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Oral solid dosage forms are most frequently administered with a glass of water which empties from the stomach relatively fast, but with a certain variability in its emptying kinetics. The purpose of this study was thus to simulate different individual water gastric emptying (GE) patterns in an in vitro glass-bead flow-through dissolution system. Further, the effect of GE on the dissolution of model drugs from immediate-release tablets was assessed by determining the amount of dissolved drug in the samples pumped out of the stomach compartment. Additionally, different HCl solutions were used as dissolution media to assess the effect of the variability of pH of the gastric fluid on the dissolution of three model drugs: paracetamol, diclofenac sodium, and dipyridamole. The difference in fast and slow GE kinetics resulted in different dissolution profiles of paracetamol in all studied media. For diclofenac sodium and dipyridamole tablets, the effect of GE kinetics was well observed only in media, where the solubility was not a limiting factor. Therefore, GE kinetics of co-ingested water influences the drug release from immediate-release tablets, however, in certain cases, other parameters influencing drug dissolution can partly or fully hinder the expression of this effect., (© 2024 Tjaša Felicijan et al., published by Sciendo.)

Objective: To utilize the global system analysis (GSA) in oral absorption modeling to gain a deeper understanding of system behavior, improve model accuracy, and make informed decisions during drug development., Methods: GSA was utilized to give insight into which drug substance (DS), drug product (DP), and/or physiological parameter would have an impact on peak plasma concentration (C max ) and area under the curve (AUC) of dipyridamole as a model weakly basic compound. GSA guided the design of in vitro experiments and oral absorption risk assessment using FormulatedProducts v2202.1.0. The solubility and precipitation profiles of dipyridamole in different bile salt concentrations were measured. The results were then used to build a mechanistic oral absorption model., Results: GSA warranted further investigation into the precipitation kinetics and its link to the levels of bile salt concentrations. Mechanistic modeling studies demonstrated that a precipitation-integrated modeling approach appropriately predicted the mean plasma profiles, C max , and AUC from the clinical studies., Conclusions: This work shows the value of GSA utilization in early development to guide in vitro experimentation and build more confidence in identifying the critical parameters for the mathematical models., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this study, we developed and validated a method to determine dipyridamole-related impurities in pharmaceutical dosage forms using the reversed-phase-HPLC technique. All impurities were separated on a YMC pack C8 (150 mm × 4.6 mm, 3.0 μm) analytical column using a suitable mobile phase. Mobile phase A was 10 mM concentration of phosphate buffer (pH adjusted to 4.7 by adding diluted orthophosphoric acid) and mobile phase B was buffer:acetonitrile:methanol (at the ratio of 30:40:30 v/v). The optimized chromatographic conditions used in the experiment were as follows: flow rate, 1.0 mL/min; injection volume, 10 μL and column temperature, 35°C. Chromatographic detection was performed at 295 nm. The stressed samples were analyzed for degradation under acidic, basic, peroxide, water hydrolysis, and physical degradation conditions. The proposed method was validated according to International Conference on Harmonization (ICH) guidelines, and found to be specific, linear, accurate and have a robust stability-indicating nature. The method showed excellent linearity from limit of quantification (LOQ) to 150% level of concentrations for all impurities. The correlation coefficient (r 2 ) for all impurities was between 0.995 and 0.999. The recovery study was performed from LOQ to 150% level concentrations, with mean recovery values between 92.9% and 103.2%, respectively. The developed method can be used to determine dipyridamole and its relative impurities. The degradation and validated study results indicate its stability-indicating nature. Therefore, the method can be used in pharmaceutical research and development and quality control departments., (© 2021 John Wiley & Sons, Ltd.)

Unfractionated heparin (UFH) is the main anticoagulante used in intensive care unit. The anticoagulant effect is monitored by activated partial thrombin time (aPTT) and anti-Xa activity (anti-Xa) measurement. However, delayed centrifugation induces platelet factor 4 (PF4) release and anti-Xa decrease. Several studies have concluded that aPTT and anti-Xa measurement should be performed within 2 hours in citrated anticoagulant but may be delayed longer in citrate theophylline adenosine and dypiridamol (CTAD) anticoagulant. The objective of this study was to compare the stability of both aPTT and anti-Xa in citrate and CTAD samples, and to determine the effect of delayed centrifugation on both aPTT, anti-Xa results, and PF4 release in citrate samples only., Methods: aPTT and anti-Xa were measured in citrate and CTAD anticoagulant samples from 93 patients. Delayed centrifugation was performed in citrate samples from 31 additional patients, with hourly aPTT and anti-Xa measurement from 1 to 6 hours. In 14 of these last patients, PF4 release was also evaluated with Human CXCL4/PF4 Quantikine ELISA Kit., Results: We observed a significant correlation between citrate and CTAD anticoagulant for aPTT (r 2 =0.94) and anti-Xa (r 2 =0.95). With Bland-Altman correlation, a minor bias was observed for anti-Xa (-0.025±0.041). Delayed centrifugation in citrated anticoagulant showed an excellent concordance from 1 to 4 hours for aPTT (-4.0±5.3 s) and anti-Xa (1.10 -9 ±0.058 UI/mL) measurements. Moreover, PF4 release was not different between 1 hour (31.5±14.7 ng/mL) and 4 hours (33.8±11.8 ng/mL)., Conclusion: We have demonstrated that anti-Xa measurement for unfractionated heparin should be done 4 hours in citrated plasma and that CTAD was not better than citrate. However, these initial findings require confirmation using other aPTT and calibrated anti-Xa assays.

One of the main tasks of modern pharmaceutics is enhancing the solubility of drugs. The approaches for solving this problem include producing active pharmaceutical ingredients in the amorphous state. However, the use of amorphous drugs requires the determination of their kinetic stability. The latter is often assessed using isothermal techniques, which are time-consuming. Alternatively, non-isothermal methods can be employed, allowing to determine the kinetic triplet more rapidly. Also, such techniques can be used to develop predictive models for storage stability. The production of the amorphous state itself typically requires fast cooling rates, which may not be easily accessible. Fast scanning calorimetry is a promising tool for the investigation of amorphous drug systems. In the present work, the crystallization of the model drug dipyridamole was investigated using the fast scanning calorimetry method. The kinetic stability of the amorphous form of the drug was evaluated using both, isothermal and non-isothermal methods. The Nakamura crystallization model was found to be applicable for the prediction of the temporal stability of the amorphous drug forms. The obtained results may find applications in the investigation of the kinetic stability of amorphous drug systems., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Dipyridamole (DP) elevates cyclic Adenosine Monophosphate (cAMP) levels in platelets, erythrocytes, and endothelial cells and also blocks adenosine reuptake. It is used to dilate blood vessels in people with peripheral arterial disease and coronary artery disease (CAD). The flexible backbone, hydrophobic nature, and several available hydrogen bond (H-bond) donors and acceptors are well suited structural features of DP for inhibition/activation of enzymes. Substrates of α-amylase (α-Amy) and α-Glucosidase (α-Glu), known as key absorbing enzymes, have functional groups (OH groups) similar to DP. Since hypoglycemia can occur in diabetes disease and there is a significant link between diabetes and cardiovascular diseases (CVD), thus this study aimed to evaluate the inhibitory properties of DP against α-Amy and α-Glu, as enzyme targets of interest under hypoglycemia condition. DP inhibited the α-Glu and α-Amy activity in a dose dependent manner with IC 50 values 19.4 ± 0.3 and 30.1 ± 0.4 µM, respectively. Further, the K i values of DP for α-Glu and α-Amy were determined as 2.9 ± 0.2 and 3.1 ± 0.4 µM in a competitive-mode and mixed-mode inhibition, respectively. Also, DP had binding energies of -7.3 and -6.5 kcal/mol, to communicate with the active site of α-Glu and α-Amy, respectively. In addition, in-vivo studies revealed that the blood glucose concentration diminished after taking of DP compared to positive control group (p < 0.01). Accordingly, the results of the current work may prompt the scientific community to investigate the possible interconnection between DP clinical (side) effects and its α-Glu and α-Amy inhibitory properties., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Supersaturating formulations are widely used to improve the oral bioavailability of poorly soluble drugs. However, supersaturated solutions are thermodynamically unstable and such formulations often must include a precipitation inhibitor (PI) to sustain the increased concentrations to ensure that sufficient absorption will take place from the gastrointestinal tract. Recent advances in understanding the importance of drug-polymer interaction for successful precipitation inhibition have been encouraging. However, there still exists a gap in how this newfound understanding can be applied to improve the efficiency of PI screening and selection, which is still largely carried out with trial and error-based approaches. The aim of this study was to demonstrate how drug-polymer mixing enthalpy, calculated with the Conductor like Screening Model for Real Solvents (COSMO-RS), can be used as a parameter to select the most efficient precipitation inhibitors, and thus realize the most successful supersaturating formulations. This approach was tested for three different Biopharmaceutical Classification System (BCS) II compounds: dipyridamole, fenofibrate and glibenclamide, formulated with the supersaturating formulation, mesoporous silica. For all three compounds, precipitation was evident in mesoporous silica formulations without a precipitation inhibitor. Of the nine precipitation inhibitors studied, there was a strong positive correlation between the drug-polymer mixing enthalpy and the overall formulation performance, as measured by the area under the concentration-time curve in in vitro dissolution experiments. The data suggest that a rank-order based approach using calculated drug-polymer mixing enthalpy can be reliably used to select precipitation inhibitors for a more focused screening. Such an approach improves efficiency of precipitation inhibitor selection, whilst also improving the likelihood that the most optimal formulation will be realized., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Biphasic dissolution models were proposed to provide good predictive power for in vivo absorption kinetics. However, up to date the impact of hydrodynamics in mini-scale models are not well understood. Consequently, the aim of this work was to investigate different setups of a previously published mini-scale biphasic dissolution model (miBIdi-pH-II) to better understand the relevance of hydrodynamics for evaluating kinetic parameters and to simultaneously increase the robustness of the experimental model. As a first step, the hydrodynamics within the aqueous phase were characterized by in silico simulations of the flow patterns. Different settings, such as higher rotation speeds of the paddles, the implementation of a second propeller into the aqueous phase, and different shapes of aqueous stirrers were investigated. Second, to evaluate the results of the in silico simulations, in vitro experiments with glitter were carried out. Last, the same settings were applied in the miBIdi-pH-II using dipyridamole (DPD) as model compound to estimate kinetic parameters by applying a compartment-based modelling approach. Both in vitro experiments with glitter or DPD demonstrated the adequateness of the previous in silico hydrodynamic simulations. The use of higher rotation speeds and a second aqueous propeller resulted in more homogeneous mixing of the aqueous phase. This resulted in faster distribution of dissolved active pharmaceutical ingredient (API) into the octanol phase. A kinetic model was successfully applied to quantify the influence of hydrodynamics on the partitioning rate of the API into the octanol phase. In conclusion, the combination of in silico and in vitro methods was demonstrated to be powerful for investigating the flow patterns within the miBIdi-pH-II. A comprehensive understanding of the hydrodynamics and the respective influence on the dissolution and apparent partitioning into the octanol phase in the biphasic dissolution model was obtained and completed by using a compartmental kinetic model. This model allowed successful quantification of how the hydrodynamics influence the partitioning of API into the octanol phase., (Copyright © 2018. Published by Elsevier B.V.)

