Polymer–drug interactions and wetting of solid dispersions

We demonstrate the ability of drugs to influence the wetting of solid dispersion tablets in unexpected ways. Five model drugs of different water solubility and ability to interact with the involved polymers were incorporated in hydrophilic polymer matrices, made of either hydroxypropyl methylcellulose (HPMC) or polyvinyl pyrrolidone (PVP). The physical mixtures of all combinations of drug and polymer presented surface hydrophobicities, as measured by the equilibrium advancing contact angle of water, which are expected for materials that do not influence the interactions of each other with water. However, the solid dispersions containing HPMC deviated from this regular behaviour and displayed contact angles below those of the pure compounds involved, either drug or polymer. This behaviour is explained by changed surface exposure of HPMC side groups, as a result of changes in intermolecular hydrogen bonds. In addition to water contact angle measurements, we employed NMR imaging to monitor the time course of water ingress and swelling.     

Role of polymer–drug conjugates in organ-specific delivery systems

Polymers have been utilized to deliver the drug to targeted site in controlled manner, achieving the high-therapeutic efficacy. Polymeric drug conjugates having variable ligands as attachments have been proved to be biodegradable, stimuli sensitive and targeted systems. Numerous polymeric drug conjugates having linkers degraded by acidity or intracellular enzymes or sensitive to over expressed groups of diseased organ/tissue have been synthesized during last decade to develop targeted delivery systems. Most of these organs have number of receptors attached with different cells such as Kupffer cells of liver have mannose-binding receptors while hepatocytes have asialoglycoprotein receptors on their surface which mainly bind with the galactose derivatives. Such ligands can be used for achieving high targeting and intracellular delivery of the drug. This review presents detailed aspects of receptors found in different cells of specific organ and ligands with binding efficiency to these specific receptors. This review highlights the need of further studies on organ-specific polymer–drug conjugates by providing detailed account of polymeric conjugates synthesized till date having organ-specific targeting.     

The drug–drug interaction of sorafenib mediated by P-glycoprotein and CYP3A4

1.?The aim of this study was to investigate the potential drug–drug interaction of sorafenib mediated by P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4).

2.?In this research, a sensitive and reliable LC-MS/MS method was developed and applied for the determination of sorafenib in rat plasma. The pharmacokinetic profiles of orally administered sorafenib from rats with and without verapamil pretreatment were investigated.

3.?The results indicated that when the rats were pretreated with verapamil, the C_max of sorafenib increased from 55.73?ng/ml to 87.72?ng/ml (57.40%), and the AUC_(0?t) increased by approximately 58.2% when sorafenib was co-administered with verapamil. Additionally, the effects of verapamil on the absorption of sorafenib were investigated using the Caco-2 cell transwell model, and the effects of verapamil on the metabolic stability of sorafenib were also studied using rat liver microsomes incubation systems. A markedly higher transport of sorafenib across the Caco-2 cells was observed in the basolateral-to-apical direction and was abrogated in the presence of the P-gp inhibitor, verapamil. The results indicated that P-gp was involved in the transport of sorafenib, and verapamil could increase its absorption in the Caco-2 cell model, and the metabolic stability of sorafenib was prolonged by the pretreatment with verapamil.

4.?In conclusion, the drug–drug interaction of sorafenib might happen when sorafenib was co-administered with P-gp or CYP3A4 inhibitors.     

Clinical disposition,metabolism and in vitro drug–drug interaction properties of omadacycline

1.?Absorption, distribution, metabolism, transport and elimination properties of omadacycline, an aminomethylcycline antibiotic, were investigated in vitro and in a study in healthy male subjects.

2.?Omadacycline was metabolically stable in human liver microsomes and hepatocytes and did not inhibit or induce any of the nine cytochrome P450 or five transporters tested. Omadacycline was a substrate of P-glycoprotein, but not of the other transporters.

