An in vitro approach to assessing a potential drug interaction between MDMA (ecstasy) and caffeine

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a popular recreational drug which causes long-term neurotoxicity and increased risk of fatality. In rats, MDMA toxicity is exacerbated by co-administration of caffeine. The aim of this study was to investigate whether caffeine altered the effects of MDMA in a battery of in vitro tests selected to model some of the known actions of MDMA in vivo. In cytotoxicity studies, caffeine modestly enhanced the effect of MDMA on neuronal N2a cell viability but not that of liver, intestinal or kidney cells. MDMA inhibited the formation of fluorescent metabolites by CYP2D6 ≫ CYP3A4 > CYP1A2 but this was not altered by caffeine. Similarly, the inhibition of synaptosomal [³H] 5-HT uptake by MDMA was not affected by the presence of caffeine. Thus, these in vitro tests failed to detect any substantial interaction between caffeine and MDMA, highlighting the difficulty of modelling in vivo drug interactions using in vitro tests. However, the results show that the inhibition of synaptosomal [³H] 5-HT uptake by MDMA was greater at 41 °C and 25 °C than at 37 °C which raises the possibility that MDMA’s effect on SERT in vivo may be increased as body temperature increases, contributing to its harmful effects in users.     

Behavioural and neurochemical comparison of chronic intermittent cathinone,mephedrone and MDMA administration to the rat

The synthetic cathinone derivative, mephedrone, is a controlled substance across Europe. Its effects have been compared by users to 3,4-methylenedioxymethamphetamine (MDMA), but little data exist on its pharmacological properties. This study compared the behavioural and neurochemical effects of mephedrone with cathinone and MDMA in rats. Young-adult male Lister hooded rats received i.p. cathinone (1 or 4 mg/kg), mephedrone (1, 4 or 10 mg/kg) or MDMA (10 mg/kg) on two consecutive days weekly for 3 weeks or as a single acute injection (for neurochemical analysis). Locomotor activity (LMA), novel object discrimination (NOD), conditioned emotional response (CER) and prepulse inhibition of the acoustic startle response (PPI) were measured following intermittent drug administration. Dopamine, 5-hydroxytryptamine (5-HT) and their major metabolites were measured in striatum, frontal cortex and hippocampus by high performance liquid chromatography 7 days after intermittent dosing and 2 h after acute injection. Cathinone (1, 4 mg/kg), mephedrone (10 mg/kg) and MDMA (10 mg/kg) induced hyperactivity following the first and sixth injections and sensitization to cathinone and mephedrone occurred with chronic dosing. All drugs impaired NOD and mephedrone (10 mg/kg) reduced freezing in response to contextual re-exposure during the CER retention trial. Acute MDMA reduced hippocampal 5-HT and 5-HIAA but the only significant effect on dopamine, 5-HT and their metabolites following chronic dosing was altered hippocampal 3,4-dihydroxyphenylacetic acid (DOPAC), following mephedrone (4, 10 mg/kg) and MDMA. At the doses examined, mephedrone, cathinone, and MDMA induced similar effects on behaviour and failed to induce neurotoxic damage when administered intermittently over 3 weeks.     

Cytotoxic effects of amphetamine mixtures in primary hepatocytes are severely aggravated under hyperthermic conditions

Amphetamine consumers are often, deliberately or not, polydrug abusers. Predicting combination effects based on concentration–response analysis of individual components is a valid strategy for accurate toxicological assessment of mixtures. We previously reported that joint effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and three other often co-ingested amphetamines (methamphetamine, 4-methylthyoamphetamine and D-amphetamine) could be predicted by the concentration addition (CA) model in HepG2 cells. We sought to further evaluate the relevance of these findings by extending these studies to a cell model that more closely mimics the in vivo situation.Detailed cytotoxic information of the four individual amphetamines on primary rat hepatocytes was recorded by the MTT assay, at 37 °C and 40.5 °C, simulating the rise in body temperature that could be induced following amphetamine intake. Mixture expectations were calculated using CA and independent action (IA) models.At 37 °C, concentration-dependent cytotoxicity occurred for the drugs individually and combined. Mixture effects were accurately predicted by the CA model, while the IA model underestimated cytotoxicity. At 40.5 °C these cytotoxic effects were aggravated. Our findings provide evidence of the increased risks associated with the abuse of amphetamine mixtures, especially during hyperthermia, emphasising the need to increase awareness of misinformed users who believe these drugs are safe.     

