Nanoparticle Drug Dosage Form

A Review of the Current Challenges and Opportunities

Introduction

For many decades, researchers have explored and improved nanoparticle drug delivery systems, and several products based on nanoparticles have been approved or are in clinical trials for different diseases, especially cancer.  A 2020 report by Grand View Research says that in 2019, the worldwide market for drug delivery using nanoparticles was worth USD 36.1 billion, and it will increase by 18.2% every year from 2020 to 2027. 

Increased prevalence of chronic diseases has led to surge in demand for targeted and personalized therapies and thus the advancement of nanotechnology and biotechnology-based drug dosage forms. Physical and chemical characteristics of nanoscale materials developed as nanoparticles are widely used for biomedical purposes. One of the most promising applications of nanoparticles is drug delivery, where nanoparticles can be used as a vehicle for therapeutic purposes to improve the efficacy, stability and specificity of the drug dosage form. Among the different routes of Administration, I.V. is the most preferred route of administration for systemic delivery of nanoparticles.

Types Of Nanoparticle Based Dosage Form

Nanoparticles are classified based on their physicochemical characteristics, structure and function. Liposomes, polymeric nanoparticles, metallic nanoparticles, and quantum dots are some of the most common types of nanoparticles for I.V. drug delivery. The suitability and limitations of each type of nanoparticle vary according to the purpose and the required characteristics.

1. Liposomes are spherical structures comprised of one or more phospholipid bilayers. It can thus encapsulate hydrophilic or hydrophobic drugs in their hydrophilic – aqueous cores or hydrophobic – lipid membranes respectively.

Given the biocompatibility, biodegradability and resourceful nature of the liposomes; nanoparticle based dosage form can be designed and developed with diverse array of ligands, polymers, or molecules to ameliorate the stability, targeting and functionality and specificity of the liposomes. However, liposomes development has its own challenges with leakage of drug, susceptibility to opsonization and phagocytosis by a reticuloendothelial system, low drug loading, etc. Nevertheless, Liposomes – nanoparticle-based dosage forms have been extensively studied and used for I.V. Drug delivery, especially for anticancer drugs, doxorubicin, paclitaxel, and vincristine.

2. Polymeric Nanoparticles are natural or synthetically sourced polymers either solid or hollow vesicles that can be utilized as drug carriers by entrapment, adsorption, or covalent bonds. In comparison to liposomes, polymeric nanoparticles have a high drug loading capacity.  In addition, tunable size and shape, and controllable degradation and release kinetics makes it a better candidate for designing nanoparticle-based dosage form.  Furthermore, stability, specificity and functionality can be improved by functionalizing with diverse molecules. However, polymeric nanoparticles have their own challenges, with potential toxicity, immunogenicity, aggregation and precipitation of the molecules in the biological environment. Despite the challenges, polymeric nanoparticles are most popularly utilized for development of anticancer, anti-inflammatory, anti-infective agents. Some of the approved, polymeric nanoparticles dosage forms under development and in market are; Abraxane (paclitaxel albumin-bound nanoparticles), a nanoscale formulation of the anticancer drug paclitaxel, in 2005; BIND-014, a targeted polymeric nanoparticle conjugate of docetaxel (phase II clinical trials) for prostate cancer and non-small cell lung cancer. 

3. Metallic Nanoparticles are comprised of metal oxides, gold, silver, iron, or zinc, that can function as delivery systems for drugs or as theragnostic agents that integrate drug delivery with imaging or therapy. The characteristic optical, magnetic, electrical and catalytical features of metallic nanoparticles can be utilized to alter the stability, targeting and functionality. However, potential toxicity, accumulation of metals in the body, oxidation of nanoparticles in the body, and likely interactions with biological environment and processes. Despite its challenges, it is widely utilized for photothermal therapy, magnetic resonance imaging, biosensing. AuroLase Therapy is a product in phase II clinical trials that uses gold nanoshells to treat solid tumors. The product works by injecting gold nanoshells into the tumor and heating them up with near-infrared light to kill the tumor cells. Another product is Feraheme, which is an iron oxide nanoparticle product approved in 2009 for iron deficiency anemia in patients with chronic kidney disease. The product can also help with MRI of the liver 

