DOCSLIB.ORG

A Comparative Study of Molecular Structure, Pka, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Comparative Study of Molecular Structure, Pka, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs International Journal of Molecular Sciences Article A Comparative Study of Molecular Structure, pKa, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs Milan Remko 1,*, Anna Remková 2 and Ria Broer 3 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, SK-832 32 Bratislava, Slovakia 2 Department of Internal Medicine, Faculty of Medicine, Slovak Medical University, Limbová 12, SK–833 03 Bratislava, Slovakia; [email protected] 3 Department of Theoretical Chemistry, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands; [email protected] * Correspondence: [email protected]; Tel.: +421-2-5011-7291 Academic Editor: Michael Henein Received: 18 February 2016; Accepted: 11 March 2016; Published: 19 March 2016 Abstract: Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor) and several thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of density functional theory. Computed dissociation constants show that the active metabolites of prodrugs (ticlopidine, clopidogrel and prasugrel) and drugs elinogrel and cangrelor are completely ionized at pH 7.4. Both ticagrelor and its active metabolite are present at pH = 7.4 in neutral undissociated form. The thienopyridine prodrugs ticlopidine, clopidogrel and prasugrel are lipophilic and insoluble in water. Their lipophilicity is very high (about 2.5–3.5 logP values). The polar surface area, with regard to the structurally-heterogeneous character of these antiplatelet drugs, is from very large interval of values of 3–255 Å2. Thienopyridine prodrugs, like ticlopidine, clopidogrel and prasugrel, with the lowest polar surface area (PSA) values, exhibit the largest absorption. A high value of polar surface area (PSA) of cangrelor (255 Å2) results in substantial worsening of the absorption in comparison with thienopyridine drugs. Keywords: antiplatelet agents; molecular structure; solvent effect; pKa; lipophilicity; solubility; absorption; polar surface area 1. Introduction Arterial thrombosis is a common cause of ischemic stroke, myocardial infarction and limb gangrene. This disease is a leading cause of morbidity and mortality in developed countries [1]. Atherothrombosis is essentially a platelet-driven process [2–4]. Pharmaceutical research has focused on the development of antiplatelet drugs targeting key pathways of platelet activation [2–6]. Three classes of antiplatelet agents are currently approved for clinical use: (i) cyclooxygenase-1 (COX-1) inhibitors (aspirin); (ii) adenosine diphosphate (ADP) P2Y12 receptor antagonists (clopidogrel); and (iii) glycoprotein IIb/IIIa inhibitors (abciximab) [2,3]. Besides the cornerstone of antiplatelet therapy, aspirin, also thienopyridines (ticlopidine, clopidogrel, prasugrel), especially in dual therapy with aspirin, have become standard antiplatelet therapies [7]. Owing to known clinical limitations of traditional drugs, like clopidogrel, a number of novel drugs are currently at various stages of clinical development. Three agents, prasugrel, cangrelor and ticagrelor, were already approved for antiplatelet therapy. Int. J. Mol. Sci. 2016, 17, 388; doi:10.3390/ijms17030388 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2016, 17, 388 2 of 18 Int. J. Mol. Sci. 2016, 17, 388 2 of 17 Ample experimental biological evidence is available for the relationship between the chemical and biologicalAmple experimental properties ofbiological new antiplatelets evidence is avai targetinglable for the relationship P2Y12 platelet between receptor the chemical and their biologicaland biological activity. properties Nevertheless, of new experimental antiplatelets studiestargeting engaged the P2Y1 in2 theplatelet systematic receptor comparisonand their of biological activity. Nevertheless, experimental studies engaged in the systematic comparison of the the physicochemical and pharmacokinetic parameters of these antiplatelet agents are not very well physicochemical and pharmacokinetic