The effects of elevated carbon dioxide and temperature levels on tilapia (Oreochromis mossambicus): Respiratory enzymes,blood pH and hematological parameters

Oreochromis mossambicus were exposed to two different temperature and carbon dioxide partial pressure levels for about two weeks, as the ambient (Control; 25 °C, 3.3 mg/L CO₂), high CO₂ (25 °C, 14 mg/L CO₂), high temperature (30 °C, 3 mg/L CO₂) and combined (30 °C, 14.1 mg/L CO₂) groups. No mortality was observed during the experiments. As a result of the study, elevated CO₂ concentrations cause negative effects on the hematological parameters. At the end of the study, while the blood Carbonic Anhydrase (CA) activity, in the high CO₂ group (25 °C, 14 mg/L CO₂), statistically increased at the 7th day compared to the control group, it decreased at the 14th day (p < 0.05). In addition, the blood CA activity, in the combined (30 °C, 14.1 mg/L CO₂) group, showed a decrease at the 14th day compared to the control group (p < 0.05). At the end of study, unlike the blood CA activity, gill, liver and kidney CA activity showed an increase in the tissues compared to the control groups (p < 0.05). Furthermore, the Na⁺, K⁺-ATPase activities were stimulated significantly in the gills in both high CO₂ and temperature groups at day 7, but it showed a significant amount of inhibition at the 14th day compared to the control groups. Overall, increasing carbon dioxide concentration in different temperatures has negative effects on the hematological parameters and respiratory enzyme of the tilapia fish. In addition, it is observed that the fish survive at negative conditions with adaptation mechanisms.     

Carvedilol stability in paediatric oral liquid formulations

ObjectiveTwo carvedilol aqueous solutions and one carvedilol aqueous suspension for paediatric oral use (1 mg/ml) were studied to determine their stability.MethodAll samples were stored at 4, 25 and 40° C. Carvedilol content of each of the three formulations was tested using high performance liquid chromatography (HPLC). Each sample was analysed in triplicate at 0, 3, 7, 14, 28 and 56 days.ResultsCarvedilol stayed stable in the acidic aqueous solution at the three different temperatures during the 56 days of the study. In the alkaline solution, carvedilol was stable during 56 days at 25° C, but only 28 days at 4 and 40° C. In the aqueous suspension, carvedilol was stable during 56 days at 4 and 25° C, but only 28 days at 40° C.ConclusionsAll the formulations that were tested can be stored at 25° C for at least 56 days.     

Tissue accumulation and toxicity of isothiazolinone in Ctenopharyngodon idellus (grass carp): Association with P-glycoprotein expression and location within tissues

Isothiazolinone is widely used as a broad-spectrum fungicide in various industries, such as oil, paper, pesticide, dyes, tanning and cosmetics. There is an increasing concern over protection of the aquatic environment due to its large-scale use. The acute toxicity (LC₅₀) of isothiazolinone in Ctenopharyngodon idellus was investigated. The residual time and accumulation in tissues, P-glycoprotein mRNA level and localization of P-glycoprotein in the liver and kidney were also analyzed. The LC₅₀ (48 h) values of isothiazolinone to C. idellus were 0.53 ± 0.17 mg/L and 0.41 ± 0.08 mg/L at 15 °C and 25 °C, respectively. The LC₅₀ values decreased as the temperature increased. The accumulation of isothiazolinone in livers and kidneys in the high temperature group (25 °C) was significantly greater than that of the low temperature group (15 °C). Prolonged tissue residual time of isothiazolinone was seen in all the groups. There were significant differences in P-glycoprotein mRNA expression between isothiazolinone-treated groups and control samples (P < 0.05–0.01). Temperature affected accumulation and toxicity of isothiazolinone.     

A validated bioanalytical method in mouse,rat, rabbit and human plasma for the quantification of one of the steroid glycosides found in Hoodia gordonii extract

