For the last several decades parenteral long-acting oily depots for intramuscular injection (IM) and subcutaneous injection (SC), have been used in the treatment of schizophrenia and in hormone replacement therapy (e.g Fluphenazine decanoate in sesame oil , Prolixin Decanoate® (Bristol-Myers Squibb). The extended release is achieved by using a vegetable oil-based vehicle and a lipophilic prodrug derivative of the parent drug. Also researched by ourselves and other groups for extended release are organogel formulations where the oily matrix is immobilized within a three-dimensional fibrous network formed by self-assembly of a gelator.
We have interesting and encouraging results obtained for in vitro for extended drug release performed in buffered saline for our injectable organogels. However, we believe that these current in vitro data might not be fully predictive of in vivo release. Indeed, the drug release mechanism is thought to be multi-faceted and to involve enzyme-triggered degradation/erosion in addition to other mass transport mechanisms such as drug dissolution and drug diffusion in the oil. The later are can be predicted to some extent by in vitro dissolution in buffer, however the enzyme-triggered erosion could not be predicted by this simplistic approach.
Hence, the objective of this project is to develop in vitro biorelevant drug release conditions for more accurate prediction of the in vivo drug release from organogels and oily depots. Lipases present in subcutaneous adipose tissues and muscle, have been shown to degrade the exogenous triglycerides in lipid implants. It is therefore highly likely (and supported by recent literature) that these lipases may participate in the biodegradation of the oil matrix of oily depots and organogels. Hence, we will develop an in vitro lipolysis method to more accurately predict drug release from oily depots and organogels by modifying our currently fully established model of in vitro lipolysis in the gastrointestinal tract.
Therefore, the aims of this PhD project will be focused on:- developing an in vitro dissolution model including lipolysis; plasma esterase conversion of the prodrug and microsomal stability that is predictive of the plasma PK for an oily depot (marketed formulation of an anti-psychotic (e.g Fluphenazine decanoate); developing two prodrug (fluphenazine decanoate and apomorphine prodrugs (developed by Dr Michael Stocks)) organogel formulations and evaluation of in vitro dissolution including lipolysis for these organogels; and lastly to generate rat PK data on the organogels to further validate the developed in vitro model.
The project will be co-supervised by Dr Maria Marlow, Dr Pavel Gershkovich and Dr Michael Stocks at the University of Nottingham, UK.
Applications are invited from self-funded students.