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Utilizing 505(b)(2) Regulatory Pathway for New Drug Applications: An Overview on the Advanced Formulation Approach and Challenges

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Copyright © DrugPatentWatch. Originally published at Utilizing 505(b)(2) Regulatory Pathway for New Drug Applications: An Overview on the Advanced Formulation Approach and Challenges

This article was originally published by Jiayi Chen, Zhifeng Zhao, Xinyu Wang and Jingjun Huang in Drug Repurposing – Advances, Scopes and Opportunities in Drug Discovery and is republished here under a  Creative Commons Attribution 3.0 License

Table of Contents

Abstract

More than 50% of approved drugs on the market contain poorly water-soluble APIs, which typically are associated with poor bioavailability, suboptimal drug delivery, ineffective drug efficacy, and side effects. This creates a huge opportunity in generating 505(b)(2) products, which address unmet medical needs by applying formulation technologies to overcome those difficulties. A key feature of the 505(b)(2) pathway is the 505(b)(2) sponsor can rely upon clinical data or literature produced by other companies. The 505(b)(2) pathway allows manufacturers to acquire FDA approval without performing all the work required with a traditional NDA. The 505(b)(2) strategy can be an option to improve existing drug products with a new indication, dosage form, dosing regimen, strength, combination with other products, new route of administration, elimination of food effect, switching from a prescription drugs (Rx) to an over-the-counter (OTC), non-prescription product that differs from the OTC monograph, and orphan drug indications. Both generic and brand companies are turning to more complex 505(b)(2) products to avoid the commoditized generic competition. Revitalization of older marketed drug products using innovative drug delivery technologies or platforms can provide new marketing exclusivity and new patent protection, and thus offer an effective tool for product life cycle management.

Introduction

The United States Food and Drug Administration (FDA) published the Draft Guidance for Industry Applications Covered by Section 505(b)(2) in 1999 which for the first time introduced this section of the Federal Food, Drug, and Cosmetic Act (FFDC). By definition, the 505(b)(2) application is “a new drug application (NDA) that contains full reports of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference.” [1] It is submitted under Section 505(b)(1) of the Act and approved under Section 505(c) of the Act. Compared to the other two types of application described under Section 505, i.e., Section 505(b)(1), an application that contains full reports of investigations of safety and effectiveness; and Section 505(j), sometimes referred to as abbreviated new drug application (ANDA), an application that contains information to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics, and intended use, among other things, to a previously approved product, 505(b)(2) pathway offers unique benefits for drug developers and sponsors: (i) Low risk, time and cost effectiveness. 505(b)(2) allows the sponsor to rely on the FDA’s previous findings of approved drug’s safety and effectiveness, and publicly available literature without the right of reference. The substantially reduced studies and required resources result in a 2–5 years program prior to the FDA approval as compared to 8–15 years for a full NDA, and meanwhile cut the cost from 0.5–2 billion to 3–7 million dollars [2]. (ii) Flexibility. Contrary to 505(j) pathway which only permits certain degree of flexibility in terms of additional physicochemical characterization to demonstrate therapeutically equivalence (TE), 505(b)(2) encourages additional clinical studies to assess drug safety and efficacy profiles, which renders a scientifically more robust alternative for approving complex generics with unnecessarily a TE rating. (iii) Market exclusivity. The 505(b)(2) approved drug product may be warranted by FDA a 3 to 5 years market exclusivity depending upon the extent of changes to the reference product and the type of clinical data included, new intellectual property rights and/or an “AB” substitution rating in the Orange Book (AB: actual or potential bioequivalence problems have been resolved through adequate in vivo and/or in vitro testing) [3].

In short, 505(b)(2) provides a midway between 505(b)(1) and 505(j) in terms of the volume of new evidence required to be generated and submitted to the FDA. For sponsors and investors, 505(b)(2) pathway presents as a lower risk, time and cost option, and meantime a great market potential especially as many of the “blockbuster drugs” patents and other protected drugs are expiring. Figure 1 is a schematic representation of the three FDA approval pathways [4]. Table 1 lists some major differences and similarities in the registration process among the three pathways [2].

Figure 1. Schematic representation of the three FDA drug approval pathways [4].
Component505(b)(1)505(b)(2)505(j)
StudiesFullPartialBA/BE
New ingredientsYesYesNo
New FormulationsYesYesNo
PatentedYesYesNo
Market exclusivity5 years3–5 years6 months
Agency meetingsYesYesNo
Review classification9 months9 months6–12 months
Timing8–15 years2–5 years1–2 years
Costs$500 m – 2b$3 m – 7 m$50 k – 750 k
Clinical trialsYesMaybeNo
Non-clinical / Toxicology dataYesMaybeNo
PK/BA/BE studies with RLDN/AYesYes
New dosage form/strengthYesYesNo
Combination productYesYesMaybe

Table 1. Differences and similarities in the registration process as per NDA (505(b)(1)), 505(b)(2), and ANDA (505(j)) [2].

The aforementioned features of 505(b)(2) have driven industry’s growing interest to utilize this pathway. It was barely used following the first a few years after it was codified by the Hatch-Waxman Act. However, the number of 505(b)(2) approvals slowly increased in the beginning of the 1990s and sharply increased around 2003–2004, when the number of approved drugs through 505(b)(2) superseded new molecular entities (NMEs) approved through 505(b)(1). Nowadays, 505(b)(2) accounts for more than 60% of the total approved new drug applications. Figure 2 shows the number of drugs approved through 505(b)(2) compared with 505(b)(1) [5].

