A Quantitative Disintegration Method for Polymeric Films

Purpose

Current in vitro disintegration methods for polymeric films are qualitative and introduce significant user bias. The goal of these studies is to develop a novel, quantitative disintegration technique which can be used to characterize polymeric films in vitro.

Methods

A method was developed using a Texture Analyzer instrument to evaluate film disintegration. Solvent-casted, clinically advanced, anti-HIV, vaginal films as well as marketed vaginal films were used throughout these studies. Method development followed a quality by design (QbD) process and was used to evaluate film products.

Results

The current method developed provided reproducible, quantitative disintegration times for the commercially available vaginal contraceptive film (57.88?±?5.98 s). It distinguished between two clinically advanced antiretroviral containing films based on disintegration time (p value <?0.001): the tenofovir film (41.28?±?3.35 s) and the dapivirine film (88.36?±?10.61 s). This method could also distinguish between tenofovir and dapivirine films which had been altered in terms of volume (p?<?0.0001) and formulation (p?<?0.0001) based on disintegration time.

Conclusions

This method can be applied for pharmaceutical films for ranging indications as part of vigorous in vitro characterization. Parameters of the test can be altered based on site of application or indication.

     

Denatured Whey Protein Powder as a New Matrix Excipient: Design and Evaluation of Mucoadhesive Tablets for Sustained Drug Release Applications

Purpose

In earlier study, we proposed denatured whey protein (DWP) powder obtained by atomization as a new excipient to promote oral drug delivery. In this work, we evaluate the possibility to formulate tablets based on DWP powders and to characterize their role as a matrix mucoadhesive excipient.

Methods

Tablets containing increased amount of DWP (10 to 30%) were produced by direct compression after mixing with theophylline, microcrystalline cellulose, Aerosil® and magnesium stearate. Dissolution behaviors of obtained tablets were evaluated in different USP buffers (pH 1.2, 4.5 and 6.8) and in simulated gastric and intestinal fluids and mechanisms analyzed by multiple mathematical models. Swelling, erosion and mucoadhesion were also evaluated. Finally, release and absorption were studied in the artificial digestive system (TIM 1).

Results

Tablets based on DWP and containing 300 mg of theophylline were obtained by direct compression. These tablets exhibited controlled release driven by diffusion starting from 15% DWP content whatever the pH studied. They also showed a great extent of swelling and water uptake while matrix weight loss was limited. Addition of enzymes accelerated drug release which became governed by erosion according to Peppas model.

Conclusions

The present study shows that DWP powders can be successfully used as a pharmaceutical excipient, and in particular as a matrix mucoadhesive controlled release tablets.

     

Screening and <Emphasis Type="Italic">In Vitro</Emphasis> Evaluation of Mucoadhesive Thermoresponsive System Containing Methylene Blue for Local Photodynamic Therapy of Colorectal Cancer

Purpose

Photodynamic therapy (PDT) with methylene blue (MB) constitutes a potentially useful modality for colorectal cancer treatment. The limitations of the formulations containing MB are problems of administration and the inability to get the closeness contact at the site during the appropriate residence time. Present study aimed to develop and characterize mucoadhesive thermoresponsive system containing MB designed as platform for colorectal cancer therapy.

Methods

Formulations composed of different amounts of poloxamer 407 (Polox), Carbopol 934P (Carb), and MB were developed and characterized as rheological, compressional, mucoadhesive and syringeability properties, toxicity, photodynamic action, in vitro MB release profile, and ex vivo MB intestinal permeation.

Results

The different compositions resulted in formulations with distinctive macroscopic characteristics and wide range of gelation temperatures. The compressional flow, mucoadhesive, syringeability, and rheological properties were significantly influenced by temperature and/or composition. The MB release from formulation was governed by anomalous transport. In addition, it was observed that MB permeated the intestinal membrane; the formulation possesses photodynamic activity and low toxicity.

Conclusions

The data obtained from the system composed of 20% Polox, 0.15% Carb, and 0.25% MB indicated a potentially functional role in PDT of the colorectal cancer and suggest it is worthy of clinical evaluation.

