Initial Drug Dissolution from Amorphous Solid Dispersions Controlled by Polymer Dissolution and Drug-Polymer Interaction

Purpose

To identify the key formulation factors controlling the initial drug and polymer dissolution rates from an amorphous solid dispersion (ASD).

Methods

Ketoconazole (KTZ) ASDs using PVP, PVP-VA, HMPC, or HPMC-AS as polymeric matrix were prepared. For each drug-polymer system, two types of formulations with the same composition were prepared: 1. Spray dried dispersion (SDD) that is homogenous at molecular level, 2. Physical blend of SDD (80% drug loading) and pure polymer (SDD-PB) that is homogenous only at powder level. Flory-Huggins interaction parameters (χ) between KTZ and the four polymers were obtained by Flory-Huggins model fitting. Solution ¹³C NMR and FT-IR were conducted to investigate the specific drug-polymer interaction in the solution and solid state, respectively. Intrinsic dissolution of both the drug and the polymer from ASDs were studied using a Higuchi style intrinsic dissolution apparatus. PXRD and confocal Raman microscopy were used to confirm the absence of drug crystallinity on the tablet surface before and after dissolution study.

Results

In solid state, KTZ is completely miscible with PVP, PVP-VA, or HPMC-AS, demonstrated by the negative χ values of ?0.36, ?0.46, ?1.68, respectively; while is poorly miscible with HPMC shown by a positive χ value of 0.23. According to solution ¹³C NMR and FT-IR studies, KTZ interacts with HPMC-AS strongly through H-bonding and dipole induced interaction; with PVPs and PVP-VA moderately through dipole-induced interactions; and with HPMC weakly without detectable attractive interaction. Furthermore, the “apparent” strength of drug-polymer interaction, measured by the extent of peak shift on NMR or FT-IR spectra, increases with the increasing number of interacting drug-polymer pairs. For ASDs with the presence of considerable drug-polymer interactions, such as KTZ/PVPs, KTZ/PVP-VA, or KTZ /HPMC-AS systems, drug released at the same rate as the polymer when intimate drug-polymer mixing was ensured (i.e., the SDD systems); while drug released much slower than the polymer when molecular level mixing or drug-polymer interaction was absent (SDD-PB systems). For ASDs without drug-polymer interaction (i.e., KTZ/HPMC systems), the mixing homogeneity had little impact on the release rate of either the drug or the polymer thus SDD and SDD-PB demonstrated the same drug or polymer release rate, while the drug released slowly and independently of polymer release.

Conclusions

The initial drug release from an ASD was controlled by 1) the polymer release rate; 2) the strength of drug-polymer interaction, including the intrinsic interaction caused by the chemistry of the drug and the polymer (measured by the χ value), as well as that the apparent interaction caused by the drug-polymer ratio (measure by the extent of peak shift on spectroscopic analysis); and 3) the level of mixing homogeneity between the drug and polymer. In summary, the selection of polymer, drug-polymer ratio, and ASD processing conditions have profound impacts on the dissolution behavior of ASDs.

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Graphical Abstract Relationship between initial drug and polymer dissolution rates from amorphous solid dispersions with different mixing uniformity and drug-polymer interactions

     

Impact of Drug-Polymer Miscibility on Enthalpy Relaxation of Irbesartan Amorphous Solid Dispersions

Purpose

Drug-polymer miscibility has been proposed to play a critical role in physical stability of amorphous solid dispersions (ASDs). The purpose of the current work was to investigate the role of drug-polymer miscibility on molecular mobility, measured as enthalpy relaxation (ER) of amorphous irbesartan (IBS) in ASDs.

Methods

Two polymers, i.e. polyvinylpyrrolidone K30 (PVP K30) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), were used to generate ASDs with 10% w/w of the polymer. Drug-polymer miscibility was determined using melting point depression (MPD) method. Molecular mobility was assessed from ER studies at a common degree of undercooling (DOU) (T_g???13.0°C?±?0.5°C).

Results

IBS exhibited higher miscibility in PVP K30 as compared to HPMCAS at temperature?>?140°C. However, extrapolation of miscibility data to storage temperature (62°C) using Flory-Huggins (F-H) theory revealed a reversal of the trend. Miscibility of IBS was found to be higher in HPMCAS (2.6%) than PVP K30 (1.3%) at 62°C. Stretched relaxation time (τ^β) of 17.4365 h and 7.0886 h was obtained for IBS-HPMCAS and IBS-PVP K30 ASDs, respectively.

