Amid the global GLP-1 receptor-agonist boom, oral peptide technology is trying to crack the "daily injection" compliance problem.

But another path — long-acting injectables (LAI) — is reshaping chronic-disease care with a "one shot, months of relief" model.

In 2025-2026, this track saw multiple milestone breakthroughs.

The world's first self-developed aripiprazole microsphere was approved in China.

Ascletis' ASC30 achieved subcutaneous depot formulation with a 46-75 day ultra-long half-life.

Nature Chemical Engineering published a new design paradigm: self-aggregating long-acting injectable microcrystals (SLIM).

Membrane emulsification continuous manufacturing lifted microsphere production efficiency from 40% to 99%.

This Zhihe Research issue provides an in-depth analysis of microspheres, implants, and next-generation long-acting injection technology.

It covers PLGA platform evolution, competitive landscape, core CMC challenges, and Zhihe's strategic positioning.

1. Background and Core Mechanisms: Four Paradigms of Long-Acting Injection

(1) PLGA Microspheres: Evolution of a Mature Platform

Poly(lactic-co-glycolic acid) (PLGA) microspheres are the "old king" of long-acting injectables.

Since FDA approval of the first PLGA microsphere product Lupron Depot (leuprolide acetate) in 1989, 27 PLGA/PLA-based LAI products have been approved globally.

PLGA microsphere release is driven by "matrix erosion plus diffusion coupling".

The drug is dispersed in the PLGA matrix and released as the polymer hydrolyzes and degrades, theoretically for 1-6 months.

But PLGA is by no means yesterday's news.

In May 2025, Livzon's self-developed injectable aripiprazole microspheres (brand: Alive) were approved in China.

It is the world's first long-acting aripiprazole microsphere for monthly intramuscular injection in schizophrenia.

It has been included in the 2025 National Reimbursement Drug List and the Chinese Guidelines for the Prevention and Treatment of Schizophrenia (2025 edition).

This marks Chinese firms entering the global first tier of independent PLGA microsphere innovation.

On the release mechanism side, a University of Michigan team published a systematic methodology for coacervation-prepared PLGA microspheres in Drug Delivery and Translational Research in December 2025.

It revealed how solvent/non-solvent ratio, polymer MW, and mixing rate regulate microsphere internal pore structure.

These are core variables governing initial burst release and plateau release rate.

(2) In-Situ Forming Implants (ISFI): From Large to Small Needles

ISFI is another classic long-acting injection strategy.

A polymer (typically PLGA) is dissolved in a biocompatible organic solvent (e.g., NMP, DMSO), mixed with the drug, and injected subcutaneously or intramuscularly.

After solvent diffusion, the polymer precipitates and solidifies in situ to form a solid implant, achieving sustained release for months or longer.

FDA-approved products include Atridox (doxycycline hyclate, periodontitis), Eligard (leuprolide acetate, prostate cancer), and Sublocade (buprenorphine, opioid use disorder).

ISFI's core bottleneck is syringe selection.

Traditional ISFI systems need high polymer concentration for mechanical integrity, raising viscosity and forcing the use of 18-20G large-bore needles.

This causes patient pain and limits self-administration feasibility.

(3) SLIM Self-Aggregating Microcrystal Technology: A 2025 Paradigm Breakthrough

In March 2025, Nature Chemical Engineering published a breakthrough study from MIT's Giovanni Traverso group.

Self-aggregating long-acting injectable microcrystals, or SLIM.

The design is ingenious: drug microcrystals (2-3 μm) are suspended in a partially water-miscible solvent (e.g., benzyl benzoate, BB).

Only a tiny amount of polymer excipient is needed (polymer/drug weight ratio of just 0.0625:1, more than an order of magnitude lower than traditional ISFI).

After injection, the solvent slowly exchanges with interstitial fluid, driving microcrystals to self-aggregate and pack into a dense monolithic implant.

SLIM's core advantages are as follows:

1. Ultra-high drug loading: 293 mg/ml, far exceeding traditional ISFI.

2. Small-bore needles: PCL formulation can be injected through 25G needles, and the formulation without PCL through 30G needles (traditional ISFI needs 18-20G).

3. Long-acting release: In rats over 97 days, the LNG-BB+PCL formulation had an AUC only 1/5.6 of LNG-PBS.

μCT analysis showed 99.5% packing efficiency.

4. Universality: applicable to hydrophobic drugs with logP > 3.

Especially suitable for low-potency drugs requiring high doses for long-term release.

