Long-Acting Injectable Suspensions

René Holm - University of Southern Denmark, Department of Physics, Chemistry and Pharmacy, Campusvej 55, 5230 Odense, Denmark; corresponding email address: [email protected]

Long Acting Injectables (LAIs) are a drug formulation option that provide a slow and sustained release of the Active Pharmaceutical Ingredient (API) after administration.¹ LAI formulations have several advantages relative to classical oral formulations, including reduced frequency of administration, enhanced therapy adherence and patient compliance, and potentially also a lower level of adverse effects, when these are associated with peak plasma concentrations. Experience from the antipsychotic area have shown that these attributes of the LAIs often lead to improved therapeutic effect,² whereby the formulation approach provides improved quality of life for the patients using them.^3-7 The first LAI products were approved by the Food and Drug Administration (FDA) in the 1950s, including formulations based on oil solutions and aqueous suspensions. Some products have been approved since, but from 2000 and onwards a larger amount of LAI products have been approved in multiple different therapeutic areas. LAIs are particularly relevant in areas with longer or chronic treatment, such as schizophrenia, hormone replacement therapies, immunodeficiency virus (HIV), and tuberculosis.^8-11 There is no agreed classification of the different LAIs in the academical literature, however, they can roughly be categorized into four main formulation classes as depicted in Figure 1, with some special systems not falling into any of these categories.

The field of LAI formulations is a broad and very interesting field, however, in the present article the focus will be on aqueous suspensions, which is the most frequently used formulation strategy for the marketed LAIs. A suspension is a dispersed multi-phased heterogenous system of insoluble particles – for parenteral applications primarily intended for intramuscular or subcutaneous injection. Suspensions are inherently thermodynamic unstable, and it is one of the most difficult parenteral formulations to both formulate and also to manufacture. An aqueous suspension for parenteral injection contains up to seven different component types, see Table 1, which should be defined as a part of the formulation work, as appropriate.

Compounds Suited for an Aqueous Suspension

For a compound to be formulated into an aqueous suspension one of the critical properties to ensure physical stability and to obtain the desired release rate is lack of solubility in the dispersing media, i.e., the compound should be relatively insoluble in both water and the micelles a potential stabilizer may form. The compounds used in current commercial LAI products are for the majority compounds that have been used orally for a period of time and then at a later stage been used in a LAI formulation. These compounds have clearly lacked the right physical chemical properties for a suspension, as most have been adjusted by conversion of the drug into a different solid form than used in the tablet or a prodrug. Esterification of an alcohol group with fatty acids have been the general approach. Esters can be hydrolyzed in vivo by the various esterases present at the administration site. The in vivo drug release is thereby driven by the slow dissolution rate of the crystalline prodrug, which is subsequently rapidly hydrolyzed. This provides a sustained plasma concentration profile of the active drug, but with negligible concentrations of the prodrug in the systemic circulation.^12-14 The atypical antipsychotic paliperidone (PAL) prodrug, has been developed based on this principle. The compound is esterified with palmitoyl ester and used in the aqueous LAI suspension. Similar examples exist of aripiprazole, where an N-methyl-ester have been formed to get a two months release relative to the one-month release for the hydrate of the parent drug molecule. Another way to decrease the aqueous solubility of a drug is by salt of solvate formation. Alternative new solid forms can be considered, which have been done in the olanzapine and aripiprazole LAI formulation.

Formulating an Aqueous Suspension

A critical formulation parameter for LAI suspensions is the particle size, as this defines the dissolution rate. Reducing the drug particle size results in an increased surface area, which leads to an increased dissolution rate, as described in the modified Noyes-Whitney equation, i.e., Nernst-Brunner equation, see equation 1. where dC/dT is the drug dissolution rate, D the diffusion coefficient, S the surface area, V the volume of dissolution medium, h the diffusion layer thickness, Cs the saturation concentration, C the concentration in the solvent, and t time. The size needs to be adjusted to the individual compound and to the release duration aimed for, e.g., three months.

This size has to be defined experimentally as the Nernst-Brunner equation can only be used conceptually to explain the concept, not accurately to calculate the particle size that would match the needed release rate. The particle size will vary as a function of both the release rate and the compound. For instance, the size of medroxyprogesterone acetate in the epo-Provera formulation have a mean particle size (Dv50) of around 10 μm, whereas cabotegravir in the Vocabria formulation is around 200 nm.

