An evaluation of naloxone transit for opioid overdose using drones: A case study using real-world coroner data.

BACKGROUND AND AIMS: Opioids are now the most cited class in fatal overdoses. However, the antidote for opioid overdose-naloxone-is not always readily available. Our aim was to evaluate the feasibility of naloxone transit via drone to provide rapid access at the point of care. METHODS AND FINDINGS: Real-world data pertaining to opioid overdoses, which occurred in the Teesside area of the UK 2015-2019, were extracted from the National Programme on Substance Abuse Deaths (NPSAD). The original locations of these opioid overdoses were used to compare the projected response times of ambulances with that of drones when considering the impacts of actual traffic and weather conditions, respectively; 58 cases were identified where a bystander-who could have called for and administered emergency naloxone-was likely present. RESULTS: In 78% of cases (n = 45/58) a class C1 commercial-off-the-shelf drone carrying naloxone could have reached the overdose location in 7 min-the benchmark time for the arrival of emergency services for Category 1 calls in England. With the implementation of recent advances in drone engineering, such as increased speeds and temperature-controlled cargo cradles, it is estimated that 98% of overdoses could have been reached in this timeframe (n = 57/58). Ambulances were able to reach a significantly lower number of cases in 7 min, even when considering best-case scenario traffic conditions (14%, n = 8/58, χ2 P < 0.001). CONCLUSIONS: This study provides proof-of-concept that, in the Teesside area of the UK, drones are more likely than ambulance to get naloxone to the site of an opioid overdose in 7 min.

Laser-cutting: A novel alternative approach for point-of-care manufacturing of bespoke tablets.

A novel subtractive manufacturing method to produce bespoke tablets with immediate and extended drug release is presented. This is the first report on applying fusion laser cutting to produce bespoke furosemide solid dosage forms based on pharmaceutical-grade polymeric carriers. Cylindric tablets of different sizes were produced by controlling the two-dimensional design of circles of the corresponding diameter. Immediate and extended drug release patterns were achieved by modifying the composition of the polymeric matrix. Thermal analysis and XRD indicated that furosemide was present in an amorphous form. The laser-cut tablets demonstrated no significant drug degradation (<2%) nor the formation of impurities were identified. Multi-linear regression was used to quantify the influences of laser-cutting process parameters (laser energy levels, scan speeds, and the number of laser applications) on the depth of the laser cut. The utility of this approach was exemplified by manufacturing tablets of accurate doses of furosemide. Unlike additive or formative manufacturing, the reported approach of subtractive manufacturing avoids the modification of the structure, e.g., the physical form of the drug or matrix density of the tablet during the production process. Hence, fusion laser cutting is less likely to modify critical quality attributes such as release patterns or drug contents. In a point-of-care manufacturing scenario, laser cutting offers a significant advantage of simplifying quality control and a real-time release of laser-cut products such as solid dosage forms and implants.

Non-salt based co-amorphous formulation produced by freeze-drying.

Amino acids-based co-amorphous system (CAM) has shown to be a promising approach to overcome the dissolution challenge of biopharmaceutics classification system class II drugs. To date, most CAM formulations are based on salt formation at a 1:1 M ratio and are prepared by mechanical activation. However, its use in medicinal products is still limited due to the lack of in-depth understanding of non-ionic based molecular interactions. There are also limited studies on the effect of drug-to-co-former ratio, the development of more scalable, less aggressive, manufacturing processes such as freeze drying and its dissolution benefits. This work aims to investigate the effect of the ratio of tryptophan (a model non-ionic amino acid) to indomethacin (a model drug) on a non-salt-based CAM prepared via freeze-drying with the tert-butyl alcohol-water cosolvent system. The CAM material was systemically characterized at various stages of the freeze-drying process using DSC, UV-Vis, FT-IR, NMR, TGA and XRPD. Dissolution performance and physical stability upon storage were also investigated. Freeze-drying using the cosolvent system has been successfully shown to produce CAMs. The molecular interactions involving H-bonding, H/π and π-π between compounds have been confirmed by FT-IR and NMR. The drug release rate for formulations with a 1.5:1 drug: amino acid molar ratio (or 1:0.42 wt ratio) or below is found to be significantly improved compared to the pure crystalline drug. Furthermore, formulation with a 2.3:1 drug:amino acid molar ratio (or 1:0.25 wt ratio) or below have shown to be physically stable for at least 9 months when stored at dry condition (5% relative humidity, 25 °C) compared to the pure amorphous indomethacin. We have demonstrated the potential of freeze-drying using tert-butyl alcohol-water cosolvent system to produce an optimal non-salt-based class II drug-amino acid CAM.

