title: An Extrusion Spheronization Approach to Enable a High Drug Load Formulation of a Poorly Soluble Drug with a Low Melting Surfactant.
abstract: Vitamin E tocopherol polyethylene glycol succinate (TPGS) is a non-ionic surface active agent, known to enhance the bioavailability of lipophilic compounds via wettability, solubility, and in some cases permeability enhancement. MK-0536 is an anti-retroviral drug with poor wettability and solubility and a high dose. Based on pharmacokinetic studies in dogs and humans, use of vitamin E TPGS in oral solid formulations of MK-0536 provides desired PK characteristics. The use of vitamin E TPGS, however, in solid dosage forms is limited because of the processing challenges resulting from its waxy nature and low melting temperature (∼37°C). The current study, for the first time, demonstrates the use of an alternative low pressure extrusion and spheronization approach to enable high loadings of the poorly soluble, poorly compactable drug and relatively high levels of vitamin E TPGS. This approach not only aided in mitigating processing challenges arising from most high energy process steps such as milling, compression, and coating, but also enabled a higher drug load formulation that provided superior bioperformance relative to a conventional high shear wet granulated formulation. An encapsulated dosage form consisting of pellets prepared by extrusion spheronization with 75% (w/w) MK-0536 and 10% (w/w) vitamin E TPGS was developed.
authors.affiliation: Pharmaceutical Sciences, Merck & Company, West Point, Pennsylvania 19486. Electronic address: aditya_tatavarti@merck.com.
authors.forename: Aditya
authors.initials: A
authors.lastname: Tatavarti
authors.affiliation: Pharmaceutical Sciences, Merck & Company, West Point, Pennsylvania 19486.
authors.forename: Filippos
authors.initials: F
authors.lastname: Kesisoglou
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry*; D005615:Freezing; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D044966:Anti-Retroviral Agents; D004337:Drug Carriers; D005079:Excipients; D013501:Surface-Active Agents; D014810:Vitamin E; D011092:Polyethylene Glycols; C014225:tocophersolan
keywords: absorption; extrusion; formulation; low melting; poorly soluble; spheronization; surfactants; vitamin E TPGS