Hoodia gordonii extract contains steroid glycosides, fatty acids, plant sterols and polar organic material. Certain steroid glycosides show appetite suppressant activities following oral ingestion. This study describes the validation of a bioanalytical method for the quantification of one of the steroid glycosides, H.g.-12 (～10% (w/w) of the extract), in mouse, rat, rabbit and human plasma. The method utilises a liquid–liquid extraction with methyl-tert-butyl ether followed by chromatographic separation on a 2.1 × 50 mm C₁₈ Genesis high performance liquid chromatography (HPLC) column and detection on a triple quadrupole mass spectrometer. Detection of H.g.-12 and its stable isotope internal standards is performed using positive TurboIonspray? ionisation in multiple reaction monitoring mode. The validation procedure demonstrated assay sensitivity, linearity, accuracy, precision and selectivity over the calibration range of 0.5–150 ng/mL in human plasma (500 μL sample volume), 1.0–100 ng/mL in rat and rabbit plasma (150 μL sample volume) and 1.0–250 ng/mL in mouse plasma (150 μL sample volume) with good recoveries (≥77%). H.g.-12 was stable in plasma for ≥6 months at ?20 °C, for up to 4 h at ambient temperature (ca 22 °C) and after 3 freeze–thaw cycles. Plasma extracts were stable for up to 24 h at ambient temperature.     

Results of an international drug testing service for cryptomarket users

IntroductionUser surveys indicate that expectations of higher drug purity are a key reason for cryptomarket use. In 2014–2015, Spain's NGO Energy Control conducted a 1-year pilot project to provide a testing service to cryptomarket drug users using the Transnational European Drug Information (TEDI) guidelines. In this paper, we present content and purity data from the trial.Methods219 samples were analyzed by gas chromatography associated with mass spectrometry (GC/MS). Users were asked to report what substance they allegedly purchased.Results40 different advertised substances were reported, although 77.6% were common recreational drugs (cocaine, MDMA, amphetamines, LSD, ketamine, cannabis). In 200 samples (91.3%), the main result of analysis matched the advertised substance. Where the advertised compound was detected, purity levels (m ± SD) were: cocaine 71.6 ± 19.4%; MDMA (crystal) 88.3 ± 1.4%; MDMA (pills) 133.3 ± 38.4 mg; Amphetamine (speed) 51.3 ± 33.9%; LSD 123.6 ± 40.5 μg; Cannabis resin THC: 16.5 ± 7.5% CBD: 3.4 ± 1.5%; Ketamine 71.3 ± 38.4%. 39.8% of cocaine samples contained the adulterant levamisole (11.6 ± 8%). No adulterants were found in MDMA and LSD samples.DiscussionThe largest collection of test results from drug samples delivered from cryptomarkets are reported in this study. Most substances contained the advertised ingredient and most samples were of high purity. The representativeness of these results is unknown.     

The effect of caffeine on MDMA-induced hydroxyl radical production in the mouse striatum

BackgroundThe psychostimulant 3,4-methylenedioxymethamphetamine (MDMA) with a strong addictive potential is widely used as a recreational drug. Neurotoxicity of MDMA is related with the generation of highly reactive free radicals.MethodsMDMA was given in doses of 20 and 40 mg/kg ip alone or in combination with caffeine (CAF) 10 mg/kg ip. Extracellular concentration of hydroxyl radical was measured using microdialysis in freely moving mice and was assayed by HPLC with electrochemical detection.ResultsMDMA dose-dependently increased production of hydroxyl radical in the mouse striatum and its effect was reversed by caffeine.ConclusionsThe data show that caffeine may have neuroprotective properties as it decreased oxidative stress induced by MDMA.     

A pragmatic approach for engineering porous mannitol and mechanistic evaluation of particle performance

The importance of mannitol has increased recently as an emerging diluent for orodispersible dosage forms. The study aims to prepare spray dried mannitol retaining high porosity and mechanical strength for the development of orally disintegrating tablets (ODTs).Aqueous feed of d-mannitol (10% w/v) comprising ammonium bicarbonate, NH₄HCO₃ (5% w/v) as pore former was spray dried at inlet temperature of 110–170 °C. Compacts were prepared at 151 MPa and characterized for porosity, hardness and disintegration time. Particle morphology and drying mechanisms were studied using thermal (HSM, DSC and TGA) and polymorphic (XRD) methods.Tablet porosity increased from 0.20 ± 0.002 for pure mannitol to 0.53 ± 0.03 using fabricated porous mannitol. Disintegration time dropped by 50–77% from 135 ± 5.29 s for pure mannitol to 75.33 ± 2.52–31.67 ± 1.53 s for mannitol 110–170 °C. Hardness increased by 150% at 110 °C (258.67 ± 28.89 N) and 30% at 150 °C (152.70 ± 10.58 N) compared to pure mannitol tablets (104.17 ± 1.70 N). Increasing inlet temperature resulted in reducing tablet hardness due to generation of ‘micro-sponge’-like particles exhibiting significant elastic recovery. Impact of mannitol polymorphism on plasticity/elasticity cannot be ruled out as a mixture of α and β polymorphs formed upon spray drying.     