parameters of these antiplatelet agents are not very well characterized.characterized. The The absence absence of experimentalof experimental structural structural data data of of new new syntheticsynthetic antiplatelets targeting targeting the P2Y12the platelet P2Y12 platelet receptor receptor presents presents a challenge a challenge to the to applicationthe application of molecularof molecular modeling modeling methods methods with the aimwith to the enhance aim to our enhance understanding our understanding of the subtle of pharmacologicalthe subtle pharmacological effects of these effects antithrombotics. of these antithrombotics.Here, we use density functional methods [8–10] to investigate the structure of six P2Y12 platelet receptor inhibitorsHere, we use (approved density functional drugs ticlopidine, methods [8–10] clopidogrel, to investigate prasugrel, the structure cangrelor of six and P2Y12 ticagrelor) platelet and experimentalreceptor inhibitors drug elinogrel, (approved respectively drugs ticlopidine, (Figure clopidogrel,1). The polarizable prasugrel, cangrelor continuum and methodticagrelor) was and used to accountexperimental for the drug effect elinogrel, of solvent respectively on the (Figure equilibrium 1). The conformation polarizable continuum of these method drugs. was Our used interest to is also focusedaccount for on the the effect evaluation of solvent of on the the important equilibrium physicochemical conformation of these properties drugs. ofOur drugs interest studied is also (pKa, focused on the evaluation of the important physicochemical properties of drugs studied (pKa, lipophilicity, solubility, absorption and polar surface area). The results of the molecular modeling lipophilicity, solubility, absorption and polar surface area). The results of the molecular modeling investigationsinvestigations of these of these antiplatelets antiplatelets were were compared compared to to the the available available experimental experimental structural structural data dataand and discusseddiscussed in relation in relation to theto the present present theories theories ofof actionaction of of these these agents. agents. Cl 1 3 5 2 4 N S Cl Ticlopidine O 9 7 1 3 5 8 2 4 6 N OH SH Ticlopidine metabolite DBMET01202 CH3 7 O O Cl 6 1 3 5 2 4 N S Clopidogrel CH3 7 O O 11 Cl 6 O 1 3 5 9 10 2 4 8 N OH SH Clopidogrel metabolite H4 Figure 1. Cont. Int. J. Mol. Sci. 2016, 17, 388 3 of 18 Int. J. Mol. Sci. 2016, 17, 388 3 of 17 1 F 2 3 5 8 4 N 6 9 10 O 11 CH O 7 3 S 12 Prasugrel O 1 F 2 5 3 b 9 4 8 10 OH 6 N O 7 a SH O 11 Prasugrel metabolite R-138727 CH3 H HN N O 1 2 4 N 3 5 F O O O 6 12 O 7 9 S 11 S N 8 N 10 Cl Elinogrel Hb Ha 5 4 3NH 2 1 N F N N 6 OH F N7 N 8 H C S 9 3 OH O Ticagrelor OH 5 4 3 NH 2 N 1 F N N6 OH F N 7 N 8 H C S 9 3 OH Ticagrelor metabolite AR-C124910XX OH Figure 1. Cont. Int. J. Mol. Sci. 2016, 17, 388 4 of 18 Int. J. Mol. Sci. 2016, 17, 388 4 of 17 H3C S 4 3 NH 2 N 1 5 N 6 N 7 8 S N O 9 10 O OH HO O O P OH Cangrelor 11 12 OH O P HO CF3 OH 13 14 15 P16 Cl Cl O 17 FigureFigure 1. Structure 1. Structure and and atom atomlabeling labeling in th thee antiplatelet antiplatelet drugs drugs investigated. investigated. 2. Results2. Results and and Discussion Discussion 2.1. Molecular Structures 2.1. Molecular Structures The prediction of the equilibrium structure of drugs is one of the main goals of modern quantum Thechemistry prediction [11]. Quantum of theequilibrium chemical calculations structure are of now drugs an iseffective one of tool the in main drug goals design of and modern quantumdevelopment. chemistry They [11 are]. Quantum used for an chemical accurate calculationsdetermination are of molecular now an effective structures tool and in properties drug design for and development.use in a wide They variety are usedof computer-aided for an accurate drug determination design (CADD) of studies molecular [12,13]. structures and properties for use in a wideThe relative variety orientations of computer-aided of important drug functional design (CADD)groups of studies the antiplatelet [12,13]. agents studied here Theare defined relative by