     

Formulation and Evaluation of Chitosan-Based Buccal Bioadhesive Films of Zolmitriptan

Purpose

Therapeutic efficacy of zolmitriptan in oral therapy is primarily limited by the biopharmaceutical issues. The objective of this study is to design and optimize chitosan-based buccal bioadhesive system for the effective delivery of zolmitriptan in the treatment of migraine.

Methods

Factorial design (3²) is constructed and conducted in a fully randomized manner to study all nine possible experimental runs. The films were prepared by solvent casting method by varying the content of chitosan (X₁) and polyvinyl alcohol (X₂). The effect of these two independent variables on swelling index (Y1), percent drug release in 15 min (Y2) and 5 h (Y3), and mucoadhesive strength (Y4) of prepared films was evaluated.

Results

The physical and chemical characteristics displayed by the prepared films (F1–F9) were found to be optimal. It was observed that the factor X₁ has positive and X₂ has negative effect on response Y1. In contrast, factor X₁ showed negative effects on drug release at both time intervals (15 min and 5 h) while X₂ displayed positive responses for these variables (Y2 and Y3). However, the mucoadhesion increased with an increase in factor X₁ and decreased when the factor X₂ was increased. Indeed, the desirable characteristics exhibited by the film F7 are ideal for buccal application. Greater flux (63.93?±?12.51 μg/cm²/h) demonstrated in ex vivo studies substantiated the potential of optimized film to effectively deliver zolmitriptan across the buccal membrane.

Conclusions

This study concludes that the chitosan-based buccal film (F7) could be used in both prophylaxis and acute treatment of migraine, although need to be proved in vivo.

     

Synthesis and Characterisation of Photocrosslinked poly(ethylene glycol) diacrylate Implants for Sustained Ocular Drug Delivery

Purpose

To investigate the sustained ocular delivery of small and large drug molecules from photocrosslinked poly(ethylene glycol) diacrylate (PEGDA) implants with varying pore forming agents.

Methods

Triamcinolone acetonide and ovalbumin loaded photocrosslinked PEGDA implants, with or without pore-forming agents, were fabricated and characterised for chemical, mechanical, swelling, network parameters, as well as drug release and biocompatibility. HPLC-based analytical methods were employed for analysis of two molecules; ELISA was used to demonstrate bioactivity of ovalbumin.

Results

Regardless of PEGDA molecular weight or pore former composition all implants loaded with triamcinolone acetonide released significantly faster than those loaded with ovalbumin. Higher molecular weight PEGDA systems (700 Da) resulted in faster drug release of triamcinolone acetonide than their 250 Da counterpart. All ovalbumin released over the 56-day time period was found to be bioactive. Increasing PEGDA molecular weight resulted in increased system swelling, decreased crosslink density (Ve), increased polymer-water interaction parameter (χ), increased average molecular weight between crosslinks (Mc) and increased mesh size (ε). SEM studies showed the porosity of implants increased with increasing PEGDA molecular weight. Biocompatibility showed both PEGDA molecular weight implants were non-toxic when exposed to retinal epithelial cells over a 7-day period.

Conclusion

Photocrosslinked PEGDA implant based systems are capable of controlled drug release of both small and large drug molecules through adaptations in the polymer system network. We are currently continuing evaluation of these systems as potential sustained drug delivery devices.

     

Drug Regulation and Oversight,from Local to Global

Purpose

The purpose of this perspective piece is to address the potential for drug and medical product innovation through sound regulation and strengthened international harmonization.

Methods

Current literature, recommendations and guidelines in regulatory agencies assisted in this perspective review.

Results

Multiple guidelines and recommendations provide for strategic planning and process improvement capabilities at local, national and international levels.