Investigation of PEG Crystallization in Frozen PEG-Sucrose-Water Solutions. I. Characterization of the Nonequilibrium Behavior during Freeze-Thawing

Our objective was to characterize the nonequilibrium thermal behavior of frozen aqueous solutions containing PEG and sucrose. Aqueous solutions of (i) sucrose (10%, w/v) with different concentrations of PEG (1–20%, w/v), and (ii) PEG (10%, w/v) with different concentrations of sucrose (2–20%, w/v), were cooled to ? 70°C at 5°C/min and heated to 25°C at 2°C/min in a differential scanning calorimeter. Annealing was performed at temperatures ranging from ? 50 to ? 20°C for 2 or 6 h. Similar experiments were also performed in the low-temperature stage of a powder X-ray diffractometer. A limited number of additional DSC experiments were performed wherein the samples were cooled to ? 100°C. In unannealed systems with a fixed sucrose concentration (10%, w/v), the T′_g decreased from ? 35 to ? 48°C when PEG concentration was increased from 1% to 20% (w/v). On annealing at ? 25°C, PEG crystallized. This was evident from the increase in T′_g and the appearance of a secondary melting endotherm in the DSC. Low- temperature XRD provided direct evidence of PEG crystallization. Annealing at temperatures ≤?40°C did not result in crystallization and a devitrification event was observed above the T′_g. In unannealed systems with a fixed PEG concentration (10%, w/v), the T′_g increased from ? 50 to ? 40°C when sucrose concentration was increased from 5% to 50%, w/v. As the annealing time increased (at ? 25°C), the T′_g approached that of a sucrose-water system, reflecting progressive PEG crystallization. A second glass transition at ~? 65°C was evident in unannealed systems [10%, w/v sucrose and 10 (or 20%), w/v PEG] cooled to ? 100°C. Investigation of the nonequilibrium behavior of frozen PEG-sucrose-water ternary system revealed phase separation in the freeze-concentrate. Annealing facilitated PEG crystallization.     

Levosimendan and its metabolite OR-1896 elicit KATP channel-dependent dilation in resistance arteries in vivo

BackgroundLevosimendan and its long-lived metabolite OR-1896 produce vasodilation in different types of vessels by activating ATP-sensitive (K_ATP) and other potassium channels.MethodsIn the present study we applied intravital videomicroscopy to investigate the in situ effects of levosimendan and OR-1896 on the diameters of real resistance arterioles (rat cremaster muscle arterioles with diameters of ~ 20 μm).ResultsLevosimendan and OR-1896 induced concentration-dependent (1 nM – 100 μM) dilations to similar extents in these arterioles (maximal dilation from 23 ± 2 to 33 ± 2 μm and from 22 ± 1 to 32 ± 1 μm, respectively). The arteriolar dilations induced by the selective K_ATP channel opener pinacidil (1 nM – 10 μM) (maximal dilation from 22 ± 4 μm to 35 ± 3 μm) were diminished in the presence of the selective K_ATP channel blocker – glibenclamide (5 μM) (maximal diameter attained: 22 ± 1 μm). Glibenclamide also counteracted the maximal dilations in response to levosimendan or OR-1896 (to 23 ± 3 μm or 22 ± 5 μm, respectively).ConclusionsIn conclusion, this is the first demonstration that levosimendan and OR-1896 elicit arteriolar dilation in vivo, via activation of K_ATP channels in real resistance vessels in the rat.     

Impact of probable interaction of low temperature and ambient fine particulate matter on the function of rats alveolar macrophages

The present study aimed to explore the probable interaction of low temperature and ambient fine particulate matter (PM_2.5) on rat alveolar macrophages (AMs). AMs were separated from rat BALF and exposed to PM_2.5 (0, 25, 50, 100 μg/ml) under different temperature (18, 24, 30, 37 °C) for 8 h. Results indicated that viability and phagocytosis function of AMs decreased with the decline of temperature and the rise of PM_2.5 dose, and the strongest toxicity was shown in the highest PM_2.5 (100 μg/ml) exposure group at 18 °C. Both PM_2.5 and lower temperature increased the releasing of tumor necrosis factor alpha (TNF-α), macrophage inflammatory protein 1α (MIP-1α) and interleukin-6 (IL-6), while significant interaction was only found in MIP-1α production. No obvious change was found in granulocyte-macrophage colony-stimulating factor (GM-CSF) detection. These results indicated that both the two factors are harmful to rat AMs and lower temperature could increase the toxicity of PM_2.5 on the AMs.     

