Drug Recovery Research Articles

Novel Chiral Drug Recovery and Enantioseparation Method: Hollow Fiber Membrane Extraction and In Situ Coupling of Back-Extraction with Crystallization

A novel method was developed for the recovery and enantioseparation of the active pharmaceutical ingredient (S)-amlodipine from pharmaceutical wastewater: hollow fiber membrane extraction and in si...

Sponges containing tetracycline loaded-PLGA-zein microparticles as a periodontal controlled release device

This paper aimed to design collagen sponges containing tetracycline-loaded PLGA-zein microparticles with controlled release characteristics as an alternative for periodontal treatment. Tetracycline microparticles were prepared by spray-drying technique, while the sponges were prepared by their dispersion in collagen suspension and subsequent freeze-drying. Release studies of two microparticles compositions loaded and unloaded-collagen sponges were carried over a 10 days period. Antibiogram tests were used to ensure the sustained antibacterial activity against Staphylococcus aureus. SEM imagens demonstrated spherical and non-aggregated microparticles (2–5 μm) and their effective dispersion within the sponges, what together with the pronounced water sorption promoted by the collagen fibers enhanced the drug release from the unitary particles. The dissolution profiles showed a sustained-release pattern for both sponges and microparticles formulations, reaching in some cases almost the complete drug recovery. The sponge formulations increased the release of tetracycline up to 45 and 60% in the first 12 h, while their microparticles pairs released less than 30 and 10%, respectively, as a result of their aggregation. Antibiograms showed that the sponges sustained released tetracycline over 10 days and could represent an alternative for periodontal insertion as well as for those applications where the prevention and control of bacterial infections is needed. The incorporation of tetracycline microparticles to collagen sponges improved the release rates of this antimicrobial agent and therefore represents an alternative for controlled antimicrobial activity.

Exploiting Kinetic Solubility Differences for Low Level Detection of Crystallinity in Amorphous Drug Formulations

Background: Enabling formulations have been implemented by the pharmaceutical industry as an effective tool for keeping Active Pharmaceutical Ingredient (API) in an amorphous state. Upon dosing in the amorphous state, many drugs which fail to demonstrate bioactivity due to the limited solubility and bioavailability of their crystalline form become bioavailable. Purpose: The analytical techniques use today for crystallinity detection are challenged by the sensitivity and robustness needed to achieve a 5% quantitation limit in low dose drug products. Our laboratory has developed a novel procedure capable of meeting this sensitivity and selectivity requirement. This is achieved by exploiting the differences in kinetic solubility of the formulated amorphous and free crystalline forms of API currently being used in dosage form platforms. Methods: Representative amorphous drug formulations were prepared and spiked with varying levels of crystalline drug substances to evaluate the selectivity and recovery of the crystalline drug substance from the product formulation. Kinetic solubility testing using a (i) Particle wetting phase, (ii) Particle suspending/erosion phase, (iii) Sampling time point and (iv) A total recovery determination for the drug substance. Results: The method selectively and quantitatively distinguishes crystalline drug substance from amorphous drug substance for samples spiked from 2.5% to 10% of the nominal label concentration of the API in the dosage form matrix. Conclusion: The kinetic solubility approach reported here achieves sensitive crystallinity quantitation for low drug level amorphous drug formulations at levels not yet achieved by complimentary analytical techniques.

Tear film concentrations of topically applied 0.5% oxytetracycline ointment in normal canine eyes.

To determine the tear film levels of oxytetracycline in normal canine eyes after application of the ophthalmic ointment, Terramycin™ (0.5% oxytetracycline, polymyxin B sulfate), to guide appropriate treatment frequency. Ten research beagles. Ten research beagles with confirmed normal eyes were administered 0.02mL of Terramycin™ ophthalmic ointment onto the dorsal bulbar conjunctival surface of the right eye. Tear samples were collected via dye-less Schirmer tear strips at 2, 4, 6, 8, and 12hours post-administration. The sample for each timepoint was collected on a separate day, and concentrations of oxytetracycline were determined using high-performance liquid chromatography (HPLC). There was a semi-logarithmic decline in the median tear concentration of oxytetracycline. The median (2.5th and 97.5th percentiles) tear concentrations of oxytetracycline at 2, 4, 6, 8, and 12hours were 43.5μg/mL (11.1-302.2μg/mL), 28.7μg/mL (8.04-113.7μg/mL), 16.1μg/mL (4.96-37.7μg/mL), 9.2μg/mL (4.52-28.1μg/mL), and 6.11μg/mL (4.36-26.7μg/mL), respectively. Mean (±SD) drug recovery via HPLC was 88% (±7.5%). Ophthalmic Terramycin™ achieves a substantially higher tear level than the MIC for common bacterial corneal pathogens up to 12hours post-administration in normal eyes. Anti-collagenolytic tear levels were not achieved at the timepoints evaluated or with the manufacturer-prescribed dosing frequency. HPLC can be used to analyze tear concentrations of ophthalmic ointment formulations.

