Attaining effective concentration drugs at the site of action is of paramount importance to combat any disease. Suboptimal concentrations will lead to poor therapeutic response in chronic diseases and emergence of multidrug resistant strains in the case of infections. Advanced drug delivery systems such as lipid based systems (liposomes, microemulsions, mixed micelles), cyclodextrin based complexes, nanoparticulates (solid lipid nanoparticles, nanosuspension and polymeric nanoparticles) can be explored to address the challenges associated with the poor delivery of the active to obtain the desired therapeutic response.
Progress in the field of molecular pharmacology and improved understanding of disease pathophysiology have highlighted the importance of targeting specific cells involved in disease initiation and progress. For life-threatening diseases such as cancer, the use of therapeutic agents often leads to adverse events compromising patient compliance and resulting in the discontinuation of the therapy. Anti-infective therapies dealing with bacterial and viral infections necessitate attaining therapeutic concentrations at the site of the infections. Sub-optimal concentrations of the antiinfective agents at the target site led to the emergence of the multi-drug resistant strains which has become a global concern. Modern medicines are formulated using advanced drug delivery systems to achieve drug delivery at the site of action (specific target site), thus improving therapeutic efficacy and minimising the off-target accumulation of the drug. This plays an important role in the management and treatment of the disease.
Advanced drug delivery systems such as nanoparticulate systems (nanoparticles, solid lipid nanoparticles, nanosuspensions), solid dispersion, mesoporous silica particles, lipid-based systems (liposomes, intralipid emulsions, self-emulsifying/micro emulsifying drug delivery system, mixed micelles) provide multiple advantages including biocompatibility, cellspecific targeting, extended shelf life, higher solubilisation and stabilisation potential of the drugs. These factors lead to superior performance, precise target delivery, and improved efficacy.
Advanced drug delivery systems offer numerous advantages over traditional dosage forms such as tablets, capsules, and oral solutions/suspensions. Conventional oral drug delivery systems were developed using standard excipients to ascertain the shelf life during storage, ease of administration, and achieve desired dissolution at the site of absorption. Hence, these systems have their limitations such as lower patient compliance, high levels of variations in the plasma concentrations, increased incidence of adverse events, and more frequency of drug administration. The cumulative effect of these drawbacks has resulted in increased toxicity, decreased efficiency, and unpleasant side effects. As the pharmaceuticals industry has evolved, advanced drug delivery systems were developed to address the shortcomings of the conventional dosage forms.
The basis for developing advanced drug delivery systems is to ensure the stabilisation of the drug in the dosage form and at the site of action (e.g. pH sensitive drugs), enhancing the bioavailability of the poorly soluble drugs (BCS Class-II) and achieving cell-specific targeting. Hence, advanced drug delivery systems provide advantages such as better patient compliance, less variability in the plasma concentrations, reduced incidence of side effects, and lesser frequency of drug administration.
Advanced drug delivery systems are composed of dosage forms using specific technology or functional excipients to enhance solubility, stability or cell/tissuespecific targeting of the drug.
Following are some of the examples of the ADDS (but not limited to)
• Solid dispersions
• Cyclodextrin complexes
• Mesoporous silica particles
• Nanoparticles (Nanosuspensions, polymeric nanoparticles, solid lipid nanoparticles)
• Lipid-based systems (microemulsions, intralipid emulsions, mixed micelles, liposomes)
• Implants
• Specific advanced drug delivery systems such as nanoparticles, liposomes, and implants are discussed below.
Nanoparticles:
Nanotechnology deals with the conversion of particulate matter into a physical state of between 1 to 100 nm. This particulate matter can be rearranged into nano-systems with improved function. Nanoparticles are increasingly being explored for their potential applications as a drug delivery system. Specifically, nanoparticles are investigated as carriers to deliver drugs to specific cells or tissues in the body. The engineering of nanoparticles allows specific surface properties that allow them to selectively target diseased cells and sparing healthy cells. This phenomenon leads to increased efficacy and reduced side effects. Sustained release of the drug is also possible using nanoparticle-based formulation since they can release their cargo in a controlled manner. The field of diagnostics also finds applications in nanoparticles.
Liposomes:
Liposomes are delivery systems comprised of self-assembled phospholipid-based drug vesicles that form a bilayer (unilamellar) and/or a concentric series of multiple bilayers (multilamellar) enclosing a central aqueous compartment. This delivery system represents a size range from 30nm to micrometer scale and phospholipid bilayer nanosusthickness is 4-5 nm. Liposomes have been considered promising and versatile drug vesicles. In comparison to the conventional drug delivery systems, liposomes exhibit superior properties such as site targeting, sustained or controlled release, avoidance of drug degradation, superior therapeutic efficacy, and decreased incidence of adverse events. Due to the unique features of these delivery systems, several liposome-based products have been successfully approved for use in the clinic.
