Long-Acting Injectable Solid Drug Nanoparticle (SDN) Platform

Sponsor(s)

Unitaid https://unitaid.org

Partnerships

No partner indicated

Type of technology

Aqueous drug particle suspension

Administration route

To be determined

Development state and regulatory approval

Anti-infectives for systemic use, Glecaprevir and pibrentasvir (G/P), Rifapentine

Pre-clinical

Not provided

Description

The use of particle processing technology to generate long-acting injectable nanoparticle formulations for long-acting delivery.

Technology highlight

The generation of high drug-loading nanoparticles with prolonged release for poorly water-soluble drugs with the potential for co-formulation strategies.

Technology main components

Active pharmaceutical ingredients, FDA/CDER listed excipients.

Delivery device(s)

No delivery device

API desired features

Water-insoluble molecules

Unit: mg/mL
To be determined.

Small molecules

Multiple.

Additional solubility data

None.

Additional stability data

-

API loading: Maximum drug quantity to be loaded

75-90 wt%

API co-administration

2 different APIs : API dependent.

LogP

Not provided

Scale-up prospects

To be determined

Tentative equipment list for manufacturing

To be determined

Manufacturing

To be determined

Specific analytical instrument required for characterization of formulation

To be determined

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

No novel excipient or existing excipient used

Residual solvents used

No residual solvent used

Other features of the technology

Not provided

Release properties

To be determined

Injectability

To be determined

Safety

To be determined

Stability

To be determined

Storage conditions and cold-chain related features

To be determined

Therapeutic area(s)

Use case(s)

Not provided

Use of technology

Technology patent families

Glecaprevir/Pibrentasvir (LAI candidate)

Publications

<p><a href="https://pubmed.ncbi.nlm.nih.gov/29777772/" rel="noopener noreferrer" target="_blank" style="color: rgb(33, 33, 33);">Improving maraviroc oral bioavailability by formation of solid drug nanoparticles. </a></p><p><span style="color: rgb(33, 33, 33);">Savage AC, Tatham LM, Siccardi M, Scott T, Vourvahis M, Clark A, Rannard SP, Owen A. </span></p><p><span style="color: rgb(33, 33, 33);">Eur J Pharm Biopharm. 2019 May;138:30-36. </span></p><p><span style="color: rgb(33, 33, 33);">doi: 10.1016/j.ejpb.2018.05.015.</span></p>

Oral drug administration remains the preferred approach for treatment of HIV in most patients. Maraviroc (MVC) is the first in class co-receptor antagonist, which blocks HIV entry into host cells. MVC has an oral bioavailability of approximately 33%, which is limited by poor permeability as well as affinity for CYP3A and several drug transporters. While once-daily doses are now the favoured option for HIV therapy, dose-limiting postural hypotension has been of theoretical concern when administering doses high enough to achieve this for MVC (particularly during coadministration of enzyme inhibitors). To overcome low bioavailability and modify the pharmacokinetic profile, a series of 70 wt% MVC solid drug nanoparticle (SDN) formulations (containing 30 wt% of various polymer/surfactant excipients) were generated using emulsion templated freeze-drying. The lead formulation contained PVA and AOT excipients (MVCSDNPVA/AOT), and was demonstrated to be fully water-dispersible to release drug nanoparticles with z-average diameter of 728 nm and polydispersity index of 0.3. In vitro and in vivo studies of MVCSDNPVA/AOT showed increased apparent permeability of MVC, compared to a conventional MVC preparation, with in vivo studies in rats showing a 2.5-fold increase in AUC (145.33 vs. 58.71 ng h ml−1). MVC tissue distribution was similar or slightly increased in tissues examined compared to the conventional MVC preparation, with the exception of the liver, spleen and kidneys, which showed statistically significant increases in MVC for MVCSDNPVA/AOT. These data support a novel oral format with the potential for dose reduction while maintaining therapeutic MVC exposure and potentially enabling a once-daily fixed dose combination product.

<p><a href="https://pubmed.ncbi.nlm.nih.gov/23997027/" rel="noopener noreferrer" target="_blank" style="color: rgb(33, 33, 33);">Antiretroviral solid drug nanoparticles with enhanced oral bioavailability: production, characterization, and in vitro-in vivo correlation. </a></p><p><span style="color: rgb(33, 33, 33);">McDonald TO, Giardiello M, Martin P, Siccardi M, Liptrott NJ, Smith D, Roberts P, Curley P, Schipani A, Khoo SH, Long J, Foster AJ, Rannard SP, Owen A. </span></p><p><span style="color: rgb(33, 33, 33);">Adv Healthc Mater. 2014 Mar;3(3):400-11. </span></p><p><span style="color: rgb(33, 33, 33);">doi: 10.1002/adhm.201300280. </span></p>