As mentioned above, suspensions are inherently thermodynamically unstable, hence they can potentially be subject to a number of physical instability phenomenon’s, see Figure 2. To prevent this a stabilizer/surfactant is added to the formulation. The main physical instabilities include particle interaction which may lead to flocculation, agglomeration or Ostwald Ripening dependent upon the way the change occurs. Some of these changes are reversible, e.g., sedimentation, others irreversible, e.g., Ostwald ripening. Stabilizers help prevent flocculation, coalescence and Ostwald ripening, which sometimes can be sufficient to stabilize the suspension. If the stabilizer is not sufficient it is possible to lower the chemical activity in the system by increasing the viscosity, i.e., adding a viscosity inducing agent such as sodium carboxymethylcellulose (sodium CMC) and if not sufficient the addition of a thixotropic excipient as Avicel CL-611 may help and as a last resort lyophilization can be considered. In short, a thixotropic system, is a gel when not exposed to extensive physical stress, e.g., shaking, but when exposed to physical stress it becomes like a liquid. This means that the suspension would be almost physically locked when on the shelf but can be activated into a liquid by the user or health care provider just before administration. Temperature is also an important parameter to consider for dispersed systems, when selecting stabilizers and when defining the storage temperature.

As described above, stabilizers, needs to be defined to e.g., prevent particle size growth in the suspension during shelf-life and to prevent caking, which would complicate resuspendability before administration. To support this, properties such as zeta potential, rheology, are particle size distribution are important parameters that need to be followed also as a part of the formal stability study. The stabilizers used should preferably, be well tolerated, and approved for parenteral use, however, as only a limited number of stabilizing excipients have been approved for parenteral use it may be needed to look beyond this point for a specific compound. Approved stabilizers include polymers such as cellulose derivatives (e.g., HPMC, HPC), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) and polyethylene glycols (PEG) and surfactants such as polysorbate 20 and 80, poloxamers 188, sorbitan monooleate (Span 80), and D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), and lecithin. Combination of these is obviously a possibility, which provide a lot of potential options to investigate. The stabilizing excipient selection can be challenging due to the lack of a fundamental understanding of their interactions within suspensions, where the DLVO theory forms the fundamental understandings. The stabilizers are first chosen for its ability to stabilize the suspensions from physical instability, but important for the formulator to consider is the potential impact the stabilizer may also have on the in vivo performance of the suspension, which may be influenced by a surfactant.^15,16 The drug to stabilizer ratio seen in literature has been described to vary from 1:3 to 50:1,^17,18 but specific compounds and stabilizer combinations may not necessarily fall inside this range.

The concentration of the solid (active pharmaceutical ingredient) in the suspension can vary significantly, from single digit %w/v up to 50% w/v, but as a good rule of thumb, achievable concentrations for most compounds will be in the range of 200-300 mg/mL. Beyond the stabilizer and viscosity increasing excipient isotonic agents, buffers, antioxidants etc. should also be considered.

Manufacturing an Aqueous Suspension

Reduction of particle size for suspensions for injection can be produced either by the top-down or the bottom-up methods. The production method will influence particle characteristics, such as particle size, crystallinity and surface properties and potentially also the selection of stabilizer. Therefore, the chosen method of production may play a role on drug suspensions stability and composition. The bottom-up approach includes precipitation of the compound into the desired particle range, which may be obtained by the anti-solvent method. Here the compound is solubilized in an organic solvent, when introduced into an aqueous media it will crystallize out. While no commercial products are currently produced by this approach, developments in crystallization technology may change this in the future.

The top-down approach is the current state-of-the-art method to obtain particles of reduced size and all current marketed parenteral suspension products are manufactured using top-down methods, which produce the desired particle sizes from bigger sized particles.

The most used top-down techniques are wet and jet milling, and homogenization using rotor stator or high-pressure homogenization (HPH).^19,20 In the case of HPH, the suspension goes through either a jet-stream homogenizer or a piston gap homogenizer. Wet ball milling is obtained by milling the suspension with beads, where the grinding is obtained by rotation or other methods of mechanical motion of the bulk.

