Hyperthermia-Induced In Situ Drug Amorphization by Superparamagnetic Nanoparticles in Oral Dosage Forms

Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) generate heat upon exposure to an alternating magnetic field (AMF), which has been studied for hyperthermia treatment and triggered drug release. This study introduces a novel application of magnetic hyperthermia to induce amorphization of a poorly aqueous soluble drug, celecoxib, in situ in tablets for oral administration. Poor aqueous solubility of many drug candidates is a major hurdle in oral drug development. A novel approach to overcome this challenge is in situ amorphization of crystalline drugs. This method facilitates amorphization by molecular dispersion of the drug in a polymeric network inside a tablet, circumventing the physical instability encountered during the manufacturing and storage of conventional amorphous solid dispersions. However, the current shortcomings of this approach include low drug loading, toxicity of excipients, and drug degradation. Here, doped SPIONs produced by flame spray pyrolysis are compacted with polyvinylpyrrolidone and celecoxib and exposed to an AMF in solid state. A design of experiments approach was used to investigate the effects of SPION composition (Zn 0.5 Fe 2.5 O 4 and Mn 0.5 Fe 2.5 O 4 ), doped SPION content (10−20 wt %), drug load (30−50 wt %), and duration of AMF (3−15 min) on the degree of drug amorphization. The degree of amorphization is strongly linked to the maximum tablet temperature achieved during the AMF exposure (r = 0.96), which depends on the SPION composition and content in the tablets. Complete amorphization is achieved with 20 wt % Mn 0.5 Fe 2.5 O 4 and 30 wt % celecoxib in the tablets that reached the maximum temperature of 165.2 °C after 15 min of AMF exposure. Furthermore, manganese ferrite exhibits no toxicity in human intestinal Caco-2 cell lines. The resulting maximum solubility of in situ amorphized celecoxib is 5 times higher than that of crystalline celecoxib in biorelevant intestinal fluid. This demonstrates the promising capability of SPIONs as enabling excipients to magnetically induce amorphization in situ in oral dosage forms.

Pharmaceutical Quality by Design Approach to Develop High-Performance Nanoparticles for Magnetic Hyperthermia

“…Detailed morphological characterization of Mn 0.5 Fe 2.5 O 4 was conducted by using scanning TEM combined with energy-dispersive X-ray spectroscopy and energy-loss spectroscopy. Figure e illustrates the high-angle annular dark-field scanning TEM images and corresponding elemental maps. , The nanoparticles exhibit a polyhedron shape, which is in good agreement with previously reported flame-made SPIONs. ,, The elemental mapping indicates a uniform distribution of the dopant throughout the nanoparticle. The energy-dispersive X-ray spectra (Figure S7a) also show the elemental composition of Mn 0.5 Fe 2.5 O 4 nanoparticles to be in excellent agreement with the ICP-OES results.…”

“…Further elucidation of the phase composition and cation distribution in doped SPIONs was performed by using Mössbauer spectroscopy. Figure c shows the Mössbauer fitting patterns obtained for midsized Mn 0.5 Fe 2.5 O 4 nanoparticles, chosen based on previous reports of promising hyperthermia performance for this particle composition . The fitting was performed by using a central doublet and two sextet patterns.…”

“…This is equivalent to a production rate of up to 2000 doses of SPIONs per hour . The versatility of FSP in synthesizing highly pure SPIONs with reproducible control over particle size has been extensively demonstrated. − FSP also enables the control of SPION composition by doping with metals, achieved by careful selection of the precursor salts, solvents, and the application of fundamental techniques in chemistry. , Recent advances in theoretical and experimental investigations of FSP have significantly improved our understanding of the empirical laws governing it. However, studies investigating the effects of FSP parameters on nanoparticle properties mainly use the one-factor-at-a-time method.…”

Hyperthermic triggers for drug delivery platforms

“…The synthesis of controlled drug release platforms resulting from the incorporation of biocompatible nanomaterials to biocompatible polymers seems to be technically easy and very effective to study electromagnetic interactions. In particular, superparamagnetic nanoparticles (SPMNPs) can be used as triggers for localized delivery of drugs using electromagnetic mechanisms [15][16][17]. SPMNPs have the capability to absorb and transform externally applied electromagnetic energy into thermal energy.…”

Hydrophilic Copolymers with Hydroxamic Acid Groups as a Protective Biocompatible Coating of Maghemite Nanoparticles: Synthesis, Physico-Chemical Characterization and MRI Biodistribution Study

“…There is a plethora of synthetic pathways leading to iron oxide nanoparticles, including the sol–gel method [ 27 ], hydrothermal method [ 28 ], flow injection method [ 29 ], electrochemical method [ 30 , 31 ], aerosol/vapor-phase method [ 32 ], sonochemical decomposition method [ 33 , 34 ], supercritical fluid method [ 35 ], synthesis using nanoreactors method [ 36 ] and microbial method [ 37 , 38 ]. However, thermal decomposition of iron-organic precursors [ 39 , 40 ] and coprecipitation of ferrous and ferric salts with an aqueous base [ 41 , 42 ] became the most-preferred ways.…”