Journal articles on the topic 'Drugs – Solubility – Testing'
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1
D’Souza, Malcolm J., Ghada J. AlAbed, Melissa Earley, Natalia Roberts, and Fady J. Gerges. "Manipulating In-House Designed Drug Databases For The Prediction Of pH-Dependent Aqueous Drug Solubility." American Journal of Health Sciences (AJHS) 4, no. 3 (August 14, 2013): 137–50. http://dx.doi.org/10.19030/ajhs.v4i3.8010.
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Chemical, pharmacokinetic, and pharmacodynamics properties are available in the package inserts of every Food and Drug Administration (FDA) approved prescription drug, including all available chemotherapy drugs. These inserts follow a specific format imposed by the FDA. Whether chemotherapy drugs are administered via the parenteral route or alimentary tract, a significant factor affecting their bioavailability, elimination, and consequently, the drug’s effectiveness and potency, is its state of aqueous solubility. Water solubility has always lent itself poorly to the different predictive and experimental measures employed in the determination of a useful quantitative assessment. In this project, we first built a chemical structure-based searchable database for 85 FDA approved chemotherapy drugs and then used Bio-Rad’s KnowItAll® Informatics suite to focus on the drugs pH-dependent water solubility prediction. We compared the predicted values for water solubility to the available values reported in the drug inserts, testing the practical utility and the predictive ability of our model in reporting such a clinically relevant, underreported pharmacokinetic parameter. A relational cancer drug database (MySQL) was created to further facilitate analysis and/or prediction of a chemotherapy compound’s missing pharmacokinetic properties.
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de Vos, Dick, Rudolph Willem, Marcel Gielen, Kyra E. van Wingerden, and Kees Nooter. "The Development of Novel Organotin Anti-Tumor Drugs: Structure and Activity." Metal-Based Drugs 5, no. 4 (January 1, 1998): 179–88. http://dx.doi.org/10.1155/mbd.1998.179.
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An overview of the development of anti-tumor organotin derivatives in selected classes of compounds is presented and discussed. High to very high in vitro activity has been found, sometimes equaling that of doxorubicin. Solubility in water is an important issue, dominating the in vivo testing of compounds with promising in vitro properties. The cytotoxicity of the compounds was increased by the presence of a bulky group, an active substituent or one or more polar substituents. Polar substituents may also improve the water solubility. Although organotin derivatives constitute a separate class of compounds, the comparison with cisplatin is inevitable. Among the observed toxicities, neurotoxicity, known from platinum cytostatics, and gastrointestinal toxicity, typical for many oncology drugs, have been detected. Further research to develop novel, useful organotin anti-tumor compounds should be carried out.
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Grimberg, Dominic C., Ankeet Shah, Wei Phin Tan, Wiguins Etienne, Ivan Spasojevic, and Brant A. Inman. "Hyperthermia Improves Solubility of Intravesical Chemotherapeutic Agents." Bladder Cancer 6, no. 4 (December 14, 2020): 461–70. http://dx.doi.org/10.3233/blc-200350.
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BACKGROUND: Nearly 70% of all new cases of bladder cancer are non-muscle invasive disease, the treatment for which includes transurethral resection followed by intravesical therapy. Unfortunately, recurrence rates approach 50% in part due to poor intravesical drug delivery. Hyperthermia is frequently used as an adjunct to intravesical chemotherapy to improve drug delivery and response to treatment. OBJECTIVE: To assess the solubility profile of intravesical chemotherapies under varying conditions of pH and temperature. METHODS: Using microplate laser nephelometry we measured the solubility of three intravesical chemotherapy agents (mitomycin C, gemcitabine, and cisplatin) at varying physical conditions. Drugs were assessed at room temperature (23°C), body temperature (37°C), and 43°C, the temperature used for hyperthermic intravesical treatments. To account for variations in urine pH, solubility was also investigated at pH 4.00, 6.00, and 8.00. RESULTS: Heat incrementally increased the solubility of all three drugs studied. Conversely, pH largely did not impact solubility aside for gemcitabine which showed slightly reduced solubility at pH 8.00 versus 6.00 or 4.00. Mitomycin C at the commonly used 2.0 mg/mL was insoluble at room temperature, but soluble at both 37 and 43°C. CONCLUSIONS: Hyperthermia as an adjunct to intravesical treatment would improve drug solubility, and likely drug delivery as some current regimens are insoluble without heat. Improvements in solubility also allow for testing of alternative administration regimens to improve drug delivery or tolerability. Further studies are needed to confirm that improvements in solubility result in increased drug delivery.
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Sopyan, Iyan, Dolih Gozali, and Eka Paramudya. "Formulation and Stability Testing of Microemulsion Griseovulfin." Indonesian Journal of Pharmaceutics 2, no. 2 (June 17, 2020): 32. http://dx.doi.org/10.24198/idjp.v2i2.27574.
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The use of drugs that are less soluble in water will become clinically less efficient, this is caused by the low penetration of the drug into the body. A microemulsion is a dispersion system such as an emulsion that can increase the solubility of drugs that are sometimes difficult to dissolve in water. Microemulsions have long-term stability, clear, transparent, and good penetration capabilities. In this study, a microemulsion formulation with active ingredients griseofulvin and virgin coconut oil was conducted as an oil phase. The resulting microemulsion evaluates physical stability during 35 storage days. The results showed that the microemulsion preparation remained stable during storage time without changes in color, odor, and consistency, while the pH and dosage viscosity experienced less significant changes. The consequences of the centrifugation test at 3700 rpm for 5 hours and freezing tests for 24 days showed stable preparation and cannot be separated. The diffusion test results obtained by FG2 had the largest permeation percentages of 3.6136%, FG3 2.8724%, and the smallest FG1 2.0477%.Keywords: microemulsion, griseofulvin, stability, diffusion test
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Viviane Annisa, Teuku Nanda Saifullah Sulaiman, and Agung Endro Nugroho. "Biorelevant dissolution models to assess precipitation of weak base drug." International Journal of Research in Pharmaceutical Sciences 11, SPL4 (December 21, 2020): 2165–72. http://dx.doi.org/10.26452/ijrps.v11ispl4.4438.
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The impact of precipitation can affect the amount of drug absorbed, thereby affecting the amount of drug in the systemic body. The precipitation process is preceded by a supersaturation phase, caused by decreased drug solubility in the gastrointestinal tract. This precipitation occurs for weak base drugs with low solubility. When the drug entering the small intestine, the solubility of weak base drugs decrease, then occurs supersaturation, which leads to precipitation, so that drug precipitation is one of a challenge for the pharmaceutical industry in drug development. Precipitation testing of water-soluble weak base drugs can be carried out by the pH shift method to describe the gastrointestinal pH gradient from gastric to small intestine. This pH change can cause supersaturation and then trigger precipitation, especially for weak base drugs. The methods that can used to assess precipitation drug is modification of the USP dissolution which are two compartment and multi compartment model. The choice of dissolution medium play an important role in the test results. The use of bio relevant medium can produce closer in vitro and in vivo correlations than the use of buffers. Generally, the medium used to simulate the weakly condition in the small intestine is FaSSIF (Fasted State Simulated Intestinal Fluid) or FeSSIF (Fed State Stimulate Intestinal Fluid) medium. The medium used to simulate the acidic condition in the stomach is FaSSGF (Fasted state simulated gastric fluid) or FeSSGF (Fed state simulated gastric fluid) medium.
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Shin, Hey-Won, Joo-Eun Kim, and Young-Joon Park. "Nanoporous Silica Entrapped Lipid-Drug Complexes for the Solubilization and Absorption Enhancement of Poorly Soluble Drugs." Pharmaceutics 13, no. 1 (January 6, 2021): 63. http://dx.doi.org/10.3390/pharmaceutics13010063.
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This study aims to examine the contribution of nanoporous silica entrapped lipid-drug complexes (NSCs) in improving the solubility and bioavailability of dutasteride (DUT). An NSC was loaded with DUT (dissolved in lipids) and dispersed at a nanoscale level using an entrapment technique. NSC microemulsion formation was confirmed using a ternary phase diagram, while the presence of DUT and lipid entrapment in NSC was confirmed using scanning electron microscopy. Differential scanning calorimetry and X-ray diffraction revealed the amorphous properties of NSC. The prepared all NSC had excellent flowability and enhanced DUT solubility but showed no significant difference in drug content homogeneity. An increase in the lipid content of NSC led to an increase in the DUT solubility. Further the NSC were formulated as tablets using D-α tocopheryl polyethylene glycol 1000 succinate, glyceryl caprylate/caprate, and Neusilin®. The NSC tablets showed a high dissolution rate of 99.6% at 30 min. Furthermore, NSC stored for 4 weeks at 60 °C was stable during dissolution testing. Pharmacokinetic studies performed in beagle dogs revealed enhanced DUT bioavailability when administered as NSC tablets. NSC can be used as a platform to develop methods to overcome the technical and commercial limitations of lipid-based preparations of poorly soluble drugs.
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Hopkinson, Desirée, Peter Scheiner, and Frank A. Barile. "In Vitro Cytotoxicity Testing of Potentially Active Anti-HIV Drugs with Cultured Cells." Alternatives to Laboratory Animals 24, no. 3 (June 1996): 413–18. http://dx.doi.org/10.1177/026119299602400316.
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This study compared the ability of two continuous cell lines to predict the cytotoxicity of potentially active anti-HIV drugs. Human fetal lung fibroblasts (HFL1) and CD4+ T-lymphocytes (CEM-IW) were incubated in the absence or presence of increasing concentrations of 12 antiviral compounds. These six-membered unsaturated nucleoside analogues were stereospecifically synthesised in our laboratories, and were evaluated for cytotoxicity as well as for antiviral activity. Cells were incubated for six days and mitochondrial activity (XTT and MTT assays) was used to assess cytotoxicity. IC50 values were derived from concentration–effect curves after linear regression analysis. Comparison of the two sets of cytotoxicity data suggests that the experimental IC50 values from HFL1 cells correlate well with the values obtained in lymphocyte studies performed at the National Cancer Institute laboratories (r value = 0.93). For the 12 antiviral chemicals, and those we have tested previously, these methods probably detect basal cytotoxicity, i.e. the toxicity of a chemical to basic cellular functions and structures common to all mammalian specialised cells. However, as with any testing procedure, some chemicals may elude the cytotoxicity screen, as a result of false negatives due to solubility, miscibility and organ-specific effects, and could be mislabelled as having low toxic potential. It is therefore conceivable that tests involving continuous differentiated cell lines of various origins could be developed to cover a large percentage of toxic effects, thereby reducing the need to introduce many laborious assay systems with freshly-isolated primary cultures.
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Santhosh Raja M and Venkataramana K. "Formulation Characterization And Invitro, Invivo Evaluation Of Stabilized Rosuvastatin Calcium Nanosuspension." International Journal of Research in Pharmaceutical Sciences 11, no. 2 (June 13, 2020): 2657–64. http://dx.doi.org/10.26452/ijrps.v11i2.2280.
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Rosuvastatin calcium is a BCS class II drug which is used as hyper lipidemic. Many of BCS class II drugs offer the disadvantage of solubility, to overcome the issue of solubility nanoparticle preparation is an promisable approach. A simple and efficient technique for the preparation of nanoparticles is precipitation technique. Polymeric nano particles have been prepared by employing nano precipitation technique. The nanosuspensions were prepared by using PVP K30, HPMC K15M, Eudragit L100 in various ratios using precipitation technique. The compatibility between the drug and various ingredients are tested by DSC. The formed nanoparticles were evaluated for various testing parameters like particle size, zetapotential, drug content and dissolution testing. Among all the formulations the nanosuspension prepared with Eudragit L 100 showed better characteristics. The dissolution test showed the drug release for 12 hours. The best formulation showed the particle size of 100.5 ± 5.4 nm and zeta potential of -55.1 mv. The invivo studies on the wistar rats showed better pharmacokinetic parameters when compared to the pure drug. Nano precipitation method was successfully employed to prepare Rosuvastatin calcium nanosuspension to improve the dissolution as well as bioavailability.
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Viana, Olimpia Maria, Ramon Alves, Jennifer Jacon, Antonio Carlos Doriguetto, Magali Araújo, and Rudy Bonfilio. "Evaluation of the polymorphism effects in the dissolution of Carvedilol tablets." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1577. http://dx.doi.org/10.1107/s2053273314084228.
