sealing of AMCs: Different formulations of FDC (constant amount) with varying concentration of osmogen and solubilizer IV: Preparation of Dense semipermeable membrane capsules 1. Preparation of Capsule shell: Various DSM capsules by trying different polymers in different concentration/combination with a varying concentration of plasticizer

2. Filling and sealing of DSM systems: Two approaches with varying concentration of osmogen, solubilizer and solubility retardant 3. Drilling V: Evaluation of AMCs and DSM systems 1. Physical evaluation 2. In-vitro drug release 3. Study of influence of variables like porosity, membrane thickness, concentration of osmogen, solubilizer etc. on the release profile from two systems 4. Scanning electron microscopy 5. Kinetics of Drug release 6. Statistical analysis to optimize a system for further development VI: Formulation of Modified Asymmetric system 1. Modification of optimized AMC to release both the drugs simultaneously in a controlled manner 2. Different MAS with different hydrophilic polymer matrix system in varying concentration VI: Evaluation of MAS 1. In-vitro drug release 2. Statistical analysis to compare in vitro drug release from AMCs, DSM and MAS systems and further to optimize MAS system 3. Kinetics of Drug release 4. Scanning electron microscopy 5. Weight variation 6. Content uniformity VI: In vivo evaluation 1. In vivo studies of optimized MAS in rabbits 2. Determination of PK parameters

3. Comparison of optimized MAS with reference formulation (Oral marketed formulation of FDC) VII: Stability studies of optimized MAS Six month accelerated stability studies of the optimized formulation to evaluate the effect of storage conditions on various parameters