Preparation of magnetic metal organic framework and development of solid phase extraction method for simultaneous determination of fluconazole and voriconazole in rat plasma samples by HPLC

Fluconazole and voriconazole are the two broad-spectrum triazole antifungals. The present work described the fabrication method for the synthesis of the amino-modified magnetic metal–organic framework. This material was applied as a pre-sample treatment sorbent for the selective extraction of fluconazole and voriconazole in rat plasma samples. The material was fabricated by the chemical bonding approach method and was characterized by different parameters. The factors which affect the extraction efficiency of the sorbent material were also optimized in this study. Due to the optimization of solid-phase extraction conditions, the nonspecific interaction was reduced and the extraction recoveries of target drugs were increased in plasma samples. The extraction method was combined with the HPLC-UV method for the analysis. Excellent linearity (0.1–25 µg/mL), detections (0.02, 0.03 µg/mL) and quantification limits (0.04, 0.05 µg/mL) were resulted for fluconazole and voriconazole respectively. The maximum recoveries from spiked plasma samples of fluconazole and voriconazole were 86.8% and 78.6% and relative standard deviation were 0.9–2.8% and 2.2–3.6% respectively. Moreover, this sorbent material was used multiple times which was an improvement over single-use commercial sorbent materials. This validated method has practical potential for the simultaneous determination of these drugs in therapeutic drug monitoring studies as well as for routine pharmacokinetic evaluations.

Plumbagin-Serum Albumin Interaction: Spectral, Electrochemical, Structure-Binding Analysis, Antiproliferative and Cell Signaling Aspects with Implications for Anticancer Therapy.

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a small molecule with potent anticancer activity. Like other 1,4-naphthoquinones, it exhibits electrophilic reactivity towards biological nucleophiles. We demonstrate that plumbagin and structurally related 1,4-naphthoquinones with at least one unsubstituted quinoid carbon (C2 or C3) bind to albumin, an ubiquitously present nucleophile, with minimum recovery of free drug. Extraction recovery of plumbagin from albumin in solution showed one-phase exponential decline with a half-live of 9.3 min at 10 μmol/L. In the presence of albumin, plumbagin exhibited instant changes in UV/Vis absorption bands. Electrochemical analysis using cyclic voltammetry showed a decrease in redox peak currents over time until electro-inactivity, thus suggesting the formation of a supramolecular adduct inaccessible for electron transfer. The adduct inhibited cell growth and caused cell-cycle arrest of prostate cancer cells, in part by decreasing levels of the cell-cycle regulator RBBP. The conjugate displayed similar cellular effects to those described for plumbagin, such as decreased levels of androgen receptor and protein kinase C epsilon. The effect of plumbagin-albumin on cancer cells was species-specific, suggesting a receptor-mediated mechanism. Furthermore, it was blocked by cathepsin inhibitor pepstatin A, indicating that lysosomal degradation is involved in the processing of plumbagin-albumin adduct. The spontaneously formed adduct of plumbagin with serum albumin is likely to mediate the biological activities of plumbagin in vivo and to fundamentally influence its pharmacodynamics.

Design of Drug Recovery Scheme Based on Path Optimization

Countries with the upsurge of garbage sorting, all over the Word attach importance to the recycling of expired medical products. The design of reverse logistics network of expired drugs has become a key problem in the field of pharmaceutical safety. Considering that expired drugs can not be recovered effectively, this paper studies the problem of drug recovery logistics by using TSP model and mileage saving model. It is beneficial to arouse the enthusiasm of enterprises and residents to participate in the recovery of expired drugs, thus reducing the production and manufacturing costs of pharmaceutical enterprises in China and reducing the pollution of waste drugs to the environment.