Computer numerical control (CNC) carving as an on-demand point-of-care manufacturing of solid dosage form: A digital alternative method for 3D printing.

Computer numerical control (CNC) carving is a widely used method of industrial subtractive manufacturing of wood, plastics, and metal products. However, there have been no previous reports of applying this approach to manufacture medicines. In this work, the novel method of tablet production using CNC carving is introduced for the first time. This report provides a proof-of-concept for applying subtractive manufacturing as an alternative to formative (powder compression) and additive (3D printing) manufacturing for the on-demand production of solid dosage forms. This exemplar manufacturing approach was employed to produce patient-specific hydrocortisone (HC) tablets for the treatment of children with congenital adrenal hyperplasia. A specially made drug-polymer cast based on polyethene glycol (PEG 6,000) and hydroxypropyl cellulose was produced using thermal casting. The cast was used as a workpiece and digitally carved using a small-scale 3-dimensional (3D) CNC carving. To establish the ability of this new approach to provide an accurate dose of HC, four different sizes of CNC carved tablet were manufactured to achieve HC doses of 2.5, 5, 7.5 and 10 mg with a relative standard deviation of the tablet weight in the range of 3.69-4.79%. In addition, batches of 2.5 and 5 mg HC tablets met the British Pharmacopeia standards for weight uniformity. Thermal analysis and X-ray powder diffraction indicated that the model drug was in amorphous form. In addition, HPLC analysis indicated a level of purity of 96.5 ± 1.1% of HC. In addition, the process yielded mechanically strong cylindrical tablets with tensile strength ranging from 0.49 to 1.6 MPa and friability values of <1%, whilst maintaining an aesthetic look. In vitro, HC release from the CNC-carved tablets was slower with larger tablet sizes and higher binder contents. This is the first report on applying CNC carving in the pharmaceutical context of producing solid dosage forms. The work showed the potential of this technology as an alternative method for the on-demand manufacturing of patient-specific dosage forms.

Investigating the influence of drone flight on the stability of cancer medicines.

Monoclonal Antibodies (mAbs) are being used in the treatment of both malignant and non-malignant diseases and whilst highly effective, certain products have very short expiry times. Clinical deterioration and supply chain disruption can often lead to wastage and there is a need to reduce this by improving efficiency in logistics practices between manufacturing sites and administration locations. This study aimed to investigate the influence of drone flight on the stability of cancer medicines. Clinically expired, premanufactured monoclonal antibodies (mAbs) were investigated, contained inside instrumented Versapaks, and flown in a Skylift (Mugin) V50 vertical take-off and landing drone through seven phases of flight, (take-off, hover, transition, cruise, transition, hover, and landing). Storage specifications (2-8°C) were met, and any vibrations emanating from the drone and transmitted through the packaging during flight were monitored using accelerometers. Vibration occurred largely above 44 Hz which was consistent with rotor speeds during operation and was significantly greater in amplitude during transition than in forward flight or in hover. Bench experiments validated assurance practices, exploring the edge-of-quality failure by applying extremes of rotational vibration to the mAbs. Aggregation and fragmentation represented a loss of quality in the mAbs and would pose a risk to patient safety. No significant difference was identified in the aggregation and fragmentation of all flown mAbs samples, indicating structural integrity. Flown mAbs in their infusion bags had similar particle sizes compared to controls, (Bevacizumab 11.8±0.17 nm vs. 11.6±0.05 nm, Trastuzumab 11.2±0.05 nm vs. 11.3±0.13 nm, Rituximab 11.4±0.27 nm vs. 11.5±0.05 nm) and aggregate content (Bevacizumab 1.25±0.03% vs 1.32±0.02% p = 0.11, Trastuzumab 0.15±0.06% vs. 0.16±0.06% p = 0.75, Rituximab 0.11±0.02% vs. 0.11±0.01% p = 0.73). The quality of the three mAbs was assured, suggesting that the V50 drone did not induce sufficient levels of vibration to adversely affect their quality.