This study aimed to evaluate the usefulness of the dissolution/permeation system (D/P system) as an in vitro tool for early screening of oral formulations of weakly basic drugs containing an acidic pH-modifier. Dipyridamole, having a prominent pH-dependent solubility, was used as a model drug, and various granules containing different amounts of fumaric acid were prepared. Prepared granules were administered orally to hypochlorhydria model rats. It was confirmed that fumaric acid improved the absorption of dipyridamole depending on its amount in the granules. Separately, dissolution and permeation of dipyridamole were observed in vitro in the D/P system. When using a medium with a low buffer capacity which mimicked the human intestinal fluid, rank order of the permeated amount of dipyridamole from various granules in the D/P system did not correlate with its absorption in hypochlorhydric rats. In contrast, when applying a medium with high buffer capacity, the permeated amount in the D/P system well reflected the effects of fumaric acid on the in vivo absorption of dipyridamole. In conclusion, by setting appropriate experimental protocols according to the properties of test compounds and formulations, D/P system can be a potent in vitro tool to predict in vivo performance of oral formulations., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

This study reports the development of a novel family of biodegradable polyurethanes for use as tissue engineered cardiovascular scaffolds or blood-contacting medical devices. Covalent incorporation of the antiplatelet agent dipyridamole into biodegradable polycaprolactone-based polyurethanes yields biocompatible materials with improved thromboresistance and tunable mechanical strength and elasticity. Altering the ratio of the dipyridamole to the diisocyanate linking unit and the polycaprolactone macromer enables control over both the drug content and the polymer cross-link density. Covalent cross-linking in the materials achieves significant elasticity and a tunable range of elastic moduli similar to that of native cardiovascular tissues. Interestingly, the cross-link density of the polyurethanes is inversely related to the elastic modulus, an effect attributed to decreasing crystallinity in the more cross-linked polymers. In vitro characterization shows that the antiplatelet agent is homogeneously distributed in the materials and is released slowly throughout the polymer degradation process. The drug-containing polyurethanes support endothelial cell and vascular smooth muscle cell proliferation, while demonstrating reduced levels of platelet adhesion and activation, supporting their candidacy as promising substrates for cardiovascular tissue engineering., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A method for the production of liquid capsules with the potential of modifying drug dose and release is presented. For the first time, the co-ordinated use of fused deposition modelling (FDM), 3D printing and liquid dispensing to fabricate individualised dosage form on demand in a fully automated fashion has been demonstrated. Polymethacrylate shells (Eudragit EPO and RL) for immediate and extended release were fabricated using FDM 3D printing and simultaneously filled using a computer-controlled liquid dispenser loaded with model drug solution (theophylline) or suspension (dipyridamole). The impact of printing modes: simultaneous shell printing and filling (single-phase) or sequential 3D printing of shell bottom, filling and shell cap (multi-phase), nozzle size, syringe volume, and shell structure has been reported. The use of shell thickness of 1.6 mm, and concentric architecture allowed successful containment of liquid core whilst maintaining the release properties of the 3D printed liquid capsule. The linear relationship between the theoretical and the actual volumes from the dispenser reflected its potential for accurate dosing (R 2  = 0.9985). Modifying the shell thickness of Eudragit RL capsule allowed a controlled extended drug release without the need for formulation change. Owing to its low cost and versatility, this approach can be adapted to wide spectrum of liquid formulations such as small and large molecule solutions and obviate the need for compatibility with the high temperature of FDM 3D printing process. In a clinical setting, health care staff will be able to instantly manufacture in small volumes liquid capsules with individualised dose contents and release pattern in response to specific patient's needs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The interaction of bovine milk α- and β-caseins as an efficient drug carrier system with Dipyridamole (DIP) was investigated using spectroscopy and molecular docking studies at different temperatures (20-37 °C). FTIR, CD, and fluorescence spectroscopy methods demonstrated that α- and β-caseins interact with DIP molecule mainly via hydrophobic and hydrophilic interactions and change in secondary structure of α- and β-caseins. DIP showed a higher quenching efficiency and binding constant of α-casein than β-casein. There was only one binding site for DIP and it was located on the surface of the protein molecule. The thermodynamic parameters of calculation showed that the binding process occurs spontaneously and demonstrated that α- and β-caseins provide very good binding and entrapment to DIP via hydrogen bonds, Van der Waals forces, and hydrophobic interactions. Fluorescence resonance energy transfer, synchronous fluorescence spectroscopy, and docking study showed that DIP binds to the Trp residues of α- and β-casein molecules with short distances. Docking study showed that DIP molecule made several hydrogen bonds and van der Waals interactions with α- and β-caseins. The study of cell culture and micellar solubility of DIP demonstrated α- and β-caseins relatively the same helping in delivery of DIP. Milk α- and β-caseins are considered as a useful vehicle for the solublization and stabilization of DIP in aqueous solution at natural pH.