4. Quantum Dots are nanocrystals comprised of semiconductor nanoparticles. Depending on the size, quantum dots possess quantum mechanical, optical and electronic properties. Due to their ability to emit fluorescence of diverse colors; quantum dots nanocrystals have found application in tracking and imaging and thus utilized for photodynamic therapy, and drug tracking, etc. However, Quantum dots have its challenges of instability, quenching of fluorescence in biological environment and uncontrolled drug release profile in the biological systems. Despite the challenges, in 2011 FDA approved its 1st quantum dot for clinical trial phase – I in human beings, filed through its original developers Hybrid Silica Technologies, Cambridge, MA. C dots are silica spheres (<8 mm in diameter); can enclose dye molecule and for clinical trials are coated with PEG, to allow compatibility with biological environment. By modifying the C-dots surface through conjugation and modified functionality; it can be utilized for targeting and tracking dosage delivery to the tumor cells.

I.V. based nanoparticle drug delivery has many benefits, but also many challenges and limitations. Some of the main challenges are the complex interactions of nanoparticles with biological systems, the fate and distribution of nanoparticles in the body, the possible toxicity and immune response of nanoparticles, and the fine-tuning of the size, shape, and surface of nanoparticles for specific purposes. Moreover, the development of an I.V. based nanoparticle drug product requires attention to the formulation, production, characterization, and quality aspects, as well as the regulatory and ethical issues.

The performance and safety of nanoparticles administered through I.V. route can be influenced by its interaction with different biological fluids and components, such as blood, plasma, serum proteins, cells, and organs, etc. The pharmacodynamics and pharmacokinetics of the nanoparticle based dosage form is significantly dependent on  its physicochemical characteristics, such as size, shape, charge, surface chemistry, and stability, etc.

·       The Size of nanoparticles is a key factor that affects how they are distributed, eliminated, and toxic in the body. Usually, nanoparticles that are smaller circulate longer, leak more, and clear less than nanoparticles that are larger. But nanoparticles may be cleared by the kidneys or stored in the liver and spleen if they are too small. I.V. drug delivery works best with nanoparticles between 10 and 200 nm, depending on the tissue and the drug.

· Shape influences how biodistribution, clearance, efficacy and toxicity of the nanoparticles-based dosage form. For instance, spherical nanoparticles are less prone to opsonization and phagocytosis than non-spherical shapes such as; rods, disks, or stars, etc. However, depending upon the intended purpose for the drug delivery; non-spherical shapes may also penetrate, target, and function better than spherical nanoparticles. The best shape for I.V. drug delivery depends on the drug, the target, and the biology.

· Charge determines the fate of pharmacokinetics and pharmacodynamic of nanomedicine. In general, nanoparticles with charge are more likely to be opsonized and phagocytosed than nanoparticles without charge, as they have stronger interactions with the blood components that have negative charge. However, nanoparticles with charge may also be more stable, targeted, and functional than nanoparticles without charge, depending on the application and the type of charge. The optimal charge for delivering drugs through I.V. depends on the drug, the target, and the biological setting.

· Surface Chemistry: Usually, hydrophilic nanoparticles stay longer in blood, avoid opsonization and phagocytosis, and are less toxic than hydrophobic nanoparticles, as they have less interaction with the hydrophobic blood parts. But hydrophobic nanoparticles may also load more drug, be more stable, and more functional than hydrophilic nanoparticles, depending on the use. The best surface chemistry for I.V. drug delivery depends on the drug, the target, and the biology.

· Stability: Nanoparticles that are stable can circulate longer, leak less drug content, and have less toxicity than nanoparticles that are unstable, because they keep their shape and function in the biological fluids. But nanoparticles that are unstable might also deliver more drug, target better, and have more function than nanoparticles that are stable, depending on the use. The best stability for I.V. drug delivery varies with the drug, the target, and the biological environment.