3.?Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300?mg oral dose of [¹⁴C]-omadacycline (36.6 μCi). Absorption was rapid with peak radioactivity (～610 ngEq/mL) between 1–4?h in plasma or blood. The AUC_last of plasma radioactivity (only quantifiable to 8?h due to low radioactivity) was 3096 ngEq?h/mL and apparent terminal half-life was 11.1?h. Unchanged omadacycline reached peak plasma concentrations (～563?ng/mL) between 1–4?h. Apparent plasma half-life was 17.6?h with biphasic elimination. Plasma exposure (AUC_inf) averaged 9418?ng?h/mL, with high clearance (CL/F, 32.8?L/h) and volume of distribution (Vz/F 828?L). No plasma metabolites were observed.

4.?Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.     

Characterisation of the thermal,spectroscopic and drug dissolution properties of mefenamic acid and polyoxyethylene–polyoxypropylene solid dispersions

The aim of this study was to investigate the solubility of mefenamic acid (MA), a highly cohesive, poorly water-soluble drug in a copolymer of polyoxyethylene–polyoxypropylene (Lutrol F68®), and to understand the effect drug polymer solubility has on in vitro dissolution of MA. Solid dispersions (SD) of MA were prepared by a hot melt method, using Lutrol F68® as a thermoplastic polymeric platform. High-speed differential scanning calorimetry (Hyper-DSC), Raman spectroscopy, powder X-ray diffractometry (PXRD) and hot-stage/fluorescence microscopy were used to assess the solubility of the drug in molten and solid polymer. Drug dissolution studies were subsequently conducted on single-phase solid solutions and biphasic SD using phosphate buffer pH 6.8 as dissolution media. Solubility investigations using Hyper-DSC, Raman spectroscopy and hot-stage microscopy suggested MA was soluble in molten Lutrol F68® up to a concentration of 35% (w/w). Conversely, the solubility in the solid-state matrix was limited to <15% (w/w); determined by Raman spectroscopy, PXRD and fluorescence microscopy. As expected the dissolution properties of MA were significantly influenced by the solubility of the drug in the polymer matrix. At a concentration of 10% (w/w) MA (a single phase solid solution) dissolution of MA in phosphate buffer 6.8 was rapid, whereas at a concentration of 50% (w/w) MA (biphasic SD) dissolution was significantly slower. This study has clearly demonstrated the complexity of drug–polymer binary blends and in particular defining the solubility of a drug within a polymeric platform. Moreover, this investigation has demonstrated the significant effect drug solubility within a polymeric matrix has upon the in vitro dissolution properties of solid polymer/drug binary blends. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4545–4556, 2009     

In vitro assessment of the roles of drug transporters in the disposition and drug–drug interaction potential of olaparib

1.?In vitro assessments were conducted to examine interactions between olaparib (a potent oral inhibitor of poly[ADP-ribose] polymerase) and drug transporters.

2.?Olaparib showed inhibition of the hepatic drug uptake transporters OATP1B1 (IC₅₀ values of 20.3?μM and 27.1?μM) and OCT1 (IC₅₀ 37.9?μM), but limited inhibition of OATP1B3 (25% at 100?μM); inhibition of the renal uptake transporters OCT2 (IC₅₀ 19.9?μM) and OAT3 (IC₅₀ 18.4?μM), but limited inhibition of OAT1 (13.5% at 100?μM); inhibition of the renal efflux transporters MATE1 and MATE2K (IC₅₀s 5.50?μM and 47.1?μM, respectively); inhibition of the efflux transporter MDR1 (IC₅₀ 76.0?μM), but limited inhibition of BCRP (47% at 100?μM) and no inhibition of MRP2. At clinically relevant exposures, olaparib has the potential to cause pharmacokinetic interactions via inhibition of OCT1, OCT2, OATP1B1, OAT3, MATE1 and MATE2K in the liver and kidney, as well as MDR1 in the liver and GI tract. Olaparib was found to be a substrate of MDR1 but not of several other transporters.

3.?Our assessments indicate that olaparib is a substrate of MDR1 and may cause clinically meaningful inhibition of MDR1, OCT1, OCT2, OATP1B1, OAT3, MATE1 and MATE2K.     

Dissolution enhancement of felodipine by amorphous nanodispersions using an amphiphilic polymer: insight into the role of drug–polymer interactions on drug dissolution

Context: Felodipine, a poorly soluble drug, is widely used in the treatment of angina pectoris and hypertension.