Simulation of HME processes is a valuable tool for increased process understanding and ease of scale-up. However, the experimental determination of all required input parameters is tedious, namely the melt rheology of the amorphous solid dispersion (ASD) in question. Hence, a procedure to simplify the application of hot-melt extrusion (HME) simulation for forming amorphous solid dispersions (ASD) is presented. The commercial 1D simulation software Ludovic ® was used to conduct (i) simulations using a full experimental data set of all input variables including melt rheology and (ii) simulations using model-based melt viscosity data based on the ASDs glass transition and the physical properties of polymeric matrix only. Both types of HME computation were further compared to experimental HME results. Variation in physical properties (e.g. heat capacity, density) and several process characteristics of HME (residence time distribution, energy consumption) among the simulations and experiments were evaluated. The model-based melt viscosity was calculated by using the glass transition temperature (T g ) of the investigated blend and the melt viscosity of the polymeric matrix by means of a T g -viscosity correlation. The results of measured melt viscosity and model-based melt viscosity were similar with only few exceptions, leading to similar HME simulation outcomes. At the end, the experimental effort prior to HME simulation could be minimized and the procedure enables a good starting point for rational development of ASDs by means of HME. As model excipients, Vinylpyrrolidone-vinyl acetate copolymer (COP) in combination with various APIs (carbamazepine, dipyridamole, indomethacin, and ibuprofen) or polyethylene glycol (PEG 1500) as plasticizer were used to form the ASDs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of our work was to study and define a computationally-based adiabatic scale-up methodology for a hot-melt extrusion (HME) process to produce an amorphous solid dispersion (ASD). As a drug product becomes commercially viable, there is a need for scaling up the manufacturing process. In the case of HME used for the formation of ASDs, scale-up can be challenging due to the fundamental differences in how heat is generated in extruders of differing scale, i.e. conduction vs. viscous dissipation and the significant role heat generation plays in determining the final product attributes. Using a 30%w/w dipyridamole-in-copovidone formulation, 11 mm-, 16 mm- and 24 mm-diameter extruders with L/D 40, solid-state characterization tools, a geometric scaling equation, and Ludovic® twin-screw extrusion software, we compared the total imparted material energy, the conducted energy and the difference between barrel and melt temperature at die exit for various feed rates and screw speeds. Numerical simulation identified desirable adiabatic conditions at multiple extruder scales in agreement with the chosen scaling factor. With the use of computational tools, the energetics in an extrusion process can be evaluated and processing conditions can be selected to identify the most efficient scaling of a HME process., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Fibers of poly(L-lactic acid) (PLLA)/polyhydroxybutyrate (PHB) with different concentrations of the drug dipyridamole (DPD) were prepared using solvent-free melt electrospinning to obtain a polymeric drug delivery system. The electrospun fibers were morphologically, structurally, thermally, and dynamically characterized. Crazes that resemble lotus root crevices were interestingly observed in the 7:3 PLLA/PHB fibers with 1% DPD. The crystallinity of PLLA slightly decreased as PHB was incorporated, and the addition of DPD significantly reduced the melting temperature of the composite. The interactions between PLLA and PHB mainly occurred at a proportion of 7:3, and drug encapsulation in the fibers was verified. The kinetic profiles of drug release demonstrated the predominant multiple patterns involving a diffusional stage in the short-term mode of release and kinetic process related to the hydrolysis of the biopolymers. Furthermore, the dynamic behavior of the polymer molecules was evaluated based on the segmental mobility using probe electron spin resonance spectroscopy. The segmental mobility in the amorphous fraction of PLLA decreased with increasing PLLA content. The 9:1 PLLA/PHB system was more resistant to polymer hydrolysis than to the 7:3 system and the rate of diffusion transport was approximately two times higher for the 7:3 PLLA/PHB fibers than for the 9:1 PLLA/PHB fibers.

In this study, the dissolution behaviour of dipyridamole (DPM) and cinnarizine (CNZ) spray-dried amorphous solid dispersions (ASDs) using polyvinyl pyrrolidone (PVP) and polyacrylic acid (PAA) as a carrier matrix were evaluated and compared. The drug concentrations achieved from the dissolution of PVP and PAA solid dispersions were significantly greater than the equilibrium solubility of crystalline DPM and CNZ in phosphate buffer pH 6.8 (PBS 6.8). The maximum drug concentration achieved by dissolution of PVP and PAA solid dispersions did not exceed the theoretically calculated apparent solubility of amorphous DPM and CNZ. However, the degree of supersaturation of DPM and CNZ increased considerably as the polymer weight fraction within the solid dispersion increased. In addition, the supersaturation profile of DPM and CNZ were studied in the presence and absence of the polymers. PAA was found to maintain a higher level of supersaturation compared to PVP. The enhanced drug solution concentration following dissolution of ASDs can be attributed to the reduced crystal growth rates of DPM and CNZ at an equivalent supersaturation. We have also shown that, for drugs having high crystallization tendency and weak drug-polymer interaction, the feasible way to increase dissolution might be increase the polymer weight fraction in the ASD. Solution 1 H NMR spectra were used to understand dissolution mechanism and to identify drug-polymer interaction. The change in electron densities of proton attached to different groups in DPM and CNZ suggested drug-polymer interaction in solution. The relative intensities of peak shift and nature of interaction between drug and polymer in different systems are different. These different effects suggest that DPM and CNZ interacts in a different way with PVP and PAA in solution which goes some way towards explaining the different polymeric effect, particularly in terms of inhibition of drug recrystallization and dissolution of DPM and CNZ ASDs. These results established that the different drug/polymer interactions in the solid state and in solution give rise to the variation in dissolution profile observed for different systems., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Three dimensional (3D) extrusion-based printing is a paste-based rapid prototyping process, which is capable of building complex 3D structures. The aim of this study was to explore the feasibility of 3D extrusion-based printing as a pharmaceutical manufacture technique for the fabrication of gastro-floating tablets. Novel low-density lattice internal structure gastro-floating tablets of dipyridamole were developed to prolong the gastric residence time in order to improve drug release rate and consequently, improve bioavailability and therapeutic efficacy. Excipients commonly employed in the pharmaceutical study could be efficiently applied in the room temperature 3D extrusion-based printing process. The tablets were designed with three kinds of infill percentage and prepared by hydroxypropyl methylcellulose (HPMC K4M) and hydroxypropyl methylcellulose (HPMC E15) as hydrophilic matrices and microcrystalline cellulose (MCC PH101) as extrusion molding agent. In vitro evaluation of the 3D printed gastro-floating tablets was performed by determining mechanical properties, content uniformity, and weight variation. Furthermore, re-floating ability, floating duration time, and drug release behavior were also evaluated. Dissolution profiles revealed the relationship between infill percentage and drug release behavior. The results of this study revealed the potential of 3D extrusion-based printing to fabricate gastro-floating tablets with more than 8h floating process with traditional pharmaceutical excipients and lattice internal structure design., (Copyright © 2017. Published by Elsevier B.V.)

Dipyridamole (DIP), having a short biological half-life, has a narrow absorption window and is primarily absorbed in the stomach. So, the purpose of this study was to prepare controlled-release floating (CRF) tablets of dipyridamole by the dry-coated method. The influence of agents with different viscosity, hydroxypropylmethylcellulose (HPMC) and polyvinylpyrollidon K30 (PVP K30) in the core tablet and low-viscosity HPMC and PVP K30 in the coating layer on drug release, were investigated. Then, a study with a three-factor, three-level orthogonal experimental design was used to optimize the formulation of the CRF tablets. After data processing, the optimized formulation was found to be: 80 mg HPMC K4M in the core tablet, 80 mg HPMC E15 in core tablet and 40 mg PVP K30 in the coating layer. Moreover, an in vitro buoyancy study showed that the optimized formulation had an excellent floating ability and could immediately float without a lag time and this lasted more than 12 h. Furthermore, an in vivo gamma scintigraphic study showed that the gastric residence time of the CRF tablet was about 8 h.

CTAD (citrate-theophylline-adenosine-dipyridamole) has been shown to be an almost universal anticoagulant in human and feline medicine, allowing most hematology, coagulation, and biochemical analyses. Forty canine blood specimens were collected in CTAD, EDTA, heparin, and citrate for hematology, biochemistry, and coagulation analyses. CTAD partially limited platelet aggregation observed in EDTA blood smears. CTAD specimens gave similar and well-correlated results for most variables of a complete blood cell count, except for mean corpuscular volume, which was moderately higher, and mean corpuscular hemoglobin concentration, which was moderately lower in CTAD than in EDTA; reticulocyte and platelet indexes were poorly correlated. CTAD plasma gave similar results to citrate for fibrinogen, antithrombin, and D-dimers, and relatively similar results for prothrombin time, but activated partial thromboplastin time was poorly correlated. Triglycerides, cholesterol, glucose, total proteins, phosphate, iron, alanine aminotransferase, γ-glutamyl transferase, and lipase were similar and well correlated in CTAD and heparin plasmas. Urea, creatinine, albumin, alkaline phosphatase, amylase, and aspartate aminotransferase showed moderate-to-marked bias, but these variables could be measured in CTAD plasma if new reference intervals were determined. Creatine kinase activity, potassium, chloride, and total carbon dioxide measurements are not recommended in CTAD plasma. CTAD is a prospective candidate as an almost universal anticoagulant for routine hematology, some plasma coagulation, and many biochemistry variables in dogs. Definitive recommendations will require study of abnormal canine blood specimens.