Conclusion

Miscibility of drug-polymer at storage temperature explained the behavior of the molecular mobility, while miscibility near the melting point provided a reverse trend. Results suggest that drug-polymer miscibility determined at temperatures higher than the storage temperature should be viewed cautiously.

     

Immediate Release 3D-Printed Tablets Produced Via Fused Deposition Modeling of a Thermo-Sensitive Drug

Purpose

Dissolution speeds of tablets printed via Fused Deposition Modeling (FDM) so far are significantly lower compared to powder or granule pressed immediate release tablets. The aim of this work was to print an actual immediate release tablet by choosing suitable polymers and printing designs, also taking into account lower processing temperatures (below 100°C) owing to the used model drug pantoprazole sodium.

Methods

Five different pharmaceutical grade polymers polyvinylpyrrolidone (PVP K12), polyethylene glycol 6000 (PEG 6000), Kollidon® VA64, polyethylene glycol 20,000 (PEG 20,000) and poloxamer 407 were successfully hot-melt-extruded to drug loaded filaments and printed to tablets at the required low temperatures.

Results

Tablets with the polymers PEG 6000 and PVP K12 and with a proportion of 10% pantoprazole sodium (w/w) demonstrated a fast drug release that was completed within 29 min or 10 min, respectively. By reducing the infill rate of PVP tablets to 50% and thereby increase the tablet porosity it was even possible to reduce the mean time for total drug release to only 3 min.

Conclusions

The knowledge acquired through this work might be very beneficial for future FDM applications in the field of immediate release tablets especially with respect to thermo-sensitive drugs.

     

Dissolution Performance of High Drug Loading Celecoxib Amorphous Solid Dispersions Formulated with Polymer Combinations

Purpose

The aims of this study were twofold. First, to evaluate the effectiveness of selected polymers in inhibiting solution crystallization of celecoxib. Second, to compare the release rate and crystallization tendency of celecoxib amorphous solid dispersions (ASDs) formulated with a single polymer, or binary polymer combinations.

Methods

The effectiveness of polymers, polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) or HPMC acetate succinate (HPMCAS), in maintaining supersaturation of celecoxib solutions was evaluated by performing nucleation induction time measurements. Crystallization kinetics of ASD suspensions were monitored using Raman spectroscopy. Dissolution experiments were carried out under non-sink conditions.

Results

Pure amorphous celecoxib crystallized rapidly through both matrix and solution pathways. Matrix and solution crystallization was inhibited when celecoxib was molecularly mixed with a polymer, resulting in release of the drug to form supersaturated solutions. Cellulosic polymers were more effective than PVP in maintaining supersaturation. Combining a cellulosic polymer and PVP enabled improved drug release and stability to crystallization.

Conclusions

Inclusion of an effective solution crystallization inhibitor as a minor component in ternary dispersions resulted in prolonged supersaturation following dissolution. This study shows the feasibility of formulation strategies for ASDs where a major polymer component is used to achieve one key property e.g. release, while a minor polymer component is added to prevent crystallization.

     

Rheological Characterization of Molten Polymer-Drug Dispersions as a Predictive Tool for Pharmaceutical Hot-Melt Extrusion Processability

Purpose

The aim of this study was to investigate (i) the influence of drug solid-state (crystalline or dissolved in the polymer matrix) on the melt viscosity and (ii) the influence of the drug concentration, temperature and shear rate on polymer crystallization using rheological tests.

Methods

Poly (ethylene oxide) (PEO) (100.000 g/mol) and physical mixtures (PM) containing 10–20–30–40% (w/w) ketoprofen or 10% (w/w) theophylline in PEO were rheologically characterized. Rheological tests were performed (frequency and temperature sweeps in oscillatory shear as well as shear-induced crystallization experiments) to obtain a thorough understanding of the flow behaviour and crystallization of PEO-drug dispersions.

Results

Theophylline did not dissolve in PEO as the complex viscosity (η*) of the drug-polymer mixture increased as compared to that of neat PEO. In contrast, ketoprofen dissolved in PEO and acted as a plasticizer, decreasing η*. Acting as a nucleating agent, theophylline induced the crystallization of PEO upon cooling from the melt. On the other hand, ketoprofen inhibited crystallization upon cooling. Moreover, higher concentrations of ketoprofen in the drug-polymer mixture increasingly inhibited polymer crystallization. However, shear-induced crystallization was observed for all tested mixtures containing ketoprofen.