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Polymorphism in solids is a common phenomenon in drugs, which occurs when an active pharmaceutical ingredient shows up in two or more crystalline forms. The polymorphism may influence the physical and chemical properties of pharmaceutical solids, particularly, solubility and dissolution rates which are very important properties because changes in these parameters may affect the absorption and consequently the bioavailability of drugs (especially those that have a low solubility). Carvedilol is an alpha and beta blocking agent that is used for the treatment of various cardiovascular disorders such as angina pectoris, congestive heart failure and hypertension. This work aims to prepare and characterize the forms II and III of Carvedilol drug and compare them in terms of solubility and dissolution rates. Carvedilol raw material was used as source of form II and Form III, and the last is a hemihydrate of Carvedilol that was obtained by a recrystallization process in ethanol/water 1:1 v/v. Both of the crystalline forms have been identified in this study by Powder X-Ray Diffraction experiments and attenuated total reflectance Fourier transform infrared spectroscopy studies demonstrated that the spectra of forms II and III of Carvedilol have no significant differences. The Thermal Analysis curves, as expected, allowed us to discriminate between the two forms due to a hydratation of Form III. In the solubility study, it was found that the polymorphic Form II is more soluble than Form III in certain conditions (pH 1.0 to 7.2). Dissolution studies have shown that polymorphism may influence the quality of Carvedilol tablets, since form III showed a higher drug release after 20 minutes of dissolution testing. Our results suggest that the identification of polymorphic phases should be a mandatory test for Carvedilol in an official compendium. Acknowledgments: We thank FAPEMIG, FINEP, CAPES and CNPq for their financial support.
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Tay, Erin, Tri-Hung Nguyen, Leigh Ford, Hywel D. Williams, Hassan Benameur, Peter J. Scammells, and Christopher J. H. Porter. "Ionic Liquid Forms of the Antimalarial Lumefantrine in Combination with LFCS Type IIIB Lipid-Based Formulations Preferentially Increase Lipid Solubility, In Vitro Solubilization Behavior and In Vivo Exposure." Pharmaceutics 12, no. 1 (December 22, 2019): 17. http://dx.doi.org/10.3390/pharmaceutics12010017.
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Lipid based formulations (LBFs) are commonly employed to enhance the absorption of highly lipophilic, poorly water-soluble drugs. However, the utility of LBFs can be limited by low drug solubility in the formulation. Isolation of ionizable drugs as low melting, lipophilic salts or ionic liquids (ILs) provides one means to enhance drug solubility in LBFs. However, whether different ILs benefit from formulation in different LBFs is largely unknown. In the current studies, lumefantrine was isolated as a number of different lipophilic salt/ionic liquid forms and performance was assessed after formulation in a range of LBFs. The solubility of lumefantrine in LBF was enhanced 2- to 80-fold by isolation as the lumefantrine docusate IL when compared to lumefantrine free base. The increase in drug loading subsequently enhanced concentrations in the aqueous phase of model intestinal fluids during in vitro dispersion and digestion testing of the LBF. To assess in vivo performance, the systemic exposure of lumefantrine docusate after administration in Type II-MCF, IIIB-MCF, IIIB-LCF, and IV formulations was evaluated after oral administration to rats. In vivo exposure was compared to control lipid and aqueous suspension formulations of lumefantrine free base. Lumefantrine docusate in the Type IIIB-LCF showed significantly higher plasma exposure compared to all other formulations (up to 35-fold higher). The data suggest that isolation of a lipid-soluble IL, coupled with an appropriate formulation, is a viable means to increase drug dose in an oral formulation and to enhance exposure of lumefantrine in vivo.
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Stahr, Pascal-L., Rekha Grewal, Gunter P. Eckert, and Cornelia M. Keck. "Investigating hesperetin nanocrystals with tailor-made sizes for the prevention and treatment of Alzheimer’s disease." Drug Delivery and Translational Research 11, no. 2 (January 12, 2021): 659–74. http://dx.doi.org/10.1007/s13346-020-00888-0.
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Abstract Poor aqueous solubility of drug substances is associated with poor bioavailability and thus hampers the effective use of many potent active pharmaceutical ingredients. Various strategies to overcome poor solubility are available, whereby drug nanocrystals represent one of the most powerful formulation strategies to enhance the kinetic solubility and dissolution rate of poorly soluble drugs. Nanocrystals are simply obtained by milling large-sized drug powders to sizes < 1 µm. The so obtained nanocrystals possess an increased dissolution rate and kinetic solubility when compared with larger-sized bulk material. The aim of this study was to produce differently sized hesperetin nanocrystals and to investigate the influence of nanocrystal size on the bioefficacy of the natural antioxidant hesperetin in two cell culture models for the prevention and treatment of Alzheimer’s disease. Results showed that the testing of poorly soluble compounds is challenging and requires incredibly careful characterization. Reasons for this are possible changes of the formulations in cell culture media which can occur due to various reasons. If the changes are not considered, results obtained can be misleading and even lead to a false interpretation of the results obtained. Besides, results demonstrate the increase in dissolution rate with decreasing particle size that is especially pronounced with particle sizes < 200 nm. Data also provide clear evidence that smaller nanocrystals with higher kinetic solubility possess higher antioxidant capacity. This results in lower amounts of free radicals in the cell culture models, suggesting that hesperetin nanocrystals, that improve the poor aqueous solubility of hesperetin, are promising for the prevention and treatment of Alzheimer’s disease. Graphical abstract "Image missing"
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Webster, Gregory K., Cynthia A. Pommerening, Whitney W. Harman, Mathew A. Gragg, Jian-Hwa Han, and Daniel J. Taylor. "Exploiting Kinetic Solubility Differences for Low Level Detection of Crystallinity in Amorphous Drug Formulations." Current Pharmaceutical Analysis 16, no. 5 (June 15, 2020): 529–38. http://dx.doi.org/10.2174/1573412915666181210144338.
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Background: Enabling formulations have been implemented by the pharmaceutical industry as an effective tool for keeping Active Pharmaceutical Ingredient (API) in an amorphous state. Upon dosing in the amorphous state, many drugs which fail to demonstrate bioactivity due to the limited solubility and bioavailability of their crystalline form become bioavailable. Purpose: The analytical techniques use today for crystallinity detection are challenged by the sensitivity and robustness needed to achieve a 5% quantitation limit in low dose drug products. Our laboratory has developed a novel procedure capable of meeting this sensitivity and selectivity requirement. This is achieved by exploiting the differences in kinetic solubility of the formulated amorphous and free crystalline forms of API currently being used in dosage form platforms. Methods: Representative amorphous drug formulations were prepared and spiked with varying levels of crystalline drug substances to evaluate the selectivity and recovery of the crystalline drug substance from the product formulation. Kinetic solubility testing using a (i) Particle wetting phase, (ii) Particle suspending/erosion phase, (iii) Sampling time point and (iv) A total recovery determination for the drug substance. Results: The method selectively and quantitatively distinguishes crystalline drug substance from amorphous drug substance for samples spiked from 2.5% to 10% of the nominal label concentration of the API in the dosage form matrix. Conclusion: The kinetic solubility approach reported here achieves sensitive crystallinity quantitation for low drug level amorphous drug formulations at levels not yet achieved by complimentary analytical techniques.
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Berginc, Katja, Nadica Sibinovska, Simon Žakelj, Jurij Trontelj, and Igor Legen. "Biopharmaceutical classification of desloratadine – not all drugs are classified the easy way." Acta Pharmaceutica 70, no. 2 (June 1, 2020): 131–44. http://dx.doi.org/10.2478/acph-2020-0006.
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AbstractThe biopharmaceutical classification of drugs was designed as a basis for bio-waivers – a mechanism with the double ethical benefit of delivering new drug formulations to the market with less human testing and lower cost. However, many drugs defy simple classification because in vitro permeability and stability assessment can be challenging as shown in this study for desloratadine. Literature shows that desloratadine is highly soluble, while data on luminal stability and permeability are circumstantial. Combined with borderline bioavailability and not really known fraction of absorbed dose, desloratadine was found to be a good example for showing the innovative in vitro approaches necessary to unambiguously classify desloratadine according to Biopharmaceutical Classification System (BCS) guideline. Presented study undoubtedly confirmed that desloratadine solubility is high and dissolution is very rapid for immediate release reference tablets. We have demonstrated deslorata-dine stability under legally required conditions and also in more physiologically relevant media. High in vitro desloratadine permeability was confirmed using Caco-2 and Parallel Artificial Membrane Permeability Assay (PAMPA). Well-established in vitro model with rat intestinal tissue could not be used due to reasons elaborated in this paper.
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Šoltýsová, I., D. Toropilová, and T. de Vringer. "Lipid Based Formulations of Biopharmaceutics Classification System (BCS) Class II Drugs: Strategy, Formulations, Methods and Saturation." Folia Veterinaria 60, no. 4 (December 1, 2016): 63–69. http://dx.doi.org/10.1515/fv-2016-0040.
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Abstract Active ingredients in pharmaceuticals differ by their physico-chemical properties and their bioavailability therefore varies. The most frequently used and most convenient way of administration of medicines is oral, however many drugs are little soluble in water. Thus they are not sufficiently effective and suitable for such administration. For this reason a system of lipid based formulations (LBF) was developed. Series of formulations were prepared and tested in water and biorelevant media. On the basis of selection criteria, there were selected formulations with the best emulsification potential, good dispersion in the environment and physical stability. Samples of structurally different drugs included in the Class II of the Biopharmaceutics classification system (BCS) were obtained, namely Griseofulvin, Glibenclamide, Carbamazepine, Haloperidol, Itraconazol, Triclosan, Praziquantel and Rifaximin, for testing of maximal saturation in formulations prepared from commercially available excipients. Methods were developed for preparation of formulations, observation of emulsification and its description, determination of maximum solubility of drug samples in the respective formulation and subsequent analysis. Saturation of formulations with drugs showed that formulations 80 % XA and 20 % Xh, 35 % XF and 65 % Xh were best able to dissolve the drugs which supports the hypothesis that it is desirable to identify limited series of formulations which could be generally applied for this purpose.
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Khalikov, S., Oripov, Isaev, and Ulashev. "PROPERTIES OF ALBENDAZOLE SOLID DISPERSIONS OBTAINED BY MECHANOCHEMICAL MODIFICATION WITH POLYMERS." THEORY AND PRACTICE OF PARASITIC DISEASE CONTROL, no. 21 (May 29, 2020): 456–64. http://dx.doi.org/10.31016/978-5-9902341-5-4.2020.21.456-464.
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Given the potential for using methods of mechanochemical modification of difficultly soluble substances of drugs using water soluble polymers of synthetic and natural origin, we conducted studies to improve the solubility of the anthelmintic substance of albendazole (ABZ) by coprocessing ABZ with polymers chitosan and PVP. In this case, solid dispersions (SD) of the ABZ compositions – chitosan = 1:9 and ABZ : PVP = 1:9 – were obtained, which were easy loose powders that formed stable suspension concentrates suitable for the use on animals. Moreover, the solubility of ABZ in these SDs was 20 and 27 times higher respectively than that of the initial substance. When studying the anthelmintic activity of the obtained SDs against the causative agents of fascioliasis, monieziasis, marshallagiasis, nematodirosis and other gastrointestinal strongylatoses in sheep, their high efficiency was established. Thus, if before ABZ : chitosan = 1: 9 was used, sheep were infected with Marshallagia at 88.8%, Nematodirus at 58.0%, and other gastrointestinal strongylates (Ostertagia, Trychostrongilus, etc.) at 80.6%, Fasciola at 96.7%, Moniezia at 6.4%, and the total invasion rate was 96.7%, the prevalence (EI) of these helminths amounted to 58.0%, 3.2%, 9.6%, 5.8%, 0% and 83.8% respectively after 5 days following the use of the drug. When testing the drug composition ABZ : PVP = 1:9 on sheep infected with Marshallagia at 88.8%, Nematodirus at 66.6%, other gastrointestinal strongylates at 72.2%, Fasciola at 24.0%, Moniezia at 5.5%, and all helminths at 100%, decrease in the invasion was observed to 50.0%, 0%, 5.5%, 27.7%, 0% and 50.0% respectively. These experimental data allowed the authors to recommend the ABZ-based drugs for practical use.