Conclusions

Seeking best practice starts with identifying and improving individual nation drug regulatory bodies, including the US Food and Drug Administration (FDA). Inefficiency causes and process improvement solutions have been suggested and outlined in strategic plans at the FDA as well as with multiple stakeholder organizations and public-private partnerships. Cohesively, these groups should be tasked with formal, consistent updates on improvement as well as ongoing supportive research and evaluation of the changes implemented. Simultaneously, the international community has a tremendous opportunity to act on best practice for drug and medical product innovation by aligning sound and consistent approach to regulation.

     

Preparation of Organosilane Coatings via Chemically Pre-conjugated Graphene Oxides for Enhanced Dispersion and Hardness

Objective

Use of transparent organosilane hybrid films to protect substrates such as glasses and plastics is of great importance for electronic applications. In this study, graphene oxides (GOs) were chemically conjugated with organosilane oligomers to improve the dispersibility and hardness of organosilane coatings.

Methods

The GO-conjugation with organosilane oligomers (GO-oSi) was prepared through a two-step route featuring amine-carboxyl coupling reaction and oligomerization with silica precursors. The structural properties of GO-oSi were characterized using Fourier transform infrared spectroscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy.

Results

The stability of the GO-organosilane coating dispersion was confirmed after storage in ethanol for 10 days via Tyndall effect analysis. After photopolymerization with organosilane coating agent, the transparencies of the GO-organosilane films were 94% or more, the enhanced hardness was characterized from 3H to 5H through pencil hardness testing.

Conclusion

The simple strategy of pre-conjugation of GOs with organosilane oligomers has the potential to enhance dispersion and hardness of a wide variety of coating materials.

     

Hybrid Electrospun Polycaprolactone Mats Consisting of Nanofibers and Microbeads for Extended Release of Dexamethasone

Purpose

We designed electrospun polycaprolactone mats consisting of nanofibers and microbeads for extended delivery of dexamethasone.

Methods

Thin flexible dexamethasone loaded polycaprolactone mats were prepared by electrospinning. The solvents, polymer loading, voltage and tip-to-collector distance were varied to explore the effects on microstructure of the mats. The microstructure was determined by scanning electron microscope imaging; drug transport was measured and modeled, and X-ray diffraction was used to gauge the crystallinity. Drug transport and X-ray diffraction studies were also conducted with a spin cast film for comparison.

Results

Thin mats, about 10 μm in thickness, were prepared by electrospinning. By controlling the voltage and tip-to-collector distance, we achieved a hybrid structure comprising of nanorods (nanofibers) and microbeads. The release profiles were fitted to the diffusion equation to obtain the diffusivities in the spheres and the rods. The diffusivity in the electrospun nanofibers was significantly lower compared to the casted films due to increased crystallinity, which was estimated from X-ray diffraction analysis. The electrospun hybrid mats sustained drug release for the desired duration of a month, in spite of the small thickness of about 10 μm. By comparison, a ten-fold thicker cast film sustains release for about the same duration suggesting about 100-fold decrease in diffusivity in the electrospun mats due to increased crystallinity.

Conclusions

Electrospun polycaprolactone mats are optimal for achieving long release durations due to increased crystallinity. Designing a hybrid structure by controlling the electrospinning parameters can be a useful approach to increase the release durations.

     

A Tunable,Biodegradable, Thin-Film Polymer Device as a Long-Acting Implant Delivering Tenofovir Alafenamide Fumarate for HIV Pre-exposure Prophylaxis

Purpose

The effectiveness of Tenofovir based HIV pre-exposure prophylaxis (PrEP) is proven, but hinges on correct and consistent use. User compliance and therapeutic effectiveness can be improved by long acting drug delivery systems. Here we describe a thin-film polymer device (TFPD) as a biodegradable subcutaneous implant for PrEP.

Methods

A thin-film polycaprolactone (PCL) membrane controls drug release from a reservoir. To achieve membrane controlled release, TAF requires a formulation excipient such as PEG300 to increase the dissolution rate and reservoir solubility. Short-term In vitro release studies are used to develop an empirical design model, which is applied to the production of in vitro prototype devices demonstrating up to 90-days of linear release and TAF chemical stability.

