Poloxamer-poly(acrylic acid)-based thermoresponsive LAI technology

Sponsor(s)

Partnerships

Sefako Makgatho Health Science University https://www.smu.ac.za/

Type of technology

Polymer-based particles

Administration route

Intramuscular

Development state and regulatory approval

Drugs for treatment of tuberculosis

Pre-clinical

Not provided

Description

The SnPPIX thermoresponsive injectable formulation (SnPPIX-TIF) is an advanced drug delivery platform for managing tuberculosis: 1) Pharmacology: It delivers tin protoporphyrin IX, an immunomodulating host-directed therapy that activates host defenses rather than directly targeting the pathogen. 2) Formulation: The microparticulate poloxamer-poly(acrylic acid) carrier is liquid at room temperature for easy injection but forms a localized solid gel at body temperature. 3) Kinetics: It vastly improves the drug's half-life and overall absorption, allowing for once-weekly dose adminstration

Technology highlight

The SnPPIX thermoresponsive injectable formulation (SnPPIX-TIF) is a cutting-edge platform engineered for tuberculosis management. The technology relies on a microparticulate poloxamer-poly(acrylic acid) polymeric carrier that is liquid at room temperature, ensuring rapid and effortless syringeability. Following intramuscular administration, it undergoes an immediate phase transition at body temperature, forming a localized solid gel depot. This depot strategically delivers tin protoporphyrin IX (SnPPIX), a potent host-directed therapy that boosts immune defenses instead of directly attacking the pathogen, circumventing drug resistance. By significantly improving pharmacokinetic profiles and sustaining drug release, SnPPIX-TIF enables convenient, safe and effective weekly dosing regimen.

Technology main components

The main components of the SnPPIX thermoresponsive injectable formulation (SnPPIX-TIF) include: 1) Tin Protoporphyrin IX (SnPPIX): The active therapeutic agent that functions as an immunomodulatory, host-directed therapy. 2) Poloxamer: A temperature-sensitive polymer that enables the formulation to remain liquid at room temperature and transition into a gel at body temperature. 3) Poly(acrylic acid): A polymer integrated with the poloxamer to form the structural microparticulate carrier matrix that encapsulates the drug and controls its release.

Information on the raw materials sourcing, availability and anticipated price

Not provided

Delivery device(s)

Not provided

API desired features

Water-soluble molecules

Water-insoluble molecules

Small molecules

Tin Protoporphyrin IX is currently being evaluated using a thermoresponsive injectable delivery platform. Based on available preclinical evidence, this platform may have broader applicability for the delivery of other small-molecule therapeutics, including candidates targeting HIV and tuberculosis. Further research is warranted to assess the feasibility, safety, and efficacy of incorporating these agents into the platform.

Additional solubility data

Not provided

Additional stability data

Not provided

API loading: Maximum drug quantity to be loaded

50-75 wt%

API co-administration

1 single API :

LogP

Min: -1 Max: 5

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

1) ULTRA-TURRAX Tube Drive Control Disperser (IKA Works, Inc., Wilmington, NC, USA) 2) 0.22 µm Whatman cellulose acetate membrane syringe filter (Cytiva, MA, USA) 3) Biosafety Cabinet 4) Refrigerator

Manufacturing

The thermoresponsive injectable formulation can be manufactured using a scalable cold-process method, whereby poloxamer 407 and sodium polyacrylate are dissolved under controlled low-temperature conditions prior to direct incorporation of the active pharmaceutical ingredient. Critical quality attributes include polymer concentration, gelation temperature, viscosity, syringeability, injectability, particle size distribution, and drug content uniformity. Sterile manufacturing and aseptic filtration are essential for parenteral administration. Process controls should ensure batch-to-batch consist

Specific analytical instrument required for characterization of formulation

1) Differential Scanning Calorimetry (DSC) 2) Rotational rheometers 3) High-Performance Liquid Chromatography (HPLC) or UPLC 4) Dynamic Light Scattering (DLS) 5) UV-Vis spectrophotometry

Proprietary excipients used

No proprietary excipient used

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

1) Poloxamer 2) Poly(acrylic acid)

Residual solvents used

Not provided

Other features of the technology

• Biodegradable

Release properties

The encapsulation of the drug within the thermoresponsive polymeric carrier notably delays and improves in vivo drug release and absorption. The prolonged release profile significantly enhances overall bioavailability over 24 hours compared to conventional water-based solutions, demonstrating a higher AUC0-24 (575.10 - 38.51 mcg h/mL), maximum plasma concentration (Cmax=46.50-11.80 mcg/mL), time to peak concentration (tmax=1 h), and an extended half-life (t1/2=2.77 h).

