Long-Acting Injectable Nanoparticle Formulations

Jim Huang, PhD and Shaukat Ali, PhD - Ascendia Pharmaceuticals Inc.

Introduction

Long acting injectable (LAI) formulations have been the subject of continued interest in the recent past due, in part, to their longer systemic circulation requiring less frequent dosing of drugs.¹ Less frequent administration as illustrated in Figure 1, make LAIs more attractive from patient compliance perspectives. While delivering the extended release, LAIs can reduce toxicity and enhance the efficacy and safety of drugs. Other benefits also include the accessibility of medicines at nominal cost for underserved patient populations for treatment of life-threatening diseases like HIV as compared to long-term implants.²

Nanoparticles (NPs) continues to play an important role in the formulation and delivery of LAIs. As the interest in nanoparticles (NPs) continues to grow due to over 80% of new chemical entities and over 50% of marketed drugs being poorly soluble (in 250 ml volume and at pH 1-7.5), the industry is looking into alternative technologies for bringing insoluble Class II and Class IV molecules to market.³

LAI drugs are often formulated in appropriate carriers for their performance and longer shelf life. Those carriers in the formulations are for the most part lipids, polymers and surfactants that make them attractive as delivery vehicles because of their commercial availability and suitability with the route of administration such as intramuscular, intravenous and/or subcutaneous.⁴ Figure 2 illustrates the mode of injection of drugs. For example, intramuscular (IM) requires a deep injection at a 90° angle in the muscles, thereby, allowing drugs to be available in circulation for an extended period. On the other hand, in intravenous (IV) injection, the drug is administered at 25° angle directly in the bloodstream, avoiding the body defense systems; and in subcutaneous administration the drug is administered at 45° angle under the skin for systemic absorption, while in intradermal, it requires a 10°-25° angle administration for accessibility of drugs under the skin.⁵

As illustrated in Figure 2, the major modes of injection include intravenous, intramuscular, subcutaneous, and intradermal, among others. Injectable route of administration remains an indispensable method of treatments for practically all the modalities. In comparison with the oral route of administration, the parenteral route is most stringent and widely accepted for many unmet needs. It requires careful selection of ingredients free of bioburdens and endotoxins with greater compatibility for rapid onset, thus avoiding first-pass metabolism and to bypass the harsh gastrointestinal environment, and most of all improving patient safety. All these challenges also bring opportunities to drug developers and contract manufacturers as long the products critical attributes are satisfied to meet the FDA’s safety standards and guidelines.

Landscape of Nanoparticles and Injectable Drugs

Considering the efforts made over the years, specifically in parenteral NPs, the number of approved drugs is limited, and that is, due, in part, to challenges with poorly soluble molecules and challenges with tissues targeting.⁶ Perhaps it is no surprise and no different from the limited number of approved drugs such as amorphous polymeric solid dispersions in oral dosages or lipid-based SEDDSs solution/ dispersions in oral liquids, but the effort continues. As innovative NP technologies continue to unfold for yielding better and smarter formulations, the industry is open to adapt for bringing the new molecules to market.⁷ The lack of appropriate regulatory guidelines on NPs for addressing the often complex dosage requiring novel excipients or technologies for example, could be an impediment in the approval of new drug products.⁸ Other challenges stemming, for instance, from lack of guidance on method, validation, manufacturing, particle size reduction, high-pressure homogenization, sonication, extrusion, milling, use of organic solvents and impurities, stabilization and lyophilization among others, may lead to further delays.