orientations dihedral angles of important (α, β, γ, functionalδ, ε, ζ, η, ν, groups θ, μ and of ξ the; Table antiplatelet 1). The overall agents studiedview of the here are definedoptimized by dihedral geometry angles of the (α ,drugsβ, γ, isδ, presented", ζ, η, ν, inθ, thµeand Supplementaryξ; Table1). TheMaterial. overall The view relevant of the values optimized of geometrythe torsion of the angles drugs are is presentedreported in inTable the 1. Supplementary In all cases studied, Material. except The for cangrelor relevant valuestetrasodium, of the the torsion angleswater are reportedhad only a in small Table effect1. In on all the cases equilibrium studied, ge exceptometry for of cangrelor the antiplatel tetrasodium,et agents investigated the water had (Table 1). Table 2 shows the solvation energies obtained from combining calculations performed in a only a small effect on the equilibrium geometry of the antiplatelet agents investigated (Table1). Table2 vacuum with calculations based on the solvation method used. B3LYP/6-311++G (d,p) calculations in showswater the yielded solvation conformers energies not obtained significantly from different combining
Load more

Recommended publications
  • Additions and Deletions to the Drug Product List
    Prescription and Over-the-Counter Drug Product List 40TH EDITION Cumulative Supplement Number 09 : September 2020 ADDITIONS/DELETIONS FOR PRESCRIPTION DRUG PRODUCT LIST ACETAMINOPHEN; BUTALBITAL; CAFFEINE TABLET;ORAL BUTALBITAL, ACETAMINOPHEN AND CAFFEINE >A> AA STRIDES PHARMA 325MG;50MG;40MG A 203647 001 Sep 21, 2020 Sep NEWA ACETAMINOPHEN; CODEINE PHOSPHATE SOLUTION;ORAL ACETAMINOPHEN AND CODEINE PHOSPHATE >D> AA WOCKHARDT BIO AG 120MG/5ML;12MG/5ML A 087006 001 Jul 22, 1981 Sep DISC >A> @ 120MG/5ML;12MG/5ML A 087006 001 Jul 22, 1981 Sep DISC TABLET;ORAL ACETAMINOPHEN AND CODEINE PHOSPHATE >A> AA NOSTRUM LABS INC 300MG;15MG A 088627 001 Mar 06, 1985 Sep CAHN >A> AA 300MG;30MG A 088628 001 Mar 06, 1985 Sep CAHN >A> AA ! 300MG;60MG A 088629 001 Mar 06, 1985 Sep CAHN >D> AA TEVA 300MG;15MG A 088627 001 Mar 06, 1985 Sep CAHN >D> AA 300MG;30MG A 088628 001 Mar 06, 1985 Sep CAHN >D> AA ! 300MG;60MG A 088629 001 Mar 06, 1985 Sep CAHN ACETAMINOPHEN; HYDROCODONE BITARTRATE TABLET;ORAL HYDROCODONE BITARTRATE AND ACETAMINOPHEN >A> @ CEROVENE INC 325MG;5MG A 211690 001 Feb 07, 2020 Sep CAHN >A> @ 325MG;7.5MG A 211690 002 Feb 07, 2020 Sep CAHN >A> @ 325MG;10MG A 211690 003 Feb 07, 2020 Sep CAHN >D> AA VINTAGE PHARMS 300MG;5MG A 090415 001 Jan 24, 2011 Sep DISC >A> @ 300MG;5MG A 090415 001 Jan 24, 2011 Sep DISC >D> AA 300MG;7.5MG A 090415 002 Jan 24, 2011 Sep DISC >A> @ 300MG;7.5MG A 090415 002 Jan 24, 2011 Sep DISC >D> AA 300MG;10MG A 090415 003 Jan 24, 2011 Sep DISC >A> @ 300MG;10MG A 090415 003 Jan 24, 2011 Sep DISC >D> @ XIROMED 325MG;5MG A 211690
    [Show full text]
  • Ticlopidine in Its Prodrug Form Is a Selective Inhibitor of Human Ntpdase1
    Hindawi Publishing Corporation Mediators of Inflammation Volume 2014, Article ID 547480, 8 pages http://dx.doi.org/10.1155/2014/547480 Research Article Ticlopidine in Its Prodrug Form Is a Selective Inhibitor of Human NTPDase1 Joanna Lecka,1,2 Michel Fausther,1,2 Beat Künzli,3 and Jean Sévigny1,2 1 Departement´ de Microbiologie-Infectiologie et d’Immunologie, FacultedeM´ edecine,´ UniversiteLaval,Qu´ ebec,´ QC, Canada G1V 0A6 2 Centre de Recherche du CHU de Quebec,´ 2705 Boulevard Laurier, Local T1-49, Quebec,´ QC, Canada G1V 4G2 3 Department of Surgery, Klinikum Rechts der Isar, Technische Universitat¨ Munchen,¨ 81675 Munich, Germany Correspondence should be addressed to Jean Sevigny;´ [email protected] Received 12 May 2014; Accepted 21 July 2014; Published 11 August 2014 Academic Editor: Mireia Mart´ın-Satue´ Copyright © 2014 Joanna Lecka et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), like other ectonucleotidases, controls extracellular nucleotide levels and consequently their (patho)physiological responses such as in thrombosis, inflammation, and cancer. Selective NTPDase1 inhibitors would therefore be very useful. We previously observed that ticlopidine in its prodrug form, which does not affect P2 receptor activity, inhibited the recombinant form of human NTPDase1 ( =14M). Here we tested whether ticlopidine can be used as a selective inhibitor of NTPDase1. We confirmed that ticlopidine inhibits NTPDase1 in different forms and in different assays. The ADPase activity of intact HUVEC as well as of COS-7 cells transfected with human NTPDase1 was strongly inhibited by 100 M ticlopidine, 99 and 86%, respectively.