Injectability

This technology is intended to be adminstered by intramuscular route (IM) through 25G hypodermic needle equipped with a 1 mL syringe.

Stability

Not provided

Storage conditions and cold-chain related features

Not provided

Safety

Histopathological evaluation revealed no TEAE safety concerns in preclinical animal studies.

Efficacy

1) Mean bacterial colony-forming unit (CFU) loads in the IM SnPPIX-TIF-treated cohort were 5.8 logs. This was significantly lower (p< 0.0001) than the average values recorded for untreated infected animals (7.2 logs) and placebo-TIF treated animals (7.4 logs).

Evidence Summary

Preclinical histopathological evaluations identified no treatment-related safety concerns. Furthermore, once-weekly intramuscular administration of the SnPPIX-TIF formulation demonstrated antimicrobial efficacy comparable to that of daily intramuscular injections of the aqueous SnPPIX formulation (SnPPIX-WBS), achieving a 6.0-log reduction in bacterial burden. Overall, treatment with SnPPIX-TIF reduced pulmonary bacterial loads by more than 1 log, supporting its potential as a less frequent dosing strategy without compromising therapeutic efficacy.

Therapeutic area(s)

Use case(s)

Use of technology

There are either no relevant patents or these were not yet submitted to LAPaL

Publications

Adeleke OA, Fisher L, Moore IN, Nardone GA, Sher A. A Long-Acting Thermoresponsive Injectable Formulation of Tin Protoporphyrin Sustains Antitubercular Efficacy in a Murine Infection Model. ACS Pharmacol Transl Sci. 2020 Dec 18;4(1):276-287. doi: 10.1021/acsptsci.0c00185. PMID: 33615179; PMCID: PMC7887855.

Adeleke OA — ACS Pharmacology & Translational Science — 2020-12-18

Link: https://pubs.acs.org/aptsfn/article/4/1/276/1464994/A-Long-Acting-Thermoresponsive-Injectable

Tuberculosis is the leading cause of death from a single infectious agent, ranking above the human immunodeficiency virus (HIV). Effective treatment using antibiotics is achievable, but poor patient compliance constitutes a major challenge impeding successful pharmacotherapeutic outcomes. This is often due to the prolonged treatment periods required and contributes significantly to the rising incidence of drug resistance, which is a major cause of tuberculosis mortality. Thus, innovative interventions capable of encouraging compliance and decreasing lengthy and frequent dosing are needed. Previously, aqueous tin protoporphyrin IX (SnPPIX), a heme oxygenase-1 inhibitor, administered as multiple daily intraperitoneal (IP) injections, showed considerable antitubercular efficacy and treatment shortening capabilities as a host-directed therapy in infected mice. Since daily IP injection is a clinically impractical administration approach, this proof-of-concept study aims to develop a novel, sustained action injectable formulation of SnPPIX for safe intramuscular (IM) administration. Herein, a SnPPIX-loaded poloxamer-poly(acrylic acid)-based thermoresponsive injectable formulation (SnPPIX-TIF) is designed for effective IM delivery. Results show SnPPIX-TIF is microparticulate, syringeable, injectable, and exhibits complete in vitro/in vivo gelation. Administered once weekly, SnPPIX-TIF significantly prolonged absorption and antimicrobial efficacy in infected mice. In addition, SnPPIX-TIF is well-tolerated in vivo; results from treated animals show no significant histopathologic alterations and were indistinguishable from the untreated control group, thus supporting its biocompatibility and preclinical safety. Overall, the IM delivery of the thermoresponsive injectable formulation safely sustains antitubercular effect in an infected murine model and decreases the number of injections required, signifying a potentially practical approach for future clinical translation.

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