Objective: This study aimed at the preparation of amorphous solid dispersion (SD) of felodipine using an amphiphilic polymer, soluplus, for the potential enhancement in solubility of the drug.

Materials and methods: Solid dispersions with varying proportions of drug and soluplus were prepared and the rate and extent of dissolution from SDs was compared with that of the pure drug. FT-IR and ¹H NMR spectroscopic analysis were carried out to examine the formation mechanism of SDs. Various techniques were used for solid state characterization of designed SDs.

Results: Formation of amorphous solid dispersions with particle size in nanometer range indicated suitability of polymer and method used in the preparation. FT-IR and ¹H NMR spectroscopy revealed that soluplus was involved in strong hydrogen bonding with felodipine molecules which resulted in the conversion of crystalline felodipine into amorphous form. Solid dispersion with 1:10 drug/polymer ratio showed more than 90% drug dissolution in 30?min whereas pure felodipine showed less than 19% drug dissolution in 1?h.

Discussion and conclusion: Amorphous SDs of felodipine were prepared using soluplus resulting in substantial enhancement in the rate and extent of dissolution of felodipine.     

Inhibition of surface crystallisation of amorphous indomethacin particles in physical drug–polymer mixtures

Surface coverage may affect the crystallisation behaviour of amorphous materials. This study investigates crystallisation inhibition in powder mixtures of amorphous drug and pharmaceutical excipients. Pure amorphous indomethacin (IMC) powder and physical mixtures thereof with Eudragit^® E or Soluplus^® in 3:1, 1:1 and 1:3 (w/w) ratios were stored at 30 °C and 23 or 42% RH. Samples were analysed during storage by X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and scanning electron microscopy (SEM). IMC Eudragit^® mixtures showed higher physical stability than pure IMC whereas IMC Soluplus^® mixtures did not.     

Evaluation of community pharmacists’ knowledge about drug–drug interaction in Central Saudi Arabia

IntroductionAlthough all implemented and ongoing initiatives, drug-drug interactions (DDIs) are still a global problem. Most published studies about DDIs in Saudi Arabia are carried out in hospital settings. In addition, assessing the knowledge of drug interactions in Saudi Arabia is limited. The aim of our study is to evaluate the knowledge of potential common drug-drug interactions among community pharmacists particularly in Saudi Arabia.MethodologyA crosses-sectional study utilizing a self- administered questionnaire was conducted among community pharmacy in Riyadh city Saudi Arabia. DDIs' knowledge was assessed by 26 drug pairs. Community pharmacists were asked to select the DDIs as “contraindication”, “may be used together with monitoring”, “no interaction” and “not sure”.ResultsA total of 283 of community pharmacists completed the survey with response rate of 80.9%. Among the 26 drug pairs only 5 of them were identified correctly by most of the participants. To add more 3 out of the 5 pairs had a cutoff of less than 10% between the correct and wrong answer, meaning there still a majority that couldn't identify the correct answer. All the 26 pairs had a statistically significant difference between the correct and incorrect answer.ConclusionThe results of this study showed that knowledge of community pharmacists about DDIs was inadequate. Community pharmacist should have specific courses in drug interactions to cover the most possible interactions that can be seen in this setting.     

Drug–drug interaction of rabeprazole and clopidogrel in healthy Chinese volunteers

Purpose

This study was aimed to determine the impact of rabeprazole (RBRZ) on the antiplatelet efficacy of clopidogrel (CPG) in healthy Chinese volunteers, and further to predict the effect of CYP2C19 genetic polymorphism on the efficacy of rabeprazole and clopidogrel.

Methods

The open-label, two period cross-over study was conducted in 20 healthy Chinese subjects with different CYP2C19 genotypes receiving clopidogrel, rabeprazole or the two drugs, respectively. All the volunteers were divided into two groups, poor metabolizers (PMs) and extensive metabolizers (EMs), depending on CYP2C19 genotypes. Blood samples were collected at baseline and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h after administration. The plasma concentrations of rabeprazole and clopidogrel were analyzed by LC-MS/MS and ADP-induced platelet aggregation was detected by the optical turbidimetric method.