Results

The size and shape of the TFPD are tunable, achieving release rates ranging from 0.5 to 4.4 mg/day in devices no larger than a contraceptive implant. Based on published data for oral TAF, subcutaneous constant-rate release for HIV PrEP is estimated at <2.8 mg/day. Prototype devices demonstrated linear release at 1.2 mg/day for up to 90 days and at 2.2 mg/day for up to 60 days.

Conclusions

We present a biodegradable TFPD for subcutaneous delivery of TAF for HIV PrEP. The size, shape and release rate of the device are tunable over a >8-fold range.

     

Intranasal Fentanyl Intoxication Leading to Diffuse Alveolar Hemorrhage

Context

Increasing rates of opioid abuse, particularly fentanyl, may lead to more presentations of unusual effects of opioid toxicity. Diffuse alveolar hemorrhage is a rare complication of fentanyl overdose.

Case Details

A 45-year-old male presented in hypoxic respiratory failure secondary to diffuse alveolar hemorrhage requiring intubation. Comprehensive drug screening detected fentanyl without exposure to cocaine. Further history upon the patient’s recovery revealed exposure to snorted fentanyl powder immediately prior to presentation.

Discussion

Diffuse alveolar hemorrhage is a potential, though rare, presentation of opioid intoxication.

Conclusions

Recognition of less common complications of opioid abuse such as diffuse alveolar hemorrhage is important in proper management of overdoses.

     

Combination of SEDDS and Preactivated Thiomer Technology: Incorporation of a Preactivated Thiolated Amphiphilic Polymer into Self-Emulsifying Delivery Systems

Purpose

The aim of the study was to create novel mucoadhesive drug delivery systems by incorporating amphiphilic hydrophobically modified, thiolated and preactivated polymers (preactivated thiomers) into self-emulsifying drug delivery systems (SEDDS).

Methods

L-Cysteine methyl ester was covalently attached to the polymeric backbone of Pemulen TR-2 and preactivated using 2-mercaptonicotinic acid (2-MNA). These thiomers were incorporated in a concentration of 0.3% (w/v) into SEDDS. The size distribution and the zeta potential of the emulsions were evaluated by dynamic light scattering. Mucoadhesive properties of thiomers-SEDDS spiked with FDA (fluorescein diacetate) were examined utilizing rheological measurement, permeation studies and in vitro residence time study on porcine mucosa. Cell viability tests were additionally performed.

Results

734 ± 58 μmol L-Cysteine methyl ester and 562 ± 71 μmol 2-MNA could be attached per gram polymer of Pemulen TR-2. Emulsions exhibited a droplet size range between 180 and 270 nm. Blank SEDDS possessed a zeta potential value between ?5.7 and ?8.6 mV, whereas thiomers-SEDDS between ?14.6 and ?17.2 mV. Viscous modulus of thiomer and preactivated thiomer containing SEDDS-mucus mixture was 8-fold and 11-fold increased in comparison to reference. The amount of FDA permeated the mucus layer was 2-fold lower in case of thiomers-SEDDS compared to blank SEDDS. A prolonged residence time was observed for thiomers-SEDDS over 45 min. During cell viability studies no severe toxic effects were detected.

Conclusion

The novel developed SEDDS with incorporated thiomers might be a promising tool for mucoadhesive oral drug delivery.

     

Structural Stability of Recombinant Human Growth Hormone (r-hGH) as a Function of Polymer Surface Properties

Purpose

Despite the fact that r-hGH was first approved for use by FDA in 1995 and the conventional dosage form in the market has a limitation of daily subcutaneous injections, there remains a lack of sustained delivery system in the market. Nutropin depot, a long-acting dosage form of r-hGH was approved for marketing by FDA in 1999, however, it was discontinued in 2004. Since then, unabating efforts have been made to develop biodegradable polymer based formulations for r-hGH delivery. However, grey area is the comprehension of structural stability of r-hGH at an interface with the polymer and it is of utmost important to attain safe and efficacious sustained delivery system. The purpose of this study was to evaluate the changes in structure of r-hGH upon adsorption at biodegradable PLGA nanoparticles of different hydrophobicity as a function of pH.