An understanding of physical characteristics of NPs is important to address the risks in a drug product. Nanoparticles (NPs) are characterized as nanoemulsions, liposomes, polymeric nanoemulsions, micro-emulsions and saturated lipid nanoparticles and nanostructured lipid carriers. Lipids and/or polymeric aggregates have abilities to incorporate drugs in the interior lipophilic core allowing the exposure of hydrophilic moieties to outside aqueous media. The encapsulation of drugs, depends on hydrophilic lipophilic balance (HLB) values of lipids/solubilizers. Longer retention of drug within the inner assemblies due to stronger interactions with lipophilic carriers, recrystallization and precipitation, and premature leakage of drugs in storage over longer shelf lives, could pose challenges in design of robust NPs, especially, with fragile molecules like proteins and peptides in lipid based emulsions, microemulsions and nanoemulsions, liposomes, and to a lesser extend SLN and NLC. In such cases, the polymeric nanoparticles are widely considered, which are relatively more stable than surfactant/lipid-based NPs, and, therefore, they are better suited for sustained release applications.^9,10 Factors affecting the development of long acting injectable formulations also include, but are not limited to, reaction at the injection site or dilutions leading to drug recrystallization or minimizing the interactions of drugs with matrix leading to precipitation. All these challenges can be off set by designing and characterizing the right NPs by overcoming their solubility challenges. Figure 3 illustrates the evolution of NPs over the years, leading to more widely and predictable use of SLN and NLC for encapsulation, longer stability and efficient delivery of drugs.¹¹

Figure 4 illustrates the nanoplatform technologies for LAI formulations.¹² These formulation technologies have been used as the drug delivery carriers for parenteral, intramuscular and subcutaneous formulations for different modalities. Those include nanocrystals, polymeric nanoparticles, depots, hydrogels, SLN/NLC, liposomes, and liquid crystalline lamellar assemblies.

Relevance for Smaller Particle size

Particle size reduction is one of the important attributes leading to higher dissolution rates caused by higher surface area as it can be predicted by Noyes-Whitney equation 1. dm/dt is the dissolution rate, D is the diffusion coefficient, A is the surface area, h is the diffusion layer thickness, Cs is saturation concentration, Ci is concentration in solvent, and t is time.

$$ \frac{dm} {dt}=\Alpha.[D/h].(Cs-Ci) $$

Thus, smaller particle size means larger surface area, faster rate of dissolution and faster the rate of absorption of drugs.

From a manufacturing perspective, the particle size reduction is important which plays an important role in designing better and smarter LAI injectable formulations. The size reduction by mechanical devices can be achieved by a number of techniques. For example, producing the LAI nanosized suspension involves a top down approach wherein the API and the ingredients are mechanically mixed and homogenized or milled together avoiding the use of organic solvents altogether.¹³ This method also requires use of stabilizers and/or solubilizers to keep the particles small without flocculating or aggregating, and to maintain the longer shelf life. The top-down approach is probably the most widely used for manufacturing of liquid suspensions for parenterals because it can produce the desired particles size from larger ones. It involves techniques such as wet and jet milling where the grinding of the larger particles takes place through mechanical motion of the ball milling beads, and by high pressure homogenization process, in which the particle size reduction takes place through a jet stream homogenizer. There are other challenges associated with developing and characterizing LAI nanosized particles, which are not limited to, for example, lack of cGMP manufacturing and characterization protocols, drug loading and targeting, and release characteristics as it is all dependent upon the particle size distribution of nanoparticles.¹⁴

From mechanism perspectives, the particle size reduction plays an important role in cell recognition for their therapeutic efficacies. Nanoparticles (NPs) contribute to immunotherapy by tagging the protein moieties that triggers the activation of receptor signals on the T-cells.¹⁵ Medium sized NPs of about 300 nm have shown to trigger stronger immunogenic response as compared to smaller particles with 50 nm in size.¹⁶ It is also known that NPs with specific size promote their recognition and able to tag on by various circulating antibodies in the blood stream and/or able to activate the complement proteins upon interaction with blood opsonins. These pathways lead to phagocytosis by macrophages.¹⁷ In another scenario, NPs can be surface modified to substantially minimize the interactions with complements to trigger the immune response, thereby, they can be used in long acting injectables by enabling longer systemic circulation.¹⁸ These attributes are essential, for example, in the development of immunotherapeutics and vaccines with NPs engineered by enabling significant interactions, and/or posing a lesser degree of interactions for development of long acting formulations. These are important questions and embarked on with the notion of engineering these surface-modified NPs to be amenable to meet the product’s critical attributes.