LC–MS bioanalytical method for simultaneous determination of latanoprost and minoxidil in the skin

The association of minoxidil sulphate and latanoprost is currently emerging as a promising strategy for the treatment of androgenic alopecia, which is the most common type of scalp hair loss. In order to support the development of new pharmaceutical products containing such drugs combination, this study proposes a simple and efficient LC–MS bioanalytical method to simultaneously quantify minoxidil sulphate and latanoprost in different skin layers. Compounds separation was performed by liquid chromatography using a C18 column with gradient elution of a mobile phase composed of 0.1 % formic acid in acetonitrile and water at a flow rate of 0.5 mL min−1. Determinations were executed using mass spectrometry equipped with an ESI interface operating in a positive ionization mode. Quantification was performed using selective ion mode monitoring of m/z 210.1 for minoxidil sulphate and 433.3 for latanoprost. The matrix effect was very pronounced in samples containing some skin layers or electrolyte solution. Accordingly, a calibration curve for each contaminant group was built, leading to correlation coefficient values higher than 0.99. Additionally, lower limits of detection and quantification were obtained, and precision (repeatability and intermediate precision) achieved results with a coefficient of variation less than 15 %. Drug recovery from skin samples was higher than 70 %, fulfilling the recommendations. Also, the bioanalytical method was successfully tested in in vitro skin penetration studies proving its effectiveness in the development of topical formulations containing both drugs.

Stigmatization of opioid addiction based on prescription, sex and age

With opioid abuse becoming a nationwide epidemic, it is important to understand what is contributing to societal views of opioid dependence. Difference in stigmatization of drug users may exist between sexes, ages and type of drugs being used. Social perceptions may impact drug use and recovery. To assess which opioid users are stigmatized most, we administered an experimenter-created vignette that experimentally manipulated the type of opioid (Prescribed Vicodin vs. Non-prescribed Vicodin vs. heroin) as well as the sex of the opioid user (Male vs. Female) and the age of the user (23 years-old vs. 53 years-old) to 4300 people on Amazon’s Mechanical Turk (a survey hosting website). Participants were told in a vignette that the target person they were reviewing was “addicted”. Results confirmed that the stigmatization of drug use is dependent on a series of items, including type of opioid, as well as the age and sex of the participant. Specifically, prescribed opioids were least stigmatized, while heroin was most stigmatized. Also, there was a significant difference between heroin, non-prescribed Vicodin and prescribed Vicodin use and whether or not participants stigmatized the opioid user as an “addict”. More specifically, participants were more likely to identify heroin and non-prescribed Vicodin users as having an opioid addiction. Lastly, young male opioid users were stigmatized more than any other group. Results are discussed.

Development and Characterization of a Novel Peptide-Loaded Antimicrobial Ocular Insert.

Infectious ocular keratitis is the leading cause of blindness worldwide. Bacterial resistance to classical pharmacological treatments raised the interest of researchers towards antimicrobial peptide (AMP)-based therapy. hLF 1-11, a synthetic antimicrobial peptide derived from the N-terminus of human lactoferrin, proved effective against different bacteria and yeast but, like all proteinaceous materials, it is unstable from chemical, physical, and biological points of view. In this study, new freeze-dried solid matrices containing mucoadhesive polymers were prepared and characterized in terms of rheology, hydration time, bioadhesion, drug content, and in vitro release. The formulation HPMC/T2/HA/hLF 1-11fd was selected for the delivery of hLF 1-11, since it showed good drug recovery and no chemical degradation up to at least 6 months (long-term stability). Furthermore, the HPMC/T2/HA/hLF 1-11fd matrix allowed for the release of the drug in a simulated physiological environment, linked to an optimal hydration time, and the peptide antimicrobial activity was preserved for up to 15 months of storage, a very promising result considering the chemical liability of proteinaceous material. For its properties, the freeze-dried matrix developed in this study could be a good platform for the delivery of antimicrobial peptides in the precorneal area to treat infectious phenomena of the ocular surface.