Figure 2. FDA approvals of 505(b)(1) (NMEs only) and 505(b)(2) applications, 2003–2020.

By nature, 505(b)(2) is an NDA which can be an option to improve existing drug products with new indication, route of administration, dosage form, formulation, strength, multiple drugs combination, dosing regimen, over-the-counter (OTC) switch from prescription drug (Rx), and orphan drug indications, etc. [6], which means that there are numerous approaches to fully take advantage of the 505(b)(2) pathway. A retrospective analysis revealed that out of 224,505(b)(2) NDAs approved by FDA between January 2012 and December 2016, the most prevalent type of FDA submission class fell in type 5 (new formulation or new manufacturer; 43.3%), followed by type 3 (new dosage form; 28.6%) and type 4 (new drug-drug combination; 12.9%) [7]. It is clear that both generic and brand companies are turning to more complex 505(b)(2) products to avoid the commoditized generic competition [4]. In addition, reformulation of a conventional drug product by newly emerged technologies is an effective way to improve the drug efficacy, safety and patient compliance, and to grant new marketing exclusivity and patent protection.

This chapter, hence, aims to provide an overview on selected advanced formulation technologies including liposome, nanoemulsion, long-acting suspension, polymeric microsphere and their respective 505(b)(2) approved products. The features of each formulation approach are elaborated. Typical case is illustrated. The challenges within the analytical characterizations and testing of these complex 505(b)(2) products, and the potential obstacles with regards to the manufacturing and regulatory perspectives are also highlighted.

Liposome

Tracing back to as early as 1960’s, liposomes – the microscopic phospholipid bubbles with single or several concentric lipid bilayered structure, have drawn tremendous research interest as potential pharmaceutical carriers due to attractive biological properties. They are biocompatible; they have capability of entrapping hydrophilic pharmaceutical moiety in the inner aqueous compartment as well hydrophobic pharmaceutical agent into the lipid membrane; liposomes are highly tunable in size (from less than 100 nm to several micron), charge and surface properties (PEGylated or ligand modified) by formulation and/or preparation methods to achieve favorable physicochemical and biological features; they also offer unique opportunity to protect the encapsulated cargo from undesired environment and to deliver pharmaceutical agents to target cells, or even sub-cellular compartments. These advantages and highly tunability have made liposome an ideal drug delivery system (DDS) for various pharmaceutical agents including water-soluble/insoluble small molecules, peptides, proteins, DNAs, imaging agents, etc., in therapeutical and diagnostic applications. The research and development effort, and clinical investigation led to the breakthrough as Doxil® (liposomal doxorubicin) was approved by the FDA as the first nanodrug. Thereafter, numerous liposomal drugs have been successfully developed and marketed (Table 2).

Product nameIndicationRoute of administrationActive substance/StrengthExcipient formulation
AbelcetInvasive fungal infectioni.v. infusionAmphotericin B / 5 mg/mLl-α-dimyristoylphosphatidylcholine (DMPC) 3.4 mg/mL, l-α-
dimyristoylphosphatidylglycerol (DMPG) 1.5 mg/mL, NaCl 9.0 mg/mL, WFI q.s. 1 mL
AmbisomeSevere fungal infectioni.v. infusion after reconstitutionAmphotericin B / 50 mg/vialAlpha tocopherol 0.64 mg, cholesterol 52 mg, distearoylphosphatidylglycerol 84 mg, hydrogenated soy phosphatidylcholine 213 mg, disodium succinate hexahydrate 27 mg, sucrose 900 mg, and HCl and/or NaOH
Arikayce1Mycobacterium avium complex (MAC) lung diseaseOral inhalationAmikacin sulfate / 590 mg/8.4 mL baseCholesterol, dipalmitoylphosphatidylcholine (DPPC), NaCl2, NaOH and WFI
Daunoxome2HIV related Kaposi’s sarcomai.v. infusionDaunorubicin citrate 2 mg/mL baseDistearoylphosphatidylcholine 28.2 mg/mL, cholesterol 6.7 mg/mL, sucrose 85.0 mg/mL, glycine 3.8 mg/mL, calcium chloride dihydrate 0.3 mg/mL
Depocyt2Lymphomatous meningitisIntrathecalCytarabine / 10 mg/mLCholesterol 4.1 mg/mL, triolein 1.2 mg/mL, dioleoylphosphatidylcholine
(DOPC) 5.7 mg/mL, dipalmitoylphosphatidylglycerol (DPPG) 1.0 mg/mL, NaCl 9.0 mg/mL
Depodur1,2Surgery painEpidural administrationMorphine sulfate pentahydrate/ 10 mg/mL1,2-dioleoyl-sn-glycero3-phosphocholine (DOPC) 4.2 mg/mL, cholesterol 3.3 mg/mL, 1,2-dipalmitoyl-sn-glycero3-phospho-rac-(1-glycerol) (DPPG) 0.9 mg/mL, tricaprylin 0.3 mg/mL, triolein 0.1 mg/mL, NaCl 9 mg/mL
DoxilKaposi’s sarcoma, ovarian/breast cancer, multiple myelomai.v. infusionDoxorubicin hydrochloride / 2 mg/mL baseN-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-
3-phosphoethanolamine sodium salt (MPEG-DSPE) 3.19 mg/mL, fully hydrogenated soy
phosphatidylcholine (HSPC) 9.58 mg/mL, cholesterol 3.19 mg/mL, ammonium sulfate, approximately 2 mg, histidine, sucrose, HCl or NaOH
Exparel1Postsurgical analgesiaLocal infiltrationBupivacaine / 13.3 mg/mLCholesterol 4.7 mg/mL, 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG) 0.9 mg/mL, tricaprylin 2.0 mg/mL, 1, 2-dierucoylphosphatidylcholine (DEPC) 8.2 mg/mL, NaCl 9.0 mg/mL
Marqibo1,2Acute lymphoblastic leukemiai.v. infusionVincristine sulfate / 0.16 mg/mL after preparationKit contains vincristine sulfate injection, USP (5 mg/5 mL), sphingomyelin/cholesterol liposome injection (103 mg/mL), sodium phosphate injection (355 mg/25 mL)
Onivyde1Metastatic pancreas adenocarcinomai.v. infusionIrinotecan hydrochloride trihydrate / 4.3 mg/mL base1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) 6.81 mg/mL, cholesterol 2.22 mg/mL, methoxy-terminated polyethylene glycol (MW 2000)-distearoylphosphatidyl ethanolamine (MPEG-2000-DSPE) 0.12 mg/mL, 2-[4-(2-hydroxyethyl) piperazin-1-yl] ethanesulfonic acid (HEPES) 4.05 mg/mL, NaCl 8.42 mg/mL
VisudyneMacular degenerationi.v. injectionVerteporfin / 15 mg for reconstitutionLactose, egg phosphatidylglycerol, dimyristoyl phosphatidylcholine, ascorbyl
palmitate and butylated hydroxytoluene
Vyxeos1Acute myeloid leukemiai.v. infusionDaunorubicin and cytarabine / 44 and 100 mgDistearoylphosphatidylcholine 454 mg,
distearoylphosphatidylglycerol 132 mg, cholesterol HP 32 mg, copper gluconate 100 mg,
triethanolamine 4 mg, and sucrose 2054 mg