A study of solid-state epimerisation within lactose powders and implications for milk derived ingredients stored in simulated tropical environmental zones.

Isolated from milk, lactose is a food ingredient and an excipient in medicines. Its chiral forms are known to undergo epimerisation in solution but understanding whether this chemical reaction occurs in lactose powders exposed to tropical environments is of great importance for medicine stability and food quality. Thus, the aim of this study was to investigate epimerisation within lactose powders stored under specified conditions that model hot and humid climates. Powdered α-lactose monohydrate was stable under all conditions, whereas ß-lactose stored at 40 °C and 75 % RH suffered epimerisation, falling to 3.9 ± 0.3 ß-content after 6-months. Zero-order kinetics observed by NMR, indicated a shelf-life (5 % degradation) of 4.55-days for ß-lactose containing powders. Thermal analysis revealed monohydrate formation as ß-lactose epimerised, seen as tomahawk shaped α-lactose monohydrate crystals by SEM. Therefore, it is recommended ß-rich lactose containing powders, e.g., infant formula or direct compression tablet formulations, are stored hermetically in tropical zones.

Design and manufacture of a lyophilised faecal microbiota capsule formulation to GMP standards.

Faecal microbiota transplant (FMT) is an established and effective treatment for recurrent Clostridioides difficile infection (CDI) and has many other potential clinical applications. However, preparation and quality of FMT is poorly standardised and clinical studies are hampered by a lack of well-defined FMT formulations that meet regulatory standards for medicines. As an alternative to FMT suspensions for administration by nasojejunal tube or colonoscopy, which is invasive and disliked by many patients, this study aimed to develop a well-controlled, standardised method for manufacture of lyophilised FMT capsules and to provide stability data allowing storage for extended time periods. Faecal donations were collected from healthy, pre-screened individuals, homogenised, filtered and centrifuged to remove dietary matter. The suspension was centrifuged to pellet bacteria, which were resuspended with trehalose and lyophilised to produce a powder which was filled into 5 enteric-coated capsules (size 0). Live-dead bacterial cell quantitative PCR assay showed <10 fold viable bacterial load reduction through the manufacturing process. No significant loss of viable bacterial load was observed after storage at -80 °C for 36 weeks (p = 0.24, n = 5). Initial clinical experience demonstrated that the capsules produced clinical cure in patients with CDI with no adverse events reported (n = 7). We provide the first report of a detailed manufacturing protocol and specification for an encapsulated lyophilised formulation of FMT. As clinical trials into intestinal microbiota interventions proceed, it is important to use a well-controlled investigational medicinal product in the studies so that any beneficial results can be replicated in clinical practice.

Mechanistic study of the solubilization effect of basic amino acids on a poorly water-soluble drug.