Results

There were no significant differences in the mean plasma concentration–time curves of clopidogrel (CPG), the inactive metabolite clopidogrel carboxylic acid (CPG-CA), the active metabolite clopidogrel-MP-Derivative (MP-AM), and rabeprazole (RBRZ) according to the co-administration of CPG and RBRZ. There were no major changes in the pharmacokinetics of CPG and RBRZ. The maximal ADP-induced platelet aggregation (2 μmol/L) was decreased in EMs compared with PMs.

Conclusion

Co-administration of rabeprazol and clopidogrel did not affect the antiplatelet efficacy of clopidogrel. The CYP2C19 genetic polymorphism may impact the efficacy of clopidogrel.     

Development of a simultaneous LC–MS/MS method to predict in vivo drug–drug interaction in mice

Cocktail substrates are useful in investigating drug–drug interactions (DDI) that can rapidly identify the cytochrome P450 (CYP) isoforms that interact with test drugs. In this study, we developed and validated five probe drugs for CYP1A, CYP2B, CYP2C, CYP2D, and CYP3A using LC–MS/MS to determine CYP activities in mice. The five probe substrates were caffeine (2 mg/kg), bupropion (30 mg/kg), omeprazole (4 mg/kg), dextromethorphan (40 mg/kg), and midazolam (2 mg/kg) for CYP1A, CYP2B, CYP2C, CYP2D, and CYP3A, respectively. The cocktail substrates were orally administered to male 5-week-old ICR mice over 0–240 min. The analytical method was validated; it showed high selectivity, linearity, and acceptable accuracy. We confirmed the lack of interaction of this cocktail in the control state (no effect of CYP inducer or inhibitor) and suggested AUC_ratio (metabolite/substrate) as a unit to evaluate DDI in vivo. In addition, the cocktail assay was applied for the determination of pharmacokinetic parameters against phenobarbital as a selective CYP2B inducer and ketoconazole as a strong CYP3A inhibitor. The concentration of cocktail substrates and the LC–MS/MS method were optimized. In conclusion, we developed a simultaneous and comprehensive analysis system for predicting potential DDI in mice.     

Smart linkers in polymer–drug conjugates for tumor-targeted delivery

To achieve effective chemotherapy, many types of drug delivery systems have been developed for the specific environments in tumor tissues. Polymer–drug conjugates are increasingly used in tumor therapy due to several significant advantages over traditional delivery systems. In the fabrication of polymer–drug conjugates, a smart linker is an important component that joins two fragments or molecules together and can be cleared by a specific stimulus, which results in targeted drug delivery and controlled release. By regulating the conjugation between the drug and the nanocarriers, stimulus-sensitive systems based on smart linkers can offer high payloads, certified stability, controlled release and targeted delivery. In this review, we summarize the current state of smart linkers (e.g. disulfide, hydrazone, peptide, azo) used recently in various polymer–drug conjugate-based delivery systems with a primary focus on their sophisticated design principles and drug delivery mechanisms as well as in vivo processes.     

Prediction of drug–drug interaction potential using physiologically based pharmacokinetic modeling

The occurrence of drug–drug interactions (DDIs) can significantly affect the safety of a patient, and thus assessing DDI risk is important. Recently, physiologically based pharmacokinetic (PBPK) modeling has been increasingly used to predict DDI potential. Here, we present a PBPK modeling concept and strategy. We also surveyed PBPK-related articles about the prediction of DDI potential in humans published up to October 10, 2017. We identified 107 articles, including 105 drugs that fit our criteria, with a gradual increase in the number of articles per year. Studies on antineoplastic and immunomodulatory drugs (26.7%) contributed the most to published PBPK models, followed by cardiovascular (20.0%) and anti-infective (17.1%) drugs. Models for specific products such as herbal products, therapeutic protein drugs, and antibody–drug conjugates were also described. Most PBPK models were used to simulate cytochrome P450 (CYP)-mediated DDIs (74 drugs, of which 85.1% were CYP3A4-mediated), whereas some focused on transporter-mediated DDIs (15 drugs) or a combination of CYP and transporter-mediated DDIs (16 drugs). Full PBPK, first-order absorption modules and Simcyp^® software were predominantly used for modeling. Recently, DDI predictions associated with genetic polymorphisms, special populations, or both have increased. The 107 published articles reasonably predicted the DDI potentials, but further studies of physiological properties and harmonization of in vitro experimental designs are required to extend the application scope, and improvement of DDI predictions using PBPK modeling will be possible in the future.     