Conclusion

The obtained rheological results are relevant for understanding and predicting HME processability (e.g., barrel temperature selection) and downstream processing such as injection moulding (e.g., mold temperature selection).

     

The Combined Use of Imaging Approaches to Assess Drug Release from Multicomponent Solid Dispersions

Purpose

Imaging methods were used as tools to provide an understanding of phenomena that occur during dissolution experiments, and ultimately to select the best ratio of two polymers in a matrix in terms of enhancement of the dissolution rate and prevention of crystallization during dissolution.

Methods

Magnetic resonance imaging, ATR-FTIR spectroscopic imaging and Raman mapping have been used to study the release mechanism of a poorly water soluble drug, aprepitant, from multicomponent amorphous solid dispersions. Solid dispersions were prepared based on the combination of two selected polymers - Soluplus, as a solubilizer, and PVP, as a dissolution enhancer. Formulations were prepared in a ratio of Soluplus:PVP 1:10, 1:5, 1:3, and 1:1, in order to obtain favorable properties of the polymer carrier.

Results

The crystallization of aprepitant during dissolution has occurred to a varying degree in the polymer ratios 1:10, 1:5, and 1:3, but the increasing presence of Soluplus in the formulation delayed the onset of crystallization. The Soluplus:PVP 1:1 solid dispersion proved to be the best matrix studied, combining the abilities of both polymers in a synergistic manner.

Conclusions

Aprepitant dissolution rate has been significantly enhanced. This study highlights the benefits of combining imaging methods in order to understand the release process.

     

Polymer/Amorphous Salt Solid Dispersions of Ciprofloxacin

Purpose

To improve the pharmaceutical properties of amorphous ciprofloxacin (CIP) succinate salts via formulation as polymer/amorphous salt solid dispersions (ASSDs).

Methods

ASSDs consisting of an amorphous CIP/succinic acid 1:1 or 2:1 salt dispersed in PVP or Soluplus were produced by spray drying and ball milling. The solid state characteristics, miscibility, stability, solubility and passive transmembrane permeability of the ASSDs were then examined.

Results

The ASSDs had higher glass transition and crystallization temperatures than the corresponding amorphous succinate salts, and were also more stable during long-term stability studies. The results of inverse gas chromatography and thermal analysis indicated that the salts and polymers form a miscible mixture. The solubility of the pure drug in water and biorelevant media was significantly increased by all of the formulations. The permeability of the ASSDs did not differ significantly from that of the amorphous CIP succinate salts, however all samples were less permeable than the pure crystalline drug.

Conclusions

The formulation of amorphous CIP succinate salts as ASSDs with polymer improved their long-term stability, but did not significantly affect their solubility or permeability.

     

Solid-State NMR Investigation of Drug-Excipient Interactions and Phase Behavior in Indomethacin-Eudragit E Amorphous Solid Dispersions

Purpose

To investigate the nature of drug-excipient interactions between indomethacin (IMC) and methacrylate copolymer Eudragit® E (EE) in the amorphous state, and evaluate the effects on formulation and stability of these amorphous systems.

Methods

Amorphous solid dispersions containing IMC and EE were spray dried with drug loadings from 20% to 90%. PXRD was used to confirm the amorphous nature of the dispersions, and DSC was used to measure glass transition temperatures (T_g). ¹³C and ¹⁵N solid-state NMR was utilized to investigate changes in local structure and protonation state, while ¹H T₁ and T_1ρ relaxation measurements were used to probe miscibility and phase behavior of the dispersions.

Results

T_g values for IMC-EE solid dispersions showed significant positive deviations from predicted values in the drug loading range of 40–90%, indicating a relatively strong drug-excipient interaction. ¹⁵N solid-state NMR exhibited a change in protonation state of the EE basic amine, with two distinct populations for the EE amine at ?360.7 ppm (unprotonated) and ?344.4 ppm (protonated). Additionally, ¹H relaxation measurements showed phase separation at high drug load, indicating an amorphous ionic complex and free IMC-rich phase. PXRD data showed all ASDs up to 90% drug load remained physically stable after 2 years.