Amino acids have shown promising abilities to form complexes with poorly water-soluble drugs and improve their physicochemical properties for a better dissolution profile through molecular interactions. Salt formation via ionization between acidic drugs and basic amino acids is known as the major contributor to solubility enhancement. However, the mechanism of solubility enhancement due to non-ionic interactions, which is less pH-dependent, remains unclear. The aim of this study is to evaluate non-ionic interactions between a model acidic drug, indomethacin (IND), and basic amino acids, arginine, lysine and histidine, in water. At low concentrations of amino acids, IND-arginine and IND-lysine complexes have shown a linear relationship (AL-type phase solubility diagram) between IND solubility and amino acid concentration, producing ∼1 : 1 stoichiometry of drug-amino acid complexes as expected due to the strong electrostatic interactions. However, IND-histidine complexes have shown a nonlinear relationship with lower improvement in IND solubility due to the weaker electrostatic interactions when compared to arginine and lysine. Interestingly, the results have also shown that at high arginine concentrations, the linearity was lost between IND solubility and amino acid concentration with a negative diversion from linearity, following the type-AN phase solubility. This is indicative that the electrostatic interaction is being interrupted by non-electrostatic interactions, as seen with histidine. The IND-lysine complex, on the other hand, showed a complex curvature phase solubility diagram (type BS) as lysine self-assembles and polymerizes at higher concentrations. The freeze-dried drug-amino acid solids were further characterized using thermal analysis and infrared spectroscopy, with results showing the involvement of weak non-ionic interactions. This study shows that the solubility improvement of an insoluble drug in the presence of basic amino acids was due to both non-ionic and ionic interactions.

Evaluation of Latent Fingerprints for Drug Screening in a Social Care Setting.

Sweat deposited via latent fingerprints (LFPs) was previously used to detect cocaine, opioids, cannabis and amphetamine via a point-of-care test (POCT). This screening method combined non-invasive sampling with a rapid result turnaround to produce a qualitative result outside of the laboratory. We report the novel application of a LFP drug screening test in a social care setting. Clients were tested on either an ad hoc or a routine basis using the POCT DOA114 (Intelligent Fingerprinting Ltd) drug screening cartridge. Screening cutoff values were 45, 35 and 95 pg/fingerprint for benzoylecgonine (BZE), morphine and amphetamine analytes, respectively. Confirmation LFP samples (DOA150, Intelligent Fingerprinting Ltd) and oral fluid (OF) were analyzed using ultra-performance liquid chromatography with tandem mass spectrometry. Thirty-six clients aged 36 ± 11 years participated (53% females). Individuals self-reported alcohol consumption (39%) and smoking (60%). Of 131 screening tests collected over 8 weeks, 14% tested positive for cocaine, 2% tested positive for opioids and 1% tested positive for amphetamine. Polydrug use was indicated in 10% of tests. Of 32 LFP confirmation tests, 63% were positive for cocaine and BZE. Opioids were also detected (31%), with the metabolite 6-monoacetylmorphine (6-MAM) being the most common (16%). In OF, cocaine was the dominant analyte (9%) followed by 6-MAM (5%). On comparing positive LFP screening tests with positive OF samples, we found that 39% and 38% were cocaine and opiate positive, respectively. Of the drugs screened for via the LFP POCT, cocaine was the most prevalent analyte in LFP and OF confirmation samples. The study is a step change in the routine drug screening procedures in a social care setting, especially useful for on-site cocaine detection in clients whose drug use was being monitored. Additionally, testing was easily accepted by clients and social care workers.

Development of a point-of-care test for the detection of MDMA in latent fingerprints using surface plasmon resonance and lateral flow technology.

To date, a specific point-of-care test (POCT) for 3,4-methylenedioxymethamphetamine (MDMA, ecstasy, 'E') in latent fingerprints (LFPs) has not been explored. Other POCTs identify MDMA in sweat by detecting the drug as a cross-reactant rather than target analyte, thus decreasing the test's sensitivity. The study's aim was to design a sensitive POCT for the detection of MDMA in LFPs using surface plasmon resonance (SPR) and lateral flow immunoassay (LFA) technology. A high-affinity antibody binding pair was identified using the former technique, deeming the pair suitable for a LFA. Titrations of fluorescently labelled antibody and antigen concentrations were tested to identify a sharp drop-in signal upon the addition of MDMA to allow a clear distinction between negative and positive outcomes. We trialled the LFA by producing dose response curves with MDMA and a group of drugs that share a similar chemical structure to MDMA. These were generated through spiking the LFA with increasing levels of drug (0-400 pg/10 µl of MDMA; 0-10,000 pg/10 µl of cross-reactant). Fluorescent test signals were measured using a cartridge reader. The cut-off (threshold) 60 pg/10 µl calculated better cartridge performance (1.00 sensitivity, 0.95 specificity and 0.98 accuracy), when compared with 40 pg/10 µl. The biggest cross-reactant was PMMA (250%), followed by MDEA (183%), MBDB (167%), MDA (16%) and methamphetamine (16%). A sensitive LFP screening tool requiring no sample preparation was successfully designed.