Long-Acting Injectable Marketed Drugs

Table 1 shows the list of FDA drugs approved in lipid and polymeric based NPs.¹²

Over the years several LAI drugs have been approved. Those drugs are marketed in crystal nanosuspensions, liposomes, polymeric nanoparticles, and also in oil suspensions, and/or hydrogels. In liposomes, for example, the drug is encapsulated within the bilayers, allowing the drug to release through a membrane. In LAI prodrug formulations, the fatty acid-derived drug is released slowly by cleavage of the lipophilic chains, or by slowly dissolving and releasing in systemic circulation.¹⁹ Olanzapine pamoate, for example, a prodrug of olanzapine slowly releases the parent molecule upon intramuscular (IM) injection. Invega Sustenna®, Invega Trinza®, and Invega Hafyera® marketed as prodrugs for treatment of schizophrenia and dosed as LAI suspensions monthly, every three months, or every six months, respectively, also release slowly by cleavage of parent molecules over extended periods. Commercially available first generation and second generation of LAI anti-psychotic drugs are shown in Table 2 (first generation) and Table 3 (second generation).²⁰

Table 4 shows the PLGA based LAI microspheres/implants marketed drugs.⁸

Several marketed LAI products have been developed utilizing oil-based systems, aqueous suspensions, polymeric microspheres, hydrogels among others.²¹ Long-acting injectable lipid-based formulations are the first wave of products entering the market utilizing an oil-based solution in which drug is dissolved in the oil with or without a cosolvent. As the number of poorly soluble molecules continues to rise, the LAI approach has been more relevant for maintaining the drug in systemic circulation with longer efficacies and with less frequent dosing for treatment of life-threatening ailments. In other words, the sustained release achieved by subcutaneous, intramuscular or intravenous solution oil/emulsions and suspensions, probably bears the hallmarks of long-acting injectable formulations. The molecular weight and size of the particulates play a key role in long-acting release. For instance, the macromolecules with MW 16 kD or less, and particle size 100 nm or less, can be cleared from the tissues by lymphatic systems, whereas, the larger particulates may retain longer and act as the long-acting formulations due to their smaller surface area to volume. Thus, an understanding of encapsulating a drug in larger nanoparticles for extended release, is important for designing the long-acting injectable systems. The oil based long acting and lipid based long injectable systems, however, face some challenges; for example, the oil based LAI can lead to long lasting pain and irritation at injection site, therefore, to overcome these issues, the lipophilic lipid based or polymeric based nanoparticles for lipophilic drugs have been used as alternatives to oil based systems.²²

Higher drug loading and stability of molecules encapsulated in NPs have been obvious reasons for concerns and opportunities. Therefore, finding an appropriate carrier with the ingredients compatible with the drug in the LAI matrix has been subject of continued interest and is used as a tool to assess the stability and release mechanism. NPs due to their outer rigid protective nature may lower the barrier for API’s penetration in the systemic circulation through blood or lymphatic systems. Local long acting and systemically injected long-acting formulations play a key role in extended release of drugs from engineered nanoparticles by prolonging the release of payload from the nanocarriers. In sustained release, however, the nanoparticles get accumulated in the targeted tissues allowing the drug release via passive mechanism.

Long-Acting Injectable Suspensions

LAI lipid-based formulations can either be oil-based solutions, suspensions or more complex lipid-based nano carriers such as liposomes, emulsions/microemulsions, or lipid-based depots such as oleogels or liquid crystals. There is a continued interest in LAI suspensions or liquid crystals for controlled release applications. As it sounds, these suspensions provide a slower or sustained release and have advantages over oral formulations because of their less frequent administration and better controlled mechanism with reduced side effects in an aqueous suspension. An aqueous LAI suspension might be thermodynamically unstable due to heterogeneous insoluble particles, but can be stabilized with lipid based like polyoxyl 35 castor oil, polysorbate 80 or polymeric based ingredients like povidone (PVP) or poloxamer, and/ or can be stabilized by lyophilization with cryoprotectants for longer shelf life and for facile reconstitution in buffer. APIs prone to hydrolysis, such as prodrugs or derived from lipophilic moieties tethered with ester linkages, can trigger the slower release over extended periods when formulated or reconstituted in aqueous suspensions from lyophilized powders The physical instability of suspensions, triggered by flocculation, phase separation and/or by Oswald ripening, could be challenging due to lack of clear understanding of the mechanisms. In cases like these, certain ingredients can be used to minimize the morphological changes and maintain the particle size with optimal drug loading. The maximum achievable concentrations of the drugs in the suspension could range 200-300 mg/ml, and with higher drug loading, it could run into instability leading to precipitation and crystal growth. In such cases, use of stabilizers, anti-oxidants, particle size reduction, viscosity inducing agents, buffer strengths among other factors, should be considered.²³

