The Road to Long-acting Injectables

If the competition of ordinary generic drugs is already a red ocean, then long-acting injections with unique clinical advantages, high technical barriers and high value-added can enable enterprises to avoid homogeneous competition to a large extent, but also because of the difficulty of its research and development and industrialization, the number of players in the domestic and global range has not shown a blowout, and the road of long-acting injections is still continuing.

01 Widely used in clinical practice

As a complex formulation, long-acting injectables are a class of long-acting sustained-release formulations in which a sufficient amount of drug is injected into the body and slowly released to allow the drug to continue to produce treatment. Compared to traditional dosage forms, long-acting injections reduce fluctuations in drug concentrations and achieve smooth drug release, while improving patient compliance by reducing the frequency of dosing, making them ideal for managing chronic conditions (such as schizophrenia, alcohol, or opioid abuse) that require frequent repeat dosing. In addition, because long-acting injections belong to the parenteral administration system, they can avoid the first-pass effect of the gastrointestinal tract, improve the bioavailability of the drug, and reduce other adverse reactions such as liver and kidney toxicity, which has broad clinical application prospects.

Among them, long-acting injections have been used in the field of psychiatric diseases for many years, and the first long-acting intramuscular antipsychotic drug Fluphenazine Enanthate was approved in 1966. First-generation antipsychotic long-acting injections are oil-based preparations in which an adequate dose of the drug is combined with an oily liquid to make an oily solution or suspension injection, and the antipsychotic is esterified to form a prodrug, which has significantly increased solubility in the injectable oil. Once the drug dissolved in an oily carrier is injected into the muscle, it forms a small reservoir in situ from which the drug is slowly released.

Second-generation antipsychotic long-acting injections work by blocking the activity of the chemicals dopamine D2 and serotonin (5-HT2A receptors) than typical antipsychotics, and are more selective for the midbrain limbic system than for the striatum system, causing less pyramidal syndrome. Second-generation antineurological drugs include benzodiazepines (clozapine, quetiapine, olanzapine) and benzisooxazoles (such as risperidone, ziprasidone), among which the long-acting formulations are risperidone microspheres, paliperidone palmitate, aripiprazole, and olanzapine, all of which have been in the market for many years, and have not even competed with generic drugs for a period of time.

In addition to decades of extensive clinical application in the field of psychiatric diseases, long-acting injections have also made great achievements in the field of anti-tumor, HIV and other diseases, especially Cabenuva, which has been approved in recent years, which is the first FDA-approved complete injection regimen for HIV-infected adult patients, and the approved regimen is administered once a month. The drug consists of rilpivirine and cabotegravir. Rilpivirine is an oral, non-nucleoside reverse transcriptase inhibitor. Cabotegravir is an integrase inhibitor that works by inhibiting the integration of viral DNA into the genome of human immune cells, and the approval of Cabenuva also represents the beginning of the era of long-acting HIV treatment, with three-month and six-month long-acting HIV injections currently in development. In addition, long-acting injections have shown great potential in the treatment of chronic diseases such as Parkinson's and Alzheimer's disease, but it will take time to confirm.

02 Market size of long-acting injections

According to data, the global long-acting injectable market is expected to grow from US$1.06 billion in 2023 to US$4.62 billion in 2035, with a compound annual growth rate of 13.1%. Although the market prospect is good and the competition is far from reaching the Red Sea, the technical barriers of long-acting injections are high, and there are high requirements for excipients, process technology and commercial production capacity in pharmaceutical research, and it is difficult to break through the original patents and be imitated.

Different from oral dosage forms, long-acting injections are difficult to simulate the physiological environment in vitro, and it is extremely challenging to predict the absorption characteristics of long-acting injections in vivo drug release machine based on in vitro drug release curves. At the same time, for long-acting injections with complex preparation structures, such as polycystic liposomes, microspheres, etc., small changes in the production process or production environment may lead to changes in the microstructure of the preparation and the microdistribution of the drug in the preparation, resulting in large differences between batches; Moreover, the preparation process of this kind of preparation is difficult to scale up linearly, and the production line is mostly personalized customization. In addition, the existing sustained-release carrier materials are still dominated by PLGA, and due to the degradation characteristics of PLGA, some preparations present an "S" type drug release curve, that is, it is composed of a sudden release period, a delayed release period, and a drug release period, which also brings great challenges to the prediction of drug release and absorption characteristics in vivo.

Taking microsphere preparation as an example, commonly used microsphere preparation methods include emulsion volatilization, phase separation, spray drying, salting out curing, etc., but the early microsphere process has limitations such as material loss, poor control of microsphere particle size, low production efficiency, low encapsulation rate or low reproducibility. At present, the relatively novel microsphere preparation technology includes composite microspheres, supercritical fluid method, membrane emulsification technology, etc., which are better in terms of preparation rate, encapsulation efficiency, batch-to-batch repeatability, stability, etc., and solve the difficulties in the preparation of microspheres such as heat-sensitive drugs and volatile drugs, but it should be noted that long-acting injections often require customized production equipment, and the workshop investment is relatively high, the applicable technologies for different drugs are different, and the debugging process of various parameters is complicated, so it is difficult to realize the industrialization linear amplification of long-acting injections to a certain extent. This has also become one of the reasons why many pharmaceutical companies are shy away from long-acting injections.

From the above, it is not difficult to see that the long development timeline, complex pharmaceutical and clinical study design, and customized manufacturing needs also make long-acting injectables a high-barrier, high-risk, and high-return investment. Although the layout of domestic enterprises is relatively late, a number of outstanding enterprises represented by Luye, Hengrui, and CSPC have emerged, and have achieved excellent results in the development of long-acting injections. In particular, the risperidone sustained-release microsphere injection developed by Luye was approved by the FDA last year, becoming the first complex preparation product from a pharmaceutical company in Chinese mainland approved by the FDA under the 505b(2) pathway, and the field of long-acting injections is still a blue ocean market, and it is expected that more pharmaceutical companies can participate in it to realize its clinical value and market value.

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