title: Amorphous Formulation and in Vitro Performance Testing of Instantly Disintegrating Buccal Tablets for the Emergency Delivery of Naloxone.
abstract: The aim of this study was to develop a freeze-dried buccal tablet for the rapid delivery of naloxone in opioid overdose. The tablet composition was optimized to produce an amorphous matrix, which was confirmed by the absence of peaks associated with crystallinity observed by differential scanning calorimetry and powder X-ray diffraction. Tablets with high gelatin content lacked adequate porosity. Mannitol was added to the formulation to bridge and intercalate gelatin's tight polymer aggregates, however sodium bicarbonate was also required to prevent crystallization within the tablets. A linear reduction in mannitol's recrystallization enthalpy was observed with increasing sodium bicarbonate concentration (ΔrecryH = -20.3[NaHCO3] + 220.9; r(2) = 0.9, n = 18). The minimum sodium bicarbonate concentration for full inhibition of mannitol crystallization was 10.9% w/w. Freeze-dried tablets with lower amounts of sodium bicarbonate possessed a crystalline fraction that PXRD identified as mannitol hemihydrate from the unique peak at 9.7° 2θ. Mannitol's greater affinity for both ions and residual water rather than its affinity for self-association was the mechanism for the inhibition of crystallization observed here. The optimized tablet (composition mannitol 24% w/w (4.26 mg), gelatin 65% w/w (11.7 mg), sodium bicarbonate 11% w/w (1.98 mg), and naloxone 800 μg) formed predominantly amorphous tablets that disintegrated in less than 10 s. Optimized tablets were chemically and physically stable over 9 months storage at 25 °C. As speed of drug liberation is the critical performance attribute for a solid dosage form designed to deliver drug in an emergency, a novel imaging based in vitro disintegration assay for buccal tablets was developed. The assay was optimized with regard to conditions in the buccal cavity: i.e., temperature 33-37 °C, volume of medium (0.1-0.7 mL), and use of mucin-containing biorelevant medium. The disintegration assay was sensitive to temperature, medium volume, and medium composition; naloxone tablet disintegration was extremely rapid, with full disintegration ranging from 5 to 20 s. In conclusion, rapidly disintegrating tablets have been developed which are suitable for proof-of-concept clinical trial in humans to determine the pharmacokinetics of naloxone delivered via the buccal route.
authors.affiliation: Institute of Pharmaceutical Science, King's College London , Franklin-Wilkins Building, 150 Stamford Street, London, U.K. , SE1 9NH.
authors.forename: Abdulmalik
authors.initials: A
authors.lastname: Alqurshi
authors.affiliation: Institute of Pharmaceutical Science, King's College London , Franklin-Wilkins Building, 150 Stamford Street, London, U.K. , SE1 9NH.
authors.forename: Zahrae
authors.initials: Z
authors.lastname: Kumar
authors.affiliation: Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London (National Addiction Centre) , Addictions Sciences Building, 4 Windsor Walk, Denmark Hill, London, U.K. , SE5 8BB.
authors.forename: Rebecca
authors.initials: R
authors.lastname: McDonald
authors.affiliation: Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London (National Addiction Centre) , Addictions Sciences Building, 4 Windsor Walk, Denmark Hill, London, U.K. , SE5 8BB.
authors.forename: John
authors.initials: J
authors.lastname: Strang
authors.affiliation: UCL School of Pharmacy, University College London , 29-39 Brunswick Square, London, U.K. , WC1N 1AX.
authors.forename: Asma
authors.initials: A
authors.lastname: Buanz
authors.affiliation: Quintiles Ltd, Quintiles Drug Research Unit at Guy's Hospital , 6 Newcomen Street London, U.K. , SE1 1YR.
authors.forename: Shagufta
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Quintiles Ltd, Quintiles Drug Research Unit at Guy's Hospital , 6 Newcomen Street London, U.K. , SE1 1YR.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Allen
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust Pharmacy Manufacturing Unit, Guy's Hospital , Great Maze Pond, London, U.K. , SE1 9RT.
authors.forename: Peter
authors.initials: P
authors.lastname: Cameron
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust Pharmacy Manufacturing Unit, Guy's Hospital , Great Maze Pond, London, U.K. , SE1 9RT.
authors.forename: James A
authors.initials: JA
authors.lastname: Rickard
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust Pharmacy Manufacturing Unit, Guy's Hospital , Great Maze Pond, London, U.K. , SE1 9RT.
authors.forename: Verity
authors.initials: V
authors.lastname: Sandhu
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust Pharmacy Manufacturing Unit, Guy's Hospital , Great Maze Pond, London, U.K. , SE1 9RT.
authors.forename: Chris
authors.initials: C
authors.lastname: Holt
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust Pharmacy Manufacturing Unit, Guy's Hospital , Great Maze Pond, London, U.K. , SE1 9RT.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Stansfield
authors.affiliation: Institute of Pharmaceutical Science, King's College London , Franklin-Wilkins Building, 150 Stamford Street, London, U.K. , SE1 9NH.
authors.forename: David
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Institute of Pharmaceutical Science, King's College London , Franklin-Wilkins Building, 150 Stamford Street, London, U.K. , SE1 9NH.
authors.forename: Ben
authors.initials: B
authors.lastname: Forbes
authors.affiliation: Institute of Pharmaceutical Science, King's College London , Franklin-Wilkins Building, 150 Stamford Street, London, U.K. , SE1 9NH.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Royall
mesh_terms: D000284:Administration, Oral; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D005079:Excipients / Q000737:chemistry; D005612:Freeze Drying / Q000379:methods; D008353:Mannitol / Q000008:administration & dosage / Q000737:chemistry; D009055:Mouth / Q000378:metabolism; D009061:Mouth Mucosa / Q000378:metabolism*; D009270:Naloxone / Q000008:administration & dosage / Q000737:chemistry*; D016062:Porosity; D011208:Powders / Q000008:administration & dosage / Q000737:chemistry; D012995:Solubility; D013607:Tablets / Q000008:administration & dosage / Q000737:chemistry*; D013696:Temperature; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D005079:Excipients; D011208:Powders; D013607:Tablets; D009270:Naloxone; D008353:Mannitol
keywords: amorphous; buccal delivery; buccal disintegration assay; freeze-dried; heroin; inhibition of crystallization; instant disintegrating tablets; naloxone; opioid overdose