Table 2. FDA approved liposomal drug products via 505(b) pathway.

Abbreviation: i.v.: intravenous; NaCl: sodium chloride; NaOH: sodium hydroxide; HCl: hydrochloric acid; WFI: sterile water for injection.

The development of Doxil® is enlightening as a showcase of an NDA using advanced formulation approach. A brief historical perspective (Table 3) is elaborated herein but readers are highly encouraged to dig through the publication by Barenholz [8] for more details. The selection of the model drug Doxorubicin (DOX), an anthracycline chemotherapeutic agent, was deliberated. DOX is effective against a broad spectra of cancer types than any other class of chemotherapy agents, thus it has remained the “first line” anticancer drug from discovery till today [9]. Nevertheless, the use of free drug solution (Adriamycin) was limited by toxicities, especially dose-dependent cardiotoxicity which causes irreversible congestive heart failure, among other side effects [10]. The drug’s physicochemical properties were well established, as were its stability [11] and ADME (Absorption, Distribution, Metabolism and Excretion) knowledge [12]. The distinct spectral properties of DOX (high molar extinction at 486 nm, long wavelength > 550 nm and high quantum yield fluorescence emission) makes the quantification sensitive and accurate [13]. Its state of aggregation, hygroscopicity, chemical degradation, pH change in its local environment, etc. are all well-known at the time of the development. Taking advantage of the aforementioned drug properties, the “first generation” liposomal DOX was developed using negatively charged, medium sized oligolamellar liposomes (OLV-DOX) composed of two low chain melting – phospholipids (egg phosphatidylcholine and egg phosphatidylglycerol) and cholesterol. DOX was passively loaded during the lipid hydration and hence membrane associated. Unfortunately, OLV-DOX did not survive in the First in Man (FIM) trial due to multiple folds of reasons: (i) rapid release of DOX in plasma, likely due to the drug location in the liposome bilayer as opposed to encapsulation in the aqueous interior [14]; (ii) high mole fraction of phosphatidylcholine in the bilayer accelerates uptake by reticular-epithelial system (RES) [15] and (iii) size is too large to allow for extravasation in extra-hepatic tissues [16] and to fully utilize the enhanced permeability and retention (EPR) effect [17, 18].

YearEvent
1979Fundamental research on liposomal doxorubicin initiated by Gabizon and Barenholz
1984“First in man” (FIM) trial with “first generation” of liposomal doxorubicin (OLV-DOX) initiated
1987OLV-DOX clinical trial failed
1988“Remote loading” of doxorubicin was patented
1989Doxil development initiated
1991FIM trial on Doxil initiated in Jerusalem, Israel
1994Major publication on Doxil clinical trials (Cancer Research 1994)
1995FDA approval of Doxil
2010US patent expired

Table 3. Historical timeline of Doxil development and regulatory affairs [8].

Though not successful, the failure of OLV-DOX served as the main driving force towards two unrelated technologies to address the shortcomings in OLV-DOX, both of which ultimately became the foundation of Doxil. Notably, Doxil does not have direct patent on itself. Rather, it is based on the two families of patents which will be further elaborated, and indeed Doxil enjoyed 14 years of patent protection in the US thanks to the underlying cornerstones. The first technology, namely “remote (active) loading”, was to achieve a viable formulation with desired intra-liposome drug concentration, usually defined as drug to lipid molar ratio [19], by pH gradient for many amphipathic weak bases [20], or in the case of Doxil, based on a transmembrane gradient of ammonium sulfate to load drug into preformed liposomes [19, 21]. The second technology was to formulate long circulating liposome with extend plasma half-life (t1/2), reduced RES uptake and increased intra-tumor accumulation. Several approaches to alter the lipid composition thus to create a steric stabilized lipid bilayer were studied to achieve the goal, which includes the addition of GM1 ganglioside [22], the use of hydrogenated phosphatidylinositol (HPI) [15] and synthetic pegylated phospholipids (PEG-DSPE) with different PEG chain length ranging from 350 to 15,000 Da [23, 24]. Small unilamellar liposomes with narrow unimodal size distribution having a mean size of ~100 nm was prepared by medium pressure extrusion using polycarbonate filters with defined pore size [25]. Considering the availability and cost, etc. factors, GM1 ganglioside-based formulation was excluded in the race [24]. Subsequently after a critical comparative PK study in Beagle dogs [26], 2000 Da PEG-DSPE was demonstrated superior over HPI as the steric stabilizer for the similar nano-liposomes, which was ultimately determined to be the integral component of Doxil.