For parenteral suspensions sterility should be considered, i.e., should the compound be isolated sterile or should it be gamma-radiated after crystallization. The vehicle that goes into the formulation should be sterile as well, which can be obtained by several methods.

However, dispersion systems are in general challenging as terminal heat sterilization is normally not an option, as it would destabilize the formulation physically and thereby reduce the quality of the product. Defining a sterile process for a disperse formulation is therefore a special case and needs to be truly considered both in small and large scale, i.e., what can be autoclaved, where can incubators be used, etc.

The LAI Development Process – the Project Management Part

Developing a formulation that releases the compound for a longer period of time needs to be done based upon diligent project planning, which would look very different when compared to plans used for development of more conventional formulations, where some of the considerations are mentioned below. It is beyond the scope of the present article to go into the detailed considerations for every step of the development process, hence this section below should be considered as a list for inspiration that is not exhaustive. Some of the important elements to consider include:

• Is there a clinical rational for a LAI and is the compound suited in a LAI?
• Compound or compound solid form
• Defining a formulation and how to obtain sterility
• In vitro dissolution studies and nonclinical studies to support the formulation development

Any project requires a clinical rational – as does an LAI project. If there are no benefits for patients, caretakers, healthcare professions or society then there is obviously not a project. However, as mentioned in the introduction experience from the antipsychotic space teaches that the patients will get a more effective treatment with LAIs, so there is reason to believe that the same experience could be obtained in other therapeutic areas. Having said this, there will of course be cases where these arguments do not apply, hence it makes sense to consider the potential benefits for all new LAIs before initiating the development work.

The compound is for most LAI projects preselected, as in most cases the compound has already been approved for oral usage. This means that information exists of the dose and clearance. A LAI formulation induces flip-flop pharmacokinetics; hence it can be evaluated in silico if there is a likelihood of using the compound in a LAI formulation reaching the clinically relevant plasma concentrations, see e.g., Rajoli et al.³ that have evaluated the possibility of converting four approved tuberculosis compounds into a LAI. It must be stressed that this evaluation cannot be translated into a formulation description, but only a risk evaluation for the project.

While the compound may be predefined, the physical form of the molecule used in the oral formulation may not be suited for a suspension, i.e., it may be too soluble which would lead to a fast release and a physically unstable suspension. The physical properties of the active compound may hence need to be adjusted by selection of a hydrate or a less soluble salt and if this does not work as a last resort a prodrug modification. As discussed above, this has been done on multiple compounds used in antipsychotic treatments, where both an oral and a LAI option is available, e.g., olanzapine and aripiprazole.

These activities need to be diligently planned and linked up to some formulation feasibility work to select the right form or prodrug. Formulation development of suspensions is largely described above, however, it is associated with a lot of experience-based decisions as there is a lot of scientific fundamental gaps in the field, e.g., defining a physically stable suspension and the suspension particle size to obtain the defined release rate is highly empirical.

The selection of the formulation needs support from both in vitro dissolution studies and nonclinical evaluations. With respect to the in vitro dissolution method, there is not much available support in the literature to develop the method, but there may be available organizational experience to support this approach if not it will be an important part of the development work – to develop discriminating in vitro dissolution methods for qualitative purposes. If a level A in vitro in vivo correlation can be obtained it would lead huge benefits for the project during development and after potential marketing.

Besides the in vitro work extensive in vivo work in nonclinical models should be considered – the advice would be to investigate as many factors as possible in the development phase to clarify the critical formulation parameters before entering clinical trials. Changing the formulation after start of clinical trials is not an easy task and it would take a considerable amount of time to do so due to the very extended-release profile. It is also highly advised to plan for more than one formulation in the initial human pharmacokinetic studies to risk deviate the project.

While a larger nonclinical package may be collected, the translatability into a human pharmacokinetic profile is not guaranteed and due to the inherent lack of scientific understanding of a suspensions physical stability this may also at a later timepoint make it needed to reconsider the selected formulation. Altogether from the start of the development to first-in-man it can easily take more than two years dependent upon the number of factors that needs clarification; however, it is the authors clear opinion that undertaking the effort will have a large and beneficial impact on the patient’s life that we serve as formulators and industry.

