Search

The oral cavity is of great importance to the performance of orally retained formulations, including: orally disintegrating tablets, taste-masked formulations, and buccal/sublingual delivery systems. With regards to in vitro dissolution assessment of these dosage forms, human saliva should be represented by the dissolution media. Currently there is no general consensus regarding oral cavity dissolution. In this study pooled human saliva was characterised and utilised as dissolution media for biorelevant oral cavity dissolution studies and to assess drug release. Lipophilic drug felodipine with challenging biopharmaceutical properties was selected for assessment in oral cavity dissolution studies. These saliva dissolution studies investigated for the first time how biorelevant dissolution can be implemented as a screening tool to guide the formulation development process and to predict dosage form performance within the mouth. In this study a combination of three dissolution enhancement strategies (cryomilling, solid dispersion, and inclusion complexation) were employed to eventually increase the concentration of felodipine in saliva 150-fold. Using this successful formulation strategy orally disintegrating tablets of felodipine were produced. Interestingly, the percentage release of felodipine in compendial dissolution apparatus was shown to be over 80% after 10 minutes. On the other hand, salivabased dissolution showed that percentage release of felodipine was only 0.2% after 10 minutes using the same formulation. This discrepancy in drug release between dissolution media highlights the need for biorelevant dissolution apparatus for the oral cavity to reliably assess performance of relevant dosage forms in vitro.

The self?assembly of specific polymers into well?defined nanoparticles (NPs) is of great interest to the pharmaceutical industry as the resultant materials can act as drug delivery vehicles. In this work, a high?throughput method to screen the ability of polymers to self?assemble into NPs using a picoliter inkjet printer is presented. By dispensing polymer solutions in dimethyl sulfoxide (DMSO) from the printer into the wells of a 96?well plate, containing water as an antisolvent, 50 suspensions are screened for nanoparticle formation rapidly using only nanoliters to microliters. A variety of polymer classes are used and in situ characterization of the submicroliter nanosuspensions shows that the particle size distributions match those of nanoparticles made from bulk suspensions. Dispensing organic polymer solutions into well plates via the printer is thus shown to be a reproducible and fast method for screening nanoparticle formation which uses two to three orders of magnitude less material than conventional techniques. Finally, a pilot study for a high?throughput pipeline of nanoparticle production, physical property characterization, and cytocompatibility demonstrates the feasibility of the printing approach for screening of nanodrug delivery formulations. Nanoparticles are produced in the well plates, characterized for size and evaluated for effects on metabolic activity of lung cancer cells.

There is an increasing need to develop bio-compatible polymers with an increased range of different physicochemical properties. Poly(glycerol-adipate) (PGA) is a biocompatible, biodegradable amphiphilic polyester routinely produced from divinyl adipate and unprotected glycerol by an enzymatic route, bearing a hydroxyl group that can be further functionalized. Polymers with an average Mn of ?13 kDa can be synthesized without any post-polymerization deprotection reactions. Acylated polymers with fatty acid chain length of C4, C8, and C18 (PGAB, PGAO, and PGAS, respectively) at different degrees of substitution were prepared. These modifications yield comb-like polymers that modulate the amphiphilic characteristics of PGA. This novel class of biocompatible polymers has been characterized through various techniques such as FT-IR, 1H NMR, surface, thermal analysis, and their ability to self-assemble into colloidal structures was evaluated by using DLS. The highly tunable properties of PGA reported herein demonstrate a biodegradable polymer platform, ideal for engineering solid dispersions, nanoemulsions, or nanoparticles for healthcare applications.

Poly (glycerol adipate) (PGA) can be produced from divinyl adipate and unprotected glycerol by an enzymatic route to generate a polymer with relatively low molar mass (12 kDa). PGA bears a pendant hydroxyl group which imparts a hydrophilic character to this water insoluble polymer. We have examined the effect of synthesis temperature on polymer characteristics through various techniques including FT-IR, 1H and 13C NMR, surface and thermal analysis, both to expand the data already present in the literature about this material and to understand better its properties for potential pharmaceutical applications. The use of a lipase (Novozym 435) as a catalyst suppresses cross-linking at the pendant glyceryl hydroxyl through steric hindrance at the active site, thus producing polymers with low degrees of branching (5–30%), and removes the need for any pre- or post-polymerization protection/deprotection reactions. Careful temperature control during synthesis can give polymers with reproducible molecular weights and reduced amounts of polymer branching compared to synthesis at higher temperatures. Due to the ability of the synthetic route to produce a range of structures, PGA generated by enzymatic routes may emerge as a useful biodegradable polymer platform to engineer solid dispersions or nanoparticles for healthcare applications.