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Franc, Aleš, Jan Muselłk, Roman Goněc, and David Vetchý. "Biphasic dissolution method for quality control and assurance of drugs containing active substances in the form of weak acid salts." Acta Pharmaceutica 66, no. 1 (March 1, 2016): 139–45. http://dx.doi.org/10.1515/acph-2016-0010.
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Abstract Substances in the form of weak acid salts have been found to be problematic for dissolution testing. Their absorption can start only after they are turned into the form of an acid following the gastric passage although they were administered in the form of a salt. Due to poor solubility, they cannot be tested in acidic gastric environment for a biased dissolution profile. The biphasic dissolution method is promising for overcoming this obstacle. Tablets with warfarin clathrate sodium salt in two concentrations and two different particle size distributions were tested as a suitable model for finding the medium and process conditions of dissolution. The dissolution method based on the use of the upper organic layer (1-octanol) and the lower aqueous layer 0.1 mol L−1 HCl) was found suitable and discriminatory for tablets containing active substances in the form of salts of weak acids. The method also reflects physical differences in the quality of used substances.
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Llinàs, Antonio, Karl J. Box, Jonathan C. Burley, Robert C. Glen, and Jonathan M. Goodman. "A new method for the reproducible generation of polymorphs: two forms of sulindac with very different solubilities." Journal of Applied Crystallography 40, no. 2 (March 12, 2007): 379–81. http://dx.doi.org/10.1107/s0021889807007832.
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Polymorphism of drugs has been the subject of intense interest in the pharmaceutical industry for over forty years. Although identical in chemical composition, polymorphs differ in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, colour, filterability, density, flow properties, and many other properties. The difference in solubility is particularly important for pharmaceuticals, as it can affect drug efficacy, bioavailability and safety. Despite significant investment in processes to find all the possible polymorphs of active pharmaceutical ingredients (APIs), new polymorphs can suddenly appear without warning. Polymorphs tend to convert spontaneously from less stable to more stable forms, and, therefore, it is best to discover and characterize the stable form as early as possible. Ideally the most stable polymorph will be found while the drug candidate is still in the discovery process, so that this is the form used for subsequent testing. The most stable polymorph will be the least soluble and solubility may be a limiting factor in the efficacy of the API. Despite the huge importance of polymorphism in the properties of materials, however, there is no method that can produce all the stable polymorphs of a compound, or even one that can provide confidence that the most stable polymorph has been obtained. Here we describe a new method, `potentiometric cycling for polymorph creation (PC)2', which is able to generate the most stable polymorph in aqueous solution. This new method has been applied to sulindac, a non-steroidal anti-inflammatory drug, which also shows promise in anticancer treatment, producing two polymorphs of this API, including a new more stable one. By adjusting the conditions, this method is able to produce either polymorph exclusively.
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Bennett-Lenane, Harriet, Joseph P. O’Shea, Jack D. Murray, Alexandra-Roxana Ilie, René Holm, Martin Kuentz, and Brendan T. Griffin. "Artificial Neural Networks to Predict the Apparent Degree of Supersaturation in Supersaturated Lipid-Based Formulations: A Pilot Study." Pharmaceutics 13, no. 9 (September 5, 2021): 1398. http://dx.doi.org/10.3390/pharmaceutics13091398.
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In response to the increasing application of machine learning (ML) across many facets of pharmaceutical development, this pilot study investigated if ML, using artificial neural networks (ANNs), could predict the apparent degree of supersaturation (aDS) from two supersaturated LBFs (sLBFs). Accuracy was compared to partial least squares (PLS) regression models. Equilibrium solubility in Capmul MCM and Maisine CC was obtained for 21 poorly water-soluble drugs at ambient temperature and 60 °C to calculate the aDS ratio. These aDS ratios and drug descriptors were used to train the ML models. When compared, the ANNs outperformed PLS for both sLBFCapmulMC (r2 0.90 vs. 0.56) and sLBFMaisineLC (r2 0.83 vs. 0.62), displaying smaller root mean square errors (RMSEs) and residuals upon training and testing. Across all the models, the descriptors involving reactivity and electron density were most important for prediction. This pilot study showed that ML can be employed to predict the propensity for supersaturation in LBFs, but even larger datasets need to be evaluated to draw final conclusions.
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Wang, Qiao-Han, Xiao-Lin Yang, Wei Xiao, Zhen-Zhong Wang, Gang Ding, Wen-Ze Huang, Zhong-Lin Yang, and Chun-Feng Zhang. "Microcrystalline Preparation of Akebia Saponin D for its Bioavailability Enhancement in Rats." American Journal of Chinese Medicine 43, no. 03 (January 2015): 513–28. http://dx.doi.org/10.1142/s0192415x15500329.
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Akebia Saponin D (ASD) or asperosaponin VI is the most abundant constituent of the rhizome of Dipsacus asper, which has been used for the treatment of lower back pain, traumatic hematoma and bone fractures. In recent years, it was reported that ASD was a potential treatment strategy for Alzheimer's disease (AD). However, the low bioavailability of ASD limited its clinical utility. Microcrystalline preparation is one of the effective methods to improve drug absorption. The drugs prepared by different methods can present different solid forms (polymorphs), and different polymorphs have significantly different bioavailabilities. The objective of this study was to prepare ASD polymorphs using the different preparation processes and to evaluate their physicochemical properties and oral absorption. ASD-2 obtained by the antisolvent process was simpler and had higher recovery (78.5%) than that of ASD-1 by a two-step macroporous resin column separation (56.5%). The ASD polymorphs were characterized using differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The results revealed that ASD-2 existed in microcrystalline form, while ASD-1 was amorphous. Furthermore, the equilibrium solubility, dissolution in aqueous solution and pharmacokinetic parameters of the samples were determined. ASD-2 showed lower aqueous solubility than that of ASD-1 (p < 0.01). In addition, ASD-2 showed lower dissolution with only 65% of the drug released while ASD-1 had a higher dissolution with 99% of drug released at the end of the 180 min testing period. Although ASD-1 significantly increased solubility and dissolution, the AUC 0-20h of ASD-2 was 4.3 times that of the amorphous ASD-1 in vivo. Data suggest that the microcrystalline preparation of ASD-2 is not only reasonable in economy and suitable for large-scale preparation, but also a promising method to enhance bioavailability of ASD.
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Khalikov, Marchenko, and Khalikov. "THE SOLVING OF PERSISTENCE PROBLEMS OF DRUGS ON THE BASIS OF IVERMEKTIN." THEORY AND PRACTICE OF PARASITIC DISEASE CONTROL, no. 20 (May 14, 2019): 671–77. http://dx.doi.org/10.31016/978-5-9902340-8-6.2019.20.671-677.
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Ivermectin-based preparations that have been intensively used in veterinary practice for more than 30 years have contributed to the development of resistance to drugs based on it, and this problem is very relevant in modern parasitology. One of the ways to solve this problem is the development of combined preparations based both on new ivermectin derivatives and the inclusion of preparations from other class-es of chemical compounds in their composition. We have proposed an alternative method, i.e. the mechanochemical modification of the substance ivermectin using water-soluble polymers. This paper presents the results of modifying the substance of ivermectin with arabinogalactan polysaccharide (AG), isolated from Siberian larch Larix sibirica by joint machining of components in a variable-voltage shred-der activator. During jointly machining ivermectin with samples of arabinogalactan from three alternative sources, compositions of "Ivermectin: AG" (1:10), which have increased solubility (more than 10 times as compared with the original substance of ivermectin), were obtained. The study of the parasiticidal efficacy of the obtained compositions of ivermectin in intestinal helminthiases was carried out on sheep. As a result of the experiments to evaluate the compositions of ivermectin with three samples of AG, it was found that their use of helminthic efficacy did not show the advantage of any of the batches of polysaccharide. To a greater extent, the effective-ness of the compositions of ivermectin was influenced by the dosage of the drug. Biological testing of the obtained compositions of ivermectin showed the possibility of reducing the dosage of ivermectin by 2 or more times while maintaining high ef-ficiency. The obtained data indicate the promising outlook for a mechanochemical approach for modifying the physicochemical and biological properties of prepara-tions based on ivermectin in solving problems of resistance.
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D’Addio, Suzanne M., Abdallah A. Bukari, Mohammed Dawoud, Heike Bunjes, Carlos Rinaldi, and Robert K. Prud’homme. "Determining drug release rates of hydrophobic compounds from nanocarriers." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 374, no. 2072 (July 28, 2016): 20150128. http://dx.doi.org/10.1098/rsta.2015.0128.
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Obtaining meaningful drug release profiles for drug formulations is essential prior to in vivo testing and for ensuring consistent quality. The release kinetics of hydrophobic drugs from nanocarriers (NCs) are not well understood because the standard protocols for maintaining sink conditions and sampling are not valid owing to mass transfer and solubility limitations. In this work, a new in vitro assay protocol based on ‘lipid sinks’ and magnetic separation produces release conditions that mimic the concentrations of lipid membranes and lipoproteins in vivo , facilitates separation, and thus allows determination of intrinsic release rates of drugs from NCs. The assay protocol is validated by (i) determining the magnetic separation efficiency, (ii) demonstrating that sink condition requirements are met, and (iii) accounting for drug by completing a mass balance. NCs of itraconazole and cyclosporine A (CsA) were prepared and the drug release profiles were determined. This release protocol has been used to compare the drug release from a polymer stabilized NC of CsA to a solid drug NP of CsA alone. These data have led to the finding that stabilizing block copolymer layers have a retarding effect on drug release from NCs, reducing the rate of CsA release fourfold compared with the nanoparticle without a polymer coating. This article is part of the themed issue ‘Soft interfacial materials: from fundamentals to formulation’.
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Kanaujia, Parijat, Ponnammal Poovizhi, Wai Kiong Ng, and Reginald B. H. Tan. "Preparation, Characterization and Prevention of Auto-oxidation of Amorphous Sirolimus by Encapsulation in Polymeric Films Using Hot Melt Extrusion." Current Drug Delivery 16, no. 7 (October 3, 2019): 663–71. http://dx.doi.org/10.2174/1567201816666190416123939.
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Background: Sirolimus (SIR) is a macrocyclic lactone antibiotic and used therapeutically as a potent immunosuppressant for prophylaxis of kidney transplant rejection. The development of an oral dosage form is challenging because of very poor aqueous solubility (2.6µg/ml). The oral bioavailability of SIR is only 15-20 % and is affected by food and other drugs. The main reasons for low bioavailability are intestinal degradation by enzymes especially by cytochrome P4503A4, efflux by P-glycoprotein and hepatic first-pass metabolism. Objective: The main objective was to prepare a mouth dissolving film dosage form of amorphous SIR to improve dissolution. Methods: Crystalline SIR was transformed to its form amorphous by milling for 2 h at room temperature. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and powder x-ray diffraction (PXRD) were used for characterisation. The stability of amorphous SIR was studied at 4°C and 40°C/75% RH. Amorphous SIR was formulated as oral films by melt extrusion with polyvinylpyrrolidone- vinyl acetate (PVP-VA), Soluplus® and hydroxypropyl cellulose (HPC) as carriers. The films were characterized for drug content, physical state, dissolution profile and stability at 4°C and 40°C/75% RH. Results: The PRXD and DSC confirmed the conversion of crystalline SIR to amorphous form by milling. The solubility of amorphous SIR was several folds higher than its crystalline form, but amorphous SIR was highly unstable at all tested temperatures (4° and 40°C). The extruded films exhibited higher dissolution and stability compared to milled SIR powder alone, but the process of extrusion had some detrimental effect on the chemical stability of amorphous SIR. Conclusion: The film formulations showed a significant improvement in the storage stability of the amorphous form of SIR and the solubility advantage of the amorphous form was evident in the dissolution testing. The oral films can potentially improve the bioavailability of SIR by absorption through the buccal mucosa.
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Wareechuensook, Marisa, Yasuhiko Tabata, and Sorada Kanokpanont. "Characteristics of Cholesterol-Grafted Gelatin Micelles." Advanced Materials Research 93-94 (January 2010): 595–98. http://dx.doi.org/10.4028/www.scientific.net/amr.93-94.595.