Thermo- and pH-sensitive dendrosomes as bi-phase drug delivery systems

Fully supramolecular dendrosomes (FSD) as bi-phase drug delivery systems are reported in this work. For preparation of FSD, amphiphilic linear-dendritic supramolecular systems (ALDSS) have been synthesized by host-guest interactions between hyperbranched polyglycerol having β-cyclodextrin core and bi-chain polycaprolactone (BPCL) with a fluorescine focal point. Self-assembly of ALDSS in aqueous solutions led to FSD. They were able to encapsulate paclitaxel with a high loading capacity. The dendrosome-based drug delivery systems were highly sensitive to pH and temperature. They were stable at 20–37 °C and pH7–8, but dissociated and released drug at temperatures lower than 20 °C or higher than 37 °C and pH lower than 7 quickly. Dissociation of FSD building blocks by temperature or pH resulted in inclusion complexes between the released drugs and polyglycerol as the secondary drug delivery system.From the Clinical EditorThis paper reports on the development of a pH- (below 7) and temperature- (below 20 °C or above 37 °C) sensitive delivery system using supramolecular dendrosomes for more specific delivery and release of drugs using paclitaxel as a model.     

Interferon-γ increases expression of the di/tri-peptide transporter,h-PEPT1, and dipeptide transport in cultured human intestinal monolayers

The di/tri-peptide transporter h-PEPT1 plays an important role in the oral absorption of di/tri-peptides and numerous drugs. Inflammatory conditions may influence intestinal xenobiotic transporter function; however, the effects of inflammation on h-PEPT1 have not been well described. This study was conducted to determine the effects of the inflammatory cytokine interferon-γ (IFN-γ) on h-PEPT1 mediated dipeptide absorption. Caco-2 monolayers were grown on permeable supports. The effective apical-to-basolateral permeability (P_eff) of glycylsarcosine (Gly-Sar) was measured following incubation with IFN-γ or control media. Additional experiments were conducted at 4 °C, and with escalating concentrations of Gly-Sar. h-PEPT1 expression was determined using semiquantitative RT-PCR. IFN-γ 50 ng/ml increased Gly-Sar P_eff 28.6% compared to controls (p = 0.03). In experiments conducted at 4 °C, Gly-Sar P_eff decreased 39.6% in IFN-γ treated cells (p = 0.003) and 28.4% in controls (p = 0.006). In controls and IFN-γ treated cells, concentration dependent transport was seen with escalating concentrations of Gly-Sar. Compared to controls, IFN-γ 50 and 100 ng/ml increased h-PEPT1 mRNA expression by 14.2% and 11.5%, respectively (p = 0.019). In summary, IFN-γ increases h-PEPT1 expression and permeation of the dipeptide Gly-Sar in Caco-2 monolayers. These findings imply that intestinal absorption of peptides and peptidomimetic drugs may be increased in certain inflammatory conditions.     

Genotoxicity and antileishmanial activity evaluation of Physalis angulata concentrated ethanolic extract

Antileishmanial in vitro tests, as well as Ames and micronucleus assays were performed with a concentrated ethanolic extract of Physalis angulata (EEPA)ResultsEEPA did not present mutagenic effect in Salmonella typhimurium strains at concentration reaching 3000 μg/plate and did not induce mutagenic effects after two oral administrations with a 24 h interval at a dose level of 2000 mg/kg. EEPA presented antileishmanial activity and presented an IC₅₀ value of 5.35 ± 2.50 μg/mL and 4.50 ± 1.17 μg/mL against Leishmania amazonensis and Leishmania braziliensis promastigotes, respectively. In the cytotoxicity test against macrophages, the EEPA had a LC₅₀ of 6.14 ± 0.59 μg/mL. Importantly, the IC₅₀ against L. amazonensis intracellular amastigotes was 1.23 ± 0.11 μg/mL.ConclusionEEPA extract is non-mutagenic and presented a promising pharmacological effect against Leishmania parasites.     