    [Show full text]
  • Cangrelor Ameliorates CLP-Induced Pulmonary Injury in Sepsis By
    Luo et al. Eur J Med Res (2021) 26:70 https://doi.org/10.1186/s40001-021-00536-4 European Journal of Medical Research RESEARCH Open Access Cangrelor ameliorates CLP-induced pulmonary injury in sepsis by inhibiting GPR17 Qiancheng Luo1†, Rui Liu2†, Kaili Qu3, Guorong Liu1, Min Hang1, Guo Chen1, Lei Xu1, Qinqin Jin1 , Dongfeng Guo1* and Qi Kang1* Abstract Background: Sepsis is a common complication of severe wound injury and infection, with a very high mortality rate. The P2Y12 receptor inhibitor, cangrelor, is an antagonist anti-platelet drug. Methods: In our study, we investigated the protective mechanisms of cangrelor in CLP-induced pulmonary injury in sepsis, using C57BL/6 mouse models. Results: TdT-mediated dUTP Nick-End Labeling (TUNEL) and Masson staining showed that apoptosis and fbrosis in lungs were alleviated by cangrelor treatment. Cangrelor signifcantly promoted surface expression of CD40L on platelets and inhibited CLP-induced neutrophils in Bronchoalveolar lavage fuid (BALF) (p < 0.001). We also found that cangrelor decreased the infammatory response in the CLP mouse model and inhibited the expression of infamma- tory cytokines, IL-1β (p < 0.01), IL-6 (p < 0.05), and TNF-α (p < 0.001). Western blotting and RT-PCR showed that cangre- lor inhibited the increased levels of G-protein-coupled receptor 17 (GPR17) induced by CLP (p < 0.001). Conclusion: Our study indicated that cangrelor repressed the levels of GPR17, followed by a decrease in the infam- matory response and a rise of neutrophils in BALF, potentially reversing CLP-mediated pulmonary injury during sepsis. Keywords: Sepsis, Infammation, Cangrelor, Platelet, GPR17 Background Te lung is one of the initial target organ of the systemic Sepsis is a serious disease and will lead a high mortal- infammatory response caused by sepsis, leading to alve- ity rate of approximately 22% in all over the world [1].
    [Show full text]
  • Kengrexal, INN-Cangrelor Tetrasodium
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Kengrexal 50 mg powder for concentrate for solution for injection/infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains cangrelor tetrasodium corresponding to 50 mg cangrelor. After reconstitution 1 mL of concentrate contains 10 mg cangrelor. After dilution 1 mL of solution contains 200 micrograms cangrelor. Excipient with known effect Each vial contains 52.2 mg sorbitol. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for concentrate for solution for injection/infusion. White to off-white lyophilised powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Kengrexal, co-administered with acetylsalicylic acid (ASA), is indicated for the reduction of thrombotic cardiovascular events in adult patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) who have not received an oral P2Y12 inhibitor prior to the PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable. 4.2 Posology and method of administration Kengrexal should be administered by a physician experienced in either acute coronary care or in coronary intervention procedures and is intended for specialised use in an acute and hospital setting. Posology The recommended dose of Kengrexal for patients undergoing PCI is a 30 micrograms/kg intravenous bolus followed immediately by 4 micrograms/kg/min intravenous infusion. The bolus and infusion should be initiated prior to the procedure and continued for at least two hours or for the duration of the procedure, whichever is longer. At the discretion of the physician, the infusion may be continued for a total duration of four hours, see section 5.1.