The objective of this study was to evaluate the stability of 7 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend SF PH4): acetazolamide 25.0 mg/mL, baclofen 10.0 mg/mL, dipyridamole 10.0 mg/mL, mebeverine hydrochloride 10.0 mg/mL, propylthiouracil 5.0 mg/mL, quinidine sulfate 10.0 mg/mL, and topiramate 5.0 mg/mL. All suspensions were stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by measuring the percentage recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredient quantification was performed by ultraviolet (UV) high-performance liquid chromatography, via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredient + vehicle) was at least 90 days for all suspensions with regards to both temperatures. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

The development of formulations and the assessment of oral drug absorption for Biopharmaceutical Classification System (BCS) class IIb drugs is often a difficult issue due to the potential for supersaturation and precipitation in the gastrointestinal (GI) tract. The physiological environment in the GI tract largely influences in vivo drug dissolution rates of those drugs. Thus, those physiological factors should be incorporated into the in vitro system to better assess in vivo performance of BCS class IIb drugs. In order to predict oral bioperformance, an in vitro dissolution system with multiple compartments incorporating physiologically relevant factors would be expected to more accurately predict in vivo phenomena than a one-compartment dissolution system like USP Apparatus 2 because, for example, the pH change occurring in the human GI tract can be better replicated in a multi-compartmental platform. The Gastrointestinal Simulator (GIS) consists of three compartments, the gastric, duodenal and jejunal chambers, and is a practical in vitro dissolution apparatus to predict in vivo dissolution for oral dosage forms. This system can demonstrate supersaturation and precipitation and, therefore, has the potential to predict in vivo bioperformance of oral dosage forms where this phenomenon may occur. In this report, in vitro studies were performed with dipyridamole and ketoconazole to evaluate the precipitation rates and the relationship between the supersaturation levels and oral absorption of BCS class II weak base drugs. To evaluate the impact of observed supersaturation levels on oral absorption, a study utilizing the GIS in combination with mouse intestinal infusion was conducted. Supersaturation levels observed in the GIS enhanced dipyridamole and ketoconazole absorption in mouse, and a good correlation between their supersaturation levels and their concentration in plasma was observed. The GIS, therefore, appears to represent in vivo dissolution phenomena and demonstrate supersaturation and precipitation of dipyridamole and ketoconazole. We therefore conclude that the GIS has been shown to be a good biopredictive tool to predict in vivo bioperformance of BCS class IIb drugs that can be used to optimize oral formulations., (Copyright © 2017. Published by Elsevier B.V.)

Bone defects resulting from trauma or infection need timely and effective treatments to restore damaged bone. Using specialized three-dimensional (3D) printing technology we have created custom 3D scaffolds of hydroxyapatite (HA)/beta-tri-calcium phosphate (β-TCP) to promote bone repair. To further enhance bone regeneration we have coated the scaffolds with dipyridamole, an agent that increases local adenosine levels by blocking cellular uptake of adenosine. Nearly 15% HA:85% β-TCP scaffolds were designed using Robocad software, fabricated using a 3D Robocasting system, and sintered at 1100°C for 4 h. Scaffolds were coated with BMP-2 (200 ng mL -1 ), dypiridamole 100 µM or saline and implanted in C57B6 and adenosine A2A receptor knockout (A2AKO) mice with 3 mm cranial critical bone defects for 2-8 weeks. Dipyridamole release from scaffold was assayed spectrophotometrically. MicroCT and histological analysis were performed. Micro-computed tomography (microCT) showed significant bone formation and remodeling in HA/β-TCP-dipyridamole and HA/β-TCP-BMP-2 scaffolds when compared to scaffolds immersed in vehicle at 2, 4, and 8 weeks (n = 5 per group; p ≤ 0.05, p ≤ 0.05, and p ≤ 0.01, respectively). Histological analysis showed increased bone formation and a trend toward increased remodeling in HA/β-TCP- dipyridamole and HA/β-TCP-BMP-2 scaffolds. Coating scaffolds with dipyridamole did not enhance bone regeneration in A2AKO mice. In conclusion, scaffolds printed with HA/β-TCP promote bone regeneration in critical bone defects and coating these scaffolds with agents that stimulate A2A receptors and growth factors can further enhance bone regeneration. These coated scaffolds may be very useful for treating critical bone defects due to trauma, infection or other causes. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 366-375, 2017., (© 2015 Wiley Periodicals, Inc.)

The aim of this study was to develop a pH-independent release formulation of dipyridamole (DP) by the combined use of pH-modifier technology and solid dispersion (SD) technology employing enteric polymer, Eudragit ® S100 (Eud). Tartaric acid (TA) was selected as an appropriate pH-modifier in terms of improving the dissolution behavior of DP under neutral conditions. Upon optimization of the ratio of TA to DP, SD of DP with Eud and TA (SD-Eud/DP/TA) was prepared by a freeze-drying method. Scanning electron microscopic images revealed that DP was dispersed in the polymer in SD-Eud/DP/TA, and DP in SD-Eud/DP/TA was in an amorphous state, supported by powder X-ray diffraction and differential scanning calorimetry analyses. The dissolution behavior of SD-Eud/DP/TA was not dependent on the pH of the medium, although SD-Eud/DP exhibited very limited dissolution behavior under neutral conditions. Spectroscopic analysis suggested that there might be inter-molecular interaction among DP, TA and enteric polymer in SD-Eud/DP/TA, possibly leading to the stable pH-independent dissolution behavior of SD-Eud/DP/TA. TA in SD-Eud/DP/TA promoted the degradation of DP, suggesting that improving the stability of DP in SD-Eud/DP/TA might be key for its practical use. From these results, pH-independent dissolution behavior of SD-Eud/DP/TA could be achieved by an enteric polymer-based solid dispersion with a pH-modifier.

Purpose. Myocardial blood flow (MBF) quantification with 82 Rb positron emission tomography (PET) is gaining clinical adoption, but improvements in precision are desired. This study aims to identify analysis variants producing the most repeatable MBF measures. Methods. 12 volunteers underwent same-day test-retest rest and dipyridamole stress imaging with dynamic 82 Rb PET, from which MBF was quantified using 1-tissue-compartment kinetic model variants: (1) blood-pool versus uptake region sampled input function (Blood/Uptake-ROI), (2) dual spillover correction (SOC-On/Off), (3) right blood correction (RBC-On/Off), (4) arterial blood transit delay (Delay-On/Off), and (5) distribution volume (DV) constraint (Global/Regional-DV). Repeatability of MBF, stress/rest myocardial flow reserve (MFR), and stress/rest MBF difference (ΔMBF) was assessed using nonparametric reproducibility coefficients (RPC np = 1.45 × interquartile range). Results. MBF using SOC-On, RVBC-Off, Blood-ROI, Global-DV, and Delay-Off was most repeatable for combined rest and stress: RPC np = 0.21 mL/min/g (15.8%). Corresponding MFR and ΔMBF RPC np were 0.42 (20.2%) and 0.24 mL/min/g (23.5%). MBF repeatability improved with SOC-On at stress ( p < 0.001) and tended to improve with RBC-Off at both rest and stress ( p < 0.08). DV and ROI did not significantly influence repeatability. The Delay-On model was overdetermined and did not reliably converge. Conclusion. MBF and MFR test-retest repeatability were the best with dual spillover correction, left atrium blood input function, and global DV., Competing Interests: R. Klein and R. deKemp received royalties from the sales of FlowQuant and rubidium generator technologies licensed to Jubilant DraxImage. R. Klein, J. M. Renaud, R. Beanlands, and R. deKemp are consultants to Jubilant DraxImage. R. Klein, J. M. Renaud, and R. deKemp received royalties from FlowQuant software sales. R. Beanlands has been a consultant for and received grant support from Jubilant DraxImage, GE Healthcare, and Lantheus Medical Imaging.

Purpose: The fabrication of ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing., Methods: Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of the drugs and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus., Results: Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication of immediate release tablets at temperatures as low as 110°C. The integrity of two model drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in-batch variability and an immediate in vitro release pattern., Conclusions: Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms.