Long-Acting Injectable Lipid-Based Formulations

Lipid-based LAIs are oils, aqueous suspensions and olegels. There are several oil-based LAIs approved in the market drugs, for examples, with castor oil (Fulvestrat - Faslodex®), cotton seed oil (Testosterone cypionate - Depo-Testosterone®), sesame oil (Haloperidol decanoate-Haldol®), and cotton seed oil (Zuclopenthixol decanate - Clopixol®), are all administered intramuscularly (IM). LAI activities of these drugs stem from lipophilic fatty acid tethered prodrugs that allow the release of a parent molecule by hydrolysis or by cleavage of the ester linkages. While the longer fatty acid slows down the release of drug due to higher partition barrier from oil phase to aqueous phase in an oil-based or suspension based LAIs, but it also runs the risk for reducing the potency of parent molecules, that could lead to failure in toxicological studies.²⁴ Lipophilicity and higher log P tend to slower release following IM injection, allowing the API uptake predominantly by lymphatic systems.²⁵ In cases where API is hydrophilic, for example, olanzapine, molecular modification with fatty acid can further reduce the solubility to offset the rapid release of drug, making it ideal for sustained release and uptake by lymphatic systems.²⁶

Other factors such as viscosity of injectable oils may have a significant impact on the release of drugs. Sesame oil and organogels with higher viscosity and an excellent tolerability by IM, can lead to slower release and partitioning by diffusion mechanism from oil/gel into body fluid. Suspensions in oil of drug crystals is an alternative to oil-based LAIs. It is different from the suspensions in aqueous for injection. Oil based suspensions have limited scope because of injection difficulties and pain as the injection site, therefore, the aqueous solutions-based LAI suspensions are preferably and are better alternative than oil based suspensions. Lipid based liquid crystal forming systems are another alternative to LAIs formulations. The liquid crystalline ability of lipids can provide a controlled release mechanism by entrapping the drugs into the inner core of the fatty acid lipids. Hence, the sustained release is the result of of slower diffusion of drug through mesophase membrane. There are three mesophase, lamellar, hexagonal and cubic with hexagonal and cubic are being most widely studied.

In Vitro Drug Release Characterization

There is no reliable pharmacopeial guidance on in vitro drug release assessment of IM drug formulations. Though there are some methods used in vitro for the assessment of drug release but none is without any challenges. Larsen and Larsen, 2009, used several methods for oil based parenteral solutions, the in vitro methods have been modified. Table 5 shows the in vitro methods for assessment of drug release from lipid-based LAI oleogel/liquid formulations.²⁷

Sterilization Methods

The sterility of the LAI suspensions is also of relevance in maintaining the stability of nanosized particles. Thus, not all the methods used for sterilization are suited for these formulations. For instance, autoclaving or terminal heat sterilization are less likely used as they can destabilize the physical stability and compromise the product’s critical quality attributes, especially those derived from lipid nanoparticles. Gamma radiation sterilization might be a better option for suspensions or by aseptic filling conditions in closed containers or syringes to avoid cross-contamination.²⁸ As shown in Table 6, a number of sterilization methods have been used for NPs that might be extended for other formulations.²⁹ The excipients in the formulation should also be sterilized by several methods. When considering the scale-up and sterilization of these LAI nanosized suspensions, the process is cumbersome and may lead to batch variabilities if the processes are not optimized, leading to poor product quality attributes and compromised performance of drug products.

It is obvious that the choice for method of sterilization is based on the formulations and nature of the ingredients used in the NPs and LAIs.

Sterile Aseptic Filing and Lyophilization Injectable Formulation Capabilities

Ascendia is a specialty CDMO having the sterile capabilities for NPs and LAIs. Its proprietary solubilization enabling technologies aimed at improving the solubility and bioavailability of molecules are: NanoSol®, EmulSol®, and LipidSol® can handle the molecules, small, large or biologics, and enable the effi ciently delivery of these molecules. In NPs drug is encapsulated and stabilized into interior lipophilic cores of oils/ aqueous suspension or in liposomes.