Using levonorgestrel (LNG) as proof of concept, SLIM first demonstrates the feasibility of "replacing bulk polymer excipients with pre-formed microcrystals".

If successfully translated to peptides, SLIM will rewrite the formulation paradigm for long-acting peptide injectables.

(4) Implantable Delivery Devices: The Eve of a 6-Month GLP-1

If microspheres and ISFI are chemical/physical engineering solutions for "in-situ forming" implants, implantable delivery devices are a more aggressive mechanical engineering route.

Vivani Medical's NanoPortal implantable delivery device aims to extend semaglutide dosing intervals to 6 months to 1 year.

Vivani had completed Phase I for exenatide implants, but after AstraZeneca discontinued the only two exenatide products on the market (Byetta and Bydureon), it shifted focus to semaglutide implants.

Preclinical data show a 20% weight reduction in rats over a 91-day study.

Meanwhile, Ascletis' ASC30, a small-molecule GLP-1R agonist, uses a very different Ultra-Long-Acting Platform (ULAP).

Phase II US 24-week data released in March 2026: monthly subcutaneous injection without titration, achieving a placebo-adjusted 7.5% peak weight loss at Week 16.

After drug discontinuation, 5.8% weight loss was maintained at Week 24.

ASC30 showed an observed half-life of 46-75 days, all GI events were mild (Grade 1), and no participants withdrew due to adverse events.

2. Global R&D Landscape: A Multi-Track Race in a USD-Ten-Billion Market

(1) Market Size and Growth Drivers

Industry reports put the global long-acting microsphere market above USD 8.5 billion by end-2025.

China's CAGR over the past five years is close to 30%, the fastest growth region in the global value chain.

Core growth drivers include:

Chronic-disease treatment is shifting toward "long cycle, high adherence".

Long-acting demand in schizophrenia, opioid use disorder, prostate cancer, and endometriosis.

GLP-1 metabolic drugs are upgrading from weekly to monthly/quarterly dosing.

(2) International Competition: Four Parallel Routes

Four technology routes are competing in parallel in the global long-acting injection space.

1. First echelon: PLGA microspheres plus improved platforms.

Representatives include AbbVie's Lupron Depot (leuprolide 1/3/4/6-month), J&J's Invega Sustenna/Trinza/Hafyera (paliperidone 1/3/6-month), and Indivior's Sublocade (buprenorphine 1-month).

Innovation here comes mainly from new indication expansion and longer dosing intervals.

2. Second echelon: ISFI in-situ forming implants.

Representatives include Tolmar's Eligard (leuprolide 1/3/4/6-month) and Zoetis' Atridox.

However, ISFI is limited by needle size due to high polymer concentration.

It has yet to achieve large-scale application in metabolic chronic diseases.

3. Third echelon: novel microcrystal/nanocrystal suspensions.

Representatives include SLIM (MIT/Traverso) and Pfizer's PF'3944 ultra-long-acting GLP-1RA injection in development.

Pfizer's February 2026 clinical data show PF'3944 sustains weight loss after switching from oral danuglipron.

This highlights the unique value of ultra-long-acting injectables in GLP-1 maintenance therapy.

4. Fourth echelon: implantable delivery devices.

Vivani's NanoPortal, Intarcia's ITCA 650 (exenatide osmotic-pump implant, FDA-rejected in 2023 over safety), and others.

Although implants face biocompatibility and removal-surgery challenges, they are the only feasible route to "6-month-to-1-year single dosing".

Provided safety passes regulatory scrutiny.

(3) Chinese Force: Leap from Generic to Innovation

2025-2026 is the most milestone-rich period for China's microsphere industry.

1. Livzon Group.

Injectable aripiprazole microspheres (approved May 2025, world's first self-developed aripiprazole microsphere).

Brexpiprazole microsphere IND was accepted in early 2026, forming a "schizophrenia microsphere portfolio" with aripiprazole.

Progesterone injection (II) was approved in 2025 and included in the NRDL.

Livzon achieved RMB 12 billion revenue in 2025, with its innovative-drug pipeline entering the harvest period.

2. Luye Pharma.

Paliperidone extended-release injectable suspension (ERZOFRI) was FDA-approved in 2024 and began US commercialization in 2025.

It became a Chinese long-acting injectable pioneer going global.

3. Ascletis Pharma.

ASC30 ultra-long-acting subcutaneous depot, based on Ascletis' proprietary ULAP platform, has completed US Phase II.

It demonstrates feasibility of "monthly injection plus quarterly maintenance" dosing for a small-molecule GLP-1RA.