Nanoemulsion

Emulsion, a heterogeneous mixture of two or more immiscible liquids stabilized by a third component (emulsifier), can be generally categorized into two types: oil in water (o/w) and water in oil (w/o), whereas the former liquid is dispersed and stabilized in the latter liquid. Lipid emulsion of the o/w type was firstly evolved in the World War II to serve as an intravenous source of calories and essential fatty acids. The development is based on the rationale that such emulsion is very similar in structure as chylomicrons produced by human body, which is comprised of triglycerides, proteins, free cholesterol and phospholipids. After about 14 years of safe clinical use in European countries, Intralipid® was approved and launched in the US in 1975 for parenteral nutrition indication [27]. However, it was not until late 1980’s that lipid emulsion has started to draw researchers’ interest as a carrier system for drug delivery. Indeed, the generally non-toxic components of the lipid emulsion alleviate the safety concerns. Besides, lipid emulsion offers some important advantages such as:

  • reduction in pain, irritation, and thrombophlebitis when administered by injection,

  • reduced systemic toxicity from the free drug or the solvent/surfactant used,

  • improved lipophilic drug solubility, as well as stability especially in the case of susceptibility to oxidation or hydrolysis, and

  • potential targeted delivery [28].

To fully utilize emulsion as an effective DDS, a major formulation concern is the physical stability of the formulation, besides other considerations such as drug compatibility, etc. Hence, a subtype of emulsion, the nanoemulsion, has evolved and become a viable approach to deliver drug systematically or locally (Table 4). These nanoemulsions are named after their submicron droplet size ranging from 10 to 1000 nm. Unlike solution, they are thermodynamically unstable systems that trend towards separation into two discrete phases over time. However, by deliberate selection of the type of oil and surfactant type and composition ratio, the stability time frame of the formed nanoemulsion can be substantially extended to a sufficient shelf life for months or even years, given the system is kinetically stable. In addition to the improved stability, suitable droplet size (as characterized by particle size distribution (PSD)) and surface properties of nanoemulsion also dictate their in vivo performances after systemic administration, usually governed by the biodistribution, cellular uptake, etc. Studies have revealed larger sized droplets (>250 nm compared to <100 nm) were cleared faster from the body, indicating a great role of mononuclear phagocyte system (MPS) in the clearance of these nanoemulsion [29]. Moreover, droplet size has also been demonstrated to determine the intratumor distribution versus the peripheral tissues [30]. Therefore, it is in common agreement that nanoemulsions with mean droplet size of less than 150 nm and a narrow, unimodal distribution is highly favored. Besides, a slightly negative charged surface of the nanoemulsion can efficiently prevent the interaction with cells due to electrostatic repulsion thus are not readily taken up by liver and macrophage cells [31]. Therefore, egg derived phospholipids are generally formulated into the nanoemulsion to provide this negative charge besides its overall profound emulsifying and stabilizing properties. Neutral droplet surface or stealth coating can be alternative ways to provide similar “inert” effect, fulfilled by using non-ionic surfactants and/or PEG [32].