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Gelatin, a hydrophilic protein derived from collagen, has been widely used in drug delivery system because of its biocompatibility and biodegradability. However, its high water solubility limited its interaction with hydrophilic drugs. The current works propose a method to improve surface activity of gelatin by modifying it into an amphiphilic molecule via conjugating with cholesterol. High contents of cholesterol were conjugated to amino groups (-NH2) of gelatin using N,N’-Disuccinimidyl carbonate. Cholesterol contents were varied from 100% by mole of free -NH2 group in gelatin. The reduction of free -NH2 groups on gelatin determined by 2,4,6-trinitrobenzenesulfonic acid (TNBS) decreased with the increases of cholesterol used in the conjugation. The percentage of reduction of -NH2 content was 74.63 by mole respectively. Hydrophilicity/hydrophobicity changes were evaluated from water and ethylene glycol contact angles. The conjugated-gelatin were aggregated to form micelles at a critical micelle concentration (CMC) of 8 mg/ml in DI water (pH 5), determined by surface tension testing. Average size of the micelles were in range of 459.05±54.59 nm. The micelles were tested for curcumin entrapment for a cancer research.
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Kaushik, Ritu, Vikas Budhwar, and Deepak Kaushik. "An Overview on Recent Patents and Technologies on Solid Dispersion." Recent Patents on Drug Delivery & Formulation 14, no. 1 (October 13, 2020): 63–74. http://dx.doi.org/10.2174/1872211314666200117094406.
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The oral bioavailability enhancement of poorly water-soluble medicaments is still one of the most complicated aspects of the formulation development. Various approaches are currently available for solubility and rate of dissolution enhancement such as salt formation, solubilization and reduction of particle size, each with its own limitations and advantages. Solid dispersion is one of the most suitable approaches for the formulation development of poorly water-soluble drugs. The popularity of solid dispersion is evident from the increasing number of patent applications and patents granted in this field during recent years. This article reviews the various approaches for the preparation of solid dispersion such as a solvent melting, hot-melt extrusion method, solvent evaporation method, cryogenic processing approaches etc. from the perspective of patents filed or granted for these techniques. Some of the aspects taken into account before the preparation of solid dispersions are carrier selection and physicchemical testing along with an insight into the molecular arrangement of medicaments in solid dispersion. The manuscript further highlights various commercial patented technology platforms such as Solumertm, Hovione and Kinetisol which are based on the concept of solid dispersions.
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Kogawa, Ana Carolina, Selma Gutierrez Antonio, and Hérida Regina Nunes Salgado. "Characterization of Polymorphic Forms of Rifaximin." Journal of AOAC INTERNATIONAL 99, no. 4 (July 1, 2016): 964–71. http://dx.doi.org/10.5740/jaoacint.16-0053.
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Abstract Rifaximin is a gut-selective oral antimicrobial that has no systemic adverse effects compared with placebo. It is used for the treatment of hepatic encephalopathy, traveler's diarrhea, irritable bowel syndrome, Clostridium difficile infection, ulcerative colitis, and acute diarrhea. The crystalline form present in rifaximin, α, has minimal systemic absorption compared to the amorphous form. The objective of this study was to obtain polymorphic forms of rifaximin using recrystallization processes. The forms were characterized and studied by thermal analysis, X-ray powder diffraction, scanning electron microscopy, and solubility testing. Six polymorphic forms of rifaximin, designated I–VI, were obtained by the crystallization process by evaporation of the solvent. Some polymorphic forms obtained in this work may not have the same excellent tolerability as the reference medicine; therefore, studies such as these are extremely important and point to the need for greater requirements by the regulatory agencies overseeing polymorph analysis of the raw materials used in the manufacture of medicines marketed globally. These analyses are not required in the majority of official compendia. Partnerships among industries, research centers, and universities would be a viable way to consolidate research in this area and contribute to improving the quality of solid drugs.
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Mudie, Deanna M., Aaron M. Stewart, Jesus A. Rosales, Nishant Biswas, Molly S. Adam, Adam Smith, Christopher D. Craig, Michael M. Morgen, and David T. Vodak. "Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs." Pharmaceutics 13, no. 4 (April 15, 2021): 557. http://dx.doi.org/10.3390/pharmaceutics13040557.
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Calquence® (crystalline acalabrutinib), a commercially marketed tyrosine kinase inhibitor (TKI), exhibits significantly reduced oral exposure when taken with acid-reducing agents (ARAs) due to the low solubility of the weakly basic drug at elevated gastric pH. These drug–drug interactions (DDIs) negatively impact patient treatment and quality of life due to the strict dosing regimens required. In this study, reduced plasma drug exposure at high gastric pH was overcome using a spray-dried amorphous solid dispersion (ASD) comprising 50% acalabrutinib and 50% hydroxypropyl methylcellulose acetate succinate (HPMCAS, H grade) formulated as an immediate-release (IR) tablet. ASD tablets achieved similar area under the plasma drug concentration–time curve (AUC) at low and high gastric pH and outperformed Calquence capsules 2.4-fold at high gastric pH in beagle dogs. In vitro multicompartment dissolution testing conducted a priori to the in vivo study successfully predicted the improved formulation performance. In addition, ASD tablets were 60% smaller than Calquence capsules and demonstrated good laboratory-scale manufacturability, physical stability, and chemical stability. ASD dosage forms are attractive for improving patient compliance and the efficacy of acalabrutinib and other weakly basic drugs that have pH-dependent absorption.
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Han, Jing, Siwang Zhang, Junxin Niu, Chunli Zhang, Weichen Dai, Yuanyuan Wu, and Lihong Hu. "Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma." Molecules 25, no. 23 (November 27, 2020): 5586. http://dx.doi.org/10.3390/molecules25235586.
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Background: Microtubule-targeted drugs are the most effective drugs for adult patients with certain solid tumors. Taccalonolide AJ (AJ) can stabilize tubulin polymerization by covalently binding to β-tubulin, which enables it to play a role in the treatment of tumors. However, its clinical applications are largely limited by low water solubility, chemical instability in water, and a narrow therapeutic window. Clear-cell renal-cell carcinoma (cc RCC) accounts for approximately 70% of RCC cases and is prone to resistance to particularly targeted therapy drugs. Methods: we prepared a water-soluble cyclodextrin-based carrier to serve as an effective treatment for cc RCC. Results: Compared with AJ, taccalonolide AJ-hydroxypropyl-β-cyclodextrin (AJ-HP-β-CD) exhibited superior selectivity and activity toward the cc RCC cell line 786-O vs. normal kidney cells by inducing apoptosis and cell cycle arrest and inhibiting migration and invasion of tumor cells in vitro. According to acute toxicity testing, the maximum tolerated dose (MTD) of AJ-HP-β-CD was 10.71 mg/kg, which was 20 times greater than that of AJ. Assessment of weight changes showed that mouse body weight recovered over 7–8 days, and the toxicity could be greatly reduced by adjusting the injections from once every three days to once per week. In addition, we inoculated 786-O cells to generate xenografted mice to evaluate the anti-tumor activity of AJ-HP-β-CD in vivo and found that AJ-HP-β-CD had a better tumor inhibitory effect than that of docetaxel and sunitinib in terms of tumor growth and endpoint tumor weight. These results indicated that cyclodextrin inclusion greatly increased the anti-tumor therapeutic window of AJ. Conclusions: the AJ-HP-β-CD complex developed in this study may prove to be a novel tubulin stabilizer for the treatment of cc RCC. In addition, this drug delivery system may broaden the horizon in the translational study of other chemotherapeutic drugs.
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Kuzmin, V. S., V. V. Chernyshev, and A. I. Luttseva. "X-RAY POWDER DIFFRACTION IN QUALITY CONTROL OF MEDICINES." Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products 8, no. 3 (September 26, 2018): 158–61. http://dx.doi.org/10.30895/1991-2919-2018-8-3-158-161.
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X-ray powder diffraction is one of the methods used for detection and analysis of polymorphic forms of pharmaceutical substances. The article elucidates the concept of polymorphism, briefly explains physical characteristics of this phenomenon, conditions of polymorphic transformations and the prevalence of polymorphic forms among drug substances. It should be noted that polymorphism is observed in drug substances belonging to different pharmacologic classes. Polymorphic forms of the same drug substance have different solubility, melting point, resistance to oxidation and to other destructive processes, and, consequently, different surface properties which affect both the rate of absorption of the drug substances and their stability as components of dosage forms. This calls for the need to control the quality of drug substances for potential presence of polymorphic forms. The use of diffraction methods for examination of cryomodified forms of various biologically active compounds obtained by evaporation and subsequent precipitation at low temperatures resulted in obtaining polycrystalline substances with new properties. The article provides results of examination of crystalline modifications of phenazepam in the form of α- and β-polymorphs, tilorone, fabomotizole, zolendronic acid and dehydroepiandrosterone. It was demonstrated that the use of X-ray diffraction analysis for examination and quality control of polymorphic forms of drugs is a necessary component of identification testing.
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Islam, Mohammad Saiful, Faradae Renner, Kimberly Foster, Martin S. Oderinde, Kevin Stefanski, and Somenath Mitra. "Hydrophilic and Functionalized Nanographene Oxide Incorporated Faster Dissolving Megestrol Acetate." Molecules 26, no. 7 (March 31, 2021): 1972. http://dx.doi.org/10.3390/molecules26071972.
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The aim of this work is to present an approach to enhance the dissolution of progestin medication, megestrol acetate (also known as MEGACE), for improving the dissolution rate and kinetic solubility by incorporating nano graphene oxide (nGO). An antisolvent precipitation process was investigated for nGO-drug composite preparation, where prepared composites showed crystalline properties that were similar to the pure drug but enhanced aqueous dispersibility and colloidal stability. To validate the efficient release profile of composite, in vitro dissolution testing was carried out using United States Pharmacopeia, USP-42 paddle method, with gastric pH (1.4) and intestinal pH (6.5) solutions to mimic in vivo conditions. Pure MA is practically insoluble (2 µg/mL at 37 °C). With the incorporation of nGO, it was possible to dissolve nearly 100% in the assay. With the incorporation of 1.0% of nGO, the time required to dissolve 50% and 80% of drug, namely T50 and T80, decreased from 138.0 min to 27.0 min, and the drug did not dissolve for 97.0 min in gastric media, respectively. Additionally, studies done in intestinal media have revealed T50 did not dissolve for 92.0 min. This work shows promise in incorporating functionalized nanoparticles into the crystal lattice of poorly soluble drugs to improve dissolution rate.
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Warren, Cirle A., Edward van Opstal, T. Eric Ballard, Andrew Kennedy, Xia Wang, Mary Riggins, Igor Olekhnovich, et al. "Amixicile, a Novel Inhibitor of Pyruvate:Ferredoxin Oxidoreductase, Shows Efficacy against Clostridium difficile in a Mouse Infection Model." Antimicrobial Agents and Chemotherapy 56, no. 8 (May 14, 2012): 4103–11. http://dx.doi.org/10.1128/aac.00360-12.
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ABSTRACTClostridium difficileinfection (CDI) is a serious diarrheal disease that often develops following prior antibiotic usage. One of the major problems with current therapies (oral vancomycin and metronidazole) is the high rate of recurrence. Nitazoxanide (NTZ), an inhibitor of pyruvate:ferredoxin oxidoreductase (PFOR) in anaerobic bacteria, parasites,Helicobacter pylori, andCampylobacter jejuni, also shows clinical efficacy against CDI. From a library of ∼250 analogues of NTZ, we identified leads with increased potency for PFOR. MIC screens indicatedin vitroactivity in the 0.05- to 2-μg/ml range againstC. difficile. To improve solubility, we replaced the 2-acetoxy group with propylamine, producing amixicile, a soluble (10 mg/ml), nontoxic (cell-based assay) lead that produced no adverse effects in mice by oral or intraperitoneal (i.p.) routes at 200 mg/kg of body weight/day. In initial efficacy testing in mice treated (20 mg/kg/day, 5 days each) 1 day after receiving a lethal inoculum ofC. difficile, amixicile showed slightly less protection than did vancomycin by day 5. However, in an optimized CDI model, amixicile showed equivalence to vancomycin and fidaxomicin at day 5 and there was significantly greater survival produced by amixicile than by the other drugs on day 12. All three drugs were comparable by measures of weight loss/gain and severity of disease. Recurrence of CDI was common for mice treated with vancomycin or fidaxomicin but not for mice receiving amixicile or NTZ. These results suggest that gut repopulation with beneficial (non-PFOR) bacteria, considered essential for protection against CDI, rebounds much sooner with amixicile therapy than with vancomycin or fidaxomicin. If the mouse model is indeed predictive of human CDI disease, then amixicile, a novel PFOR inhibitor, appears to be a very promising new candidate for treatment of CDI.