Defect occurrence within polymers was successfully predicted in 85% of cases using a PLS regression model based upon molecular descriptors., Polymer microarrays are a key enabling technology for the discovery of novel materials. This technology can be further enhanced by expanding the combinatorial space represented on an array. However, not all materials are compatible with the microarray format and materials must be screened to assess their suitability with the microarray manufacturing methodology prior to their inclusion in a materials discovery investigation. In this study a library of materials expressed on the microarray format are assessed by light microscopy, atomic force microscopy and time-of-flight secondary ion mass spectrometry to identify compositions with defects that cause a polymer spot to exhibit surface properties significantly different from a smooth, round, chemically homogeneous ‘normal’ spot. It was demonstrated that the presence of these defects could be predicted in 85% of cases using a partial least square regression model based upon molecular descriptors of the monomer components of the polymeric materials. This may allow for potentially defective materials to be identified prior to their formation. Analysis of the PLS regression model highlighted some chemical properties that influenced the formation of defects, and in particular suggested that mixing a methacrylate and an acrylate monomer and/or mixing monomers with long and linear or short and bulky pendant groups will prevent the formation of defects. These results are of interest for the formation of polymer microarrays and may also inform the formulation of printed polymer materials generally.

Polymer microarrays are a key enabling technology for the discovery of novel materials. This technology can be further enhanced by expanding the combinatorial space represented on an array. However, not all materials are compatible with the microarray format and materials must be screened to assess their suitability with the microarray manufacturing methodology prior to their inclusion in a materials discovery investigation. In this study a library of materials expressed on the microarray format are assessed by light microscopy, atomic force microscopy and time-of-flight secondary ion mass spectrometry to identify compositions with defects that cause a polymer spot to exhibit surface properties significantly different from a smooth, round, chemically homogeneous ‘normal’ spot. It was demonstrated that the presence of these defects could be predicted in 85% of cases using a partial least square regression model based upon molecular descriptors of the monomer components of the polymeric materials. This may allow for potentially defective materials to be identified prior to their formation. Analysis of the PLS regression model highlighted some chemical properties that influenced the formation of defects, and in particular suggested that mixing a methacrylate and an acrylate monomer and/or mixing monomers with long and linear or short and bulky pendant groups will prevent the formation of defects. These results are of interest for the formation of polymer microarrays and may also inform the formulation of printed polymer materials generally., Burroughs Wellcome Fund (grant number 085245), Royal Society (Great Britain) (Wolfson Research Merit Award)

Lyophilized protein formulations must be reconstituted back into solution prior to patient administration and in this regard long reconstitution times are not ideal. The factors that govern reconstitution time remain poorly understood. The aim of this research was to understand the influence of the lyophilization cooling profile (including annealing) on the resulting cake structure and reconstitution time. Three protein formulations (BSA 50mg/ml, BSA 200mg/ml and IgG1 40mg/ml, all in 7% w/v sucrose) were investigated after cooling at either 0.5°C/min, or quench cooling with liquid nitrogen with/without annealing. Significantly longer reconstitution times were observed for the lower protein concentration formulations following quench cool. Porosity measurements found concomitant increases in the surface area of the porous cake structure but a reduction in total pore volume. We propose that slow reconstitution results from either closed pores or small pores impeding the penetration of water into the lyophilized cake.

A miniaturized, high-throughput assay was optimized to screen polymer-drug solid dispersions using a 2-D Ink-jet printer. By simply printing nanoliter amounts of polymer and drug solutions onto an inert surface, drug:polymer micro-dots of tunable composition were produced in an easily-addressable micro-array format. The amount of material printed for each dried spot ranged from 25 ng to 650 ng. These arrays were used to assess the stability of drug:polymer dispersions with respect to recrystallization, using polarized light microscopy. One array with a panel of 6 drugs formulated at different ratios with Poly (vinylpyrrolidone-vinyl acetate) copolymer (PVPVA) was developed to estimate a possible bulk (gram-scale) approximation threshold from the final printed nano amount of formulation. Another array was printed at a fixed final amount of material to establish a literature comparison of one drug formulated with different commercial polymers for validation. This new approach may offer significant efficiency in pharmaceutical formulation screening, with each experiment in the nano-micro-array format requiring from 3 up to 6 orders of magnitude lower amounts of sample than conventional screening methods.