Nanomedicine strategies have produced many commercial products. However, no orally dosed HIV nanomedicines are available clinically to patients. Although nanosuspensions of drug particles have demonstrated many benefits, experimentally achieving >25 wt% of drug relative to stabilizers is highly challenging. In this study, the emulsion-templated freeze-drying technique for nanoparticles formation is applied for the first time to optimize a nanodispersion of the leading non-nucleoside reverse transcriptase inhibitor efavirenz, using clinically acceptable polymers and surfactants. Dry monoliths containing solid drug nanoparticles with extremely high drug loading (70 wt% relative to polymer and surfactant stabilizers) are stable for several months and reconstitute in aqueous media to provide nanodispersions with z-average diameters of 300 nm. The solid drug nanoparticles exhibit reduced cytoxicity and increased in vitro transport through model gut epithelium. In vivo studies confirm bioavailability benefits with an approximately four-fold higher pharmacokinetic exposure after oral administration to rodents, and predictive modeling suggests dose reduction with the new formulation may be possible.

<p><a href="https://www.nature.com/articles/ncomms13184" rel="noopener noreferrer" target="_blank" style="color: rgb(33, 33, 33);">Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies. </a></p><p><span style="color: rgb(33, 33, 33);">Giardiello M, Liptrott NJ, McDonald TO, Moss D, Siccardi M, Martin P, Smith D, Gurjar R, Rannard SP, Owen A. </span></p><p><span style="color: rgb(33, 33, 33);">Nat Commun. 2016 Oct 21;7:13184. </span></p><p><span style="color: rgb(33, 33, 33);"><span class="ql-cursor"></span>doi: 10.1038/ncomms13184.</span></p>

Considerable scope exists to vary the physical and chemical properties of nanoparticles, with subsequent impact on biological interactions; however, no accelerated process to access large nanoparticle material space is currently available, hampering the development of new nanomedicines. In particular, no clinically available nanotherapies exist for HIV populations and conventional paediatric HIV medicines are poorly available; one current paediatric formulation utilizes high ethanol concentrations to solubilize lopinavir, a poorly soluble antiretroviral. Here we apply accelerated nanomedicine discovery to generate a potential aqueous paediatric HIV nanotherapy, with clinical translation and regulatory approval for human evaluation. Our rapid small-scale screening approach yields large libraries of solid drug nanoparticles (160 individual components) targeting oral dose. Screening uses 1 mg of drug compound per library member and iterative pharmacological and chemical evaluation establishes potential candidates for progression through to clinical manufacture. The wide applicability of our strategy has implications for multiple therapy development programmes.

<p><a href="https://www.nature.com/articles/s41467-017-02603-z" rel="noopener noreferrer" target="_blank" style="color: rgb(34, 34, 34);">Long-acting injectable atovaquone nanomedicines for malaria prophylaxis.&nbsp;</a></p><p><span style="color: rgb(34, 34, 34);">Bakshi, R.P., Tatham, L., Savage, A.C.&nbsp;</span><em style="color: rgb(34, 34, 34);">et al.</em><span style="color: rgb(34, 34, 34);">&nbsp;</span></p><p><em style="color: rgb(34, 34, 34);">Nat Commun</em><span style="color: rgb(34, 34, 34);">&nbsp;</span><strong style="color: rgb(34, 34, 34);">9,&nbsp;</strong><span style="color: rgb(34, 34, 34);">315 (2018). </span></p><p><span style="color: rgb(34, 34, 34);"><span class="ql-cursor"></span>https://doi.org/10.1038/s41467-017-02603-z</span></p>

Chemoprophylaxis is currently the best available prevention from malaria, but its efficacy is compromised by non-adherence to medication. Here we develop a long-acting injectable formulation of atovaquone solid drug nanoparticles that confers long-lived prophylaxis against Plasmodium berghei ANKA malaria in C57BL/6 mice. Protection is obtained at plasma concentrations above 200 ng ml-1 and is causal, attributable to drug activity against liver stage parasites. Parasites that appear after subtherapeutic doses remain atovaquone-sensitive. Pharmacokinetic–pharmacodynamic analysis indicates protection can translate to humans at clinically achievable and safe drug concentrations, potentially offering protection for at least 1 month after a single administration. These findings support the use of long-acting injectable formulations as a new approach for malaria prophylaxis in travellers and for malaria control in the field.

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	Collaborate for development Consider on a case by case basis, collaborating on developing long acting products with potential significant public health impact, especially for low- and middle-income countries (LMICs), utilising the referred to long-acting technology Agree
	Share technical information for match-making assessment Provide necessary technical information to a potential partner, under confidentiality agreement, to enable preliminary assessment of whether specific medicines of public health importance in LMICs might be compatible with the referred to long-acting technology to achieve a public health benefit Agree
	Work with MPP to expand access in LMICs In the event that a product using the referred to long-acting technology is successfully developed, the technology IP holder(s) will work with the Medicines Patent Pool towards putting in place the most appropriate strategy for timely and affordable access in low and middle-income countries, including through licensing Agree

No.