JP-2026514515-A - Long-acting colloidal pharmaceutical composition of an integrase chain transfer inhibitor and related method

Abstract

A composition comprising a stable colloid of an HIV integrase inhibitor for the preparation of an injectable, long-acting pharmaceutical product for treating and preventing HIV infection.

Inventors

• ホー，ロドニー ジェイ ワイ

Assignees

• ユニバーシティ・オブ・ワシントン

Dates

Publication Date

20260511

Application Date

20240426

Priority Date

20230426

Claims (19)

1. Colloidal integrase chain transfer inhibitor particles containing an integrase chain transfer inhibitor and amino acids.
2. The particle according to claim 1, wherein the integrase chain transfer inhibitor is selected from the group consisting of dolutegravir, bictegravir, cabotegravir, raltegravir, and elvitegravir.
3. The particle according to claim 1, wherein the integrase chain transfer inhibitor is selected from the group consisting of dolutegravir, bictegravir, and cabotegravir.
4. The particle according to claim 1, wherein the integrase chain transfer inhibitor is dolutegravir.
5. The particle according to claim 1, wherein the integrase chain transfer inhibitor is selected from the group consisting of raltegravir and elvitegravir.
6. The particle according to any one of claims 1 to 5, wherein the amino acid is glutamine or tryptophan.
7. The particle according to claim 1, wherein the integrase chain transfer inhibitor is dolutegravir (DTG) and the stabilizing amino acid is glutamine (Gln).
8. The particle according to claim 1, wherein the integrase chain transfer inhibitor is dolutegravir (DTG), and the stabilizing amino acid is tryptophan (Trp).
9. The particle according to claim 1, wherein the integrase chain transfer inhibitor is bictegravir (BIC) and the stabilizing amino acid is glutamine (Gln).
10. The particle according to claim 1, wherein the integrase chain transfer inhibitor is bictegravir (BIC) and the stabilizing amino acid is tryptophan (Trp).
11. An injectable pharmaceutical composition comprising a suspension of colloidal integrase chain transfer inhibitor particles according to any one of claims 1 to 10 in an aqueous carrier.
12. The composition according to claim 11, further comprising a biocompatible pharmaceutical excipient.
13. The composition according to claim 11 or 12, further comprising a pegylation modifier.
14. A method for treating or preventing HIV in a subject, comprising the step of administering a therapeutically effective amount of integrase chain transfer inhibitor particles according to any one of claims 1 to 10 or a composition according to any one of claims 11 to 13 to a subject in need.
15. A method for treating a disease or condition that is preventable or treatable by administering an integrase chain transfer inhibitor, comprising the step of administering a therapeutically effective amount of integrase chain transfer inhibitor particles according to any one of claims 1 to 10 or a composition according to any one of claims 11 to 13 to a subject in need thereof.
16. The method according to claim 14 or 15, wherein the integrase chain transfer inhibitor particles or the composition are administered by subcutaneous or intramuscular injection.
17. The method according to claim 16, wherein the administration is performed at any interval between 30 and 365 days.
18. Integrase chain transfer inhibitor particles according to any one of claims 1 to 10, or a composition according to any one of claims 11 to 13, for use in the treatment or prevention of HIV infection in humans.
19. Integrate chain transfer inhibitor particles according to any one of claims 1 to 10, or a composition according to any one of claims 11 to 13, for the treatment or prevention of a disease or condition treatable by administering an integrase chain transfer inhibitor.

Description

(Cross-reference to related applications) This application claims the interests of U.S. Patent Application No. 63/498461, filed on 26 April 2023, which is expressly incorporated herein by reference in its entirety. (Statement of government licensing authority) This invention was made with federal government support, funded by the National Institutes of Health under Contract No. R61/33 AI149665. The government has certain rights in this invention. Successful advances in the development of many effective drug substances have made it possible to introduce single-dose or multi-dose oral drug products to maximize inhibition of HIV virus replication. However, all available oral drug products require at least daily or even more frequent administration to suppress the virus in HIV+ patients. People who have survived HIV can expect to live virus-free for a long period of time, provided they take tablets daily for an extended period. Daily tablets for HIV are called highly active antiretroviral therapy (HAART) and consist of combinations of antiretroviral agents, often referred to as cART (combinations anti-retroviral therapeutics). cART is intended to block HIV replication using drug substances that are designed to maximize inhibition of viral replication by inhibiting multiple replication checkpoints. HAART or cART typically consists of two or three drug substances intended to inhibit viral reverse transcription (RT), proteases, and/or integrases (often called integrase strand transfer inhibitors or INSTTIs). The global implementation of HAART and the global effort to identify, treat, and achieve effective viral suppression with cART have enabled people living with HIV to now live into old age. However, long-term daily oral tablets can cause tablet fatigue. Discontinuing cART can lead to viral rebound, progression to AIDS, and premature death. Interruption of treatment and non-adherence to prescribed daily doses increase the likelihood of drug-resistant viruses in patients who are also at risk of viral rebound and progression to AIDS. While the current regimen of one tablet per day has been proven to save lives, the WHO reported that in 2021, approximately 1.5 million people were newly infected with HIV, and more than 500,000 people (approximately 650,000) died from HIV. To overcome tablet fatigue, avoid preventable deaths, and address the aforementioned challenges, HIV drugs with long-acting (LA) pharmacokinetic properties that increase the dosing interval are being developed to improve treatment adherence and reduce tablet burden. A typical approach involves creating long-acting HIV drug products, which include selecting water-insoluble derivatives that exhibit a longer terminal phase half-life in the blood to create injectable dosage forms that sustain drug levels for several weeks to several months. For example, the long-acting cabotegravir (LA-CAB, INSTI) product incorporated into CABENUVA, recently approved by the FDA [consisting of two drug products, LA-cabotegravir injection and LA-rilpivirine (LA-RPV, RT inhibitor) injection, administered intramuscularly to two separate sites]. Both LA-CAB and LA-RPV are manufactured using excipients such as PEG400 and poloxamer (polymer compounds) to form small drug crystals suitable for injection. These products retain their natural crystalline state. Nanocrystalline or nanocrystals are incised to improve the solubility of water-insoluble drugs. Consequently, nanodrug crystal platforms are typically used to improve the dissolution rate of drugs by reducing the size of large, naturally occurring particulate drug crystals to enhance oral absorption. However, nanocrystals are metastable and tend to invert into larger, more stable structures of polymorphic crystalline drugs. Metastable nanocrystalline drugs are known to be unstable and have increased water solubility. Therefore, there is an urgent need for the formation of stable drug particles that achieve sustained plasma drug levels over extended periods, or for long-acting drug products based on novel and non-trivial compositions and methods. The goal is to provide a pharmaceutically acceptable injectable product that is stable, scalable, and easily resuspendable, and furthermore, to achieve long-term sustained plasma drug concentrations to overcome the requirement of daily oral administration. Even with long-acting or sustained-release drug formulations packaged in oral dosage forms, the drug is eliminated from the gastrointestinal tract (intestines) in humans within approximately 24 hours; therefore, daily tablet administration is still necessary to achieve drug levels effective in suppressing viral replication. In some embodiments, methods and techniques for producing long-acting drug products are described. Some techniques include: (1) conjugating drug molecules into an erosive biopolymer that releases drug molecules as they separate from the polymer over time; (2) encapsulating biodegradable polymer (e.g., PLGA or P