Dipyridamole (DPL) is a weakly basic BCS class II drug which precipitates upon entering into intestine leading to pH dependant and variable absorption. Thus, research envisaged focuses on developing formulations that maintain supersaturation following upon acid to neutral pH transition. In an endeavor to accomplish the objective, solid dispersion (SD) with hydroxypropylmethyl cellulose (HPMC) and polyvinylpyrrolidone (PVP) was prepared by a quench cooling method. The three molecular weight grades of HPMC (HPMC E5, HPMC E15 and HPMC E50) and two molecular weight grades of PVP (PVP K30 and PVP K90) were investigated to observe effect of increasing molecular weight on stabilizing DPL supersaturated solutions. Equilibrium solubility studies revealed increase in solubility with both HPMC and PVP with greater benefit from HPMC. In vitro supersaturated dissolution results demonstrated that HPMC formulations provided greater degree and extent of supersaturation as compared to PVP formulations. The formulation with HPMC E50 provided maximum stabilization to supersaturation upon acid to neutral pH transition. Moreover, the effect of increase in molecular weight was more pronounced in HPMC rather than PVP. Stronger interactions were observed for DPL with HPMC, while no interaction was observed with PVP which was evident from Fourier transform infra-red studies. Differential scanning calorimetry and powder X-ray diffraction studies revealed the amorphous state of DPL in SD.

Supersaturation and precipitation are common limitations encountered especially with poorly soluble basic drugs. The aims of this work were to explore the pattern of dissolution and precipitation of poorly soluble basic drugs using a United States Pharmacopoeia (USP) IV dissolution apparatus and to compare it to the widely used USP II dissolution apparatus. In order to investigate the influence of gastric emptying time on bioavailability, tables of two model drugs (dipyridamole 100 mg and cinnarizine 15 mg) were investigated and pH change from 1.2 to 6.8 were achieved after 10, 20 or 30 min using USP II or USP IV dissolution apparatuses. Using USP II, dipyridamole and cinnarizine concentrations dropped instantly as a result of drug precipitation with drug crystals evident in the dissolution vessel. At pH change times of 10, 20 and 30 min, the total amount of dissolved drug was dependent on pH change time. Using USP IV, at a flow rate of 8 ml/min, it was possible to have comparable release to agitation at 50 rpm using USP II suggesting that comparable hydrodynamic forces are possible. No drop in drug percentage occurs as the dissolved fraction was readily emptied from the flow cell, preventing drug accumulation in the dissolution medium. However, a negligible percentage of drug release took place following pH change. In conclusion, the use of the flow-through cell dissolution provided laminar flow, use of realistic fluid volumes and avoided precipitation of dissolved drug fraction in the gastric phase as it is discharged before pH change.

The purpose of this study was to develop a pH-independent drug release formulation using lipocalin-type prostaglandin D synthase, a member of the lipocalin superfamily, with the function of forming complexes together with various small lipophilic molecules. Dipyridamole, a poorly water-soluble drug, showing a pH-dependent solubility profile, was used as the model drug. The solubilization of dipyridamole was achieved by a simple complex formulation method with lipocalin-type prostaglandin D synthase. The complex formulation was produced successfully by spray drying, and the obtained powder formulation showed complete dissolution in fasted-state simulated gastric fluid (pH, 1.6) and phosphate-buffered solution (pH, 6.8). In addition, the potential stability of the complex formulation was assessed, and the dissolution profile of the produced powder at pH 6.8 was maintained after 4-week storage under several storage conditions. Furthermore, a pharmacokinetic study using hypochlorhydria model rats was performed to verify the improvement of the intestinal absorption behavior, and eventually the complex formulation overcame the problematic absorption profile of dipyridamole in the elevated gastric pH conditions. These results, taken together, demonstrate that the use of this well-designed drug-delivery carrier is feasible for the development of pH-independent drug release formulations., (Copyright © 2016. Published by Elsevier Inc.)

The purpose of the present study was to investigate the effect of seed particles on the precipitation behavior of weak base drugs in the small intestine. A simple in vitro infusion method was used to mimic in vivo processes. Dipyridamole, pioglitazone, topiroxostat, chlorpromazine, cinnarizine, and ketoconazole were used as model drugs. A drug was dissolved in 0.01 N HCl and infused into a pH 6.5 buffer. The existence of seed particles significantly affected the concentration-time profiles of the model drugs in the buffer. The maximum concentration was significantly reduced in the presence of seed particles (except for cinnarizine). In the case of dipyridamole, pioglitazone, and topiroxostat, the precipitants were crystalline from the beginning of precipitation. In contrast, the precipitants of ketoconazole, cinnarizine, and chlorpromazine were a mixture of amorphous and crystals. In conclusion, the presence of seed particles significantly affected the precipitation behavior of weak base drugs.

Amorphous drug formulations have great potential to enhance solubility and thus bioavailability of BCS class II drugs. However, the higher free energy and molecular mobility of the amorphous form drive them towards the crystalline state which makes them unstable. Accurate determination of the crystallization tendency/kinetics is the key to the successful design and development of such systems. In this study, dipyridamole (DPM) and cinnarizine (CNZ) have been selected as model compounds. Thermodynamic fragility (mT) was measured from the heat capacity change at the glass transition temperature (Tg) whereas dynamic fragility (mD) was evaluated using methods based on extrapolation of configurational entropy to zero [Formula: see text] , and heating rate dependence of Tg [Formula: see text] . The mean relaxation time of amorphous drugs was calculated from the Vogel-Tammann-Fulcher (VTF) equation. Furthermore, the correlation between fragility and glass forming ability (GFA) of the model drugs has been established and the relevance of these parameters to crystallization of amorphous drugs is also assessed. Moreover, the crystallization kinetics of model drugs under isothermal conditions has been studied using Johnson-Mehl-Avrami (JMA) approach to determine the Avrami constant 'n' which provides an insight into the mechanism of crystallization. To further probe into the crystallization mechanism, the non-isothermal crystallization kinetics of model systems were also analysed by statistically fitting the crystallization data to 15 different kinetic models and the relevance of model-free kinetic approach has been established. The crystallization mechanism for DPM and CNZ at each extent of transformation has been predicted. The calculated fragility, glass forming ability (GFA) and crystallization kinetics are found to be in good correlation with the stability prediction of amorphous solid dispersions. Thus, this research work involves a multidisciplinary approach to establish fragility, GFA and crystallization kinetics as stability predictors for amorphous drug formulations., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Weakly basic drugs typically exhibit pH-dependent solubility in the physiological pH range, displaying supersaturation or precipitation along the gastrointestinal tract. Additionally, their oral bioavailabilities may be affected by coadministration of acid-reducing agents that elevate gastric pH. The purpose of this study was to assess the feasibility of a multicompartmental in vitro dissolution apparatus, Gastrointestinal Simulator (GIS), in predicting in vivo dissolution of certain oral medications. In vitro dissolution studies of fluconazole, a BCS class I, and dipyridamole, a BCS class II weak bases (class IIb), were performed in the GIS as well as United States Pharmacopeia (USP) apparatus II and compared with the results of clinical drug-drug interaction (DDI) studies. In both USP apparatus II and GIS, fluconazole completely dissolved within 60 min regardless of pH, reflecting no DDI between fluconazole and acid-reducing agents in a clinical study. On the other hand, seven-fold and 15-fold higher concentrations of dipyridamole than saturation solubility were observed in the intestinal compartments in GIS with gastric pH 2.0. Precipitation of dipyridamole was also observed in the GIS, and the percentage of dipyridamole in solution was 45.2 ± 7.0%. In GIS with gastric pH 6.0, mimicking the coadministration of acid-reducing agents, the concentration of dipyridamole was equal to its saturation solubility, and the percentage of drug in solution was 9.3 ± 2.7%. These results are consistent with the clinical DDI study of dipyridamole with famotidine, which significantly reduced the Cmax and area under the curve. An In situ mouse infusion study combined with GIS revealed that high concentration of dipyridamole in the GIS enhanced oral drug absorption, which confirmed the supersaturation of dipyridamole. In conclusion, GIS was shown to be a useful apparatus to predict in vivo dissolution for BCS class IIb drugs.