Digital Image Disintegration Analysis: a Novel Quality Control Method for Fast Disintegrating Tablets.

Measuring tablet disintegration is essential for quality control purposes; however, no established method adequately accounts for the timeframe or small volumes of the medium associated with the dissipation process for fast disintegrating tablets (FDTs) in the mouth. We hypothesised that digital imaging to measure disintegration in a low volume of the medium might discriminate between different types of FTD formulation. A digital image disintegration analysis (DIDA) was designed to measure tablet disintegration in 0.05-0.7 mL of medium. A temperature-controlled black vessel was 3D-printed to match the dimensions of each tablet under investigation. An overhead camera recorded the mean grey value of the tablet as a measure of the percentage of the formulation which remained intact as a function of time. Imodium Instants, Nurofen Meltlets and a developmental freeze-dried pilocarpine formulation were investigated. The imaging approach proved effective in discriminating the disintegration of different tablets (p < 0.05). For example, 10 s after 0.7 mL of a saliva simulant was applied, 2.0 ± 0.3% of the new pilocarpine tablet remained, whereas at the same time point, 22 ± 9% of the Imodium Instants had not undergone disintegration (temperature within the vessel was 37 ± 0.5°C). Nurofen Meltlets were observed to swell and showed a percentage recovery of 120.7 ± 2.4% and 135.0 ± 6.1% when 0.05 mL and 0.7 mL volumes were used, respectively. Thus, the new digital image disintegration analysis, DIDA, reported here effectively evaluated fast disintegrating tablets and has the potential as a quality control method for such formulations.

Stability of α-lactose monohydrate: The discovery of dehydration triggered solid-state epimerization.

Lactose is present as an excipient in nearly half of all solid medicines. Despite the assumption of chemical stability, in aqueous solution, the chiral composition of lactose is prone to change. It is not known whether such epimerisation could also occur as solid crystalline α-lactose undergoes thermal desorption of its hydrated water. Thus, the aim of this study was to investigate the anomeric composition of lactose powders after heating in a differential scanning calorimeter. During thermal analysis, the heating cycles were interrupted to allow anomer-composition analysis by NMR. The onset for monohydrate desorption occurred at 143.8 ± 0.3 °C. Post water-loss, at 160 °C for example, α-lactose suffered partial conversion (11.6 ± 0.9%) to the ß-anomer. When held at 160 °C for 60 min this increased to 29.7 ± 0.8% ß-anomer (p < 0.05). This process of epimerisation was found to be close to zero-order with a rate constant of 0.28% per min-1. Optical microscopy indicated that the solid-state was maintained throughout thermal desorption and up to the onset of melting at 214.2 ± 0.9 °C. Only epimerisation was observed, with no additional chemical degradation detected by NMR. Similar results were observed when heating α-lactose to 190 °C, which resulted in a conversion of 29.1 ± 0.7% to ß-lactose. Thus, the exothermic peak observed after monohydrate loss, which has often been attributed to re-crystallisation, comprises a contribution from epimerisation. No epimerisation or hydrate loss was observed for ß-lactose powders when heated. In summary, it has been shown unequivocally for the first time that hydrate desorption (dehydration) leads to solid-state epimerisation in α-lactose powders.

