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Development of long-acting injectable formulations for poorly soluble anti-HIV compounds

This work aimed to investigate a novel formulation strategy for long-acting injectables for the delivery of a poorly soluble anti-HIV compound.Therefore the ideal drug delivery system should significantly increase drug solubility while providing controlled release over an extended period of time (weeks). To do so a novel formulation concept based on spray-dried microspheres for controlled release via intramuscular injection was proposed. The microspheres consisted of the combination of water-insoluble PLGA with water-soluble PVP. This combination of materials aimed tosecure both solubility enhancement by molecular dispersion of the drug (in PVP) and long-term release (by PLGA). The model drug used was an HIVprotease inhibitor.

Surface analysis techniques (ToF-SIMS, XPS, nanoTA and AFM) were combined with a bulk miscibility study (MDSC) in a first study (Chapter 3). This combination allowed in depth structural elucidation of the polymeric PLGA/PVP matrix. It was concluded that spray drying a feed solution containing PLGA and PVP results in hollow shell structured microparticles. MDSC proved that two different amorphous phases are present in the particles, namely a PLGA-rich phase containing somePVP and a PVP-rich phase containing some PLGA. The PLGA-rich phase appeared to be the surface layer of the particles, with an underlying PVP-rich layer. This finding was supported by the results of ToF-SIMS, XPS as well as nanoTA experiments. The polymer ratio had an influence on the thickness of the PLGA surface layer: the higher the weight percentage PLGApresent in the sample, the thicker the surface layer was. These findings could have implications for the development of the polymeric drug matrix to deliver the optimum drug release properties in future studies.

A detailed characterization of how this matrix structurally changed when exposed to stress conditions such as heat and humidity was performed in a follow-up study (Chapter 4). It was observed that the surface characteristics (chemical composition, phase behaviour and topography) of spray-dried PVP/PLGA microparticles were affected by exposure to heat andhumidity leading to a surface rearrangement whereby an increase of PVP at the surface was observed, coupled with a decrease in PLGA. This phenomenon could be explained based upon the relative thermal characteristicsand consequent molecular mobility of the two polymers. Furthermore it implied that exposure to elevated temperatures and humidity might influence the bulk miscibility and release behaviour of future formulations.

Inclusion of the model API in the PLGA/PVP-based matrix posed a methodological challenge as for ternary solid dispersions MDSC alone is notsufficient to characterize their phase behaviour and to gain insight into the distribution of the API in a two-phased polymeric matrix. To solve this problem MDSC was combined with the complementary surface analysistechniques ToF-SIMS and AFM (Chapter 5). This study demonstrated how this combination of techniques offers synergistic benefits for the characterisation of the phase behaviour and drug distribution of ternary solid dispersions (API/PLGA/PVP). MDSC showed that the API was present as a glass solution. ToF-SIMS demonstrated that the degree of API surface coverage varied for differently composed formulations. AFM imaging and mechanical mapping coupled nanoscale spatial information about the microspheresurface to these findings, indicating structural and compositional heterogeneity.
The ability to study the spatial distribution of the API is of great importance as the location of the API in the microspheres might significantly influence the performance of the formulation (release behaviour and physical stability). Therefore insight into how formulation and process parameters influence the spatial distribution of the drug in these ternary solid dispersions (via surface characterization) would allow rational design of controlled release profiles and stability performance.

That is why in a next study it was investigated how formulation (feed concentration) and process (feed rate, inlet air temperature and atomizing air pressure) parameters influence the characteristics of the spray-dried microspheres (Chapter 6). Differences were observed for miscibility and heterogeneity of the samples, particle size and morphology as well as API surface coverage. Observed differences are likely due to changes in the droplet evaporation and the subsequent particle formation process. Despite the observed differences, varying particle characteristics did not influence the release behaviour of the formulation studied.
Hence, for the timeframe tested, spray drying resulted in a formulation with stable drug release characteristics. This is likely due to the proposed release mechanism where the release is dominated by fast dissolution of the small domains of PVP present in the PLGA layer due tothe high solubility of PVP. The resulting pores in the PLGA surface layer allow ingression of aqueous fluids into the particles, followed by fast dissolution of the molecularly dispersed API and diffusion out of themicrospheres. This mechanism is consistent with the observed increase in PVP surface coverage after exposure of the microspheres to humidity and emphasizes the important role of PVP in these formulations. Moreover, it was confirmed that the function of the PLGA in these formulations is to form a phase separated surface layer to assure the required slow release characteristics of the formulation, whereas the underlying PVP phaseincreases the solubility and hence dissolution rate of a poorly solubledrug.

As a last step our formulation strategy was compared to other solubility enhancing strategies. First a physicochemical characterization and in vitro evaluation of the various formulation strategies was performed (Chapter 7). Our formulation strategy based on the molecular dispersion of a poorly soluble drug into a biphasic PLGA/PVP matrix was evaluated. This strategy was compared to two other solubility enhancing approaches, namely solid dispersions in a pure PLGA matrix and particle size reduction by means of an API microsuspension. In total six model formulations were tested, representing these three formulation approaches.
Depending on composition and manufacturing method, the model formulations varied in particle size, porosity, phase behaviour, surface coverage and physical state of the API. These findings gave insight in the in vitro release behaviour and resulted in understanding the observed differences and similarities in release of the various formulations. For PLGA-based formulations porosity was identified as a critical parameter influencing in vitro drug release, whereas the release rate of PLGA/PVP-based formulations could be tailored by changing the thickness of the PLGA surface layer. For the API studied, particle size reduction was a suitable strategy to increase dissolution rate but it appeared to be less applicable for the development of a sustained release formulation as it resulted in an immediate and complete in vitro drug release.

Additionally the long-term in vivo performance of our strategy was compared to that of the other solubility enhancing approaches by evaluating the exposure in male Beagle dogs. The in vivo performance of the various formulations was evaluated over a period of 28 days after intramuscular injectionby the observed initial burst release, plasma concentration-time profiles, time at which maximum plasma levels were reached and the estimated bioavailability.
In vivo evaluation of the different formulation strategies demonstrated the benefit of combining  water-soluble polymer PVP and water-insoluble PLGA as a matrix for solid dispersions to develop long-term release formulations compared to the other formulation strategies assessed (Chapter 8). The benefit is dual and comprises a more sustained release as well as a higher extent of drug release from the polymeric matrix. This was explained based on the structure of these PLGA/PVP-based matrices where the pore network originating from rapidly dissolving PVP results in an increasing access of the aqueous release medium to the API dispersed in the polymeric matrix. This increased access to drugdispersed in the matrix with depth from the surface acts as a reservoirwith a higher extent of and more prolonged drug release as a result. Moreover, the results suggest that for the PLGA/PVP-based formulations changing the amount of PLGA in the matrix is the most promising approach totailor the release profile.

Altogether, to assess the suggested formulation strategy, consecutive studies were performed. These studies represent various activities involved in the drug development process, ranging from product manufacturing over sample characterization, in vitrorelease testing and in vivo bioavailability assessment. The overall conclusion of the different studies performed is that spray drying a poorlysoluble drug as a solid dispersion in a PLGA/PVP-based matrix is a promising strategy for the development of long-acting injectable formulations.

Date:21 Sep 2009 →  12 Sep 2014
Keywords:HIV drugs, biodegradable polymers, parenteral drug administration, poorly soluble drugs
Disciplines:Chemical product design and formulation, Biomaterials engineering, Analytical chemistry, Pharmaceutical analysis and quality assurance, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences
Project type:PhD project