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Tabosa, Alinne Élida Gonçalves Alves, Aline Silva Ferreira, Natália Millena da Silva, Débora Dolores Souza da Silva Nascimento, Leslie Raphael de Moura Ferraz, José Yago Rodrigues Silva, Severino Alves Junior, Rosali Maria Ferreira da Silva, Larissa Araújo Rolim, and Pedro Jose Rolim-Neto. "Prolonged Release of Anti-Retroviral Efavirenz From System Using ZIF-8 as Carrier." Current HIV Research 18, no. 6 (November 9, 2020): 396–404. http://dx.doi.org/10.2174/1570162x18666200804130734.
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Background: Acquired Immunodeficiency Syndrome (AIDS) is a major public health problem in the world. One of the highly effective drugs in anti-HIV therapy is efavirenz (EFZ), which is classified as Class II according to the Classification System of Biopharmaceuticals, presenting low solubility and high permeability, this being an obstacle related to the drug. Objective: This study aimed to obtain an innovative system based on EFZ and the Zeolitic Imidazolate Framework (ZIF-8) to use in the development of prolonged-release pharmaceutical forms that can circumvent this problem. Methods: The EFZ: ZIF-8 system was obtained by a selected ex-situ method due to its higher incorporation efficiency. Different characterization techniques corroborated the obtainment of the system, and drug release was analyzed by dissolution testing under sink conditions, the profiles being adjusted to some kinetic models. Results: At pH 1.2, the structure of ZIF-8 breaks down rapidly, releasing a large amount of drug within either 3h or short time. In the pH 4.5 and 6.8 medium, the EFZ release from the EFZ: ZIF-8 system obtained in ethanol was prolonged, releasing 95% of the drug in 24h at pH 4.5 and 75% medium at pH 6.8. Conclusion: It is evident that a promising pH-sensitive system was obtained using ZIF-8 as a novel carrier of EFZ intended for the alternative treatment of AIDS.
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Van Sebille, Ysabella ZA, Rachel J. Gibson, Hannah R. Wardill, Thomas J. Carney, and Joanne M. Bowen. "Use of zebrafish to model chemotherapy and targeted therapy gastrointestinal toxicity." Experimental Biology and Medicine 244, no. 14 (June 11, 2019): 1178–85. http://dx.doi.org/10.1177/1535370219855334.
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Gastrointestinal toxicity arising from cancer treatment remains a key reason for treatment discontinuation, significantly compromising remission. There are drawbacks to the currently used in vitro and rodent models, and a lack of translatability from in vitro to in vivo work. A screening-amenable alternative in vivo model such as zebrafish would, therefore, find immediate application. This study utilized a transgenic reporter line of zebrafish, Tg(cyp2k18:egfp), that shows eGFP induction as an indicator of drug-induced pathology. Here, we investigate its utility as an alternative vertebrate model to bridge the gap between simple in vitro cellular studies and complex in vivo models for understanding gastrointestinal toxicity induced by chemotherapy and targeted therapy. Transgenic zebrafish larvae were administered afatinib or SN38, and assessed for viability and eGFP induction. Adult zebrafish were administered afatinib via oral gavage, and SN38 via intraperitoneal injection. Fish were killed after 24 h, and had gastrointestinal tracts removed and assessed for histopathological damage, goblet cell changes, and apoptosis. While treatment with either compound did not induce eGFP in the gastrointestinal tract of larvae, SN38 caused histopathological damage to adult intestines. The lack of eGFP induction may be due to poor solubility of the drugs. Chemotherapy agents with high solubility and permeability would be more amenable to these models. Further progress in this area would be greatly facilitated by the generation of robust and reproducible genetic models of zebrafish intestinal toxicity that mimic the known pathobiological pathways in rodents and humans, and can be readily induced in a short time-frame. Impact statement Gastrointestinal toxicity secondary to cancer treatment remains a major reason for the termination of cancer drug candidates in the development pipeline as well as withdrawal or restrictions of marketed drugs. Current cancer treatment-induced gastrointestinal toxicity models available are limited to in vitro and rodent models that lack translatability and are prohibitively expensive and time consuming. An alternative model to study cancer treatment-induced gastrointestinal toxicity that allows rapid, miniaturized, multi-organ toxicity, screening-amenable testing is therefore warranted. The newly developed Tg( cyp2k18:egfp) zebrafish reporter line was found to induce eGFP in the gastrointestinal tract if toxicity was induced in this area. This paper explored utilizing this reporter line for cancer treatment-induced gastrointestinal toxicity, but found that it was not a useful reporter line in this setting. Further progress in this area would be greatly facilitated by the generation of robust and reproducible genetic models of zebrafish intestinal toxicity that mimic the known pathobiological pathways.
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Peters, Godefridus J., Anne-Sophie Govaerts, Hans R. Hendriks, and For EORTC Pharmacology and Molecular Mechanism Group. "The role of pharmacology in anticancer drug development." ADMET and DMPK 6, no. 1 (March 25, 2018): 4. http://dx.doi.org/10.5599/admet.6.1.496.
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<p>Drug development consists of many sequential and parallel steps; failure in one of the steps can lead to discontinuation of the process. The process is time-consuming and very expensive, especially the clinical phase. In order to enhance cancer drug development in the 1980s, the National Cancer Institute (NCI) adopted a new screening system using 60 different tumour cell lines from various histologies. All standard drugs were tested in this panel and it is still open for testing of new chemical entities (NCE) of potential interest. The European NCI compounds initiative, a collaborative programme of the NCI, the Cancer Research Campaign (CRC; now CRUK) and the Pharmacology and Molecular Mechanism Group (PAMM) of the EORTC (European Organization on Research and Treatment of Cancer), was initiated in 1993. The programme aimed to help the NCI reducing its backlog of in vivo testing by further evaluation of interesting European compounds using a pharmacologically directed approach. Considerable multidisciplinary expertise in drug development was combined by the CRC and EORTC-PAMM: chemists, pharmacists, biologists, pharmacologists, oncologists. Selection criteria for European NCI compounds included novelty of the NCE, in vitro activity, if available in vivo and hollow fibre activity, and COMPARE negativity. Over a period of more than 20 years 95 out of approximately 2,000 reviewed compounds were selected. These compounds were put through a series of stepwise pharmacological tests comprising solubility (suitable formulation to administer the NCE to mice), feasibility to develop a simple analytical assay (usually HPLC), limited toxicology and angiogenic properties. This paper provides examples to illustrate the rigorousness of the elimination process of the compounds and discusses the way to improve the process by inclusion of more physico-chemical parameters.</p>
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BRKICH, Galina Eduardovna, Natalia Valeryevna PYATIGORSKAYA, Natalya Borisovna DEMINA, Elena Olegovna BAKHRUSHINA, and Mstislav Igorevich LAVROV. "DEVELOPMENT OF THE COMPOSITION AND TECHNOLOGY FOR THE PRODUCTION OF ENCAPSULATED DRUGS BASED ON 3,7-DIAZABICYCLO[3.3.1]NONANE." Periódico Tchê Química 17, no. 34 (March 20, 2020): 502–11. http://dx.doi.org/10.52571/ptq.v17.n34.2020.526_p34_pgs_502_511.pdf.
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The following biological and pharmaceutical factors influence the therapeutic efficacy and bioequivalence of drugs: physicochemical properties of a pharmaceutical substance, bioavailability, type of dosage form, route of administration, nature of excipients, their compatibility, as well as technological conditions of production, including the preparation of drugs forms. Before mass production of a drug, the technological parameters and characteristics of the pharmaceutical substance must be carefully studied and scientifically substantiated. This work is devoted to the study of the technological properties of an original pharmaceutical substance based on the derivative of 3.7-diazabicyclo[3.3.1]nonane with the chemical name IUPAC 6-[4methoxy-3- (1H-pyrazol-1-ylmethyl) benzyl] -1,11dimethyl-3,6,9-triazatricyclo[7.3.1.1]tetradecane-4,8,12-trion, used as an active substance for the development of the composition and technology for the preparation of oral dosage forms in capsule form. The article presents the results of the development and testing of a drug in the form of capsules of the original pharmaceutical substance of the nootropic action of 3,7-diazabicyclo[3.3.1]nonanane, which is practically insoluble in water. The study identified and evaluated the technological and biological properties of a pharmaceutical substance that can affect the pharmacological activity in the production of a dosage form. The study examined the key indicators: solubility, particle size, flowability, bulk density. The technological characteristics of the pharmaceutical substance are studied not only by certain values of the indicated characteristics but also by the values of the Hausner and Carr indices. The data obtained suggest the content and progress of further stages of pharmaceutical development. The presence of the lag phase when dissolving hypromellose capsules in a medium with a pH of 1,2 and relatively low disintegration rates in media with a pH of 1,2, pH 4,5, and pH 6,8 served as the basis for the choice of gelatin capsules. The developed dosage form meets modern pharmacopoeial requirements, including the dissolution kinetics: according to the results obtained, in 45 minutes (77,6 ± 2,5)% of the substance passes into the dissolution medium with a pH of 4,5. The results of the study are used to develop a technological scheme for obtaining the dosage form of 3,7-diazabicyclo[3.3.1]nonane, its indicators, and quality standards.
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Dwiastuti, Rini, and Shinta Elvina Ardiyati. "FORMULASI SEDIAAN GEL NANOPARTIKEL LIPID EKSTRAK DAUN BI-NAHONG (Anredera cordifolia (Ten.) Steenis)." Jurnal Farmasi Medica/Pharmacy Medical Journal (PMJ) 3, no. 2 (December 30, 2020): 40. http://dx.doi.org/10.35799/pmj.3.2.2020.32879.
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ABSTRACT Binahong leaf extract has low water solubility. To increase the solubility of binahong leaf extract, it is necessary to formulate lipid nanoparticle gel dosage form. Lipid nanoparticles are preparations that can deliver both hydrophilic and lipophilic drugs. This study aims to make a gel lipid nanoparticles from binahong leaf extract with the physical properties parameters of the gel preparation. This research is a experimental study with independent variables of the concentration of binahong extract and variables depending on the size of the lipid nanoparticles and the physical properties of the gel. Gel making was done by using a variation of the amount of extract 5% and 10%. Testing the physical properties of the gel includes organoleptic, viscosity, dispersibility, pH, homogeneity, and syneresis. The physical stability test carried out is accelerated stability test using the freeze thaw cycling method for 3 cycles. Based on the results of the PSA test, of the two formulas made, one formula fulfills the range 50-100 nm. After testing the physical properties of the gel, the two formulas had a dispersion capacity within the 3-5 cm range, were homogeneous, and did not occur syneresis. The results of the viscosity test showed that the two formulas did not meet the 20-30 Pa.s. The pH test results showed that the two formulas did not meet the pH range 4.5-6.5. Key word: binahong; lipid nanoparticle; soy lecithin, gel ABSTRAKEkstrak daun binahong memiliki kelarutan dalam air yang rendah. Untuk meningkatkan kelarutan ekstrak daun binahong, perlu dilakukan formulasi sediaan dalam bentuk gel nanopartikel lipid. Nanopartikel lipid merupakan sediaan yang dapat membawa obat hidrofilik maupun lipofilik. Penelitian ini bertujuan untuk membuat gel nanopartikel lipid ekstrak daun binahong yang memenuhi parameter sifat fisis sediaan gel. Penelitian ini merupakan eksperimental murni dengan variabel bebas konsentrasi ekstrak binahong dan variabel tergantung ukuran nanopartikel lipid dan sifat fisis gel. Pembuatan gel dilakukan dengan menggunakan variasi jumlah ekstrak 5% dan 10%. Pengujian sifat fisis gel meliputi organoleptis, viskositas, daya sebar, pH, homogenitas, dan sineresis.. Uji stabilitas fisis yang dilakukan adalah uji stabilitas dipercepat dengan metode freeze thaw cycling selama 3 siklus. Berdasarkan hasil uji PSA, dari dua formula yang dibuat, satu formula memenuhi rentang 50-100 nm. Setelah dilakukan uji sifat fisik gel, kedua formula memiliki daya sebar sesuai rentang 3-5 cm, homogen, dan tidak terjadi sineresis. Hasil uji viskositas menunjukkan kedua formula tidak memenuhi rentang 20-30 Pa.s. Hasil uji pH menunjukkan kedua formula tidak memenuhi rentang pH 4,5-6,5. Kata Kunci: binahong; nanopartikel lipid; soy lecithin, gel
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Zeng, Qingyun, Liquan Ou, Guowei Zhao, Ping Cai, Zhenggen Liao, Wei Dong, and Xinli Liang. "Preparation and Characterization of PEG4000 Palmitate/PEG8000 Palmitate-Solid Dispersion Containing the Poorly Water-Soluble Drug Andrographolide." Advances in Polymer Technology 2020 (March 19, 2020): 1–7. http://dx.doi.org/10.1155/2020/4239207.