Methods

DLS, fluorescence spectroscopy, and CD were collectively employed to evaluate structural changes in r-hGH.

Results

The studies revealed that r-hGH is most stable with low to high hydrophobicity PLGA grades under pH 7.2 followed by 5.3.

Conclusion

Overall, the nature and magnitude of structural changes observed has a strong dependence on the pH and differences and degree of hydrophobicity of PLGA.

     

Supramolecular Chitosan Micro-Platelets Synergistically Enhance Anti-<Emphasis Type="BoldItalic">Candida albicans</Emphasis> Activity of Amphotericin B Using an Immunocompetent Murine Model

Purpose

The aim of this work is to design new chitosan conjugates able to self-organize in aqueous solution in the form of micrometer-size platelets. When mixed with amphotericin B deoxycholate (AmB-DOC), micro-platelets act as a drug booster allowing further improvement in AmB-DOC anti-Candida albicans activity.

Methods

Micro-platelets were obtained by mixing oleoyl chitosan and α-cyclodextrin in water. The formulation is specifically-engineered for mucosal application by dispersing chitosan micro-platelets into thermosensitive pluronic^® F127 20 wt% hydrogel.

Results

The formulation completely cured C. albicans vaginal infection in mice and had a superior activity in comparison with AmB-DOC without addition of chitosan micro-platelets. In vitro studies showed that the platelets significantly enhance AmB-DOC antifungal activity since the IC₅₀ and the MIC₉₀ decrease 4.5 and 4.8-times. Calculation of fractional inhibitory concentration index (FICI?=?0.198) showed that chitosan micro-platelets act in a synergistic way with AmB-DOC against C. albicans. No synergy is found between spherical nanoparticles composed poly(isobutylcyanoacrylate)/chitosan and AmB-DOC.

Conclusion

These results demonstrate for the first time the ability of flattened chitosan micro-platelets to have synergistic activity with AmB-DOC against C. albicans candidiasis and highlight the importance of rheological and mucoadhesive behaviors of hydrogels in the efficacy of the treatment.

     

Online Spectroscopic Monitoring of Drug Release Kinetics from Nanostructured Dual-Stimuli-Responsive Conducting Polymer

Purpose

The potential of electrochemical/temperature dual stimuli-responsive conducting polymer to be used as general drug delivery systems. It allows on-demand release of incorporated drug is kinetically investigated in real time.

Methods

Online spectroscopic monitoring was used to investigate the electrochemically/thermally controlled release behavior of a model drug (naproxen) from drug-doped polypyrrole (DDPPy) film. Avrami’s equation has been used to study the kinetics and further analyzing has been carried out using the Arrhenius and the Eyring equations. Furthermore, drug release behavior, with two other electrochemical techniques was investigated.

Results

It was observed both temperature and electrical stimuli increase the rate of release while electrical potential has a greater effect as revealed in the values of release rate constant (from 0.0068 to 0.018 min^?1 at 37°C). It was also shown that a linear relationship exists between the applied electrical potentials and release activation parameters.

Conclusion

The electronic properties of the conducting polymer has an important role in release kinetics, there might be a single mechanism with the same limiting step. In addition, it was demonstrated the rate of drug release from DDPPy dramatically depends on the amounts as well as modes of applying potential which provides enhanced control of drug-release kinetics which can be accelerated or even sustained.

     

Impaired perception of self-motion (heading) in abstinent ecstasy and marijuana users

Rationale

Illicit drug use can increase driver crash risk due to loss of control over vehicle trajectory. This study asks, does recreational use of ±3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) and tetrahydrocannabinol (THC; marijuana) impair cognitive processes that help direct our safe movement through the world?

Objective

This study assesses the residual effects of combined MDMA/THC use, and of THC use alone, upon perceived trajectory of travel.

Methods

Perception of self-motion, or heading, from optical flow patterns was assessed using stimuli comprising random dot ground planes presented at three different densities and eight heading angles (1, 2, 4 and 8° to the left or right). On each trial, subjects reported if direction of travel was to the left or the right.