Heat increases MDMA-enhanced NAcc 5-HT and body temperature, but not MDMA self-administration

There is a concern that hot environments enhance adverse effects of 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”). In this study, long-term (4-weeks) daily MDMA self-administration sessions and an MDMA Challenge test were conducted with rats under normal and high thermal conditions (23° or 32 °C). During MDMA self-administration sessions, activity and body temperature were increased by heat or MDMA experience, while MDMA self-administration rates increased with experience, but were comparable between thermal conditions. At the MDMA Challenge test (3.0 mg/kg, i.v.), in vivo microdialysis showed that nucleus accumbens serotonin (NAcc 5-HT) and dopamine (DA) responses were significantly increased in both thermal conditions. In the heated environment, MDMA-stimulated 5-HT responses and core temperature (but not DA) were significantly greater than at room temperature. Though the heated environment did not acutely boost MDMA intake, exaggerated NAcc 5-HT responses to MDMA may result in 5-HT depletion; a condition associated with Ecstasy use escalation and neural dysfunctions altering mood and cognition.     

Principles of rational design of thermally targeted liposomes for local drug delivery

Drug release from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes occurs close to the main transition temperature T_m = 41 °C. The exact release temperature can be adjusted by additional lipids, which shift T_m. A major issue is drug leakage at 37 °C. We here describe a novel approach with improved drug retention yet rapid release. To obtain spherical, smooth liposomes we included: i) 2 mol% cholesterol, to soften bilayers (Lemmich et al 1997), ii) lipids, which due to their spontaneous curvature stabilize the negative and positive curvatures of the inner and outer leaflets of unilamellar liposomes. In addition to differential scanning calorimetry (DSC) and fluorescence spectroscopy, the lipid mixtures were analyzed by a Langmuir balance for their elastic properties and lipid packing, aiming at high elasticity modulus C_S^− 1. Maxima in C_S^− 1 coincided with minima in the free energy of lateral mixing. These liposomes have reduced drug leakage, yet retain rapid release.From the Clinical EditorThis paper reports the development of optimized DPPC liposomes for drug delivery, with reduced drug leakage but maintained rapid release.     

A chitosan-modified graphene nanogel for noninvasive controlled drug release

A near infrared (NIR) triggered drug delivery platform based on the chitosan-modified chemically reduced graphene oxide (CRGO) incorporated into a thermosensitive nanogel (CGN) was developed. CGN exhibited an NIR-induced thermal effect similar to that of CRGO, reversible thermo-responsive characteristics at 37-42 °C and high doxorubicin hydrochloride (DOX) loading capacity (48 wt%). The DOX loaded CGN (DOX-CGN) released DOX faster at 42 °C than at 37 °C. The fluorescence images revealed DOX expression in the cytoplasm of cancer cells when incubated with DOX-CGN at 37 °C but in the nucleus at 42 °C. Upon irradiation with NIR light (808 nm), a rapid, repetitive DOX release from the DOX-CGN was observed. Furthermore, the cancer cells incubated with DOX-CGN and irradiated with NIR light displayed significantly greater cytotoxicity than without irradiation owing to NIR-triggered increase in temperature leading to nuclear DOX release. These results demonstrate CGN's promising application for on-demand drug release by NIR light.From the Clinical EditorThese investigators report the successful development of a novel near infrared triggered drug delivery platform based on chitosan-modified chemically reduced graphene oxide (CRGO) incorporated into a thermosensitive nanogel (CGN).     

The use of dynamic mechanical analysis (DMA) to evaluate plasticization of acrylic polymer films under simulated gastrointestinal conditions

PurposeGlass transition temperature (T_g) measurements of polymers are conventionally conducted in the dry state with little attention to the environment they are designed to work in. Our aim was to develop the novel use of dynamic mechanical analysis (DMA) to measure the T_g of enteric polymethacrylic acid methylmethacrylate (Eudragit L and S) polymer films formulated with a range of plasticizers in the dry and wet (while immersed in simulated gastric media) states.MethodsPolymer films were fabricated with and without different plasticizers (triacetin, acetyl triethyl citrate, triethyl citrate, polyethylene glycol, propylene glycol, dibutyl phthalate, dibutyl sebacate). T_g was measured by a dynamic oscillating force with simultaneous heating at 1 °C/min. This was conducted on films in the dry state and while immersed in 0.1 M HCl to simulate the pH environment in the stomach.ResultsThe T_g of unplasticized Eudragit L and S films in the dry state was measured to be 150 and 120 °C, respectively. These values were drastically reduced in the wet state to 20 and 71 °C for Eudragit L and S films, respectively. The plasticized films showed similar falls in T_g in the wet state. The fall in T_g of Eudragit L films to below body temperature will have far-reaching implications on polymer functionality and drug release.ConclusionsImmersion DMA provides a robust method for measuring T_g of polymer films in the wet state. This allows better prediction of polymer behaviour in vivo.