Polyelectrolyte Multi-Layered Griseofulvin Nanoparticles: Conventional versus Continuous In-Situ Layer-by-Layer Fabrication.

Polyelectrolyte multilayers are promising drug carriers with potential applications in the delivery of poorly soluble drugs. Furthermore, the polyelectrolyte multilayer contributes towards electrostatic interactions, which enhances the physical and chemical stability of colloids when compared to those prepared by other approaches. The aim of this work was to generate a polyelectrolyte multilayer on well characterised nanoparticles of the poorly water-soluble drug, griseofulvin. Griseofulvin (GF) nanoparticles (300 nm) were produced by wet bead milling, bearing a negative surface charge due to the use of poly(sodium 4-styrenesulfonate) (PSS) as a stabiliser. Six further layers of alternating chitosan and PSS polyelectrolyte multilayer were successfully generated at the particle surface either via use of: (1) the conventional method of adding excess coating polymer followed by centrifugation, or (2) the continuous in situ approach of adding sufficient amount of coating polymer. The continuous in situ method was designed de novo by the consecutive addition of polymers under high shear rate mixing. In comparison to the continuous in situ method, the conventional method yielded nanoparticles of smaller size (282 ±9 nm vs. 497 ±34 nm) and higher stability by maintaining its size for 6 months. In conclusion, the parent griseofulvin nanosuspension proved to be a suitable candidate for the polyelectrolyte multilayer fabrication providing an avenue for a bespoke formulation with versatile and potentially enhanced drug delivery properties.

Repurposing Melt Degradation for the Evaluation of Mixed Amorphous-Crystalline Blends.

Medicine regulators require the melting points for crystalline drugs, as they are a test for chemical and physical quality. Many drugs, especially salt-forms, suffer concomitant degradation during melting; thus, it would be useful to know if the endotherm associated with melt degradation may be used for characterising the crystallinity of a powder blend. Therefore, the aim of this study was to investigate whether melt-degradation transitions can detect amorphous content in a blend of crystalline and amorphous salbutamol sulphate. Salbutamol sulphate was rendered amorphous by freeze and spray-drying and blended with crystalline drug, forming standards with a range of amorphous content. Crystalline salbutamol sulphate was observed to have a melt-degradation onset of 198.2±0.2°C, while anhydrous amorphous salbutamol sulphate prepared by either method showed similar glass transition temperatures of 119.4±0.7°C combined. Without the energy barrier provided by the ordered crystal lattice, the degradation endotherm for amorphous salbutamol sulphate occurred 50°C below the melting point, with an onset of 143.6±0.2°C. The enthalpies for this degradation transition showed no significant difference between freeze- and spray-dried samples (p>0.05). Distinct from convention, partial integration of the crystalline melt-degradation endotherm was applied to the region 193-221°C which had no contribution from the degradation of amorphous salbutamol sulphate. The linear correlation of these partial areas with amorphous content, R2=0.994, yielded limits of detection and quantification of 0.13% and 0.44% respectively, independent of drying technique. Melt-degradation transitions may be re-purposed for the measurement of amorphous content in powder blends, and they have potential for evaluating disorder more generally.

A Cyclodextrin-Stabilized Spermine-Tagged Drug Triplex that Targets Theophylline to the Lungs Selectively in Respiratory Emergency.

Ion-pairing a lifesaving drug such as theophylline with a targeting moiety could have a significant impact on medical emergencies such as status asthmaticus or COVID-19 induced pneumomediastinum. However, to achieve rapid drug targeting in vivo the ion-pair must be protected against breakdown before the entry into the target tissue. This study aims to investigate if inserting theophylline, when ion-paired to the polyamine transporter substrate spermine, into a cyclodextrin (CD), to form a triplex, could direct the bronchodilator to the lungs selectively after intravenous administration. NMR demonstrates that upon the formation of the triplex spermine protruded from the CD cavity and this results in energy-dependent uptake in A549 cells (1.8-fold enhancement), which persists for more than 20 min. In vivo, the triplex produces a 2.4-fold and 2.2-fold increase in theophylline in the lungs 20 min after injection in rats and mice, respectively (p < 0.05). The lung targeting is selective with no increase in uptake into the brain or the heart where the side-effects of theophylline are treatment-limiting. Selectively doubling the concentration of theophylline in the lungs could improve the benefit-risk ratio of this narrow therapeutic index medicine, which continues to be important in critical care.