Results

Results showed impairments in both drug groups, with the MDMA/THC group performing the worst.

Conclusions

The finding that these psychoactive agents adversely affect heading perception, even in recently abstinent users, raises potential concerns about MDMA use and driving ability.

     

Photochemically Controlled Drug Dosing from a Polymeric Scaffold

Purpose

To develop the first photoactive biomaterial coating capable of controlled drug dosing via inclusion of synthesised drug-3,5-dimethoxybenzoin (DMB) conjugates in a poly(2-methyoxyethyl acrylate) (pMEA) scaffold.

Methods

Flurbiprofen- and naproxen-DMB conjugates were prepared via esterification and characterised via NMR spectroscopy and mass spectrometry following chromatographic purification. Conjugate photolysis was investigated in acetonitrile solution and within the pMEA matrix following exposure to low-power 365 nm irradiation. Photo-liberation of drug from pMEA into phosphate buffered saline was monitored using UV-vis spectroscopy.

Results

The synthetic procedures yielded the desired drug conjugates with full supporting characterisation. Drug regeneration through photolysis of the synthesised conjugates was successful in both acetonitrile solution and within the pMEA scaffold upon UV irradiation. Conjugates were retained within the pMEA scaffold with exclusive drug liberation following irradiation and increased drug dose with increasing exposure. Multi-dosing capacity was demonstrated though the ability of successive irradiation periods to generate further bursts of drug.

Conclusion

This study demonstrates the first application of photochemically controlled drug release from a biomaterial coating and the feasibility of using pMEA as a scaffold for housing the photoactive drug-DMB conjugates.

     

Biodegradable Poly(ester-urethane) Carriers Exhibiting Controlled Release of Epirubicin

Purpose

The purpose of this study was to develop the perspective biodegradable poly(ester-urethane) (PUR) carriers based on “predominantly isotactic” and atactic polylactides (PLAs), and poly(ε-caprolactone) (PCL), for the controlled release of epirubicin (EPI).

Methods

The biodegradable PURs containing different soft segments as new and effective carriers of EPI have been obtained. The preliminary studies on toxicity and degradation of obtained polymers, and the release of the EPI from PUR carriers were carried out.

Results

We found that the kinetic release of EPI from the obtained PUR carriers tested in vitro at 37°C and pH 7.4 was strongly dependent on the kind of the polyesters, used as the soft segment in PURs synthesis. Furthermore, we demonstrated that the EPI was released from various synthesized carriers in a rather regular manner, according to the diffusion-degradation and degradation mechanisms. Importantly, in some cases, the kinetics of the EPI release was nearly zero-order.

Conclusion

The results show that the obtained PURs are very effective and perspective carriers and might be potentially applied in the technology of high controlled EPI delivery systems.

     

Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Effects of Nasal Spray Suspension Particle Size and Properties

Purpose

The objective of this study was to use a recently developed nasal dissolution, absorption, and clearance (DAC) model to evaluate the extent to which suspended drug particle size influences nasal epithelial drug absorption for a spray product.

Methods

Computational fluid dynamics (CFD) simulations of mucociliary clearance and drug dissolution were used to calculate total and microscale epithelial absorption of drug delivered with a nasal spray pump. Ranges of suspended particle sizes, drug solubilities, and partition coefficients were evaluated.

Results

Considering mometasone furoate as an example, suspended drug particle sizes in the range of 1-5 μm did not affect the total nasal epithelial uptake. However, the microscale absorption of suspended drug particles with low solubilities was affected by particle size and this controlled the extent to which the drug penetrated into the distal nasal regions.

Conclusions

The nasal-DAC model was demonstrated to be a useful tool in determining the nasal exposure of spray formulations with different drug particle sizes and solubilities. Furthermore, the model illustrated a new strategy for topical nasal drug delivery in which drug particle size is selected to increase the region of epithelial surface exposure using mucociliary clearance while minimizing the drug dose exiting the nasopharynx.