Implants
This type of delivery system provides an extended release of the drug for the desired duration, usually over months or years. Implants are fabricated using a broad range of materials both non-degradable and biodegradable. The choice of the fabrication material depends on the drug to be delivered, the type and duration of the drug release required, and whether the device will remain in place permanently or not. Most of the implants are exposed to tissues for prolonged periods and hence each material must be biocompatible with reduced cytotoxic effects.
A wide variety of implantable devices are in clinical use including subdermal implants, vaginal rings, intrauterine devices and ocular implants, and intracerebral implants.
Advanced drug delivery systems comprise a wide range of dosage forms as listed above. Depending on the rationale, composition, and process used to prepare these formulations the mechanism of these systems differs as explained below.
Solid dispersions: These delivery systems are prepared using either spray drying or hot melt extrusion. Polymeric excipients such as HPMC, PVP, PEG, Eudragits, and Poloxamers are used to convert the crystalline drug into the amorphous form and thereby enhance the dissolution rate and bioavailability. Amorphous forms are known to dissolve faster than the corresponding crystalline forms.
Mesoporous silica particles:
This system works on a similar principle as that of solid dispersion, however for this type of dosage form nanosized mesoporous silica is explored as an excipient, which has unique features like stability, adjustable pores (pores with a diameter ranging from 2 to 50 nm) and large surface area. These features make them advantageous over solid dispersion with higher drug loading capacity for poorly soluble drugs.
Cyclodextrin complexes:
Drugs with poor solubility pose a significant challenge for formulation especially at high doses.
Anti-infective drugs (antibacterials, antivirals, and antifungals) are often administered at high doses in hospital settings. Cyclodextrins are multifunctional pharmaceutical excipients able to form water-soluble host-guest inclusion complexes with poorly soluble drugs (hydrophobic drugs) and thus improve their apparent water-solubility, chemical stability, and bioavailability to obtain the formulations suitable for parenteral administration.
Nanoformulations:
Nanocrystalline ingredients (e.g. nanosusthickness pensions) and drug-loaded nanocarriers (polymeric nanoparticles, solid lipid nanoparticles) have overcome the challenges associated with conventional therapies such as limited bioavailability, poor patient compliance, and adverse drug reactions. Different synthesis methods are available for the preparation of nano-formulations. The size of Nanoformulations plays an important role in their biodistribution and clearance. The typical challenge is to have a longer circulation time and thereby have a higher half-life by achieving a size between 1 to 100 nm. The smaller size allows reduced hepatic filtration and higher intracellular uptake compared to microparticles.
Lipid-based formulations:
This class of delivery systems comprises formulations such as microemulsions, emulsions, liposomes, and mixed micelles. Drugs with high log P (lipophilic/poorly water-soluble drugs) are encapsulated/solubilised in oils/lipids and the oil phase is dispersed in the aqueous phase using surfactants. It is also possible to explore these delivery systems for water-soluble drugs where the aqueous phase-containing drug is emulsified in the external oily phase using surfactants.
The major advantages of the advanced drug delivery systems are summarised below.
• Higher bioavailability and reduced intra-individual variability of the poorly soluble drugs.
• Reduced incidence of adverse drug reactions
• Site-specific delivery (targeted drug delivery)
• Higher patience compliance
• Avoidance of multidrug resistance
• Stabilisation of the labile molecules such as peptides, proteins, and antibodies
Targeted drug delivery systems (TDDS) are the dosage forms that are used to deliver a drug to a specific site rather than the entire body or organ. TDDS are designed using knowledge from diverse disciplines such as polymer science, molecular biology, pathophysiology of disease, and drug-receptor interactions.
TDDs are mainly designed to control pharmacokinetics and pharmacodynamics, undesired toxicity, immunogenic reactions, and specific recognition of the drug at the receptor. These systems differ from the conventional dosage forms that achieve site-specific delivery of the drug while the latter relies on the drug absorption through the biological membranes.
TDDs are gaining immense importance in advanced drug delivery systems owing to
• Unmet medical needs due to poor performance of the conventional dosage forms in terms of pharmacodynamic, and pharmacokinetic effects
• Selective targeting of drugs to particular disease organs is important to enhance therapeutic effectiveness but also to reduce the toxicity associated with the smaller therapeutic window and use of high-dose drugs
• Targeting of drugs results in increased efficacy, modulated pharmacokinetics, controlled biodistribution, specific delivery of the drug, decreased toxicity, reduced dose, and patient compliance
• Use of TDDS leads to overall cost reduction due to simpler adminisadministration procedures, and reduced drug quantity needed for treatment.
