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.

Formulation for a novel inhaled peptide therapeutic for idiopathic pulmonary fibrosis

“…As mentioned earlier, CSP7 trifluoroacetate formulations were prepared in DPBS buffer, which consists of sodium chloride (NaCl), potassium chloride (KC1), dibasic sodium hydrogen phosphate dihydrate (Na2HP04 2H 2 0) and monobasic potassium phosphate (KH2PO4). There are various studies reporting the effects of buffer salts on crystallinity of the bulking agents, such as delayed lactose crystallization, polymorphic behavior of mannitol, or inhibition of mannitol crystallization (59–62). …”

Naloxone formulation for overdose reversal preference among patients receiving opioids for pain management

“…The interest in an intranasal product supports the recent FDA approval of an intranasal product (Narcan ™ ; Adapt Pharmaceuticals) (Traynor, 2016), which is a commercially available intranasal product that does not require application of an atomizer to an injection ampule to administer intranasally. While Narcan ™ is the only currently FDA-approved intranasal product, a recent international patent search identified patents for new intranasal and sublingual formulations of naloxone (McDonald et al, 2017), and recently published studies have reported the pharmacokinetics of new intranasal (Gufford et al, 2017; Mundin et al, 2017; Tylleskar et al, 2017) and buccal products (Alqurshi et al, 2016), indicating substantial interest in development of noninjected naloxone formulations.…”

The Research Updates and Prospects of Herbal Hard-Boiled Lozenges: A Classical Platform With Promising Drug Delivery Potential

“…The commonly used instruments used to study the thermodynamic properties are DSC (PerkinElmer Inc.,), DSC-2010 (TA instruments) and Shimadzu DSC-60 plus. The analysis is performed by taking 4-6 mg, of indium pan and heating with temperature gradient depending on melting temperature under nitrogen or argon flow [96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112].…”

“…Normally the dissolution time depends on the composition of the hard boiled lozenges and it varies from 6 to 10 min. Further human panel can be used to determine the actual dissolution time of the hard boiled lozenges [11,109].…”