Variability in oral drug absorption is a well-known phenomenon, but it is often overlooked for its potential effects in oral drug delivery. Understanding the mechanisms behind absorption variability is crucial to understanding and predicting drug pharmacokinetics. In this study, the solubility of furosemide and dipyridamole - drugs known to have highly variable oral bioavailabilities - was investigated in individual ileostomy fluids from 10 subjects with ulcerative colitis. For comparison, drug solubility was also determined in pooled upper gastrointestinal fluids from healthy human subjects and simulated intestinal fluids. Ileostomy fluid characterization revealed high variability in buffer capacity and to a lesser degree for pH. Drug solubility in ileostomy fluids showed high variability. Correlation analysis revealed that dipyridamole solubility in these fluids is pH-dependent, whereas furosemide solubility was highly correlated to buffer capacity and pH. The implications of these results might partly explain the high variability in bioavailability in vivo, assuming that most of the observed variability is due to the absorption, and not the elimination, process., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A multiple-unit floating alginate bead drug delivery system with prolonged stomach retention time was developed in this study. The floating alginate beads were prepared by ionic cross-linking method, using CaCO3 as the gas-forming agent. Over 92% of the beads remained floating after 9 h. In order to prepare sustained-release dosage forms of dipyridamole, the solid dispersion technique was applied using a blend of Eudragit L100 and Eudragit RLPO. Afterwards, the solid dispersions of dipyridamole were incorporated into the floating alginate beads. The drug release was modified by changing the ratio of Eudragit RLPO and Eudragit L100 in the solid dispersions. The in vivo results showed that the relative bioavailability of alginate beads was enhanced by approximately 2.52-fold compared with that of the commercial tablet. Therefore, our study illustrated the potential use of floating alginate beads combined with the solid dispersion technique for the delivery of acid-soluble compounds, such as dipyridamole.

Background: To assess different warranty periods following a normal myocardial perfusion SPECT based on patients' clinical characteristics and the type of stress performed., Methods and Results: A study was done of 2,922 consecutive patients (62.9 ± 13 years; 53.4% women) with a normal stress-rest SPECT. The warranty period was defined as the period during which patients remained at a low risk (<1% events/year) of total mortality (TM), or hard events (HE) (cardiac death or non-fatal myocardial infarction). Of these patients, 2,051 were given an exercise myocardial perfusion imaging (Ex-MPI); 461 submaximal exercise plus dipyridamole (Ex+Dipy-MPI); and 410 dipyridamole (Dipy-MPI). During a mean follow-up of 5 ± 3.3 years, a significant reduction (P < .05) of the warranty period for TM (13.5, 9.6 and 8 months) and HE (34.8, 20.5 and 8.2 months) was observed, for Ex-MPI, Ex+Dipy-MPI and Dipy-MPI, respectively. Other warranty period determinants were the clinical variables of age, sex, diabetes and known coronary artery disease. An abnormal left ventricular ejection fraction on gated-SPECT also significantly shortened the warranty period for HE in patients undergoing Ex+Dipy-MPI (P = .001) or Dipy-MPI alone (P = .007)., Conclusions: The warranty period for a normal stress-rest SPECT is highly variable since it is primarily determined by the type of stress, the patient's clinical characteristics and LVEF.

Dipyridamole was introduced on the market as coronary vasodilator drug more than half a century ago and is still used as antithrombotic and vasodilator. Among cellular targets, it inhibits phosphodiesterases and raises extracellular levels of adenosine through inhibition of adenosine reuptake by red blood cells. As a consequence, endocellular levels of cyclic nucleotides are upregulated. The rise of cGMP in vascular smooth muscle cells and of cAMP in platelets provide the mechanism of vasodilation and antithrombosis, which are further potentiated by the release of PGI2 consequent on the increase in endothelial cell cAMP. These effects support the use of dipyridamole in cardiovascular diseases in which the drug is approved for the secondary prevention of cerebrovascular events. On the other hand, dipyridamole has been shown to possess a potent, little perceived, antioxidant activity of potential use in the several fields where pathophysiological pathways are dependent on oxidative stress, including those occurring in atherosclerosis, thrombosis, CNS-related diseases, and cancer.

Acellular biodegradable small diameter vascular grafts (SDVGs) require antithrombosis, intimal hyperplasia inhibition and rapid endothelialization to improve the graft patency. However, current antithrombosis and antiproliferation approaches often conflict with endothelial cell layer formation on SDVGs. To address this limitation, biodegradable elastic polyurethane urea (BPU) and the drug dipyridamole (DPA) were mixed and then electrospun into a biodegradable fibrous scaffold. The BPU would provide the appropriate mechanical support, while the DPA in the scaffold would offer biofunctions as required above. We found that the resulting scaffolds had tensile strengths and strains comparable with human coronary artery. The DPA in the scaffolds was continuously released up to 91 days in phosphate buffer solution at 37 °C, with a low burst release within the first 3 days. Compared to BPU alone, improved non-thrombogenicity of the DPA-loaded BPU scaffolds was evidenced with extended human blood clotting time, lower TAT complex concentration, lower hemolysis and reduced human platelet deposition. The scaffolds with a higher DPA content (5 and 10%) inhibited proliferation of human aortic smooth muscle cell significantly. Furthermore, the DPA-loaded scaffolds had no adverse effect on human aortic endothelial cell growth, yet it improved their proliferation. The attractive mechanical properties and biofunctions of the DPA-loaded BPU scaffold indicate its potential as an acellular biodegradable SDVG for vascular replacement., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The purpose was the evaluation of a new miniscale biphasic dissolution model with pH-shift (miBIdi-pH). Its capability to predict supersaturation and precipitation of weak bases (e.g. dipyridamole) and the in vivo performance of various formulations of the model compound BIXX (weak base, poor solubility, good permeability) was investigated with respect to dissolution, precipitation and re-dissolution. Single phase dissolution with and without pH-shift [small scale dissolution (V = 20 ml) and USPII] and miBIdi-pH (50 ml aqueous phase covered by 15 ml octanol) were used for analyzing crystalline dipyridamole and the four BIXX-containing formulations. Precipitate was analyzed via X-ray diffraction. Bioavailability of the formulations was tested in dogs. Phoenix WinNonlin(®) was used for IVIVC. For dipyridamole, precipitation upon pH shift was less pronounced in the miBIdi-pH in comparison to the single phase dissolution (35% vs. 90%). In case of four BIXX-containing formulations, USPII revealed significant differences in their dissolution, whereas the final amounts of BIXX in the octanol phase in the miBIdi-pH were alike. Different partitioning rates into octanol were observed. The miBIdi-pH was superior to single phasic dissolution in predicting in vivo precipitation of dipyridamole. In case of the BIXX-containing formulations, it was superior in ranking the formulations and it was capable to capture the kinetics of different absorption processes in vivo., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The purpose of this study was to investigate the influence of gastric emptying patterns, surfactants, and dosage form on the supersaturation of a poorly soluble weakly basic drug, dipyridamole, using an in vitro model mimicking the dynamic environment of the upper gastrointestinal tract, and, furthermore, to evaluate the usefulness of this model in establishing correlations to in vivo bioavailability for drugs with solubility/dissolution limited absorption. A simulated stomach duodenum model comprising four compartments was used to assess supersaturation and precipitation kinetics as a function of time. It integrates physiologically relevant fluid volumes, fluid transfer rates, and pH changes of the upper GI tract. Monoexponential gastric emptying patterns simulating the fasted state were compared to linear gastric emptying patterns simulating the fed state. The effect of different surfactants commonly used in oral preparations, specifically, sodium lauryl sulfate (SLS), poloxamer-188, and polysorbate-80, on dipyridamole supersaturation was investigated while maintaining surface tension of the simulated gastric fluids at physiological levels and without obtaining artificial micellar solubilization of the drug. The supersaturation behavior of different dose strengths of dipyridamole was explored. Significant levels of dipyridamole supersaturation were observed in the duodenal compartment under all the different in vivo relevant conditions explored. Dipyridamole supersaturation ratios of up to 11-fold have been observed, and supersaturation has been maintained for up to 120 min. Lower duodenal concentrations of dipyridamole were observed under linear gastric emptying patterns compared to mononexponential gastric emptying. The mean duodenal area under concentration-time curves (AUC60min) for the dipyridamole concentration profile in the duodenal compartment is significantly different for all the surfactants explored (P < 0.05). Our investigations with the different surfactants and comparison of dosage form (solution versus suspension) on the precipitation of dipyridamole revealed that crystal growth, rather than nucleation, is the rate-limiting step for the precipitation of dipyridamole. A linear dose-response relationship was found for the mean in vitro duodenal area under concentration-time curves (AUC∞) in the dose range of 25 mg to 100 mg (R(2) = 0.886). This is in agreement with the pharmacokinetic data of dipyridamole reported in the literature. The simulated stomach duodenum model can provide a reliable and discriminative screening tool for exploring the effect of different physiological variables or formulations on the supersaturation/precipitation kinetics of weakly basic drugs with solubility limited absorption. The amount of drug in solution in the duodenal compartment of the SSD correlates to bioavailability for the weakly basic drug, dipyridamole, which has solubility limited absorption and undergoes supersaturation/precipitation.