Mechanisms and context in the San Patrignano drug recovery community, Italy: a qualitative study to inform transfer to Scotland

The San Patrignano drug recovery community, Italy, is regarded as one of the most successful in the world. However, if this model is to be transferred to other countries, it is necessary to clarify its underlying mechanisms and how far their success is context dependent. This qualitative study investigated these features of the San Patrignano model. Data collection included semi-structured interviews with six key stakeholders and 10 days’ observational field notes. Data were synthesised using frameworks and analysis was informed by realist principles. Individual level mechanisms include: commitment to change, removal from former social environment, communal living, peer mentor with lived experience and meaningful work. These operate in the context of a free of charge, long term (3–4 year) residential community. Organisational level mechanisms are: visionary leadership, staff dedication, social enterprise and adaptable learning. Organisational contextual factors include: a gap in suitable provision for drug recovery and the region’s high level of social capital. Articulating the programme theory of the recovery model and its contextual dependency helps clarify which elements should be transferred and how far they need to be adapted for different socio-cultural settings. The recognition of context is crucial when considering transfer of effective complex interventions across countries.

Quality Assurance in Drug Assaying and Pharmacokinetics-Blood Protein Evaluation in Calibration Curves

In bioanalytical drug assays, plasma protein/albumin content can challenge the biomatrix and reduce drug recovery through the albumin-binding affinity (ABA) of drug molecules. Global quality assurance in sample preparation for analyte quantification during bioavailability assessments has evolved extensively, and the quality standards of the strictly regulated current global quality controlled drug manufacturing processes (cGQMP) now apply in pharmacokinetics (PK) studies. Previous analyses in large clinical trials had found that laboratory-prepared calibrator plasma/serum protein levels differed significantly from those of patients with occasional hyperproteinemia/hypoproteinemia and disease-related hyperalbuminemia/hypoalbuminemia. We, therefore, investigated improving assay accuracy by including adjustments for patient plasma/serum protein levels in protein evaluation calibrations curves (PROTEC). Using a combined PROTEC of two calibrators (with 1.6 ± 0.5 g/dL and 4.3g/dL albumin, respectively) to test rifampicin recovery from patients with hypoalbuminemia (1.6 ± 0.5 g/dL), we found that relative accuracy of drug recovery differed by minimum 0.1% for low ABA drugs and maximum andgt;20% for moderate ABA drugs. Assay accuracy improved after accommodating for varying patient plasma/serum protein levels. We, therefore, propose using patient-calibrator PROTEC-PK in validation assay development/therapeutic drug monitoring to ensure that patient albumin levels are within acceptable validation accuracy ranges.

Hydrogel-forming microneedle arrays as a therapeutic option for transdermal esketamine delivery

Treatment resistant depression is, by definition, difficult to treat using standard therapeutic interventions. Recently, esketamine has been shown as a viable rescue treatment option in patients in depressive crisis states. However, IV administration is associated with a number of drawbacks and advanced delivery platforms could provide an alternative parenteral route of esketamine dosing in patients. Hydrogel-forming microneedle arrays facilitate transdermal delivery of drugs by penetrating the outer layer of the skins surface, absorbing interstitial skin fluid and swelling. This subsequently facilitates permeation of medicines into the dermal microcirculation. This paper outlines the in vitro formulation development for hydrogel-forming microneedle arrays containing esketamine. Analytical methods for the detection and quantitation of esketamine were developed and validated according to International Conference on Harmonisation standards. Hydrogel-forming microneedle arrays were fully characterised for their mechanical strength and skin insertion properties. Furthermore, a series of esketamine containing polymeric films and lyophilised reservoirs were assessed as drug reservoir candidates. Dissolution testing and content drug recovery was carried out, followed by permeation studies using 350 μm thick neonatal porcine skin in modified Franz cell apparatus. Lead reservoir candidates were selected based on measured physicochemical properties and brought forward for testing in female Sprague-Dawley rats. Plasma samples were analysed using reverse phase high performance liquid chromatography for esketamine. Both polymeric film and lyophilised reservoirs candidate patches achieved esketamine plasma concentrations higher than the target concentration of 0.15–0.3 μg/ml over 24 h. Mean plasma concentrations in rats, 24 h post-application of microneedle patches with drug reservoir F3 and LW3, were 0.260 μg/ml and 0.498 μg/ml, respectively. This developmental study highlights the potential success of hydrogel-forming microneedle arrays as a transdermal drug delivery platform for ESK and supports moving to in vivo tests in a larger animal model.

