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1、Pharmaceutical Polymer for Solid dispersionMing Lu Mar. 24, 2017药剂与制药程实验室 Tel: 020-39943119 E-mail: Solid Dispersion (SD)DefinitionFunctionClassificationPreparation methodsThe role of pharmaceutical polymers in solid dispersionDefinition of SDASD-Amorphous Solid DispersionBlank sugar score (45-60 me
2、sh) 10-25% Itraconazole/HPMC ASD 26-40% 39-60% PEG 2000 (a seal-coating polymer to prevent sticking of the pellets, 4-7%) 1.Vandecruys R, De Conde V, Gilis P, et al., Pellets having a core coated with an antifungal and a polymer, 1998, WO Patent 9,842,318. 2.http:/patentscope.wipo.int/search/en/deta
3、il.jsf;jsessionid=98BD275D3D08E2C7DF40330DF48D0C87.wapp1?docId=WO1998042318 50: 47-60. Approachs to improve solubilityChemical modification: Salt Soluble pro-drugsPhysical method: Micronisation Nano-crystal Cyclodexin complexation Polymorphism Solid dispersionFunctionsFunction I: SolubilisationFunct
4、ion II: Sustained-releaseFunction III: Taste mask (e.g. Zithromax)?-PLGAAstraZeneca Marketed in 1990, USA. 诺雷得（前列腺癌）Three generations of SDCarrierPhysical state of APIFirst generationSmall moleculesCrystallineSecond generationCrystalline polymerCrystallineThird generationAmorphous polymerAmorphous/C
5、rystalline磺胺噻唑-尿素 低共熔物1961年 第篇关于SD的报道Eutectic mixture? ?Phase diagram for an eutectic system ()CCtsVDS dtdC=Nernst-Noyes-Whitney Equation?1. Urea (Tm 132 oC) Prepareation method of SD: Coevaporate melt method Cases: Sulfathiazole-urea ? Ofloxacin-urea ? Phenytoin-urea ? Ursodeoxycholic acid-urea ? F
6、irst generation carriers2. Sugar and their derivatives Prepareation method of SD: melt method 1) Mannitol (Tm 165-168 oC, Td 250 oC) 2) Sorbitol (Tm 93-110 oC) Cases Nitrofurantoin-sorbitol ? Prednisoline-sorbitol ? Ofloxacin-sorbitol ? Ursodeoxycholic acid-sorbitol ? Thommes M, Ely DR, Carvajal MT,
7、 et al. Improvement of the dissolution rate of poorly soluble drugs by solid crystal suspensions. Mol Pharm 2011; 8: 727-35. ?Mannitol Drug: griseofulvin, phenytoin and spironolactone. Crystalline drug and crystalline carrier. 2011 Melting point of materials Melting point (oC)? ?Mannitol? ? 166 Gris
8、eofulvin? ? 218-224 Phenytoin? ? ? ? 295-298 Spironolactone? ? ? 205-207 Extrusion temperatures were set between melting points of Mannitol and durgs. Physical state Griseofulvin Thermal behavior Tm, mannitol Tm, griseofulvin No eutectic system forming Griseofulvin Dissolution behavior Griseofulvin
9、Physical stability Griseofulvin Spironolactone Phenytoin Dissolution enhancement: 1. Increase of wettability. 2. Decrease of size.? ? ? ? ? ? 17: 397-404. Predicted *Amorphous pharmaceuticals are markedly more soluble than their crystalline counterparts. *Their experimental solubility advantage is t
10、ypically less than that predicted form simple thermodynamic considerations. * Difficulties in measuring the true equilibrium solubility of amorphous materials. Crystal form x/crystal form y= 1.1-1.4 Crystal form/amorphous = 1.1-24 Measured Crystal form/amorphous = 12-1652 Predicted YC Li, HS Pang, e
11、t al. Journal of Pharmacy and Pharmacology. 2014, 20(3): 148-166. ? ?Improve physical stability. Inhibit recrystallisation from the supersaturated solution.烯类聚合物：PVP, PVPVA纤维素类聚合物：HPMC, HPMC AS, HPC1. ? ? ? ?Case 2 Cesamet ? Indication: relieve nausea or vomiting caused by chemotherapy (a type of ca
12、ncer treatment).? ? ? Manufacturer: Valeant Pharmaceuticals API: Nabilone Matrix: PVP Dosage form: Capsule Dose?1mg ?Povidone ?PVP? ?PVP K12 PVP K30 PVP K90 PVP K12 PVP K30 PVP K90 Case 3 Kaletra ? Indication: HIV? ? ? Manufacturer: Abbott Liberary API: Lopinavir/Ritonavir Matrix: PVP VA64 Dosage fo
13、rm: Tablet Formulations: Pale yellow tablets: 100 mg lopinavir 25 mg ritonavir copovidone sorbitan monolaurate solloidal silicon dioxide sodium stearyl fumarate Yellow tablets: 200 mg lopinavir 50 mg ritonavir The same inactive ingredients with yellow tablets. ?Copovidone (PVP VA64) Soluplus DiNunzi
14、o, J.C., et al., Melt Extrusion. Formulating Poorly Water ? ?Soluble Drugs, 2012: p. 311-362. ?2. Cellulose?Name R Water solubility Application ? HPMC H,-CH3,-CH2(CH(CH3)-O-)mH Fast/sustained release HPC H,-CH2(CH(CH3)-O-)mH? 38 oC Fast/sustained release EC H,C2H5 Sustained release HPMC P ?Tg 133-137 oC Tg 152 oC?Enteric release HPMC AS ?Tg 120-135 oC?Enteric release? Ind