    [Show full text]
  • P2 Receptors in Cardiovascular Regulation and Disease
    Purinergic Signalling (2008) 4:1–20 DOI 10.1007/s11302-007-9078-7 REVIEW P2 receptors in cardiovascular regulation and disease David Erlinge & Geoffrey Burnstock Received: 3 May 2007 /Accepted: 22 August 2007 /Published online: 21 September 2007 # Springer Science + Business Media B.V. 2007 Abstract The role of ATP as an extracellular signalling Introduction molecule is now well established and evidence is accumulating that ATP and other nucleotides (ADP, UTP and UDP) play Ever since the first proposition of cell surface receptors for important roles in cardiovascular physiology and pathophysi- nucleotides [1, 2], it has become increasingly clear that, in ology, acting via P2X (ion channel) and P2Y (G protein- addition to functioning as an intracellular energy source, the coupled) receptors. In this article we consider the dual role of purines and pyrimidines ATP, adenosine diphosphate ATP in regulation of vascular tone, released as a cotransmitter (ADP), uridine triphosphate (UTP) and uridine diphosphate from sympathetic nerves or released in the vascular lumen in (UDP) can serve as important extracellular signalling response to changes in blood flow and hypoxia. Further, molecules [3, 4] acting on 13 P2X homo- and heteromul- purinergic long-term trophic and inflammatory signalling is timer ionotropic and 8 P2Y metabotropic receptor subtypes described in cell proliferation, differentiation, migration and [5, 6] (Table 1). To terminate signalling, ectonucleotidases death in angiogenesis, vascular remodelling, restenosis and are present in the circulation and on cell surfaces, rapidly atherosclerosis. The effects on haemostasis and cardiac degrading extracellular ATP into ADP, AMP and adenosine regulation is reviewed. The involvement of ATP in vascular [7, 8].
    [Show full text]
  • Prasugrel Mylan 10 Mg Film-Coated Tablets Prasugrel
    Package leaflet: Information for the user Prasugrel Mylan 5 mg film-coated tablets Prasugrel Mylan 10 mg film-coated tablets prasugrel Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. – Keep this leaflet. You may need to read it again. – If you have any further questions, ask your doctor or pharmacist. – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. – If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Prasugrel Mylan is and what it is used for 2. What you need to know before you take Prasugrel Mylan 3. How to take Prasugrel Mylan 4. Possible side effects 5. How to store Prasugrel Mylan 6. Contents of the pack and other information 1. What Prasugrel Mylan is and what it is used for Prasugrel Mylan, which contains the active substance prasugrel, belongs to a group of medicines called antiplatelet agents. Platelets are very small cell particles that circulate in the blood. When a blood vessel is damaged, for example if it is cut, platelets clump together to help form a blood clot (thrombus). Therefore, platelets are essential to help stop bleeding. If clots form within a hardened blood vessel such as an artery they can be very dangerous as they can cut off the blood supply, causing a heart attack (myocardial infarction), stroke or death.