Many upcoming drug candidates are pH-dependent poorly soluble weak bases in the pH range of the gastrointestinal tract. This often leads to a high in vivo variability and bioavailability issues. Aiming to overcome these limitations, the design of solid dispersions for site specific dissolution improvement or maintenance of a potent supersaturation over the entire gastro-intestinal pH-range, is proposed to assure a reliable drug therapy. Solid dispersions containing different ratios of Dipyridamole (DPD) or Griseofulvin (GRI) and the enteric polymer hydroxypropylmethylcellulose-acetate succinate (HPMC-AS) and the water soluble low-viscosity hydroxypropylcellulose (HPC-SSL) were prepared by hot melt extrusion (HME). The solid dispersions were evaluated for their solid state, dissolution characteristics applying a three pH-step dissolution method following an acidic to neutral pH transition and stability. The use of HPMC-AS in binary mixtures with DPD and GRI facilitated increased solubility and supersaturation at pH-controlled release of the preserved amorphous state of the dispersed drug, which even inverted the pH-dependent solubility profile of the weakly basic model drug (Dipyridamole). I.e. a potent site specific delivery system was created. With ternary solid dispersions of API, HPMC-AS and HPC-SSL, tailored release profiles with superior supersaturation over the applied pH-range could be obtained. At the same time, binary and ternary mixtures showed favorable stability properties at a temperature difference between glass transition temperature and the applied storage temperature of down to 16°C., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The physical stability of amorphous solid dispersions (SDs) is influenced by their storage conditions. The goal of this work was to investigate the factors affecting the recrystallization of drugs in SDs after storage under conditions of high temperature and high humidity. SDs of three drugs (dipyridamole, nifedipine and indomethacin) with different functional groups (amino, carbonyl and hydroxyl) and onset times for crystallization of the amorphous state were prepared using crospovidone (CrosPVP). All of the drugs in the SDs remained in an amorphous state at 25 °C/50% relative humidity (RH) in closed glass bottles for at least six months. Under conditions of high temperature (40 °C/75%RH/closed and 60 °C/open), differences in interactions between the hydrogen bond donors of the drugs and the amide carbonyl group of CrosPVP are essential factors for recrystallization of the drugs in the SDs. On the other hand, under condition of high humidity (40 °C/75%RH/open), in addition to the difference in the interaction between the drug and CrosPVP, the rate of increase in moisture content affects their recrystallization in SDs.

The aim of this study was to establish an in vitro method for evaluating the effect of supersaturation on oral absorption of poorly water-soluble drugs in vivo. Albendazole, dipyridamole, gefitinib, and ketoconazole were used as model drugs. Supersaturation of each drug was induced by diluting its stock solution by fasted state simulated intestinal fluid (FaSSIF) (solvent-shift method), then dissolution and precipitation profile of the drug was observed in vitro. The crystalline form of the precipitate was checked by differential scanning calorimetry (DSC). For comparison, control suspension was prepared by suspending a drug powder directly into FaSSIF (powder-suspending method). In vivo intestinal absorption of the drug was observed in rats by determined the plasma concentration after intraduodenal administration of drug suspensions. For all drugs, suspensions prepared by solvent-shift method showed significantly higher dissolved concentration in vitro than that prepared by powder-suspending method, clearly indicated the induction of supersaturation. DSC analysis revealed that crystalline form of the precipitate profoundly affects the extent and the duration of supersaturation. A rat in vivo study confirmed that the supersaturation of these drugs increased the fraction absorbed from the intestine, which corresponded well to the in vitro dissolution and precipitation profile of drugs except for ketoconazole. For ketoconazole, an in vivo absorption study was performed in rats pretreated with 1-aminobenzotriazole, a potent inhibitor of CYP mediated metabolism. CYP inhibition study suggested that the high luminal concentration of ketoconazole caused by supersaturation saturated the metabolic enzymes and further increased the systemic exposure of the absorbed drug. The additional effects of supersaturation on the absorption of ketoconazole are consistent with previous studies in humans under differing gastric pH conditions. In conclusion, effects of supersaturation on the intestinal absorption of poorly water-soluble drugs could be predicted from in vitro dissolution and a precipitation study. However if supersaturation affects the pharmacokinetic profiles of drugs, such as a first-pass metabolism, a combination with in vivo study should be required to evaluate its impact on oral bioavailability.

Background: The aim of this study was to assess the correlation between global wall thickening (GWT) obtained by gated-single photon emission computed tomography (SPECT) and echocardiographic measures [ejection fraction (EF), global longitudinal strain (GLS), and strain rate (GLSR)] and to compare their prognostic value for all-cause mortality., Methods and Results: Seventy-four patients with referral for dipyridamole myocardial perfusion SPECT were prospectively included and underwent transthoracic echocardiography to measure left ventricular EF, GLS, and GLSR. The strongest correlation with GWT was for EF (R = 0.63, P < .001), followed by GLSR (R = -0.57, P < .001) and GLS (R = -0.53, P < .001). There were ten deaths over a period of 14.6 ± 5.7 months. Using the multivariate Cox analysis, summed stress score (HR 1.108; P = .023), EF (HR 1.01, P = .031), GLS (HR 1.593, P = .001), and GWT (HR 0.898, P = .034) remained independent predictors of mortality. Mean survival rate evaluated by Kaplan-Meier analysis was longer in patients with GWT ≥ 24% (21.9 ± 0.6 months) than those with GWT < 24% (13.6 ± 2.7 months; P < .001)., Conclusions: GWT assessed is a highly sensitive tool to detect early myocardial systolic dysfunction and may bring additional prognostic information.

Introduction: Recent advances have proven that the combinational therapy of extended release dipyridamole (DYP) and fast release aspirin (ASP) can improve clinical indices of heart failure in several vascular disorders. Although pharmaceutical industries always supported fast, simple and cost saving techniques in their productions, there is no simple reported method available for this purpose. The aim of this study was to check the possibility of preparing a FDC product, containing individual dosage units of extended release DYP microparticles and fast release ASP, using the spray-drying technique as a practice compatible with pharmaceutical industries., Materials and Method: Solid dispersions of DYP in different polymeric substances (ethyl cellulose, carnauba wax, and Eudragit PO 100), were prepared using the spray-drying method. The physicochemical properties and structure of the prepared microparticles were analyzed using different techniques, such as the particle size analyzer (PSA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X ray diffraction (XRD), and USP dissolution tester. ASP tablets were prepared individually and tested according to pharmacopeia., Results and Discussion: Results showed that prepared microparticles measured about 2.3 µm in size. Statistical analysis of the release data revealed that there is no significant difference in the mean release amount of the selected formulation compared to the innovative brand (Aggrenox®)., Conclusion: Findings proposed a new formulation (F7) as an alternative to innovative brand and proved spray drying as a practice compatible with pharmaceutical industries and as a successful method for sustaining the DYP release rate from prepared microparticles in a FDC dosage form., (© Georg Thieme Verlag KG Stuttgart · New York.)

