Title: Formulation of paediatric medication: powders for reconstitution of poorly soluble anti-HIV drugs
Other Titles: Formulering van pediatrische medicatie: poeders voor reconstitutie van slecht oplosbare anti-HIV geneesmiddelen
Authors: Nguyen Nhat, Duong
Issue Date: 28-Sep-2016
Abstract: In chapter 1, the general introduction firstly described a general picture about the global results from the response to the human immunodeficiency virus (HIV). These results highlighted the requirement for a more efficient and more easily accessible antiretroviral therapy (ART), especially for HIV infected paediatric patients. Fixed dose combinations (FDCs) of two or more active pharmaceutical ingredients (APIs) in a single dose form seems to be a promising strategy because it offers more comfort and convenience to patients and consequently, improves the medication compliance. Moreover, a FDC prepared as powders for reconstitution can be considered as an attractive ART, especially for children as the powders can be reconstituted into drinkable solution or sprinkle formulations and the administered dose can be easily adapted to the need of the paediatric patient. For that reason, a formulation that combines ritonavir (RTV) and darunvir (DRV) which is recently recommended by the World Health Organization (WHO) for the second line antiretroviral therapy is the subject of this study. As both drugs have poor water solubility, formulation strategies are necessary to improve their solubility and dissolution rate. The general introduction section therefore also presented several aspects (e.g. advantages and disadvantages) of two common formulation strategies which would be applied later in the project, namely solid form modification (i.e. amorphous solid dispersion) or size reduction (i.e. nanosuspension) for poorly water soluble drugs. In addition, an important part of chapter 1 is contributed to the introduction of electrospraying, an efficient and well-practiced technique to generate particulate materials with well-controlled size, shape, morphology and structure down to nanoscale for a wide variety of pharmaceutical and biomedical applications.
Chapter 2 presents the general and specific objectives of this project. The main objective was to investigate the feasibility of producing a fixed dose combination of RTV and DRV as powders for reconstitution.
In chapter 3, combination of RTV and DRV as a ternary amorphous solid dispersion was prepared by spray drying. Once an amorphous solid dispersion is dissolved, a supersaturation solution (i.e. drug concentration is higher than its thermodynamic solubility) is generated which leads to enhanced absorption. The success of amorphous solid dispersion will then depend on how the supersaturation is maintained as drug precipitation will eventually takes place (thermodynamically driven). Therefore, a first important step was to understand the effect of various polymers on maintaining supersaturation of RTV and DRV as well as possibly mutual influence between RTV and DRV on their supersaturation behavior. Using the solvent shift method, supersaturated solutions of either single RTV and DRV or combined RTV and DRV were created and the supersaturation behavior in the presence of polymers was investigated by monitoring drug concentration over time. HPMC was the most effective polymer for enhancing the supersaturation, whereas PVP K30 or PVPVA 64 had little influence on maintaining the supersaturation of both RTV and DRV. The supersaturation level of RTV and DRV in a single test is found to be related to the apparent amorphous solubility. However, in the combined test with DRV, the supersaturation level of RTV decreased significantly, especially in water (the concentration of RTV dropped to a value close to the thermodynamic solubility). The presence of RTV also made the supersaturation level of DRV to decrease two-fold. Interestingly, the release profile of RTV and DRV from the spray-dried powders showed a similar trend compared to the supersaturation study. The release of both RTV and DRV from ternary SD powders was lower than the ones from binary SD powders which suggest that these two API mutually influence each other, though the influence of DRV on RTV is more pronounced. 1H-NMR studies showed that the observed solubility behavior cannot be explained by RTV – DRV intermolecular interactions. The results obtained could be at least partially attributed to the mediated solvent process. To improve the solubility of both drugs, another approach with cyclodextrins and derivatives was applied. RTV/DRV/HP-β-CD inclusion complexes were prepared by spray drying. The complex provided higher release of both RTV and DRV and therefore highlighted the feasibility of using HP-β-CD to protect RTV from the influence of DRV and vice versa.
Since the results described in chapter 3 showed that the concurrent release of RTV and DRV reduces the supersaturation level of both DRV and RTV as these two compounds have negative influence on their solubility, an “advanced” fixed dose combination of DRV and RTV with the ability to release RTV and DRV separately and consecutively should be developed. More specifically, such system should allow RTV to be released earlier in the stomach and be absorbed before the release of DRV in the small intestine. Therefore in chapter 4, we investigated the feasibility of using coaxial electrospraying for preparation of encapsulated DRV solid dispersion within Eudragit L100, an enteric polymer. The solution of DRV and hydroxypropyl methyl cellulose (HPMC) was fed through the inner passage of a coaxial nozzle and an Eudragit L100 solution was used as the shell liquid. A series of Eudragit L100 solutions with different concentration in different organic solvents and several process parameters (applied voltage and flow rates) was tested to obtain a stable cone-jet mode during electrospraying. As long as a stable cone-jet mode is achieved, a solid dispersion of DRV was effectively prepared and coated within Eudragit L100 in one single step, though incomplete amorphization was observed by XRD. Encapsulation efficiency testing and in vitro dissolution tests showed that decreasing the ratio of the core/shell flow rates led to improvement in encapsulation efficiency and less drug release in acidic medium. Surface characterization of electrosprayed samples by atomic force microscopy and time-of-flight secondary ion mass spectroscopy revealed particles with a likely core-shell microstructure though the surface was not homogeneous as it showed the presence of DRV.
An alternative approach of using coaxial electrospraying for encapsulating DRV as nanocrystals within a Eudragit L100 shell was discussed in chapter 5. As long as a fine nanosuspension with suitable properties (viscosity, solid content, particle size and uniform size distribution) is selected as the core fluid in a coaxial electrospraying setup, a Taylor cone-jet mode can be controlled and obtained easily, which produces small core-shell structured nanoparticles with a narrow particle size distribution. Moreover, for effective encapsulation, not only the quality of the input nanosuspension, especially size and size distribution, but also the electrospraying process will determine the final properties of the resulting electrosprayed samples. In the study, DRV nanocrystals were effectively encapsulated within Eudragit L100 as a high encapsulation efficiency of 90% and a reduced DRV release of approximately 20% in acidic medium were obtained. Apparently, the electrospraying process also showed to have an influence on the crystal structure of the encapsulated DRV nanocrystals, since apparently a new crystalline phase of DRV was observed. The results suggest that coaxial electrospraying is a potential and unique technique for encapsulating drug nanocrystals within a polymeric shell, which can be considered as an innovation and breakthrough for novel biomedical applications in the near future.
In chapter 6, the general discussion highlighted the rationale of the strategies for FDC as well as some key accomplishments of the present dissertation, especially using electrospraying for encapsulating either an amorphous solid dispersion or nanocrystals of poorly water soluble API within a polymer for targeted release.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Drug Delivery and Disposition

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