    [Show full text]
  • Health Reports for Mutual Recognition of Medical Prescriptions: State of Play
    The information and views set out in this report are those of the author(s) and do not necessarily reflect the official opinion of the European Union. Neither the European Union institutions and bodies nor any person acting on their behalf may be held responsible for the use which may be made of the information contained therein. Executive Agency for Health and Consumers Health Reports for Mutual Recognition of Medical Prescriptions: State of Play 24 January 2012 Final Report Health Reports for Mutual Recognition of Medical Prescriptions: State of Play Acknowledgements Matrix Insight Ltd would like to thank everyone who has contributed to this research. We are especially grateful to the following institutions for their support throughout the study: the Pharmaceutical Group of the European Union (PGEU) including their national member associations in Denmark, France, Germany, Greece, the Netherlands, Poland and the United Kingdom; the European Medical Association (EMANET); the Observatoire Social Européen (OSE); and The Netherlands Institute for Health Service Research (NIVEL). For questions about the report, please contact Dr Gabriele Birnberg ([email protected] ). Matrix Insight | 24 January 2012 2 Health Reports for Mutual Recognition of Medical Prescriptions: State of Play Executive Summary This study has been carried out in the context of Directive 2011/24/EU of the European Parliament and of the Council of 9 March 2011 on the application of patients’ rights in cross- border healthcare (CBHC). The CBHC Directive stipulates that the European Commission shall adopt measures to facilitate the recognition of prescriptions issued in another Member State (Article 11). At the time of submission of this report, the European Commission was preparing an impact assessment with regards to these measures, designed to help implement Article 11.
    [Show full text]
  • Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations
    molecules Review Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations Deepak Gupta 1, Deepak Bhatia 2 ID , Vivek Dave 3 ID , Vijaykumar Sutariya 4 and Sheeba Varghese Gupta 4,* 1 Department of Pharmaceutical Sciences, School of Pharmacy, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA; [email protected] 2 ICPH Fairfax Bernard J. Dunn School of Pharmacy, Shenandoah University, Fairfax, VA 22031, USA; [email protected] 3 Wegmans School of Pharmacy, St. John Fisher College, Rochester, NY 14618, USA; [email protected] 4 Department of Pharmaceutical Sciences, USF College of Pharmacy, Tampa, FL 33612, USA; [email protected] * Correspondence: [email protected]; Tel.: +01-813-974-2635 Academic Editor: Peter Wipf Received: 7 June 2018; Accepted: 13 July 2018; Published: 14 July 2018 Abstract: The physicochemical and biological properties of active pharmaceutical ingredients (APIs) are greatly affected by their salt forms. The choice of a particular salt formulation is based on numerous factors such as API chemistry, intended dosage form, pharmacokinetics, and pharmacodynamics. The appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API. However, the incorrect salt form can have the opposite effect, and can be quite detrimental for overall drug development. This review summarizes several criteria for choosing the appropriate salt forms, along with the effects of salt forms on the pharmaceutical properties of APIs. In addition to a comprehensive review of the selection criteria, this review also gives a brief historic perspective of the salt selection processes. Keywords: chemistry; salt; water solubility; routes of administration; physicochemical; stability; degradation 1.
    [Show full text]
  • Preventive Medication Program
    PREVENTIVE MEDICATION PROGRAM Generics and Preferred Brands Drug List Starting July 1, 2021 Preventive medications are used to prevent certain conditions from developing, or to prevent a condition from coming back. These conditions include, but are not limited to, asthma, depression, diabetes, heart attack, high blood pressure, high cholesterol, osteoporosis, prenatal nutrient deficiency and stroke. About this drug list. Your cost-share for preventive generic and This is a list of the most commonly prescribed generic preferred brand medications. and preferred brand medications that are part of Not all plans offer the same cost-share for their Cigna’s preventive medication program as of July preventive medication program. For example, some 1, 2021.1,2 This drug list is updated often so it isn’t a plans may require you to pay a copay, coinsurance complete list of medications. Also, your specific plan’s and/or deductible for preventive generic and preferred preventive medication program may not include all brand medications; other plans may not. of these medications and/or conditions. Log in to the Log into the myCigna App or myCigna.com and use myCigna® App or myCigna.com, or check your plan the Price a Medication tool to see how much your materials, to see all of the medications included in your medication may cost you at the different pharmacies in plan’s preventive medication program and how much your plan’s network.3 they cost. Here’s some helpful information about this drug list: › Medications are listed alphabetically by condition. › Brand-name medications are capitalized and generic medications are lowercase.
    [Show full text]
  • Wo 2010/075090 A2
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 1 July 2010 (01.07.2010) WO 2010/075090 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 409/14 (2006.01) A61K 31/7028 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 409/12 (2006.01) A61P 11/06 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2009/068073 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 15 December 2009 (15.12.2009) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (26) Publication Language: English TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/122,478 15 December 2008 (15.12.2008) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): AUS- ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, PEX PHARMACEUTICALS, INC.