To identify needed human equilibrative nucleoside transporter 4 (hENT4) inhibitors, we cloned and stably expressed the recombinant protein in PK15NTD (nucleoside transporter deficient) cells, and, investigated its interaction with a series of dipyridamole analogs synthesized in our laboratory. Compounds were tested in this newly established hENT4 expressing system as well in previous stably expressed hENT1 and hENT2 expressing systems. Of the dipyridamole analogs evaluated, about one fourth of the compounds inhibited hENT4 with higher potencies than dipyridamole. The most potent of them, Compound 30 displayed an IC₅₀ of 74.4 nM, making it about 38 times more potent than dipyridamole (IC₅₀=2.8 μM), and selectivities of about 80-fold and 20-fold relative to ENT1 and ENT2, respectively. Structure-activity relationship showed nitrogen-containing monocyclic rings and noncyclic substituents at the 4- and 8-positions of the pyrimido[5,4-d]pyrimidine were important for the inhibitory activity against hENT4. The most potent and selective hENT4 inhibitors tended to have a 2,6-di(N-monohydroxyethyl) substitution on the pyrimidopyrimidine ring system. The inhibitors of hENT4 identified in this study are the most selective and potent inhibitors of hENT4 adenosine transporter function to date, and should serve as useful pharmacological/biochemical tools and/or potential leads for ENT4-based therapeutics. Also, the new hENT4-expressing PK15 cell line established will serve as a useful screening tool for the discovery and design of hENT4 ligands., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The excipient-mediated precipitation inhibition is classically determined by the quantification of the dissolved compound in the solution. In this study, two alternative approaches were evaluated, one is the light scattering (nephelometer) and other is the turbidity (plate reader) microtiter plate-based methods which are based on the quantification of the compound precipitate. Following the optimization of the nephelometer settings (beam focus, laser gain) and the experimental conditions, the screening of 23 excipients on the precipitation inhibition of poorly soluble fenofibrate and dipyridamole was performed. The light scattering method resulted in excellent correlation (r>0.91) between the calculated precipitation inhibitor parameters (PIPs) and the precipitation inhibition index (PI(classical)) obtained by the classical approach for fenofibrate and dipyridamole. Among the evaluated PIPs AUC100 (nephelometer) resulted in only four false positives and lack of false negatives. In the case of the turbidity-based method a good correlation of the PI(classical) was obtained for the PIP maximal optical density (OD(max), r=0.91), however, only for fenofibrate. In the case of the OD(max) (plate reader) five false positives and two false negatives were identified. In conclusion, the light scattering-based method outperformed the turbidity-based one and could be reliably used for identification of novel precipitation inhibitors., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: A perioperative cardiac events is one of the most important medical concerns for both surgeons and patients. The purpose of the current study was to determine the prognostic value of myocardial perfusion imaging (MPI), using dipyridamole 99m Tc-MIBI, for the prediction of perioperative cardiac events., Materials and Methods: This study included 253 patients who were candidates for non-cardiac elective surgery and underwent scanning with dipyridamole 99m Tc-MIBI. Based on normal or abnormal MPI, patients were divided into two groups and all preoperative cardiac events were recorded. Risk factors, including diabetes mellitus, dyslipidemia, hypertension, smoking and age ≥70 years, were compared between patients with normal and abnormal MPI and, also, in patients with or without cardiac events., Results: There were 197 patients with normal and 56 patients with abnormal MPI. In total, 14 patients had perioperative cardiac events, which included myocardial infarction (MI), hypotension, arrhythmia and death; of the 14 patients with perioperative cardiac events, 12 had abnormal and two had normal MPI. There were statistically meaningful differences between the two groups (p<0.001). Based on these findings, we determined that MPI had a sensitivity of 85.7%, a specificity of 81.6%, an accuracy of 81.8%, a positive predictive value of 21.4 % and a negative predictive value of 98.9%., Conclusion: The incidence of perioperative cardiac events is higher in patients with abnormal MPI. Dipyridamole 99m Tc-MIBI myocardial perfusion imaging can accurately detect the preoperative cardiac risk of patients undergoing major non-cardiac surgery. Based on these findings, the occurrence of perioperative cardiac events in patients with abnormal MPI should be considered, especially in the older age population (age ≥70).

In veterinary medicine a complete blood cell count (CBC) cannot always be performed within 24 h as usually recommended, particularly for specimens shipped to a reference laboratory. This raises the question of the stability of the variables, especially in ethylenediamine tetra-acetic acid (EDTA) feline blood specimens, known to be prone to in vitro platelet aggregation. Citrate, theophylline, adenosine and dipyridamole (CTAD) has been reported to limit platelet aggregation in feline blood specimens. The aim of this study was to measure the stability of the haematological variables and the platelet aggregation score in EDTA and EDTA plus CTAD (EDCT) feline blood specimens during 48 h of storage at room temperature. Forty-six feline EDTA and EDCT blood specimens were analysed with a Sysmex XT-2000iV analyser, and the platelet count and score of platelet aggregation were estimated immediately and after 24 and 48 h of storage. A significant increase in mean corpuscular volume, haematocrit, reticulocyte and eosinophil counts, and a significant decrease in mean corpuscular haemoglobin concentration and monocyte count were observed. Haemoglobin, mean corpuscular haemoglobin, and red blood cell, white blood cell, neutrophil and lymphocyte counts remained stable. Changes in reticulocyte indexes with time (low fluorescence ratio, medium fluorescence ratio, high fluorescence ratio and immature reticulocyte fraction) were not significant. Changes were generally more pronounced in EDTA than in EDCT. Platelet aggregation decreased markedly in initially highly aggregated EDTA specimens, and increased slightly in initially non- or mildly-aggregated EDTA or EDCT specimens. Platelet counts increased and decreased, or remained stable, respectively. CTAD can reduce storage-induced changes of the haematological variables in feline samples, thus improving the reliability of a CBC and limiting clinical misinterpretations.

Our major goals were to understand the mechanism of dipyridamole (DPD) precipitation inhibition in the presence of polymers and to correlate the polymers-mediated precipitation inhibition in solution to the amorphous stabilization in the solid state. A continuous UV spectrophotometer was used to monitor the DPD concentration with time in the absence and presence of different polymers. Six polymers: PVP K90, hydroxypropylmethylcellulose (HPMC), Eudragit E100, Eudragit S100, Eudragit L100, and PEG 8000 were screened at different drug-to-monomer ratios. Solid dispersions were characterized by X-ray powder diffraction and modulated differential scanning calorimetry, whereas infrared (IR) and Raman were used to investigate the possible drug-polymer interactions. Eudragit E100 and HPMC were found to delay both DPD precipitation initiation time and precipitation rates. Eudragit S100 delayed only the precipitation initiation time and PVP K90 decreased only the precipitation rates. In solid state, Eudragit S100, PVP K90, HPMC, and Eudragit L100 were effective stabilizers of the DPD solid dispersion. Eudragit S100 was found to be most effective DPD-stabilizing polymer. The IR and Raman spectra of the solid dispersion of Eudragit S100 and HPMC showed peak shift, indicating drug-polymer molecular interactions. It is concluded that the drug-polymer interaction plays a significant role in precipitation inhibition and amorphous stabilization., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: To develop an in vitro methodology for prediction of concentrations and potential precipitation of highly permeable, lipophilic weak bases in fasted upper small intestine based on ketoconazole and dipyridamole luminal data. Evaluate usefulness of methodology in predicting luminal precipitation of AZD0865 and SB705498 based on plasma data., Methods: A three-compartment in vitro setup was used. Depending on the dosage form administered in in vivo studies, a solution or a suspension was placed in the gastric compartment. A medium simulating the luminal environment (FaSSIF-V2plus) was initially placed in the duodenal compartment. Concentrated FaSSIF-V2plus was placed in the reservoir compartment., Results: In vitro ketoconazole and dipyridamole concentrations and precipitated fractions adequately reflected luminal data. Unlike luminal precipitates, in vitro ketoconazole precipitates were crystalline. In vitro AZD0865 data confirmed previously published human pharmacokinetic data suggesting that absorption rates are not affected by luminal precipitation. In vitro SB705498 data predicted that significant luminal precipitation occurs after a 100 mg or 400 mg but not after a 10 mg dose, consistent with human pharmacokinetic data., Conclusions: An in vitro methodology for predicting concentrations and potential precipitation in fasted upper small intestine, after administration of highly permeable, lipophilic weak bases in fasted upper small intestine was developed and evaluated for its predictability in regard to luminal precipitation.

This study was undertaken to develop new dipyridamole (DP) formulations with acidic microenvironmental pH-modifiers for improving dissolution and absorption under hypochlorhydric conditions. Dipyridamole granules (DPG) with ten acidic pH-modifiers were prepared with conventional wet granulation, and their manufacturability, stability and dissolution behavior were characterized. Pharmacokinetic profiling of the optimized DPG with acid was carried out in omeprazole-treated rats as a hypochlorhydric model. On the basis of the manufacturability, stability and dissolution behavior of new DPG formulations, p-toluenesulfonic acid (TS) was found to be a suitable acidic pH-modifier for DPG formulation. Although DPG showed pH-dependent dissolution behavior, DPG with TS exhibited a high rate and extent of dissolution in both acidic and neutral media. After oral administration of DPG (10mg DP/kg) in omeprazole-treated hypochlorhydric rats, there was ca. 40% reduction of the area under the curve of plasma concentration vs. time from zero to 3h (AUC(0-3)) for DPG compared with that in normal rats. However, AUC(0-3) for DPG/TS under hypochlorhydria was almost identical to that of DPG in normal rats. From these findings, the addition of TS as a microenvironmental pH-modifier in DP formulation might be beneficial in expanding the therapeutic potential of DP in hypochlorhydric patients., (Copyright © 2012 Elsevier B.V. All rights reserved.)