Product nameIndicationRoute of administrationActive substance / StrengthExcipient formulation
Aponvie2Postoperative nausea and vomitingShort i.v. infusion over 30 sAprepitant / 32 mg/4.4 mLIn 4.4 mL: dehydrated alcohol 0.13 g, egg lecithin 0.64 g, sodium oleate 0.02 g, soybean oil 0.42 g, sucrose 0.24 g, and WFI 2.97 g
Camcevi2Advanced prostate cancers.c. injectionLeuprolide mesylate / 42 mg/pre-filled syringeEach pre-filled syringe contains:
poly(D, L-lactide) 184 mg and N-methyl-2-pyrrolidone 136 mg
Cinvanti2Emetogenic chemotherapy associated nausea and vomitingi.v. infusionAprepitant / 130 mg/18 mLIn 18 mL: egg lecithin 2.6 g, ethanol 0.5 g, sodium oleate 0.1 g, soybean oil 1.7 g,
sucrose 1 g, and WFI 12 g
CleviprexBlood pressure reductioni.v. infusionClevidipine butyrate / 0.5 mg/mLSoybean oil 200 mg/mL, glycerin 22.5 mg/mL, purified egg yolk phospholipids 12 mg/mL, NaOH, WFI q.s.
Clinolipid 20%Parenteral nutritioni.v. infusionRefined olive oil / 160 mg/mL; Refined soybean oil / 40 mg/mLEgg phospholipids NF 12 mg/mL, glycerin 22.5 mg/mL, sodium oleate 0.3 mg/mL, NaOH, and WFI q.s.
DurezolInflammation and pain associated with ocular surgeryTopical, ophthalmicDifluprednate / 0.5 mg/mLBoric acid, castor oil, glycerin, polysorbate 80, purified water, sodium acetate, sodium EDTA, NaOH and sorbic acid 1 mg/mL
Estrasorb3Menopause associated vasomotor symptomsTopicalEstradiol hemihydrate / 2.5 mg/gSoybean oil, water, polysorbate 80 and ethanol
Kabiven2Total parenteral nutritioni.v. infusion, central vein onlyDextrose, amino acids, electrolytes, Intralipid® 20%Soybean oil 200 mg/mL, glycerin 22.5 mg/mL, purified egg yolk phospholipids 12 mg/mL, NaOH and WFI
OmegavenParenteral nutrition-associated cholestasis in pediatrici.v. infusion, central or peripheral veinFish oil / 100 mg/mLGlycerin 25 mg/mL, egg phospholipids 12 mg/mL, D,L-α-tocopherol 0.15 to 0.3 mg/mL, sodium oleate 0.3 mg/mL, NaOH and WFI
Perikabiven2Total parenteral nutritioni.v. infusion, central or peripheral veinDextrose, amino acids, electrolytes, Intralipid® 20%Soybean oil 200 mg/mL, glycerin 22.5 mg/mL, purified egg yolk phospholipids 12 mg/mL, NaOH and WFI
RestasisPromotion of tear productionTopical, ophthalmicCyclosporine / 0.5 mg/mLGlycerin, castor oil, polysorbate 80, carbomer 1342, NaOH and WFI
SmoflipidParenteral nutritioni.v. infusionSoybean oil / 60 mg/mL; MCTs / 60 mg/mL; olive oil / 50 mg/mL; fish oil / 30 mg/mLGlycerin 25 mg/mL, egg phospholipids 12 mg/mL, all-rac-α-tocopherol 0.163 to 0.225 mg/mL, sodium oleate 3 mg/mL, NaOH and WFI
Varubi3Emetogenic chemotherapy associated nausea and vomitingi.v. infusionRolapitant / 1.8 mg/mLDibasic sodium phosphate, anhydrous 2.8 mg/mL, MCTs 11 mg/mL, polyoxyl 15 hydroxystearate 44 mg/mL, sodium chloride 6.2 mg/mL, soybean oil 6.5 mg/mL, NaOH or HCl, and WFI
Verkazia2Vernal keratoconjunctivitisTopical, ophthalmicCyclosporine / 1 mg/mLCetalkonium chloride, glycerol, MCT, Poloxamer 188, tyloxapol, NaOH and WFI
Xelpros2Reduction of intraocular pressureTopical, ophthalmicLatanoprost / 0.05 mg/mLCastor oil, sodium borate, boric acid, propylene glycol, edetate disodium, polyoxyl 15 hydroxystearate, potassium sorbate 4.7 mg/mL, NaOH or HCl, and WFI

Table 4. FDA approved emulsion drug products via 505(b) pathway.

Abbreviation: i.v.: intravenous; s.c.: subcutaneous; NaOH: sodium hydroxide; MCT: medium chain triglycerides; WFI: sterile water for injection; HCl: hydrochloric acid.

Although nanoemulsion presents numerous advantages, not quite many have been successfully launched to the market. Some of the major formulation challenges preventing a broader application of nanoemulsion as DDS are: (i) The disperse phase comprised of long chain triglycerides (LCT) and/or medium chain triglycerides (MCT) are not necessarily good solvents for lipophilic drugs; (ii) Drug loading. As generally the lipid phase cannot exceed 30% in the formulation, many – time it is challenging to load therapeutic-relevant dose of drug in the lipid; (iii) The incorporated drugs may render instability of the nanoemulsion, physically and/or chemically. The hydrolysis of the lipids, usually free fatty acids, could also be detrimental to the drug. (iv) There is a very limited number of approved oils and surfactants, and strict regulatory restrictions on their total content in the product that can be used to formulate, especially injectable emulsions [28].

Suspensions

Long-acting injectables (LAIs) are parenteral drug formulations that provide a slow and sustained release of the Active Pharmaceutical Ingredient (API) following administration. Compared to conventional oral formulations, LAIs have many advantages, including sustained exposure of API, reduced administration frequency, enhanced therapy adherence and patient compliance, and potentially lower level of adverse effects [33]. Major classes of LAI formulation technologies are suspensions, polymer microspheres, multi-vesicular liposomes (MVLs), oily solutions, and in situ forming implants.

Aqueous suspensions are solid drug particles produced in micro- or nanometer ranges in water and often have a stabilizer or surfactant to stabilize the particle size distribution and particle morphology during storage. Suspensions are most likely applied for APIs with low water solubility and relatively high lipophilicity, and drug molecule dissolution occurs slowly in vivo. Suspensions can be maintained as liquid suspensions ready for injection or further lyophilized into dry powders to be reconstituted before administration [34, 35]. For APIs chemically stable in aqueous solutions, the suspension can be made as a ready-to-use product for direct injection. For APIs with poor chemical stability in aqueous solutions, the suspension is preferred to be formulated as a lyophilized powder and reconstituted prior to administration. In liquid suspension products, particles may sediment at the bottom of the container during storage, and hence the suspension would need to be resuspended prior to administration.