References

1. Kim YC, Min KA, Jang DJ, et al. Practical approaches on the long-acting injections. J Pharm Investig. 2020(50)147–57.
2. Okoli CTC, Kappi A, Wang T, Makowski A, Cooley AT. The effect of long-acting injectable antipsychotic medications compared with oral antipsychotic medications among people with schizophrenia: A systematic review and meta-analysis. Int J Ment Health Nurs. 2022;31(3):469-535.
3. Ascher-Svanum H, Faries DE, Zhu B, Ernst FR, Swartz MS, Swanson JW. Medication adherence and long-term functional outcomes in the treatment of schizophrenia in usual care. J Clin Psychiatry. 2006;67:453-460.
4. Nikam KR, Pawar MG, Jadhav SP, Bairagi VA. Novel trends in parenteral drug delivery system. Int J Pharm Technol. 2013;5:2549–2577.
5. Kovarova M, Benhabbour SR, Massud I, et al. Ultra-long-acting removable drug delivery system for HIV treatment and prevention. Nat Commun. 2018;9:4156.
6. Marmora L, Casas CP, Grubb I, McClure C. Long-acting technologies for infectious diseases in LMICs. Lancet. 2018;392:1610–1611.
7. Nachman S, Townsend CL, Abrams EJ, et al. Long-acting or extended-release antiretroviral products for HIV treatment and prevention in infants, children, adolescents, and pregnant and breastfeeding women: knowledge gaps and research priorities. Lancet HIV. 2019;6:e552–558.
8. Hirsch SR, Gaind R, Rohde PD, Stevens BC, Wing JK. Outpatient maintenance of chronic schizophrenic patients with long-acting fluphenazine: double-blind placebo trial. Report to the Medical Research Council Committee on Clinical Trials in Psychiatry. Br Med J. 1973;1:633–637.
9. Kaunitz AM. Injectable long-acting contraceptives. Clin Obstet Gynecol. 2001;44:73-91.
10. Remenar JF. Making the leap from daily oral dosing to long-acting injectables: lessons from the antipsychotics. Mol Pharm. 2014;11:1739–1749.
11. Swindells S, Siccardi M, Barrett SE, et al. Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges. Int J Tuberc Lung Dis. 2018;22:125–132.
12. Remenar JF. Making the leap from daily oral dosing to long-acting injectables: lessons from the antipsychotics. Mol Pharm. 2014;11(6):1739-49.
13. Cleton A, Rossenu S, Crauwels H, et al. A single-dose, open-label, parallel, randomized, dose-proportionality study of paliperidone after intramuscular injections of paliperidone palmitate in the deltoid or gluteal muscle in patients with schizophrenia. J Clin Pharmacol. 2014;54(9):1048-1057.
14. Rossenu S, Cleton A, Hough D, et al. Pharmacokinetic profile after multiple deltoid or gluteal intramuscular injections of paliperidone palmitate in patients with schizophrenia. Clin Pharmacol Drug Dev. 2015;4(4):270-278.
15. Wu L, Zhang J, Watanabe W. Physical and chemical stability of drug nanoparticles. Adv Drug Deliv Rev. 2011;63(6):456-469.
16. Chamanza R, Darville N, van Heerden M, De Jonghe S. Comparison of the local tolerability to 5 long-acting drug nanosuspensions with different stabilizing excipients, following a single intramuscular administration in the rat. Toxicol Pathol. 2018;46(1):85-100.
17. Patravale VB, Date AA, Kulkarni RM. Nanosuspensions: a promising drug delivery strategy. J Pharm Pharmacol. 2004;56(7):827-840.
18. Van Eerdenbrugh B, Van den Mooter G, Augustijns P. Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm. 2008;364(1):64-75.
19. Keck CM, Müller RH. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm. 2006;62(1):3-16.
20. Patravale VB, Date AA, Kulkarni RM. Nanosuspensions: a promising drug delivery strategy. J Pharm Pharmacol. 2004;56(7):827-840.

Author Biography

Dr. René Holm is a professor in pharmaceutical physical chemistry at the University of Southern Denmark, a position he has held since April 2021. Before that he worked for more than 20 years in the pharmaceutical industry. Professor Holm’s research is in the field of long acting injectables (LAI) for different modalities with a focus on the science behind the formulation systems, which will help de-risk the development process of LAI projects.

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