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1.
Sci Rep ; 8(1): 12172, 2018 08 15.
Article in English | MEDLINE | ID: mdl-30111777

ABSTRACT

A moldable and biodegradable dental material was designed for customized placement and sustained delivery of bupivacaine (BP) within an extraction cavity. Microparticles comprising poly(lactic-co-glycolic acid) (PLGA) containing BP were generated via solvent-evaporation and combined with absorbable hemostat Gelfoam®. Kinetics of drug release were evaluated by in vitro dialysis assays, showing higher release within the first 24 hours, with subsequent tapering of release kinetics. Formulations of Gelfoam® and BP-PLGA microparticles (GelBP), with three targeted dosing profiles (0.25, 0.5, and 1 mg/kg/day), were evaluated alongside acute subcutaneous BP injections (2 mg/kg) to determine analgesic efficacy in a rat model of tooth extraction pain. Molar extraction resulted in mechanical and thermal cold hyperalgesia in male and female rats. GelBP outperformed acute BP in blocking post-surgical dental pain, with the 0.25 mg/kg GelBP dose preventing hypersensitivity to mechanical (p < 0.01) and thermal cold stimuli (p = 0.05). Molar extraction also resulted in decreased food consumption and weight. Males receiving acute BP and 0.25 mg/kg GelBP maintained normal food consumption (p < 0.002) and weight (p < 0.0001) throughout 7 days. Females, receiving 0.25 mg/kg GelBP maintained weight on days 5-7 (p < 0.04). Customized, sustained release formulation of anesthetic within a tooth extraction cavity holds potential to eliminate post-operative dental pain over several days.


Subject(s)
Anesthetics, Local/administration & dosage , Bupivacaine/pharmacology , Pain, Postoperative/drug therapy , Analgesics , Animals , Delayed-Action Preparations/pharmacology , Drug Compounding , Drug Delivery Systems/methods , Female , Hyperalgesia/prevention & control , Male , Microspheres , Polyglycolic Acid/therapeutic use , Polylactic Acid-Polyglycolic Acid Copolymer , Rats , Tooth Extraction
2.
Pharm Res ; 33(7): 1649-56, 2016 Jul.
Article in English | MEDLINE | ID: mdl-26975357

ABSTRACT

PURPOSE: The effectiveness of Tenofovir based HIV pre-exposure prophylaxis (PrEP) is proven, but hinges on correct and consistent use. User compliance and therapeutic effectiveness can be improved by long acting drug delivery systems. Here we describe a thin-film polymer device (TFPD) as a biodegradable subcutaneous implant for PrEP. METHODS: A thin-film polycaprolactone (PCL) membrane controls drug release from a reservoir. To achieve membrane controlled release, TAF requires a formulation excipient such as PEG300 to increase the dissolution rate and reservoir solubility. Short-term In vitro release studies are used to develop an empirical design model, which is applied to the production of in vitro prototype devices demonstrating up to 90-days of linear release and TAF chemical stability. RESULTS: The size and shape of the TFPD are tunable, achieving release rates ranging from 0.5 to 4.4 mg/day in devices no larger than a contraceptive implant. Based on published data for oral TAF, subcutaneous constant-rate release for HIV PrEP is estimated at <2.8 mg/day. Prototype devices demonstrated linear release at 1.2 mg/day for up to 90 days and at 2.2 mg/day for up to 60 days. CONCLUSIONS: We present a biodegradable TFPD for subcutaneous delivery of TAF for HIV PrEP. The size, shape and release rate of the device are tunable over a >8-fold range.


Subject(s)
Adenine/analogs & derivatives , Biodegradable Plastics/chemistry , Fumarates/chemistry , HIV-1/drug effects , Polymers/chemistry , Adenine/chemistry , Adenine/pharmacology , Alanine , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Chemistry, Pharmaceutical/methods , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacology , Drug Delivery Systems/methods , Drug Liberation/physiology , Particle Size , Polyesters/chemistry , Pre-Exposure Prophylaxis/methods , Solubility , Tenofovir/analogs & derivatives
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