The physical stability of suspensions relies on whether the suspended solids remain dispersed or flocculate upon sedimentation [36]. If all the particles remain discrete, the suspension is considered to be physically stable. Flocculation should be carefully controlled, especially during long-term storage. The viscosity of suspensions should not be too high to make redispersion difficult [37]. To formulate a physical stable suspension, several approaches can be employed, including controlled particle size, the use of structured vehicles, and the use of flocculating agents [38]. The particle size of suspensions is crucial and must be reduced within certain range during development stage. Large particles (> 5 μm diameter) will impart a gritty texture to the product and might cause irritation upon injection or instillation into eyes. Typical structured vehicles are aqueous solutions of polymeric materials, which are usually charged to maintain the suspension [39]. Flocculating agents are added in the suspension to form loosely bound aggregates that settle rapidly but resuspend easily upon agitation. Common flocculating agents include electrolytes, surfactants, and polymers [40]. Suspensions may also be formulated with other excipients, such as solvents, wetting agents, anti-oxidants, preservatives, chelating agents, buffering agents [41]. To develop a successful suspension, the compatibility of excipients with API, the container closure system, and the manufacturing process should be investigated.

Upon administration, the API release from suspended solids is controlled by the API solubility in the surrounding fluids and the accessible surface area of the API particles [42]. API solubility is determined by the physicochemical properties of the API, in which APIs with greater lipophilicity tend to show slower release. In most long-acting suspensions, the API is designed as a prodrug with lower solubility to achieve extended release at the injection site. Accessible surface area is usually controlled by the particle size of the API. Smaller particle size means larger surface area to volume ratio, resulting in faster release. Accessible surface area can also be controlled by the microfractures or surface roughness of the API. In addition, injection volume and injection site could also affect the in vivo release of the API [43].

In the manufacturing of suspensions, critical steps include API introduction, vehicle formulation, particle size reduction, sterilization, and filling. To introduce API, it can be done in sterile or non-sterile, micronized or un-micronized manner. Aqueous vehicles are prepared by the dissolution and filtration of surfactants, flocculating agents, and other excipients. High-shear mixing is normally needed to fully wet the API in the suspension vehicle. Particle size reduction of the crystallized API is required when the API is introduced in an un-micronized manner. Microfluidics, wet milling, and high-shear homogenization are options to achieve this purpose [44, 45, 46]. Selection of the proper particle size reduction strategy depends on the final target particle size and size distribution, as well as the physicochemical property of the API.

So far, numerous suspensions have been approved by the U.S. FDA via 505(b)(2) pathway. Some of the approved long-acting suspensions and their drug product information are summarized in Table 5. One example is Aristada, which is an injectable suspension for intramuscular use. Aristada delivers aripiprazole lauroxil, an atypical antipsychotic, for the treatment of schizophrenia in adults. In clinic, Aristada Initio (675 mg dose) is used as initial regimen in Aristada-based therapy in combination with oral aripiprazole (30 mg dose). Aripiprazole lauroxil is a prodrug of aripiprazole, and it has a lower aqueous solubility than aripiprazole, which allows the preparation of a crystal suspension [47]. After intramuscular injection, the aripiprazole lauroxil crystal suspension forms a local depot, resulting in a sustained release of aripiprazole lauroxil more than 4 weeks [47]. The clinical efficacy and safety of aripiprazole lauroxil depots has been demonstrated in a randomized, double-blind, placebo-controlled trial in schizophrenia patients [48].

Product nameIndicationRoute of administrationActive substance / StrengthFormulation
AristadaSchizophreniaIntramuscular injectionAripiprazole lauroxil / 441 mg, 662 mg, and 882 mgSorbitan monolaurate (3.8 mg/mL), polysorbate 20 (1.5 mg/mL), sodium chloride (6.1 mg/mL), sodium phosphate dibasic anhydrous, sodium phosphate monobasic and WFI
Depo-MedrolAnti-inflammationIntra-articular and intra-bursalMethylprednisolone acetate / 20, 40, 80 mg/mLMethylprednisolone acetate, PEG 3350, Polysorbate 80, Monobasic sodium phosphate, Dibasic sodium phosphate, Benzyl alcohol
DexycuPostoperative inflammationIntraocular injectionDexamethasone / 9%Acetyl triethyl citrate and WFI
EYSUVISSigns and symptoms of dry eye diseaseOphthalmicLoteprednol etabonate / 0.25%Benzalkonium chloride 0.01%, glycerin, sodium citrate dihydrate, sodium chloride, Poloxamer 407, edetate disodium dihydrate, citric acid, and WFI
RyanodexMalignant hyperthermiaIntravenous injectionDantrolene sodium / 250 mg / vial125 mg mannitol, 25 mg polysorbate 80, 4 mg povidone K12 and sufficient sodium hydroxide or hydrochloric acid for pH adjustment
SIMBRINZAElevated intraocular pressure (IOP)OphthalmicBrinzolamide/brimonidine tartrate / 1%/0.2%Benzalkonium chloride 0.03 mg, propylene glycol, carbomer 974P, boric acid, mannitol, sodium chloride, tyloxapol and purified water
Zyprexa RelprevvSchizophreniaIntramuscular injectionOlanzapine Pamoate / 210, 300, 405 mgCarboxymethylcellulose sodium, mannitol, polysorbate 80, sodium hydroxide and/or hydrochloric acid for pH adjustment, and WFI
XIPEREMacular edema associated with uveitisSuprachoroidal injectionTriamcinolone acetonide / 40 mg/mL0.55% (w/v) sodium chloride, 0.5% (w/v) carboxymethylcellulose sodium, 0.02% (w/v) polysorbate 80, potassium chloride, calcium chloride (dihydrate), magnesium chloride (hexahydrate), sodium acetate (trihydrate), sodium citrate (dihydrate), and WFI

Table 5. FDA approved long-acting parenteral suspension drug products via 505(b)(2).

Information acquired from FDA Orange Book as of January 2023.