Characterization, and Evaluation of Nanoparticle Drug Dosage Forms

One must consider several factors when developing a nanoparticle drug dosage form for intravenous administration, such as the composition, preparation, evaluation, and quality assurance of the nanoparticles, and their effects on the body in terms of drug exposure, action, distribution, and safety.

Characterization of nanoparticle drug dosage form encompassed of measurement, and analysis of physical, chemical, biological properties. For instance, size, shape, charge, surface chemistry, drug loading, drug release, stability, and functionality, etc. Depending on the type of nanoparticle, several techniques such as dynamic light scattering, transmission electron microscopy, nuclear magnetic resonance spectroscopy, or mass spectrometry, scanning electron microscopy, atomic force microscopy, zeta potential, Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, fluorescence spectroscopy, etc. are widely be used usually in combination to bolster the assessment.

The nanoparticle drug dosage form undergoes quality control to ensure that it meets the pre-established criteria and norms, such as the product's identity, purity, potency, and safety, as well as the lack of contaminants, impurities, or flaws., etc. Based on the nanoparticle drug dosage form, the most popular techniques utilized for Q.C. analysis are high-performance liquid chromatography (HPLC), gas chromatography (GC), gel electrophoresis (GE), or microbiological testing.

Regulatory and Ethical Guidelines for the Clinical Development and Use of Nanoparticle Drug Dosage Forms

An I.V. nanoparticle drug dosage form must be compliant to diverse national and international agencies like FDA, EMA, WHO and ICH. Compliance with guidelines and regulations are set forth by the applicable international agencies ensures safety and efficacy of the nanomedicines for the pre- and post-marketing patients. 

Design, Development and optimization of the nanomedicine must be carefully strategized to ensure following aspects are compliant to the pre-determined regulatory guidelines: 

• Definition and category of nanomedicines, according to their dimensions, composition, shape, and role, as well as the factors that separate them from ordinary medicines. The steps and rules for testing nanomedicines before and during human trials, such as how to plan, do, analyze, and report the studies, and how to choose, enroll, inform, and safeguard the subjects.

• The criteria and techniques for making, testing, and checking the quality of nanomedicines, such as identifying, measuring, and verifying the ingredients, additives, and contaminants, as well as assessing the stability, sterility, and compatibility of the products.

• The standards and procedures for the approval, registration, and marketing of nanomedicines, such as the preparation, evaluation, and authorization of the applications, as well as the labeling, packaging, and distribution of the products.

• The practices and principles for the post-marketing surveillance, pharmacovigilance of nanomedicines, as well as the risk-benefit assessment and communication of the product.

• The moral and societal issues and difficulties of nanomedicines, such as the protection of the agency, privacy, and secrecy of the participants and the users, as well as the evaluation of the fairness, justice, and accountability of the stakeholders.

Conclusion

To sum up, the development of an I.V. nanoparticle dosage form for drug delivery is a complicated and interdisciplinary process that faces various difficulties and possibilities. Nanoparticles have many benefits for I.V. drug administration, such as improved effectiveness, stability, and delivery of therapeutic agents, as well as the potential of integrating drug delivery with imaging or therapy.

But nanoparticles have many challenges, such as their interaction with the biological fluids and components, clearance, and biodistribution in the body, possible toxicity and immune reactions, and improving their physical properties and surface modification. In addition, the development of an I.V. based nanoparticle drug dosage form involves careful attention to the aspects of formulation, production, characterization, and quality control, as well as the assessment of the pharmacokinetics, pharmacodynamics, biodistribution, and toxicity of the nanoparticles. 

Also, the development of an I.V. based nanoparticle drug dosage form requires adherence to the current regulatory and ethical standards for the clinical research and application of nanomedicines, which aim to ensure the quality, safety, and efficacy of nanomedicines, as well as the respect of human rights, dignity, and welfare of the participants and users of nanomedicines.

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