Advanced drug delivery systems have been used successfully, and there is growing demand to deliver drugs to the target site at the desired concentration. However, there are numerous limitations and challenges associated with these systems which are discussed below.
Limited amount of literature: A major challenge that limits the advancement of drug delivery systems is the limited amount of literature and discrepancies reported in the literature. Literature serves as important information for the advancement of the research especially for technologies such as nanomedicines. The discrepancy in the literature impedes the translation of the research from the laboratory to the bedside (clinical application). The safety of nanoparticles is a heavily discussed subject due to the variations in the reported literature.
Large-size particles: Few delivery systems use large particles as carriers which are not suited for the treatment because of the associated challenges such as poor absorption, low solubility and poor bioavailability, in vivo stability, absence of target-specific delivery, and higher incidence of adverse events.
Complications associated with target-specific delivery:
Although target-specific delivery is reported to reduce toxicity and show higher efficacy, the efficacy cannot be assured until the drug is delivered at the target site in a sufficient amount. Especially for nucleic acid molecules like siRNA targeted delivery is impacted by the heavy degradation of the active in the systematic circulation. Lipid-based systems such as micelles and liposomes are used for targeted delivery, but their efficacy is limited by physiological processes such as phagocytic absorption and hepatic filtration.
Toxicity of the particles:
There are reports about the toxicity risk of the particles used in advanced drug delivery systems, notably some of the nanomaterials used could be harmful to human health and the environment too. Several in vitro and in vivo studies reported adverse effects of the metallic nanoparticles (silica, silver, gold, and titanium).
Biocompatibility: An important challenge faced by the advanced drug delivery system is biocompatibility (ability to function with the physiological system in the disease condition) and acceptability (acceptance of the delivery system by the body without inciting an immune response). The body may react differently to biological materials compared to synthetic materials and hence this phenomenon could cause serious implications.
The field of advanced drug delivery systems is progressing rapidly, and the continued efforts by researchers have led to possible solutions to some of the challenges listed before.
Industry-academic collaborations: Collaborations across academic institutions and the pharmaceutical industry have helped to align academic theory, and laboratory experiments followed by translation to the clinical site. Typically, basic research at the academic institution has helped to address key topics such as the passage of the particles across the membranes, the internalisation of the particles by the cells, and the safety of the nanoparticles through numerous experiments to understand the in vivo fate of nanomaterials.
Size of the carriers: Problems related to the use of large size particles can be addressed using the much smaller particles for delivery of the drugs. Nanosizing of the drugs has helped immensely to increase the bioavailability of the poorly soluble drugs.
Target-specific drug delivery: Labile molecules are prone to degradation in the systemic circulation. Hence it's important to deliver these molecules at the site of action in a sufficient concentration. Localisation and accumulation of the liposome-loaded drugs in the tumour tissues has been achieved using targeted liposomes. Improvement of the drug efficacy and reduction of the side effects is achieved using the actively targeted liposomes. This effect is mainly achieved through two strategies a) targeting the overexpressed surface receptors of the cancer cells and b) targeting the tumour microenvironment. The ligands used for actively targeted liposomes are antibodies, proteins, peptides, vitamins, growth factors, and aptamers.
Toxicity of the particles: Nanoparticles with a size below 100 nm are reported to show major toxicological concern. Internationalisation of the smallsize nanoparticles (100nm) by the cells via the process of pinocytosis is proposed to be the reason for toxicity. The increase in size of the particles to 200nm results in the internalisation by macrophages which causes limited cell toxicity.
Biocompatibility: Biocompatibility of the delivery system is key for their acceptance in clinical use and hence researchers are continuously striving to come up with biocompatible formulations. PLGA represents a family of FDA-approved biodegradable polymers that are physically strong and biocompatible excipients. These polymers have been extensively used as delivery vehicles for drugs, proteins, and various other macromolecules such as DNA, RNA, and peptides. Another such example from the recent reports is the use of the Metal– organic frameworks (MOFs) as carriers or vehicles which are excellent platforms for a sustained and controlled release of the drugs (particularly for the poorly soluble drugs). Metal-organic frameworks are crystalline materials containing cationic metal nodes and anionic/neutral organic linkers connected through coordination bonds. These systems attracted the attention of the researchers because of their biocompatibility, biodegradability, and non-toxicity.
Personalised medicine uses information derived from the genetic and genomic data of the patient to tailor the decisions related to diagnosis, treatment, and prevention of the disease. This concept allows physicians to make effective and more informed decisions about patient care based on the patient’s genes and genome. Personalised medicine is advantageous over conventional medicine which uses one strategy across the patient population without relying on the patient’s genetic makeup.