Conclusions

¹⁵N solid-state NMR experiments show a change in protonation state of EE, indicating that an ionic complex indeed forms between IMC and EE in amorphous solid dispersions. Phase behavior was determined to exhibit nanoscale phase separation at high drug load between the amorphous ionic complex and excess free IMC.

     

A Lower Temperature FDM 3D Printing for the Manufacture of Patient-Specific Immediate Release Tablets

Purpose

The fabrication of ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing.

Methods

Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of the drugs and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus.

Results

Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication of immediate release tablets at temperatures as low as 110°C. The integrity of two model drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in-batch variability and an immediate in vitro release pattern.

Conclusions

Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms.

     

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.

     

Physical Stability of Amorphous Solid Dispersions: a Physicochemical Perspective with Thermodynamic,Kinetic and Environmental Aspects

Purpose

Amorphous solid dispersions (ASDs) have been widely used in the pharmaceutical industry for solubility enhancementof poorly water-soluble drugs. The physical stability, however, remainsone of the most challenging issues for the formulation development.Many factors can affect the physical stability via different mechanisms, and therefore an in-depth understanding on these factors isrequired.

Methods

In this review, we intend to summarize the physical stability of ASDsfrom a physicochemical perspective whereby factors that can influence the physical stability areclassified into thermodynamic, kinetic and environmental aspects.

Results

The drug-polymer miscibility and solubility are consideredas the main thermodynamicfactors which may determine the spontaneity of the occurrence of the physical instabilityof ASDs. Glass-transition temperature,molecular mobility, manufacturing process,physical stabilityof amorphous drugs, and drug-polymerinteractionsareconsideredas the kinetic factors which areassociated with the kinetic stability of ASDs on aging. Storage conditions including temperature and humidity could significantly affect the thermodynamicand kineticstabilityof ASDs.

Conclusion

When designing amorphous solid dispersions, it isrecommended that these thermodynamic, kinetic and environmental aspects should be completely investigatedand compared to establish rationale formulations for amorphous solid dispersions with high physical stability.

     

Fabricating a Shell-Core Delayed Release Tablet Using Dual FDM 3D Printing for Patient-Centred Therapy

Purpose

Individualizing gastric-resistant tablets is associated with major challenges for clinical staff in hospitals and healthcare centres. This work aims to fabricate gastric-resistant 3D printed tablets using dual FDM 3D printing.

Methods

The gastric-resistant tablets were engineered by employing a range of shell-core designs using polyvinylpyrrolidone (PVP) and methacrylic acid co-polymer for core and shell structures respectively. Filaments for both core and shell were compounded using a twin-screw hot-melt extruder (HME). CAD software was utilized to design a capsule-shaped core with a complementary shell of increasing thicknesses (0.17, 0.35, 0.52, 0.70 or 0.87 mm). The physical form of the drug and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC.

Results

A shell thickness ≥0.52 mm was deemed necessary in order to achieve sufficient core protection in the acid medium. The technology proved viable for incorporating different drug candidates; theophylline, budesonide and diclofenac sodium. XRPD indicated the presence of theophylline crystals whilst budesonide and diclofenac sodium remained amorphous in the PVP matrix of the filaments and 3D printed tablets. Fabricated tablets demonstrated gastric resistant properties and a pH responsive drug release pattern in both phosphate and bicarbonate buffers.

Conclusions

Despite its relatively limited resolution, FDM 3D printing proved to be a suitable platform for a single-process fabrication of delayed release tablets. This work reveals the potential of dual FDM 3D printing as a unique platform for personalising delayed release tablets to suit an individual patient’s needs.

     

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.

     

<Emphasis Type="BoldItalic">In Vitro</Emphasis> Skin Retention and Drug Permeation through Intact and Microneedle Pretreated Skin after Application of Propranolol Loaded Microemulsions

Purpose

Topical beta-blockers are efficacious for treating infantile hemangiomas, but no formulations have been specifically optimized for skin delivery. Our objective was to quantify skin concentrations and drug permeation of propranolol (a nonselective beta-blocker) after application of microemulsions to intact and microneedle pretreated skin.

Methods

Four propranolol-loaded microemulsions were characterized for droplet size, surface charge, conductivity, pH, drug solubility, and drug release. Skin concentrations and drug permeation through skin were quantified using LC-MS. Skin-to-receiver ratios were used to compare the microemulsion formulations to a drug-in-PBS solution.