Carvedilol, a marketed drug in tablets has been formulated @6.8% in lipid-based liposomes comprised of about 52% DMPC, 21% Cholesterol and 22% DSPE with particle size distribution of 75-150 nm and polydispersity of 0.12-19 and encapsulation efficiency of 80-90%. For comparison, carvedilol both in aqueous solution and in liposomes encapsulated @7.6% and comprised of 65% egg phospholipids and 27% cholesterol (freshly prepared and lyophilized and reconstituted) were also used to evaluate in vitro drug release and examine the pharmacokinetic profiles in rats. The carvedilol was single dosed at 2.5 mg/kg. In vitro release and pharmacokinetic (PK) data of drug from 3 animal groups (Group 1 with DMPC, Group 2 from egg PC and aq. solution Group # 3, were also evaluated and the results are shown in Figure 5.

In vitro dissolution data shows that the drug is released over several hours from the liposomes prepared with egg PC/cholesterol or DMPC/ cholesterol/DSPC. The PK data suggests that liposome entrapped carvedilol shows an extended release over 24 hours as compared to non-liposomal formulation.

There are other examples of LAIs utilizing the PLGA for sustained release of several drugs. Ascendia’s enabling solubilization technologies can overcome the challenges by designing the smarter formulations for extended-release over several weeks or months (data not shown).

Designing the LAIs for sustained release over extended period requires a careful selection of appropriate lipids, solvents and/or polymers. Wilkinson et al. (2022) describes a range of ingredient suited for such application with cautions because of toxicity/safety concerns, compatibilities and stability issues.³⁰ For example, super refined oils can minimize the oxidation and hydrolysis of drugs in LAI formulations.³¹ Thus, longer stability in fatty acids and oil phase of drugs sometimes could be problematic if it designed for over several weeks or months for delivery. Ascendia’s capabilities in long term stability ICH chambers offer clients confidence in the development of LAIs formulations for different modalities. Table 7 shows the company’s sterile for parenteral and non-sterile for oral capabilities.

Conclusion

As the new molecules continue to come out from discovery, the lack of resources persists within the industry to tackle the different modalities, especially, those requiring special techniques and handling capabilities, CDMOs like Ascendia will play an important role in formulation development and manufacturing of drug products for bringing them faster to clinics and market. The formulation and analytical expertise and cGMP manufacturing sterile, aseptic pre-fill syringes and lyophilization capabilities, would be most acceptable criteria in minds of partners when developing the LAI drugs in order to reduce time and save cost. Ascendia’s internal capabilities in LAIs having with technical expertise in R&D and cGMP manufacturing will invite the companies to build stronger partnership for launching the new life-saving medicines.

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Author Biographies

Jim Huang is the founder and CEO of Ascendia Pharmaceuticals, Inc. Dr. Huang received his Ph.D. in Pharmaceutics from the University of the Sciences in Philadelphia (formerly Philadelphia College of Pharmacy and Sciences) under Joseph B. Schwartz. He has more than 20 years of pharmaceutical experience in preclinical and clinical formulation development, manufacturing, and commercialization of oral and parenteral dosage forms. Dr. Huang’s research interests are centered on solubility/bioavailability improvement and controlled delivery of poorly water-soluble drugs through nano-based technologies.

Shaukat Ali joins Ascendia Pharmaceuticals Inc. as senior director of scientific affairs and technical marketing after having worked in the pharma and biotech industry for nearly 30 years. His areas of expertise include lipid chemistry, liposomes, surfactants base drug delivery systems, SEDDS/SMEDDS, oral and parenteral, topical and transdermal drug delivery, immediate and controlled release formulations. He received his PhD in Chemistry from the City University of New York and postdoc training at the University of Minnesota and Cornell University. Dr. Ali has published over 50 articles in the scientific journals and is inventor/co-inventor of several US and European patents. He is the recipient of IPEC’s Henk de Jong industrial research award and serving as a member of the USP panel of expert for Excipient Test Methods committee.

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