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Solid dispersion (SD) is the effective approach to improve the dissolution rate and bioavailability of class II drugs with low water solubility and high tissue permeability in the Biopharmaceutics Classification System. This study investigated the effects of polyethylene glycol (PEG) molecular weight in carrier material PEG palmitate on the properties of andrographolide (AG)-SD. We prepared SDs containing the poorly water-soluble drug AG by the freeze-drying method. The SDs were manufactured from two different polymers, PEG4000 palmitate and PEG8000 palmitate. The physicochemical properties of the AG-SDs were characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, dissolution testing, and so on. We found that AG-PEG4000 palmitate-SD and AG-PEG8000 palmitate-SD were similar in the surface morphology, specific surface area, and pore volume. Compared with the AG-PEG4000 palmitate-SD, the intermolecular interaction between PEG8000 palmitate and AG was stronger, and the thermal stability of AG-PEG8000 palmitate-SD was better. In the meanwhile, the AG relative crystallinity was lower and the AG dissolution rate was faster in AG-PEG8000 palmitate-SD. The results demonstrate that the increasing PEG molecular weight in the PEG palmitate can improve the compatibility between the poorly water-soluble drug and carrier material, which is beneficial to improve the SD thermal stability and increases the dissolution rate of poorly water-soluble drug in the SD.
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Ede, Benjamin C., Paraskevi Diamanti, David C. Williams, and Allison Blair. "Biodegradable Nanovectors As a Direct Platform for the Controlled Delivery of Chemotherapeutic Drugs Against Childhood ALL." Blood 136, Supplement 1 (November 5, 2020): 9. http://dx.doi.org/10.1182/blood-2020-141222.
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Drugs used to treat childhood acute lymphoblastic leukemia (ALL), both clinically and experimentally, are often highly insoluble making drug delivery inefficient due to precipitation and poor distribution. Toxicity is also a major issue owing to the high levels of harmful solvents used to solubilize drugs for administration. Therefore, identifying strategies to enhance the stability and solubility of poorly soluble drugs is an ongoing challenge. Data from clinical trials indicates that the pharmacokinetics of dexamethasone (Dex), commonly used in induction regimens for ALL, vary considerably between patients (pts) and prolonging drug exposure rather than increasing absolute dose may improve efficacy. Copolymeric nanovectors (NV) are an excellent candidate for the delivery of insoluble drugs. However, despite reports of multiple systems, the fabrication processes often rely on complex methodologies with purification steps to remove harmful chemicals used to load drugs. To bypass these fabrication issues, we have shown that fully biodegradable copolymer NV comprised of poly(ethylene glycol)-block-poly (trimethylene carbonate) (PEG-PTMC) can sequester highly insoluble drugs (with almost total efficiency) through a direct hydration process in 5 minutes, eliminating the need for purification and use of harmful solvents. The aim of this study was to assess the effects of this systemin vitroandin vivousing Dex. NV were formulated with Dex or 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR, a near infrared insoluble dye) to model NV distributionin vivo. Both Dex and DiR solubilization was initiated using residual (<0.025%) amounts of dimethyl sulfoxide (DMSO) prior to addition to PEG-PTMC, oligo ethylene glycol and stirring into phosphate buffered saline. The average hydrodynamic radii of NV were ca. 40nm when loaded with Dex or DiR, as measured by dynamic light scattering. All formulations had low polydispersity index values (<0.18), indicating highly uniform monodispersed populations of NV. DiR-NV were optimised to 0.125wt% to give the best linearity in fluorescence signal (r2 = 0.97) over a wide range of copolymer concentrations (0.1-20 mg/ml).In vitro, Dex-NV were equipotent with free Dex (dispersed in medium with DMSO) against primary T-ALL cells from all pts tested. The highest dose (100 µM) reduced cell viability to 45±38% in Dex-NV and 46±40% in free Dex treated cells. Crucially, the NV formulation did not reduce Dex efficacy and confirmed our previous findings using parthenolide in this system. As a control, empty (unloaded) NV were not toxicin vitro. To assess the effects of NVin vivo, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were injected with primary ALL cells from 3 pts and engraftment was measured in peripheral blood (PB) aspirates using flow cytometry. Once engrafted (>0.1% ALL cells) animals were treated daily for 5 days, over 4 weeks with 2.5 mg/kg Dex via intraperitoneal injection (IP). Both Dex-NV and free Dex delayed disease progression until day 18 in pt 1, and until after treatment cessation in pts 2 and 3 with disease levels of 0.24±0.1% and 0.55±0.1% near the end of treatment, respectively. In contrast, leukemia engraftment increased immediately following engraftment in placebo controls. Dex-NV and free Dex significantly improved the survival of NSG by up to 27 days (P<0.01) with no significant differences between treatments. Ten minutes after intravenous injection (IV) with DiR-NV, ventral imaging showed that fluorescence was detected throughout NSG with accumulations in the bone marrow, lungs, liver, spleen and the head area, indicative of uniquely broad distribution properties. Peak fluorescence was also detected in PB aspirated from the opposite tail vein to that injected, from the first time point (452±225 RFU, 30 minutes). The half-life of DiR-NV in PB was 2.25 hours for IV treated mice. As expected, in IP treated mice fluorescence levels took longer to peak (2 hours, 138±83 RFU) and had a half-life of 3.2 hours from this point. In conclusion, these results demonstrate the usefulness of PEG-PTMC NV for the delivery and consequent retention of insoluble chemotherapeutic drugs; without hindering their performancein vitroorin vivo. The generated NV are biocompatible, do not require purification and can be fabricated within 5 minutes. These data support the testing of NV against more pt samplesin vivowith Dex and other insoluble drugs. Disclosures No relevant conflicts of interest to declare.
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Kajsheva, N. Sh, A. Sh Kajshev, V. A. Mikelov, C. N. Gulbjakova, and E. A. Maslovskaya. "Chemical study of betaines isolated from the whole stillage." Proceedings of the Voronezh State University of Engineering Technologies 81, no. 2 (November 1, 2019): 257–60. http://dx.doi.org/10.20914/2310-1202-2019-2-257-260.
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The solution of the problem of import substitution by creating domestic medications similar to foreign pharmacological efficacy and safety, especially given the availability of raw materials and high profitability of the target product, represents the current trend in the development of pharmacy. This fully applies to drugs based on betaine, the isolation of which was first proposed from the post-alcohol corn bard - a multitonous and cheap secondary raw material, obtained in production conditions using traditional alcohol technologies. A method for isolating betaine hydrochloride from a bard, including the original (separation into liquid and solid phases, removal of carbohydrates from the liquid phase, neutralization thereof) and known (separation from the liquid phase of betaine hydrochloride, liberated from glutamic acid, humic acids, metal chlorides) greater by 2-4 times the technological yield (0.4%). The task of establishing analytical indicators of the target product was carried out in comparison with the standard sample obtained from the tablets Acidin-Pepsin, imported to Russia from the Republic of Belarus. Both test samples (the target product and the standard sample) are characterized by their identical physical and chemical characteristics (description, solubility in water and alcohol, pH 1% of aqueous solutions), positive results of authenticity reactions (thermal decomposition, precipitating with copper (II) ions and silver nitrate), quantitative content (respectively 99.2 and 99.9%). The high technological yield of betaine hydrochloride isolated from the post-alcohol corn bard, identical to the standard sample for the most important analytical indicators, creates the prospect of solving the problem of import substitution of the drug "Acidin-pepsin", which requires the need for in-depth preclinical testing.
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Ueno, T., Y. Eizuru, H. Katano, T. Kurata, T. Sata, S. Irie, and K. Ogawa-Goto. "Novel Real-Time Monitoring System for Human Cytomegalovirus- Infected Cells In Vitro That Uses a Green Fluorescent Protein-PML-Expressing Cell Line." Antimicrobial Agents and Chemotherapy 50, no. 8 (August 2006): 2806–13. http://dx.doi.org/10.1128/aac.01641-05.
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ABSTRACT Promyelocytic leukemia (PML) bodies are discrete nuclear foci that are intimately associated with many DNA viruses. In human cytomegalovirus (HCMV) infection, the IE1 (for “immediate-early 1”) protein has a marked effect on PML bodies via de-SUMOylation of PML protein. Here, we report a novel real-time monitoring system for HCMV-infected cells using a newly established cell line (SE/15) that stably expresses green fluorescent protein (GFP)-PML protein. In SE/15 cells, HCMV infection causes specific and efficient dispersion of GFP-PML bodies in an IE1-dependent manner, allowing the infected cells to be monitored by fluorescence microscopy without immunostaining. Since a specific change in the detergent solubility of GFP-PML occurs upon infection, the infected cells can be quantified by GFP fluorescence measurement after extraction. With this assay, the inhibitory effects of heparin and neutralizing antibodies were determined in small-scale cultures, indicating its usefulness for screening inhibitory reagents for laboratory virus strains. Furthermore, we established a sensitive imaging assay by counting the number of nuclei containing dispersed GFP-PML, which is applicable for titration of slow-growing clinical isolates. In all strains tested, the virus titers estimated by the GFP-PML imaging assay were well correlated with the plaque-forming cell numbers determined in human embryonic lung cells. Coculture of SE/15 cells and HCMV-infected fibroblasts permitted a rapid and reliable method for estimating the 50% inhibitory concentration values of drugs for clinical isolates in susceptibility testing. Taken together, these results demonstrate the development of a rapid, sensitive, quantitative, and specific detection system for HCMV-infected cells involving a simple procedure that can be used for titration of low-titer clinical isolates.
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Guzman, Monica L., Shama Nasim, Marlene Balys, Cheryl A. Corbett, Peter A. Crooks, and Craig T. Jordan. "Chemical Derivatives of the Anti-Leukemia Stem Cell Compound 4-Benzyl-2-Methyl-1,2,4-Thiadiazolidine-3,5-Dione (TDZD-8) with Improved Activity." Blood 114, no. 22 (November 20, 2009): 3764. http://dx.doi.org/10.1182/blood.v114.22.3764.3764.