A novel natural GRAS-grade enteric coating for pharmaceutical and nutraceutical products.

In this study, enteric coatings based exclusively on naturally occurring ingredients were reported. Alginate (Alg) and pectin (Pec) blends with or without naturally occurring glyceride, glycerol monostearate (GMS), were initially used to produce solvent-casted films. Incorporating GMS in the natural polymeric films significantly enhanced the acid-resistance properties in gastric medium. Theophylline tablets coated with Alg-Pec blends without GMS disintegrated shortly after incubation in gastric medium (pH 1.2), leading to a premature and complete release of theophylline. Interestingly, tablets coated with Alg-Pec blends that contain the natural glyceride (GMS) resisted the gastric environment for 2 h with minimal drug release (<5%) and disintegrated rapidly following introduction to the intestinal medium, allowing a fast and complete drug release. Furthermore, the coating system proved to be stable for six months under accelerated conditions. These findings are particularly appealing to nutraceutical industry as they provide the foundation to produce naturally-occurring GRAS based enteric coatings.

Solid-state epimerisation and disproportionation of pilocarpine HCl: Why we need a 5-stage approach to validate melting point measurements for heat-sensitive drugs.

Melting points for new drugs are reported in regulatory documents, e.g. investigational brochures, and frequently in published research; however, the authors do not typically consider that heat-induced degradation can affect the melting point measurement. Applying a single heating rate is not adequate, and thus many melting points in the literature and regulatory documentation are not valid. Our aim was to validate a five-stage approach for the melting point measurement of heat-sensitive drugs. These stages are; (1) observe melting; (2) record mass loss; (3) measure melting points at different heating rates; (4) characterise degradation and (5) test for potential isomerisation. Applying this approach to pilocarpine HCl illustrated the sensitivity of a melting point to thermal degradation. Due to salt disproportionation & loss of HCl gas, pilocarpine's melting point decreased by 14 °C when the heating rate was lowered from 20 to 1 °C/min. Epimerization occurred before melting was reached. Increasing the heating rate diminished disproportionation; however, this did not remove epimerization. Thus, the melting point of pilocarpine HCl of 205.5 ± 0.4 °C measured at 20 °C/min represents the melt of a racemic mixture containing inactive isopilocarpine. Heating above the melting point accelerated degradation, a rate of 5 °C/min recovered just 38 ± 1% of pilocarpine. Such data predicted a shelf-life of 6.6 years. Pilocarpine successfully validated the multistage approach by providing new knowledge concerning its thermal stability. Our 5-stage approach must be applied to all new drugs especially if their formulation requires heat. For example, thermal stability is an infrequently considered pre-requisite in the emerging field of 3D printing.

Anti-counterfeiting DNA molecular tagging of pharmaceutical excipients: An evaluation of lactose containing tablets.

The licensed pharmaceutical industry and regulators use many approaches to control counterfeiting, but it remains a very difficult task to differentiate between counterfeit and real products. Moreover, there is a lack of techniques available for providing a batch specific molecular bar code for tablets that has the required traceability, specificity and sensitivity to be fit for purpose. The aim of this study was to evaluate DNA molecular tags as a potential anti-counterfeiting technology in tablets. Lactose tablets (400 mg) were used as a model to investigate incorporation DNA molecular tag into a solid dosage form: DNA authentication was carried out on an Applied DNA SigNify® qPCR instrument. Tablet batches were subjected to accelerated stability conditions (40 °C and 75% RH) for up to 6 months. All batches passed the monograph specifications of the British Pharmacopoeia (hardness, friability and mass uniformity) throughout the storage period. In all of recovery plots, the number of cycles required for DNA detection (Cq values) increased as a function of storage time, which indicated a reduction in tag levels, but it should be noted for all storage experiments the tag was clearly detected. It would appear that DNA molecular tags could feasibly be applied within the pharmaceutical development cycle when a new solid dosage form is brought to the market so as to mitigate the risk and dangers of counterfeiting.