Polymer microspheres

Polymer microspheres consist of polymeric materials that encapsulate APIs in a dispersion manner or as an API core surrounded by the polymer shell, achieving controlled release purpose [49]. Over the past decades, research has been focused on degradable polymer microspheres for drug delivery. Such drug delivery systems are advantageous because microspheres can be injected or ingested, and they can be tailored for desired release profiles and sometimes even provide organ-targeted property.

Biodegradable polymers are synthetic or natural and can be degraded in vivo, either enzymatically, non-enzymatically or both, to produce biocompatible and toxicologically safe by-products which are further eliminated by the normal metabolic pathways. The number of such materials that are used in controlled drug delivery systems has increased dramatically over the past twenty years. They can be broadly classified as synthetic biodegradable polymers and naturally occurring polymers. Synthetic polymers include polyanhydrides, relatively hydrophobic materials such as polylactic-co-glycolic acid (PLGA), and others. Natural polymers include complex sugars (e.g., chitosan, hyaluronan) and inorganics (e.g., hydroxyapatite). Among these polymers, PLGA is the most attractive and successful one for formulating microspheres [50].

Microspheres can be manufactured via various microencapsulation processes, including solvent evaporation/extraction, coacervation, spray drying, ionic gelation, and others [51]. Solvent evaporation/extraction method is the most commonly used process to produce the commercial polymer microspheres. Briefly, this method involves emulsification of the organic polymer/API solution in an aqueous continuous phase and subsequent precipitation of the polymer/API. The organic solvent used to dissolve the polymer and API should have enough solubility in aqueous phase to partition and thus enable precipitation of the polymer/API [52]. Methylene chloride and chloroform are commonly used organic solvents for preparing PLGA-based microspheres via solvent evaporation/extraction method [53]. The manufacturing process can have impacts on the structure of polymer microspheres and API release. For instance, when microspheres are produced using a solvent evaporation/extraction method, steps such as emulsification and solvent removal can affect particle size, particle size distribution, surface morphology, porosity, and API release profiles of the microspheres. Typically, when the solvent removal goes fast, PLGA quickly transitions from a rubbery state to a glassy state, and loses polymer chain mobility, resulting in larger particle size and lower density compared to microspheres manufactured through a slow solvent removal process.

The in vivo API release profiles of polymer microspheres involve multiple mechanisms over different time scales, including API diffusion from the microspheres, penetration of the release media into the microspheres, and polymer degradation. For hydrophilic API, the release profile is usually continuous with or without an initial burst release phase [54]. Burst release is driven by diffusion of the API absorbed on the surface or near the surface of the microspheres. For hydrophobic API, there is typically an initial burst release, followed by a lag phase where no or minimal API is released, and then there is a secondary continuous release phase. The lag phase is the time required for polymer degradation and erosion. Once the polymer degrades to certain extent, the microspheres will go through mass loss and matrix erosion, resulting in continuous release of the API until depletion.

Long-acting injectables are crucial for the patient compliance in chronic diseases. Recently, more and more polymer microsphere formulations have been approved by the U.S. FDA and some of them are approved via 505(b)(2) pathway. A few examples are displayed in Table 6. For instance, LUTRATE DEPOT is a sterile PLGA microsphere-based formulation to treat the symptoms of Advanced Prostate Cancer, Endometriosis, and Uterine Leiomyomata. Several variants of Lupron Depot® are clinically available containing different amounts of leuprolide acetate, including 7.5, 22.5, 30 and 45 mg that are administered via intramuscular injection route in a dosing interval of 1, 3, 4 and 6 months, respectively [55]. The API in LUTRATE DEPOT is leuprolide acetate, a GnRH agonist, which acts as an inhibitor of gonadotropin secretion. Administration of leuprolide acetate has resulted in inhibition of the growth of certain hormone dependent tumors as well as atrophy of the reproductive organs [56, 57]. LUTRATE DEPOT is stored in a vial containing white to off white sterile lyophilized microspheres together with the corresponding sterile reconstitution diluent in a pre-filled syringe. When LUTRATE DEPOT and the diluent are mixed together, they become a suspension intended as an intramuscular injection.

Product nameIndicationRoute of administrationActive substance / StrengthFormulation
ArestinGum infectionSubgingivalMinocycline Hydrochloride / 1 mgPLGA
BydureonType 2 diabetes mellitusSubcutaneous injectionExenatide / 2 mgPLGA 75:25
FirmagonProstate cancerSubcutaneous injectionDegarelix acetate / 240 mgPeptide self-assembly
LUTRATE DEPOTAdvanced prostate cancerIntramuscular injectionLeuprolide acetate / 22.5 mg/vialPolylactic acid (188.4 mg), triethylcitrate (10.4 mg), polysorbate 80 (3.8 mg), mannitol (88.4 mg) and carmellose sodium (25 mg)
Nutropin DepotGH deficiencySubcutaneous injectionSomatotropin / 22.5 mgPLGA
PlenaxisProstate cancerIntramuscular injectionAbarelix / 100 mgAbarelix/carboxymethylcellulose complex
Risperdal ConstaSchizophrenia, Psychotic disordersIntramuscular injectionRisperidone /52 mgPLGA 75:25
Sandostatin LARAcromegaly, Carcinoid tumorsIntramuscular injectionOctreotide acetate / 30 mgPLGA 55/45, star polymer
Somatuline LAAcromegalyIntramuscular injectionLanreotide acetate / 30 mgPLGA 75:25
SustolVomitingSubcutaneous injectionGranisetron / 10 mgTri(ethylene glycol) poly(orthoester) (TEG-POE), 392 mg, polyethylene glycol monomethyl ether, 98 mg
Trelstar LAProstate cancerIntramuscular injectionTriptorelin pamoate / 22.5 mgPLGA
TrivarisIntraocular inflammationIntravitreal injectionTriamcinolone acetonide / 8 mg2.3% (w/w) sodium hyaluronate; 0.63% sodium chloride; 0.3% sodium phosphate, dibasic; 0.04% sodium phosphate, monobasic; and WFIf
VivitrolAlcohol dependence in adults 18 years and olderIntramuscular injectionNaltrexone / 380 mg/vial75:25 polylactide-co-glycolide (PLG) at a concentration of 337 mg of naltrexone per gram of microspheres
ZilrettaPain killerIntra-articularTriamcinolone acetonide / 32 mgPLGA 75:25