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Abstract Abstract 3764 Poster Board III-700 We have recently described the novel and unique anti-leukemic properties of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). Indeed, TDZD-8 was shown to eradicate leukemia at the bulk, stem, and progenitor level with rapid kinetics (typically < 2 h) with minimal toxicity to normal hematopoietic cells. Moreover, the cytotoxic activity of this drug is observed only in hematologic malignancies. The precise mechanism of TDZD-8 is not fully appreciated, but the compound has been shown to inhibit NFkappaB, GSK3beta, protein kinase C, FMS-like tyrosine kinase (Flt3), AKT and KDR. In addition, TDZD-8 rapidly depletes free thiols and appears to disrupt membrane integrity. Interestingly, TDZD-8 results in rapid mitochondrial swelling, followed by vacuole formation and accumulation. Despite possessing potent and specific anti-leukemia activity, the clinical utility of TDZD-8 is limited by the need for high concentrations (20 microM) and poor solubility. Therefore, to improve the pharmacological properties of TDZD-8, we initiated efforts to generate derivatives with greater anti-leukemia activity at lower concentrations and with greater water-solubility. To this end, an extensive structure-activity relationship study was carried out to examine the effects on anti-leukemic activity resulting from introduction of substituents at the C-2 and C-4- positions of the thiadiazolidine ring of TDZD-8, and of replacement of the TDZD ring with isosteric scaffolds. In total, we have screened more than 60 new analogs. Preliminary screens were performed using two different AML cell lines, evaluating the LD50 for each of the analogs relative to the parental compound. We found that introducing substitutuents into the main TDZD ring resulted in loss of anti-leukemic activity of the compounds. Moreover, substitution in the benzyl/phenyl ring does not affect anti-leukemia activity of the TDZD analogs. Importantly, we found that N-2 halogenoethyl analogs, exhibit exceptional activity against leukemic cells. Of the halogenoethyl analogs evaluated, the iodoethyl analog TD-361 was the most active compound with an LD50 of 0.49 microM in MV-411 cells. Compounds exhibiting increased anti-leukemia activity were subjected to further testing in phenotypically-defined AML stem/progenitor cells. All analogs demonstrated efficacy in primary AML cells at lower concentrations than TDZD-8. Moreover, these analogs still maintained the rapid kinetics observed with TDZD-8. Finally, we performed colony assays to determine the effect of new analogs on progenitor cells from normal and leukemic cells. These studies demonstrated that the more active TDZD analogs retained the selective ability of TDZD-8 to abate AML progenitor cells without harming normal hematopoietic cells. In summary, we have identified the critical chemical moieties for the observed activity of TDZD-8, and have also discovered analogs with improved anti-leukemia activity. Going forward, the most active derivatives are being optimized for water-solubility and will then be evaluated using primary human AML specimens engrafted into immune deficient mice. Based on evidence to date, we propose that the TDZD family of compounds may represent a new class of drugs for the treatment of leukemia and related hematologic malignancies. Disclosures: No relevant conflicts of interest to declare.
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Krstic, Marko, and Svetlana Ibric. "Application of mixture experimental design in formulation and characterization of solid self-nanoemulsifying drug delivery systems containing carbamazepine." Chemical Industry 70, no. 5 (2016): 525–37. http://dx.doi.org/10.2298/hemind150623059k.
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One of the problems with orally used drugs is their poor solubility, which can be overcame by creating solid self-nanoemulsifying drug delivery systems (SNEDDS). Aim is choosing appropriate SNEDDS using mixture design and adsorption of SNEDDS on a solid carrier to improve the dissolution rate of carbamazepine. Self-emulsifying drug delivery systems (SEDDS) consisting of oil phase (caprilic-capric triglycerides), a surfactant (Polisorbat 80 and Labrasol? (1:1)) and cosurfactant (Transcutol? HP) are formed by applying mixture design. 16 formulations were formulated, where proportion of lipids, surfactant and cosurfactant were varied (input parameters) in the following ranges: 10-30%, 40-60%, 30-50%, respectively. After dilution of SEDDS with water (90% water), the droplet size and polydispersity index (PdI) of the obtained emulsions (output parameters) were measured using photon correlation spectroscopy. After processing data, appropriate mathematical models that describe the dependence of input and output parameters were selected. The optimized SNEDDS was adsorbed on the carbamazepine and solid carrier physical mixture, containing 20% carbamazepine. Neusilin? UFl2, Neusilin? FL2, Sylysia? 320, diatomite were used as the carriers. The ratio of SNEDDS:carrier varied (1:1, 2:1). Dissolution testing was carried out in the rotation paddles apparatus. Caracterization of solid SNEDDS was performed using the hot stage microscopy (HSM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), infrared spectrophotometry with Fourier transformation (FT-IR), scanning electron microscopy (SEM) and X-ray diffraction (PXRD). Selected SNEDDS consisting of lipids (21.12%), surfactant (42.24%) and cosurfactant (36.64%) had a droplet size 157.02?34.09 nm and PDI 0.184?0.021. Drug release profiles showed that in all formulations dissolution rate increased (the fastest drug release was observed in formulations with Sylysia? 320). It can be concluded that in all formulations carbamazepine is present in the thermodynamically most stable polymorphic form III. Formulation of solid SNEDDS can significantly increase dissolution rate carbamazepine, with conservation of the polymorphic form III CBZ and potentially increased bioavailability.
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Oprea, Tudor I., Cristian G. Bologa, Bruce S. Edwards, Eric R. Prossnitz, and Larry A. Sklar. "Post-High-Throughput Screening Analysis: An Empirical Compound Prioritization Scheme." Journal of Biomolecular Screening 10, no. 5 (August 2005): 419–26. http://dx.doi.org/10.1177/1087057104272660.
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An empirical scheme to evaluate and prioritize screening hits from high-throughput screening (HTS) is proposed. Negative scores are given when chemotypes found in the HTS hits are present in annotated databases such as MDDR and WOMBAT or for testing positive in toxicity-related experiments reported in TOXNET. Positive scores were given for higher measured biological activities, for testing negative in toxicity-related literature, and for good overlap when profiled against drug-related properties. Particular emphasis is placed on estimating aqueous solubility to prioritize in vivo experiments. This empirical scheme is given as an illustration to assist the decision-making process in selecting chemotypes and individual compounds for further experimentation, when confronted with multiple hits from high-throughput experiments. The decision-making process is discussed for a set of G-protein coupled receptor antagonists and validated on a literature example for dihydrofolate reductase inhibition.
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Qian, Jianying, Xiaomeng Wang, Jie Shu, Chang Su, Jinsong Gong, Zhenghong Xu, Jian Jin, and Jinsong Shi. "A Novel Complex of Chitosan–Sodium Carbonate and Its Properties." Marine Drugs 16, no. 11 (October 30, 2018): 416. http://dx.doi.org/10.3390/md16110416.
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Chitosan has excellent properties, as it is nontoxic, mucoadhesive, biocompatible, and biodegradable. However, the poor water solubility of chitosan is a major disadvantage. Here, a novel chitosan-sodium carbonate complex was formed by adding a large amount of sodium carbonate to a chitosan/acetic acid solution, which is water-soluble. Fourier transform infrared spectroscopy, energy dispersive spectrometry, scanning electron microscopy, and solid-state nuclear magnetic resonance techniques were used to detect and characterize the aforementioned complex, which appeared to be a neat flake crystal. Solid-state nuclear magnetic resonance (SSNMR) was used to verify the connections between carbonate, sodium ions, and the protonated amino group in chitosan on the basis of 13C signals at the chemical shift of 167.745 ppm and 164.743 ppm. Further confirmation was provided by the strong cross-polarization signals identified by the SSNMR 2D 13C–1H frequency-switched Lee–Goldberg heteronuclear correlation spectrum. The cytotoxicity of a film prepared using this complex was tested using rat fibroblasts. The results show that the film promoted cell proliferation, which provides evidence to support its nontoxicity. The ease of film-forming and the results of cytocompatibility testing suggest that the chitosan-sodium carbonate complex has the potential for use in tissue engineering.
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Knight, Andrew W., Louise Birrell, and Richard M. Walmsley. "Development and Validation of a Higher Throughput Screening Approach to Genotoxicity Testing Using the GADD45a-GFP GreenScreen HC Assay." Journal of Biomolecular Screening 14, no. 1 (November 21, 2008): 16–30. http://dx.doi.org/10.1177/1087057108327065.
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There is a pressing need to develop rapid yet accurate screening assays for the identification of genotoxic liability and for early hazard assessment in drug discovery. The GADD45a-GFP human cell-based genotoxicity assay (GreenScreen HC) has been reformatted to test 12 compounds per 96-well microplate in a higher throughput, automated screening mode and the protocol applied to the analysis of 1266 diverse, pharmacologically active compounds. Testing from a fixed starting concentration of 100 µM and over 3 serial dilutions, the hit rates for genotoxicity (7.3%) and cytotoxicity (33%) endpoints of the assay have been determined in a much wider chemical space than previously reported. The degree of interference from color, autofluorescence, and low solubility has also been assessed. The assay results have been compared to an in silico approach to genotoxicity assessment using Derek for Windows software. Where carcinogenicity data were available, GreenScreen HC demonstrated a higher specificity than in silico methods while identifying genotoxic species that were not highlighted for genotoxic liability in structure-activity relationship software. Higher throughput screening from a fixed, low concentration reduces sensitivity to less potent genotoxins, but the maintenance of the previously reported high specificity is essential in early hazard assessment where misclassification can lead to the needless rejection of potentially useful compounds in drug development. ( Journal of Biomolecular Screening 2009:16-30)
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Ezawa, Toshinari, Yutaka Inoue, Sujimon Tunvichien, Rina Suzuki, and Ikuo Kanamoto. "Changes in the Physicochemical Properties of Piperine/β-Cyclodextrin due to the Formation of Inclusion Complexes." International Journal of Medicinal Chemistry 2016 (February 22, 2016): 1–9. http://dx.doi.org/10.1155/2016/8723139.
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Piperine (PP) is a pungent component in black pepper that possesses useful biological activities; however it is practically insoluble in water. The aim of the current study was to prepare a coground mixture (GM) of PP and β-cyclodextrin (βCD) (molar ratio of PP/βCD = 1/1) and subsequently evaluate the solubility of PP and physicochemical properties of the GM. DSC thermal behavior of the GM showed the absence of melting peak of piperine. PXRD profile of the GM exhibited halo pattern and no characteristic peaks due to PP and βCD were observed. Based on Job’s plot, the PP/βCD complex in solution had a stoichiometric ratio of 1/1. Raman spectrum of the GM revealed scattering peaks assigned for the benzene ring (C=C), the methylene groups (CH2), and ether groups (C-O-C) of PP that were broaden and shifted to lower frequencies. SEM micrographs showed that particles in the GM were agglomerated and had rough surface, unlike pure PP and pure βCD particles. At 15 min of dissolution testing, the amount dissolved of PP in the GM was dramatically increased (about 16 times) compared to that of pure PP. Moreover the interaction between PP and βCD cavity was detected by 1H-1H NMR nuclear Overhauser effect spectroscopy NMR spectroscopy.
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Arumov, Artavazd, Piumi Y. Liyanage, Asaad Trabolsi, Lingxiao Li, Evan R. Roberts, Daniel Bilbao, Roger M. LeBlanc, and Jonathan H. Schatz. "Targeted Delivery of Nanocarrier-Conjugated Doxorubicin to Widen the Therapeutic Window of the Most Active Drug in Lymphoma Therapeutics." Blood 134, Supplement_1 (November 13, 2019): 4061. http://dx.doi.org/10.1182/blood-2019-122599.
