ABSTRACT
This Part I paper describes the qualification of a new high performance hypromellose (hydroxypropyl methylcellulose, HPMC) capsule shell which contains no gelling agent and is dissolution friendly. The development history and the test results for a series of quality attributes including scanning electron microscopy, hygroscopicity, machineability, weight variation, powder leakage, mechanical strength, stability, cross-linking, animal and human pharmacokinetic results are reported. Comparisons to gelatin and HPMC capsule containing carrageenan showed the new HPMC capsule is superior in terms of mechanical strength, hygroscopicity and compatibility with a wide range of drugs. Specifically, the new HPMC capsule demonstrated improved weight variation, machineability and powder leakage than the HPMC capsule containing carrageenan. And the new capsule demonstrated a broader applicability than gelatin capsule for new drug development due to its inertness and compatibility for a wide range of excipients including those used for liquid fill formulations. In the second phase of qualification, disintegration and dissolution properties of the new HPMC were evaluated and reported in a Part II paper for 10 new clinical compounds with a variety of formulations optimized based on the biopharmaceutical classification system of solubility and permeability. Based on the superior performance, the new HPMC capsule is satisfactorily qualified and has since been used successfully for nearly 20 investigational new drug (IND) compounds.
Subject(s)
Drugs, Investigational/chemistry , Gelatin/chemistry , Methylcellulose/analogs & derivatives , Administration, Oral , Animals , Capsules , Carrageenan/chemistry , Chemistry, Pharmaceutical , Cross-Linking Reagents/chemistry , Cross-Over Studies , Dogs , Drug Compounding , Drugs, Investigational/administration & dosage , Drugs, Investigational/pharmacokinetics , Excipients/chemistry , Formaldehyde/chemistry , Hardness , Humans , Hypromellose Derivatives , Male , Methylcellulose/chemistry , Powders , Randomized Controlled Trials as Topic , Solubility , Stress, Mechanical , Surface Properties , Technology, Pharmaceutical/methods , Temperature , WettabilityABSTRACT
Cytosolic phospholipase A2 alpha (cPLA2 alpha) is the rate-limiting enzyme for release of arachidonic acid, which is converted primarily to prostaglandins via the cyclooxygenase (COX) 1/2 pathways, and leukotrienes via the 5-lipoxygenase (LO) pathway. We utilized inhibitors of cPLA2 alpha, COX-1/2 and 5-LO to determine the potential roles of these enzymes in development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Blocking cPLA2 alpha prevented EAE development and greatly reduced antigen-induced production of Th1-type cytokines and IL-17. Blocking COX-1/2 delayed onset and reduced severity of EAE, and reduced production of Th1-type cytokines, but not IL-17. Blocking 5-LO delayed onset and reduced cumulative severity of EAE, but did not reduce production of Th1-type cytokines or IL-17. Finally, blockade of cPLA2 alpha from the onset of clinical EAE reduced duration of EAE relapses. Therefore, cPLA2 alpha represents a potential therapeutic target for treatment of MS.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/prevention & control , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Group IV Phospholipases A2/antagonists & inhibitors , Th1 Cells/physiology , Analysis of Variance , Animals , Benzoates/pharmacology , Benzoates/therapeutic use , Cell Proliferation/drug effects , Cells, Cultured , Cyclooxygenase Inhibitors/pharmacology , Cyclooxygenase Inhibitors/therapeutic use , Cytokines/metabolism , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/enzymology , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Female , Glycoproteins , Hydroxyurea/analogs & derivatives , Hydroxyurea/pharmacology , Hydroxyurea/therapeutic use , Lipoxygenase Inhibitors/pharmacology , Lipoxygenase Inhibitors/therapeutic use , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Myelin-Oligodendrocyte Glycoprotein , Naproxen/pharmacology , Naproxen/therapeutic use , Peptide Fragments , Severity of Illness Index , Seveso Accidental Release , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Th1 Cells/drug effects , Time FactorsABSTRACT
A series of highly potent thiourea inhibitors of cytomegalovirus (CMV) with improved stability properties was prepared and evaluated. Compound 29 inhibited the virus in cultured HFF cells with IC50 of 0.2 nM.