Table 6. Example of FDA approved polymer microsphere drug products.

Information acquired from FDA Orange Book as of January 2023.

Challenges

Although most of the challenges during the development of a drug product using the advanced technologies are closely related to the formulation discussed in the previous sections, the relatively high attrition rate of the clinical translation of the advanced drug products is no less attributed to other factors, including analytical characterizations, quality assurance of pharmaceutical manufacturing, the suitable assessment of clinical trial and eventually government regulations and intellectual property (IP), etc. [58]

Taking Doxil as an example, as both free and liposomal DOX existed and have different release mechanisms where free DOX almost release instantly once being injected into the patient’s body while liposomal DOX releases slowly. Being able to determine and differentiate the two in the formulation is critical to the study and control of the drug product quality. Traditional ways of analysis rely on separating the two first, such as using ultracentrifugation, ultrafiltration, solid-phase extraction (SPE), and gel filtration, followed by quantification with HPLC or CE afterwards. However, each separation method has its own limitations: ultracentrifugation is limited by liposome size; ultrafiltration due to drug adsorption by the device; for gel chromatography it is the separation time and over dilution whereas SPE being the most used method, still suffers from overestimating the free drug due to liposomal drug release during the separation process [59]. In 2011, researchers have developed a method that allows the simultaneous determination of both free and liposomal DOX using CE and laser-induced fluorescence techniques, therefore eliminating the need of preliminary separation and its induced complication. This method was validated for the determination of free DOX only (not for both free and liposomal DOX, due to the liposomal DOX leakage) with a 0.1 μg/mL lower detection limit, which greatly helped future liposomal formulation developments [60].

Another example is the characterization of the degree of branching of poly(lactide-co-glycolide) (PLGA) for polymer-based long-acting injectables. Two kinds of PLGA have been widely used in long-acting injectable formulations approved by the FDA to control the rate of API release: linear PLGA and branched glucose star PLGA (Glu-PLGA) [61]. Comparing to linear PLGA, branched PLGA has more compacted structure, smaller hydrodynamic volume, smaller radius of gyration, lower viscosity, and greater hydrophilicity, resulting in that it behaves differently in terms of release kinetics from linear PLGA even though they might have comparable molecular weight and lactide:glycolide (L:G) ratio. Being able to reliably characterize the degree of branching of PLGA is therefore critical for establishing a drug’s bioequivalence. However, until recently, the characterization of PLGA has been limited to measuring its molecular weight and L:G ratio [61]. To address this analytical limitation, researchers from academia, industry and the FDA worked together and developed a method using gel-permeation chromatography with quadrupole detection (GPC-4D), which greatly facilitated the development process of 505(b)(2) products with PLGA embedded RLDs [62], such as Sandostatin® LAR.

In perspective of quality assurance, the issue is usually centered on reproducibility and proper control of these advanced drug products under cGMP manufacturing. More complex the DDSs, more susceptible they are to slight change in the manufacturing process which causes quality variance such as chemical instability or denaturation of the encapsulated compound in the manufacturing process, compromised long-term stability, etc. [63] Further complications arise when the advanced formulation technologies involve surface modification of a nanodrug with coating and/or ligands.

Challenges are also associated with the increased number of physicochemical variables of these advanced formulations during the assessment of pharmacokinetics (PK), pharmacodynamics (PD) and toxicokinetics (TK) in animal studies [64, 65]. The in depth understanding of the interaction of these nanodrugs with biological tissues and cells require consultation with academia, industry under the regulatory framework [66]. The human clinical trials often face more complexity than conventional formulations as a number of control groups are required to properly evaluate various aspects of the advanced drug product. Furthermore, many drug products may not demonstrate significantly improved efficacy or reduced side effects when compared to their respective approved counterparts.

Last but not the least, considering the complexity of these advanced formulation technologies incorporated into the drug product, associated often with multiple patents, there are also needs for cross-licensing arrangements. The IP practices and protocols could, therefore, be a perplexing issue which requires a simplified pathway from invention to commercialization to reduce time and save cost [67].

Conclusion

Over the past three decades since the first FDA approved nanodrug Doxil, the NDA 505(b)(2) have been actively and increasingly utilized as a preferable application pathway, thanks to the emergence of various novel drug delivery formulation technologies. The 505(b)(2) pathway offers well-balanced advantages to researchers, investors, regulatory agents, and ultimately to the patients. It stimulates new drug investigation as well as promotes the improvement of existing drugs. To take advantage of this application route by (re)formulating with advanced technologies, and to expedite the development and approval course, it is important though, for the sponsors to fully understand not only the scientific scope but also regulatory and intellectual affairs.

Conflict of interest

The authors declare no conflict of interest.

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