Optimized and Validated Stability Indicating RP-HPLC Method for Estimation of Nadolol

A stability indicating RP-HPLC method for the determination of nadolol was developed and validated using Enable C18 (250 mm × 4.6 mm, 5 μm) column with mobile phase consisting of methanol, acetonitrile and 0.01 M sodium dihydrogen phosphate buffer pH 7.0 (60:15:25 v/v). The spectrophotometric detection was carried out at 220 nm and the retention time of nadolol was found to be 4.6 min. Forced degradation studies were performed as per ICH guidelines under acid/alkaline hydrolytic, oxidative, thermal, and photolytic conditions, and the degradation products were separated chromatographically. Nadolol was found to be susceptible towards acidic and alkaline hydrolysis and oxidation, while it was stable to thermal and photolytic degradation. The acid hydrolytic degradation study was optimized using 33 factorial design to achieve 5 – 25% desired drug degradation. The proposed method was validated as per ICH guidelines. Linearity was observed in the range of 100 to 500 μg/mL (R2 = 0.999). The drug recovery was within 98.0 – 99.8%. The LOD and LOQ values for the drug were found to be 0.21 and 0.66 μg/mL, respectively.

Removal of micropollutants from water by commercially available nanofiltration membranes

The current work is focused on the use of nanofiltration in the removal of micropollutants, specially drugs (diclofenac and ibuprofen) and heavy metal (zinc sulphate and zinc nitrate) from wastewater. The commercially available nanofiltration (NF) membranes (AFC 80, AFC 40, AFC 30) were characterised by demineralised water and the ability of the membranes to reject drugs and zinc(II) was subsequently examined. The influence of the operating conditions on the rejection and the permeate flux was evaluated. The operating conditions tested included the transmembrane pressure (5–30 bar); the effect of the feed concentration on the heavy metals rejection (50–200 mg L−1); the effect of ionic strength on the diclofenac and ibuprofen rejection (0–10 g L−1 NaCl) and the volumetric flow rate (5–15 L min−1). It has been shown that increasing the transmembrane pressure increases the intensity of the permeate flow and rejection. Drugs rejection also increases with increasing bulk feed flow rates; however, decreases with increasing ionic strength (NaCl concentration in feed). Experimental data indicated that concentration polarisation existed in the membrane separation process. The stable permeation flux and high rejection of drugs and heavy metals indicated the potential of NF for the recovery of drugs and zinc(II) from wastewater.

Recovery of cefazolin and clindamycin in in vitro pediatric CPB systems.

Cardiopulmonary bypass (CPB) is often necessary for congenital cardiac surgery, but CPB can alter drug pharmacokinetic parameters resulting in underdosing. Inadequate plasma levels of antibiotics could lead to postoperative infections with increased morbidity. The influence of pediatric CPB systems on cefazolin and clindamycin plasma levels is not known. We have measured plasma levels of cefazolin and clindamycin in in vitro pediatric CPB systems. We have tested three types of CPB systems. All systems were primed and spiked with clindamycin and cefazolin. Samples were taken at different time points to measure the recovery of cefazolin and clindamycin. Linear mixed model analyses were performed to assess if drug recovery was different between the type of CPB system and sampling time point. The experiments were conducted at a tertiary university hospital. 81 samples were analyzed. There was a significant difference in the recovery over time between CPB systems for cefazolin and clindamycin (P < .001). Cefazolin recovery after 180 minutes was 106% (95% CI: 91‐123) for neonatal, 99% (95% CI: 85‐115) for infant, and 77% (95% CI: 67‐89) for pediatric systems. Clindamycin recovery after 180 minutes was 143% (95% CI: 116‐177) for neonatal, 111% (95% CI: 89‐137) for infant, and 120% (95% CI: 97‐149) for pediatric systems. Clindamycin recovery after 180 minutes compared to the theoretical concentration was 0.4% for neonatal, 1.2% for infants, and 0.6% for pediatric systems. The recovery of cefazolin was high in the neonatal and infant CPB systems and moderate in the pediatric system. We found a large discrepancy between the theoretical and measured concentrations of clindamycin in all tested CPB systems.