Delivered Lung Dose and Aerodynamic Particle Size Distribution of Salbutamol Pressurized Metered Dose Inhaler After Living Under Patients' Realistic Retention Environments.

Background: The impact of inhalers' postdispensing, real-life temperature and relative humidity (RH) environments on their delivered dose (DD) and aerodynamic particle size distribution (APSD) is usually overlooked. This work evaluated the salbutamol DD and APSD of Ventolin® Evohaler® (V) inhalers already been used and stored by respiratory patients. Methods: Adult patients, prescribed V for ≥3 months before study enrollment, were dispensed both new V to use and portable, handheld electronic temperature and RH data loggers to keep close to the given V before returning them both after 2-3 weeks. Patients' enrollment took place during summer (VS) and winter (VW) seasons. The returned V was then in vitro evaluated using the Next Generation Impactor, and compared with control V (VC) counterparts stored under 21°C and 46% RH. Results: The VS survived in fluctuating habitats of 21.2°C-40.4°C and 16.2%-63.2% RH, which significantly (p < 0.05) decreased the salbutamol DD from 80.4 to 70.5 µg compared with VC. This 12.3% DD reduction was accompanied with a decrease in the fine particle dose from 26.2 to 20.4 µg (p < 0.05), and an increase in the mass median aerodynamic diameter from 2.3 to 2.5 µm (p < 0.05). The VW and VC had equivalent DD and APSD. Conclusion: Patients using V are expected to receive smaller lung doses during the hot summer season compared with intentionally well-kept VC. To have equivalent lung deposition, V users should be advised to retain their inhalers around 20°C with minimal daily environmental fluctuations during summer times.

Ocular anti-inflammatory activity of prednisolone acetate loaded chitosan-deoxycholate self-assembled nanoparticles.

Background and purpose: Conventional topical ophthalmic aqueous solutions and suspensions are often associated with low bioavailability and high administration frequency, pulsatile dose and poor exposure to certain ocular parts. The aim of this study was to develop an ophthalmic nanoparticles loaded gel, for delivering prednisolone acetate (PA), to increase dosing accuracy, bioavailability, and accordingly, efficiency of PA in treating inflammatory ocular diseases. Methods: A novel formulation of self-assembled nanoparticles was prepared by the complexation of chitosan (CS) and, the counter-ion, sodium deoxycholate (SD), loaded with the poorly-water-soluble PA. Particle size, zeta potential, encapsulation efficiency (EE) and drug loading content (LC) of prepared nanoparticles were assessed. Moreover, the nanoparticles were characterized using differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). Drug release and eye anti-inflammatory potential of the prepared novel formulation was investigated. Results: Mean particle size of the nanoparticles have dropped from 976 nm ±43 (PDI 1.285) to 480 nm ±28 (PDI 1.396) when the ratio of CS-SD was decreased. The incorporation of 0.1-0.3% of polyvinyl alcohol (PVA), in the preparation stages, resulted in smaller nanoparticles: 462 nm ±19 (PDI 0.942) and 321 nm ±22 (PDI 0.454) respectively. DSC and FTIR results demonstrated the interaction between CS and SD, however, no interactions were detected between PA and CS or SD. Drug release of PA as received, in simulated tears fluid (pH 7.4), showed a twofold increase (reaching an average of 98.6% in 24 hours) when incorporated into an optimized nanoparticle gel formulation (1:5 CS-SD). Conclusion: The anti-inflammatory effect of PA nanoparticles loaded gel on female guinea pig eyes was significantly superior to that of the micronized drug loaded gel (P < 0.05).