Physicochemical properties of tadalafil solid dispersions – Impact of polymer on the apparent solubility and dissolution rate of tadalafil

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3 μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50 μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27 μg/ml) over 24 h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low T_g (113 °C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8 MPa^0.5) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.     

Drug–drug interaction with statins

3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors (the so-called statins: atorvastatin, fluvastatin, pravastatin, lovastatin, rosuvastatin and simvastatin) are a well-established class of drugs in the treatment of hypercholesterolemia. Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Since statins are prescribed on a long-term basis, possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment. Moreover, a combination of therapy between statins and other classes of lipid-lowering agents (e.g., ezetimibe, fibrates, resins and nicotinic acid) is recommended for some patients by current guidelines. Therefore, the potential for drug–drug interactions emerges as a relevant factor in determining the safety profile of statins. This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions.     

Concomitant use of mirtazapine and cimetidine: a drug–drug interaction study in healthy male subjects

Objective: The objective of this study was to examine the pharmacokinetics and the tolerability/safety of mirtazapine and cimetidine separately and in combination following oral administration of multiple doses. Methods: This was a double-blind, placebo-controlled, two-period cross-over, multiple-dose pharmacokinetic interaction study in 12 healthy male subjects. They received either cimetidine (800 mg b.i.d.) or placebo in combination with (commercially available, racemic) mirtazapine (30 mg nocte). Cimetidine and placebo were administered for 14 days, with mirtazapine added during days 6–12 of each period. Serial blood samples for kinetic profiling were taken on day 5 and day 12 for cimetidine and on days 12–14 for mirtazapine. Results: The co-administration of cimetidine resulted in a statistically significant increase in the area under the curve (AUC_0–24) and C_max of mirtazapine (54% and 22% respectively). The AUC_0–24 of demethylmirtazapine increased only slightly, and there was no effect on C_max. The elimination half-lives for both mirtazapine and its demethyl metabolite were unaffected by cimetidine co-administration. The trough and average plasma concentrations during the steady state were elevated during cimetidine treatment (62% and 54%, respectively). Mirtazapine had no effect on the pharmacokinetics of cimetidine. Conclusion: Co-administration of cimetidine (800 mg b.i.d.) and mirtazapine (30 mg nocte) resulted in increased steady-state plasma levels of mirtazapine (C_ss,min= +61%, P < 0.05; C_ss,av=+54%, P < 0.05), probably as a result of increased bio-availability. The C_max (+22%, P < 0.05) and AUC_0–24 (+54%, P < 0.05) also increased. Due to the variability of the mirtazapine plasma levels in patients, the clinical meaning of these increases is probably limited. Co-administration of mirtazapine did not alter cimetidine pharmacokinetics. Received: 24 November 1999 / Accepted in revised form: 15 May 2000     

Improvement in the handling of drug–drug interactions

Approximately one in 200 hospitalised patients has a serious adverse drug effect caused by drug–drug interactions (DDIs). Such adverse effects should be avoidable, but current information provided on DDIs is often incomplete and difficult or even impossible to translate into true risk and appropriate tangible action. Clinicians need to know the mean and maximal expected effect of a DDI on clinical endpoints, any dose adjustments required, and how to monitor tolerability and efficacy in patients subject to a DDI. To this end, improved study designs should take the objective of improving treatment explicitly into account, and any existing DDI data should be publicly accessible. Modelling needs to be used more extensively in order to quantitatively predict the effects of DDIs on clinical endpoints in patients and to relate clinical endpoint effects considered as acceptable to respective changes in experimental and clinical studies. Computer-based expert systems will be required to convert such DDI data into recommendations applicable to the individual patient. Therefore, the incorporation of DDIs in a more general procedure for personalisation of drug therapy is desirable.