Preparation and evaluation of orally disintegrating tablets containing taste masked microparticles of acetaminophen.

In the present work, taste masked particles of acetaminophen (AAP), a highly soluble bitter tasting drug, were developed and ODT containing the taste masked particles were prepared. Taste masked particles of AAP were prepared using different amounts of tetraglycerol polyricinoleate (TGPR) and Eudragit ®E100. Although the drug content ratio and drug recovery decreased with increasing TGPR, drug release from AAP-CR100 particles containing a large amount of TGPR was mostly suppressed for 2 min. Hence, AAP-CR100 was incorporated into ODT as taste masked particles for AAP. Three major disintegrants were used for ODT, and it was confirmed that the tensile strength of all formulations showed applicable hardness for handling. The AAP-CR100-CP(40) formulation containing crospovidone showed the shortest disintegration time and the drug release from AAP-CR100-CP(40) into pH 6.8 test solution was suppressed compared with commercial AAP tablets. Because the drug release from AAP-CR100-CP(40) into the pH 1.2 test solution was rapid, it was suggested that drug release from AAP-CR100-CP(40) is suppressed in the oral cavity, and the drug is released promptly in the stomach. Thus AAP-CR100-CP(40) may be useful as an ODT in which the dissolution of AAP in the oral cavity is suppressed.

Development and Validation of UV Spectroscopic Method for Estimation of Fisetin in Self Nanoemulsifying Drug Delivery System

Fisetin is a polyphenolic flavonoid which has been reported various pharmacological activities as a crude extract and in formulation form. This study was designed to develop and validate a simple and cost effective method for the estimation of fisetin in the liquid self nanoemulsifying drug delivery system (L-SNEDDS). Solutions having different concentration of fisetin were prepared in methanol to develop the calibration curve. The solutions were scanned at 362nm by using UV-spectrophotometer. Similarly, for validation of method recovery of drug was measured at three levels 80%, 100% and 120% of the mid concentration and data was recorded. Further, this method was used to measure the drug loading in L-SNEDDS of fisetin. The data was found to be linear in the range of 4–12μg/mL with regression coefficient of 0.999. The recovery of drug in the range of 95% to 105% indicated the accuracy of the method. The percentage relative standard deviation among all the responses was found to be less than 2% indicating the precision of the method. The LOD and LOQ was found to be 0.28 and 0.86μg/mL respectively. Drug loading in the L-SNEDDS was found to be 93.66%. A simple, accurate and cost-effective method for the estimation of the fisetin in pharmaceutical dosage forms was developed and validated using ultra violet spectroscopy.

P115 - Protein recovery and quantification of drug metabolizing enzymes and transporters in membrane extracts prepared by differential detergent fractionation: Comparison with established methods

P115 - Protein recovery and quantification of drug metabolizing enzymes and transporters in membrane extracts prepared by differential detergent fractionation: Comparison with established methods

Should Interpretative Phenomenological Analysis (IPA) be Used With Focus Groups? Navigating the Bumpy Road of “Iterative Loops,” Idiographic Journeys, and “Phenomenological Bridges”

Interpretative phenomenological analysis (IPA) is a qualitative thematic approach developed within psychology underpinned by an idiographic philosophy, thereby focusing on the subjective lived experiences of individuals. However, it has been used in focus groups of which some have been critical because of the difficulties of extrapolating the individual voice which is more embedded within the group dynamics and the added complexity of multiple hermeneutics occurring. Some have adapted IPA for use with focus groups, while others provide scant regard to these philosophical tensions. This raises the question whether IPA should be used with focus group data. To address these concerns, this article will set out a step-by-step guide of how IPA was adapted for use with focus groups involving drug using offenders (including illustrative examples with participants’ quotes). A rationale of why it was important to use both focus groups and an IPA approach will be covered including the value, merits, and challenges this presented. An overview of how participants’ idiographic accounts of their drug use, relapse, and recovery were developed will be provided. This article will conclude with a suggested way forward to satisfy the theoretical tensions and address the question raised in the title.