    [Show full text]
  • Health and Social Outcomes Associated with High-Risk Alcohol Use
    Manitoba Centre for Health Policy Health and Social Outcomes Associated with High-Risk Alcohol Use Summer 2018 Nathan C Nickel, MPH, PhD Jeff Valdivia, MNRM, CAPM Deepa Singal, PhD James Bolton, MD Christine Leong, PharmD Susan Burchill, BMus Leonard MacWilliam, MSc, MNRM Geoffrey Konrad, MD Randy Walld, BSc, BComm (Hons) Okechukwu Ekuma, MSc Greg Finlayson, PhD Leanne Rajotte, BComm (Hons) Heather Prior, MSc Josh Nepon, MD Michael Paille, BHSc This report is produced and published by the Manitoba Centre for Health Policy (MCHP). It is also available in PDF format on our website at: http://mchp-appserv.cpe.umanitoba.ca/deliverablesList.html Information concerning this report or any other report produced by MCHP can be obtained by contacting: Manitoba Centre for Health Policy Rady Faculty of Health Sciences Max Rady College of Medicine, University of Manitoba 4th Floor, Room 408 727 McDermot Avenue Winnipeg, Manitoba, Canada R3E 3P5 Email: [email protected] Phone: (204) 789-3819 Fax: (204) 789-3910 How to cite this report: Nathan C Nickel, James Bolton, Leonard MacWilliam, Okechukwu Ekuma, Heather Prior, Jeff Valdivia, Christine Leong, Geoffrey Konrad, Greg Finlayson, Josh Nepon, Deepa Singal, Susan Burchill, Randy Walld, Leanne Rajotte, Michael Paille. Health and Social Outcomes Associated with High-Risk Alcohol Use. Winnipeg, MB. Manitoba Centre for Health Policy, Summer 2018. Legal Deposit: Manitoba Legislative Library National Library of Canada ISBN 978-1-896489-90-2 ©Manitoba Health This report may be reproduced, in whole or in part, provided the source is cited. 1st printing (Summer 2018) This report was prepared at the request of Manitoba Health, Seniors and Active Living (MHSAL), a department within the Government of Manitoba, as part of the contract between the University of Manitoba and MHSAL.
    [Show full text]
  • The Delivery Strategy of Paclitaxel Nanostructured Lipid Carrier Coated with Platelet Membrane
    cancers Article The Delivery Strategy of Paclitaxel Nanostructured Lipid Carrier Coated with Platelet Membrane 1, 1, 1 2 3 Ki-Hyun Bang y, Young-Guk Na y , Hyun Wook Huh , Sung-Joo Hwang , Min-Soo Kim , Minki Kim 1, Hong-Ki Lee 1,* and Cheong-Weon Cho 1,* 1 College of Pharmacy, Chungnam National University, Daejeon 34134, Korea; [email protected] (K.-H.B.); [email protected] (Y.-G.N.); [email protected] (H.W.H.); [email protected] (M.K.) 2 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 162-1 Songdo-dong, Yeonsu-gu, Incheon 406-840, Korea; [email protected] 3 College of Pharmacy, Pusan National University, 63 Busandaehak-ro, Geumjeong-gu, Busan 609-735, Korea; [email protected] * Correspondence: [email protected] (H.-K.L.); [email protected] (C.-W.C.); Tel.: +82-42-821-5934 (H.-K.L. & C.-W.C.); Fax: +82-42-823-6566 (H.-K.L. & C.-W.C.) These authors contributed equally. y Received: 2 May 2019; Accepted: 10 June 2019; Published: 11 June 2019 Abstract: Strategies for the development of anticancer drug delivery systems have undergone a dramatic transformation in the last few decades. Lipid-based drug delivery systems, such as a nanostructured lipid carrier (NLC), are one of the systems emerging to improve the outcomes of tumor treatments. However, NLC can act as an intruder and cause an immune response. To overcome this limitation, biomimicry technology was introduced to decorate the surface of the nanoparticles with various cell membrane proteins. Here, we designed paclitaxel (PT)-loaded nanostructured lipid carrier (PT-NLC) with platelet (PLT) membrane protein because PLT is involved with angiogenesis and interaction of circulating tumor cells.
    [Show full text]