Its 75-day half-life is exceptionally rare among small molecules.

Notably, China's domestic share of the microsphere market rose from 34.6% in 2019 to 49.7% in 2024.

Independent innovation at Livzon, Luye, and others is reshaping domestic competition.

3. Key Technical Challenges and Breakthroughs

(1) Manufacturing: From Batch Homogeneity to Continuous Membrane Emulsification

The traditional "gold standard" for PLGA microsphere preparation is emulsion-solvent evaporation.

But it has three inherent defects: broad particle-size distribution (CV > 30%), large batch-to-batch variability, and unpredictable scale-up.

Worse still, material waste is severe — in one veterinary case, about 60% of product was discarded for off-spec particle size.

Membrane emulsification is fundamentally solving this problem.

UK-based Micropore Technologies' cross-flow membrane emulsification platform achieves three breakthroughs:

1. Through-pore design: drilled rather than sintered pores prevent clogging.

2. Continuous manufacturing: shifts membrane emulsification from semi-batch to true continuous operation.

3. Zero scale-up effect: lab conditions transfer directly to commercial scale, with about 99% usable product and minimal filtration losses.

Professor Cao Qingri's group at China Pharmaceutical University has also made progress in microfluidic microsphere preparation.

His team used a microfluidic chip to achieve controlled preparation of highly uniform polymer microspheres.

The work was published in Chemical Engineering Journal (2025 IF: 13.3) and provides new ideas for GMP-grade continuous PLGA microsphere manufacturing.

(2) Special CMC Challenges

CDE experts systematically pointed out the core CMC challenges for microspheres in "On the Pharmaceutical Research and Evaluation of Microsphere Preparations".

1. In vitro release methodology.

Microspheres release over 1-6 months; whether standard QC release methods (typically under 72 hours) can predict in vivo behavior is a major question.

FDA product-specific guidance for leuprolide microsphere BE has moved from "in vivo PK" toward "multiple in vitro dissolution profiles plus in vivo pilot studies".

2. Microsphere internal microstructure characterization.

Porosity, pore-size distribution, and drug distribution uniformity directly affect release.

Standardized characterization tools and release specifications are still lacking.

The nonlinear effect of PLGA molecular-weight distribution on microsphere degradation rate (where a small fraction of low-MW species in a single PLGA batch can significantly alter release kinetics) is a key blind spot in CQA control.

3. Sterility assurance.

Microspheres cannot be terminally sterilized (heat/radiation accelerates PLGA degradation) and must be produced aseptically throughout.

Membrane emulsification equipment, with no moving parts and no seals, has shown aseptic-friendly advantages in GMP Grade P2 cleanroom deployment.

4. Drug loading and encapsulation efficiency.

This is the "eternal contradiction" of PLGA microspheres.

High drug loading (>30% w/w) is usually accompanied by larger initial burst release and lower encapsulation efficiency.

SLIM achieves 293 mg/ml ultra-high loading with <5% initial burst.

Its core design philosophy — using drug microcrystals themselves to replace polymer excipients — offers a new way to resolve this contradiction.

(3) Clinical Development Strategy: Differentiated Endpoint Design

Clinical trial design for long-acting injectables faces unique challenges.

1. BE evaluation strategy.

For improved long-acting injectables (Category 2.2), CDE requires complete PK-BE studies.

But for long-acting products, debate continues over whether single-dose steady-state PK or multi-dose steady-state PK should be the primary BE endpoint.

Microsphere release curves may show a "three-phase pattern" (initial burst, diffusion-controlled slow release, erosion-controlled acceleration).

Traditional AUC and Cmax may not fully reflect release behavior differences.

2. Choice of control.

Aripiprazole microsphere (monthly) vs. immediate-release tablet (daily) trials must simultaneously demonstrate non-inferior efficacy and superior adherence.

This poses dual challenges for endpoint selection and sample size.

3. Unique advantages of GLP-1 long-acting injectables.

ASC30's Phase II used an innovative "3 doses + 16-week observation" design and serendipitously found post-treatment effects lasting 4 months.

This implies clinical feasibility of periodic (quarterly) rather than continuous maintenance dosing.

It could overturn the traditional view that GLP-1 must be used continuously long-term.

Disclaimer: This article was written by the AI research team of Nanjing Zhihe Pharmaceutical Technology Co., Ltd. for internal research reference only; not investment or medical advice.

All data sources are cited; please credit the source when quoting.

This article does not represent the official position of Nanjing Zhihe; corrections are welcome.