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Doxorubicin (Dox) remains the most active drug against aggressive lymphomas, forming the backbone of multiple potentially curative frontline combination regimens. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), for example, cures diffuse large B-cell Lymphoma (DLBCL), the most common lymphoid malignancy in the United States, greater than 60% of the time. Patients with relapsed/refractory disease, however, have poor prognosis and require new options. Advances in nanotechnology provide new opportunities to widen therapeutic windows for existing drugs by enhancing delivery to tumor cells and limiting toxicities to non-malignant tissues. Carbon-Nitride Dots (CND) are novel nanocarriers we have developed that can be conjugated with a diverse range of molecules and have an established safe pharmacologic profile. Here, we sought CND-based enhancement of Dox's anti-lymphoma activities. We generated unconjugated CNDs (~3 nm) through a hydrothermal microwave synthesis, followed by carbodiimide cross-linking bioconjugation steps to covalently link Dox and/or transferrin (TF), the protein ligand for the transferrin receptor (TFR). Because TFR is expressed on the cell surface in a range of B-cell lymphomas including DLBCL, we aimed to increase Dox delivery to tumor cells and limit delivery to non-malignant tissues. We probed a cohort of DLBCL cell lines for TFR expression via western blot, followed by baseline viability assays. Unconjugated CNDs showed no toxicity in vitro, while conjugation to Dox alone resulted in potency similar to unconjugated Dox. CND-Dox-TF, however, was 1-2 Log10 more potent than Dox alone (LD50 1.2-48.5 nM vs. 205.5->1000 nM), consistent with enhanced activity due to the entry of the nanocarrier into the cells through the TF-TFR interaction. To create a functional model, we cloned the TFR1 gene into a GFP-lentiviral expression vector. We infected previously tested cell lines with TFR1, confirmed increased TFR expression via western blot, and exposed cells to CND nanocarriers. TFR1-infected cells showed selective disadvantage during CND-Dox-TF treatment compared to uninfected and empty-vector controls, while CND and CND-Dox controls showed no differential effect. After establishing CND-Dox-TF proof of principle in vitro, we next initiated testing in vivo, beginning with maximum-tolerated dose (MTD) finding experiments. We treated three groups of non-tumor-bearing NOD scid gamma (NSG) mice intravenously with a single dose of (1) CND, (2) CND-Dox, and (3) CND-Dox-TF. Maximum dosing of CND-Dox-TF based on solubility in 100 µL PBS was roughly 1:4 molar equivalent to Dox MTD (3.3 mg/kg). This dose of CND-Dox-TF caused decreased body weight to >20% loss from starting dosing and animals had to be sacrificed, with organ pathology pending. Molar equivalent dosing of CND and CND-Dox, however, resulted in no weight loss, demonstrating biologic activity of the TF moiety but unfortunately intolerable toxicity at this initial dose. We then reduced the CND-Dox-TF dose to 1:16 molar equivalent to Dox MTD and repeated dosing to three non-tumor-bearing animals. This resulted in decreased body weight of 10% from starting dose by day 11, followed by a rebound to normal body weight by day 17. This observed body weight fluctuation is similar to what is seen under a 0.75% of Dox MTD. With a dose of 33 mg/kg identified as the MTD of the CND-Dox-TF, we are now proceeding to anti-tumor efficacy experiments in four available PDX models of DLBCL (two each from previously untreated and relapsed/refractory patients). We will compare the MTD of Dox versus the MTD of CND-Dox-TF initially as single agents. We will then compare R-CHOP to "R-nanoCHOP" (replacement of Dox with the MTD of CND-Dox-TF). We hypothesize that both through the TF-TFR interaction and enhanced tumor permeability and retention that are known properties of CNDs, CND-Dox-TF treated mice will have improved anti-lymphoma responses. In sum, we show that a TF ligand conjugated to Dox via our CND nanocarrier significantly increases the anti-lymphoma efficacy of Dox on DLBCL cell lines. Importantly, we also show these novel nanocarrier therapeutic molecules are safe to administer in vivo, and we define MTD for studies moving forward. Proof of principle that CND nanotechnology enhances anti-lymphoma activity of Dox would open the door for many such approaches aimed at a variety of malignancies. Disclosures No relevant conflicts of interest to declare.
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Garlich, Joseph R., Michael D. Becker, Candace F. Shelton, Wenqing Qi, Xiaobing Liu, Laurence Cooke, and Daruka Mahadevan. "Phase I Study of Novel Prodrug Dual PI3K/mTOR Inhibitor SF1126 In B-Cell Malignancies." Blood 116, no. 21 (November 19, 2010): 1783. http://dx.doi.org/10.1182/blood.v116.21.1783.1783.
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Abstract Abstract 1783 Background: The PI3K/Akt/mTOR signaling pathway is an attractive target to inhibit for cancer therapy because it is altered in many cancers and is vital to essential biological processes. While inhibition of specific PI3K isoforms, such as δ, has demonstrated efficacy in B-cell malignancies, recent studies suggest that inhibition of all Class IA isoforms (α, β, and δ) is essential to produce maximal inhibition of cell proliferation and to induce apoptosis. For example, the pan PI3K inhibitor LY294002 has been shown to inhibit both the viability and chemotaxis of chronic lymphocytic leukemia (CLL) B-cells, whereas a PI3K δ inhibitor did not. Dual PI3K and mTOR inhibition is also expected to offer a therapeutic advantage, as several mTOR inhibitors have demonstrated promising activity in B-cell malignancies, including the mobilization of CLL cells from tissue sites into the circulation that could enhance the cytotoxicity of other agents. Objectives: The role of PI3K in a wide range of normal biologic processes raises potential safety concerns about dual inhibition of mTOR and all PI3K Class I isoforms. The objective of this Phase I study is to demonstrate that SF1126 can overcome these concerns by accumulating preferentially in tumor tissue to both maximize efficacy and minimize toxicity. SF1126 is a peptidic prodrug that converts to LY294002, one of the most widely studied dual PI3K/mTOR inhibitors. LY294002 is conjugated to an Arg-Gly-Asp (RGD) peptide via a cleavable linker to form SF1126, which has improved properties for clinical use. As a prodrug with improved solubility and site selectivity due to targeting of RGD-recognizing integrin receptors, SF1126 opened up a new avenue for the clinical development of LY294002. Furthermore, the fact that proliferation of CLL cells requires stromal support mediated through cytokines and adhesion molecules (eg, integrins) provides additional biological rationale for testing a RGD-targeted agent as a treatment for CLL. Methods: Based on translational studies demonstrating that LY294002 induces apoptosis in CLL cells and sensitize CLL cells to cytotoxic drugs, patients with CLL and other B-cell malignancies will be enrolled on this expanded Phase I trial at the maximum administered dose of SF1126 (1110 mg/m2) as determined by 47 patients treated to date in dose-escalation studies. SF1126 will be administered intravenously over 90-minutes on days 1 and 4 weekly in cycles of 4 weeks. Patients with CLL will be assessed using the International Workshop on CLL (IWCLL) criteria and patients with indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL) will be assessed using the International Workshop Group (IWG) criteria. Correlative pharmacodynamic studies will also be conducted to evaluate the potential inhibition of PI3K in tumor cells from patients enrolled in this trial. Results: At the maximum administered dose of 1110 mg/m2, SF1126 appears to be well tolerated and demonstrates activity in relapsed and refractory CLL patients treated to date in this ongoing Phase I study. Similar to the tumor flare reaction (TFR) demonstrated in CLL patients treated with immune-modulating agents, such as lenalidomide, two patients treated with SF1126 experienced TFR during the cycle one, day 1–4 time period. TFR has been postulated to be associated with a drug-induced, immune-mediated anti-tumor response and is manifested as an acute onset of swelling of involved lymph nodes that is not associated with disease progression. Time course analysis by flow cytometry of isolated lymphocytes from the first two CLL patients treated demonstrate consistent increases in late apoptosis over time relative to baseline following the first dose of SF1126. Western blot analyses of isolated lymphocytes from the first CLL patient treated demonstrate decreased pAKT (473) signaling and increased PARP cleavage over time relative to baseline. One CLL patient with a 17p deletion genotype demonstrated clinical activity as indicated by stable disease and significant lymph node decreases accompanied by an increases in absolute lymphocyte count (ALC) as seen with the mTOR inhibitor everolimus. The trial continues to enroll patients and updated results from this study will be presented. In view of SF1126's ability to mobilize CLL cells into the circulation, combination studies with synergistic agents that are effective against circulating CLL cells are also being planned. Disclosures: Garlich: Semafore Pharmaceuticals: Employment, Patents & Royalties. Becker:Semafore Pharmaceuticals: Consultancy, Patents & Royalties. Shelton:Semafore Pharmaceuticals: Consultancy. Qi:Seamfore Pharmaceuticals: Research Funding. Liu:Semafore Pharmaceuticals: Research Funding. Cooke:Semafore Pharmaceuticals: Research Funding. Mahadevan:semafore pharmaceuticals: Research Funding.
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Kaur, Tejinder, Ashwini Madgulkar, Mangesh Bhalekar, and Kalyani Asgaonkar. "Molecular Docking in Formulation and Development." Current Drug Discovery Technologies 16, no. 1 (April 10, 2019): 30–39. http://dx.doi.org/10.2174/1570163815666180219112421.
Full textAbstract:
Background: In pharmaceutical research drug discovery and development process is timeconsuming and expensive. In many cases, it produces incompetent results due to the failure of in vitro and in vivo conventional approaches. Before any new drug is placed in the market it must undergo rigorous testing to get FDA approval. Due to the several limitations imposed by the drug discovery process, in recent times in silico approaches are widely applied in this field. The purpose of this review is to highlight the current molecular docking strategies used in drug discovery and to explore various advances in the field. Methods: In this review we have compiled database after an extensive literature search on docking studies which has found its applications relevant to the field of formulation and development. The papers retrieved were further screened to appraise the quality of work. In depth strategic analysis was carried out to confirm the credibility of the findings. Results: The papers included in this review highlight the promising role of docking studies to overcome the challenges in formulation and development by emphasizing it’s applications to predict drug excipient interactions which in turn assist to increase protein stability; to determine enzyme peptide interactions which maybe further used in drug development studies; to determine the most stable drug inclusion complex; to analyze structure at molecular level that ascertain an increase in solubility, dissolution and in turn the bioavailability of the drug; to design a dosage form that amplify the drug discovery and development process. Conclusion: This review summarizes recent findings of critical role played by molecular docking in the process of drug discovery and development. The application of docking approach will assist to design a dosage form in the most cost effective and time saving manner.
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Thakkar, Rishi, Miguel O. Jara, Steve Swinnea, Amit R. Pillai, and Mohammed Maniruzzaman. "Impact of Laser Speed and Drug Particle Size on Selective Laser Sintering 3D Printing of Amorphous Solid Dispersions." Pharmaceutics 13, no. 8 (July 27, 2021): 1149. http://dx.doi.org/10.3390/pharmaceutics13081149.
Full textAbstract:
This research demonstrates the influence of laser speed and the drug particle size on the manufacturing of amorphous solid dispersions (ASD) and dosage forms thereof using selective laser sintering 3-dimensional (3D) printing. One-step manufacturing of ASD is possible using selective laser sintering 3D printing processes, however, the mechanism of ASD formation by this process is not completely understood and it requires further investigation. We hypothesize that the mechanism of ASD formation is the diffusion and dissolution of the drug in the polymeric carrier during the selective laser sintering (SLS) process and the drug particle size plays a critical role in the formation of said ASDs as there is no mixing involved in the sintering process. Herein, indomethacin was used as a model drug and introduced into the feedstock (Kollidon® VA64 and Candurin® blend) as either unprocessed drug crystals (particle size > 50 µm) or processed hot-melt extruded granules (DosePlus) with reduced drug particle size (<5 µm). These feedstocks were processed at 50, 75, and 100 mm/s scan speed using SLS 3D printing process. Characterization and performance testing were conducted on these tablets which revealed the amorphous conversion of the drug. Both MANOVA and ANOVA analyses depicted that the laser speed and drug particle size significantly impact the drug’s apparent solubility and drug release. This significant difference in performance between formulations is attributed to the difference in the extent of dissolution of the drug in the polymeric matrix, leading to residual crystallinity, which is detrimental to ASD’s performance. These results demonstrate the influence of drug particle size on solid-state and performance of 3D printed solid dispersions, and, hence, provide a better understanding of the mechanism and limitations of SLS 3D printing of ASDs and its dosage forms.
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Germini, Giorgia, and Leena Peltonen. "3D Printing of Drug Nanocrystals for Film Formulations." Molecules 26, no. 13 (June 28, 2021): 3941. http://dx.doi.org/10.3390/molecules26133941.
Full textAbstract:
The aim of the study was to prepare indomethacin nanocrystal-loaded, 3D-printed, fast-dissolving oral polymeric film formulations. Nanocrystals were produced by the wet pearl milling technique, and 3D printing was performed by the semi-solid extrusion method. Hydroxypropyl methyl cellulose (HPMC) was the film-forming polymer, and glycerol the plasticizer. In-depth physicochemical characterization was made, including solid-state determination, particle size and size deviation analysis, film appearance evaluation, determination of weight variation, thickness, folding endurance, drug content uniformity, and disintegration time, and drug release testing. In drug nanocrystal studies, three different stabilizers were tested. Poloxamer F68 produced the smallest and most homogeneous particles, with particle size values of 230 nm and PI values below 0.20, and was selected as a stabilizer for the drug-loaded film studies. In printing studies, the polymer concentration was first optimized with drug-free formulations. The best mechanical film properties were achieved for the films with HPMC concentrations of 2.85% (w/w) and 3.5% (w/w), and these two HPMC levels were selected for further drug-loaded film studies. Besides, in the drug-loaded film printing studies, three different drug levels were tested. With the optimum concentration, films were flexible and homogeneous, disintegrated in 1 to 2.5 min, and released the drug in 2–3 min. Drug nanocrystals remained in the nano size range in the polymer films, particle sizes being in all film formulations from 300 to 500 nm. When the 3D-printed polymer films were compared to traditional film-casted polymer films, the physicochemical behavior and pharmaceutical performance of the films were very similar. As a conclusion, 3D printing of drug nanocrystals in oral polymeric film formulations is a very promising option for the production of immediate-release improved- solubility formulations.