Results

Propranolol solubility was significantly greater in microemulsions vs PBS. Cumulative drug release from the microemulsions over 24 h ranged from 13 to 26%. Skin concentrations and drug permeation through intact skin was significantly higher from PBS; however, the skin-to-receiver ratios were significantly higher for water-rich microemulsions compared to PBS or surfactant-rich microemulsions. Microneedle pretreatment significantly increased skin concentrations for all formulations. Skin-to-receiver ratios significantly increased after microneedle pretreatment for surfactant-rich microemulsions.

Conclusions

Microemulsion formulation can be altered to elicit different drug delivery profiles through MN-treated skin. This could be advantageous for maximizing local skin drug concentrations and improving dosing schedules for infantile hemangioma treatment.

     

Temperature-Induced Surface Effects on Drug Nanosuspensions

Purpose

The trial-and-error approach is still predominantly used in pharmaceutical development of nanosuspensions. Physicochemical dispersion stability is a primary focus and therefore, various analytical bulk methods are commonly employed. Clearly less attention is directed to surface changes of nanoparticles even though such interface effects can be of pharmaceutical relevance. Such potential effects in drug nanosuspensions were to be studied for temperatures of 25 and 37°C by using complementary surface analytical methods.

Methods

Atomic force microscopy, inverse gas chromatography and UV surface dissolution imaging were used together for the first time to assess pharmaceutical nanosuspensions that were obtained by wet milling. Fenofibrate and bezafibrate were selected as model drugs in presence of sodium dodecyl sulfate and hydroxypropyl cellulose as anionic and steric stabilizer, respectively.

Results

It was demonstrated that in case of bezafibrate nanosuspension, a surface modification occurred at 37°C compared to 25°C, which notably affected dissolution rate. By contrast, no similar effect was observed in case of fenofibrate nanoparticles.

Conclusions

The combined usage of analytical surface methods provides the basis for a better understanding of phenomena that take place on drug surfaces. Such understanding is of importance for pharmaceutical development to achieve desirable quality attributes of nanosuspensions.

     

Effect of Nanoparticle Surface on the HPLC Elution Profile of Liposomal Nanoparticles

Purpose

Nanoparticles have been used in diverse areas, and even broader applications are expected in the future. Since surface modification can influence the configuration and toxicity of nanoparticles, a rapid screening method is important to ensure nanoparticle quality.

Methods

We examined the effect of the nanoparticle surface morphology on the HPLC elution profile using two types of 100-nm liposomal nanoparticles (AmBisome^? and DOXIL^?).

Results

These 100-nm-sized nanoparticles eluted before the holdup time (about 4 min), even when a column packed with particles with a relatively large pore size (30 nm) was used. The elution time of the nanoparticles increased with pegylation of the nanoparticles and protein adsorption to the nanoparticles; however, the nanoparticles still eluted before the holdup time.

Conclusions

The results of this study indicate that HPLC is a suitable tool for rapid evaluation of the surface of liposomal nanoparticles.

     

Polymorphic Transformation of Indomethacin during Hot Melt Extrusion Granulation: Process and Dissolution Control

Purpose

To study and elucidate the effect of the intensity and duration of processing stresses on the possible solid-state changes during a hot melt extrusion granulation process.

Methods

Blends of α-indomethacin and PEG 3350 (w/w 4:1) were granulated using various screw sizes/designs on the melt extruder under different temperature regimes. Differential Scanning Calorimetry and X-ray Powder Diffraction were employed for characterization. The dissolution behavior of the pure polymorphs and the resulting granules was determined using in-situ fiber optic UV testing system. An XRPD quantitation method using Excel full pattern fitting was developed to determine the concentration of each constituent (amorphous, α and γ indomethacin and PEG) in samples collected from each functioning zone and in granules.

Results

Analysis of in-process samples and granules revealed that higher temperature (≥130°C) and shear stress accelerated the process induced phase transitions from amorphous and/or the α form to γ indomethacin during heating stage. However, rapid cooling resulted in an increased percentage of the α form allowing isolation of the meta-stable form.

Conclusions

By determining the conditions that either prevent or facilitate process induced transformations of IMC polymorphs during melt granulation, a design space was developed to control the polymorph present in the resulting granules. This represents the conditions necessary to balance the thermodynamic relationships between the polymorphs of the IMC system and the kinetics of the possible transformations as a function of the processing stresses.

     

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.

     

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.