Advanced drug delivery systems are investigated for the personalised treatment of a broad range of highly prevalent diseases (e.g., cancer and diabetes). Typically, pH and temperature temperature-sensitive polymers are explored for this purpose. For example, thermoresponsive polymers (poloxamers, poly (N-isopropylacrylamides)) can be mixed with drugs at room temperature and then injected into the body. When the temperature increases to 37°C, thepolymer forms a gel for sustained release of the drug. pH-sensitive polymers (chitosan, alginate, hyaluronic acid) can be used to synthesise block copolymers which will self-assemble and can be used as nanocarrier systems for anti-cancer drugs. These carriers will release the drug when triggered by the acidic nature of the tumour microenvironment, endosomal compartment, or specific organs. 3D printing has been explored to develop controlledrelease dosage forms. This technique allows to production of personalisedor unique dosage forms and thereby omplex drug release profiles. This approach helps to address the issue of inter-individual variability while treating patients of different ages, races, genders, pharmacogenetics, and pharmacokinetic characteristics. Additional novel approaches are proposed to enable a flexible and patient-appropriate therapy such as the use of various dispensers for multiparticulate drug delivery systems.
Simple approaches are also explored to contribute to personalised medicine. Dosing of the liquid formulations can be accurately achieved by using novel dropping tubes or oral syringes. For the tablet dosage forms, breaking the scored tablets into fragments presents limitations such as inaccurate dosing, formation of potent dust, and stability of the residual segments.
The COVID-19 outbreak caused a severe public health crises across the globe. Use of the nucleic acids as potential drugs to treat this epidemic was the need of the hour. However, delivery of the mRNA is a challenge because the positive charge and hydrophilic nature of the nucleic acid hinder their diffusion across the cell membrane. Lipid nanoparticles have shown a great potential to deliver nucleic acids including the mRNAs resulting in the commercialisation of the Covid-10 vaccines. These lipid nanoparticles are continuously being investigated for the delivery of nucleic acids to treat life-threatening diseases such as cancer.
Digitalisation is being widely used across all industries. Keeping pace with the digital era, the pharmaceutical industry is working hard to develop smart drug systems using small medical technologies. Standard components of the drug delivery systems can be converted into smart components using state-of-the-art sensors and electronics.
Smart drug delivery systems offer the following advantages
• Improved patient-friendliness
• Higher functional response
• In-use collection and evaluation of the data
• Aiding in the monitoring of vital functions and measured data
The new drug delivery systems coupled with digitalisation will play a significant role in improving the quality of healthcare. The input from the potential use of the drug delivery systems will help to further adapt the formulations to improve the overall efficacy, safety, and patient compliance.
Advanced drug delivery systems utilise complex processes and excipients, and it would result in increased costs for the patients compared to the conventional dosage forms. The impact of the higher cost of medication on accessibility is heavily discussed across the globe including in the United States. It covers various aspects such as the pricing strategies of pharmaceutical companies, coverage by insurance, public policies, and existing healthcare systems.
The high cost of the medication is a complex challenge that would need a comprehensive approach. Policymakers, healthcare professionals, pharmaceutical companies, and advocacy groups must work together to propose sustainable solutions to ensure accessibility of essential medications (comprising advanced drug delivery systems) without exposing patients to financial burden.
Advanced drug delivery systems such as nanoparticles/vesicles are associated with structures and components that exhibit novel physical, chemical, and biological properties due to the specific (nano) size. The ethical considerations related to nanomedicine are mainly related to risk assessment in general, the effect on somatic cells versus germline cells, the enhancement of human capabilities, research on human embryonic stem cells, toxicity, uncontrolled function, and self-assembly of nanoparticles. Ethical concerns for advanced drug delivery systems, specifically nanoparticles are more complex than those for general medicine and biotechnology. This is mainly because of the toxicity of the nanoparticles due to their particle size in the nanoscale. General ethical principles such as respect for human anatomy, beneficence, nonmaleficence, and justice are at stake.
To address these issues, a reasonable sound knowledge base acquired in the field of bioethics can be applied to advanced drug delivery systems such as nanomedicine.
The advanced drug delivery systems field has a bright future. Drug delivery systems continue to evolve because of the shift of the existing treatment landscape from small molecules to biologics.
It would be expected to see breakthrough technologies that can enhance stabilisation and targeting of the biologics as well as sustained release over a prolonged period. Efficient delivery of the molecules across complex biological barriers is also a key challenge to be addressed using the new delivery systems. The future of the drug delivery system would also rely on application of the materials that can effectively target specific biology and can be adapted to the disease pathophysiology yet remain simple for clinical translation. Future drug delivery systems will certainly impact global healthcare by improving the efficacy of treatments and making them more affordable and easier to use. Currently, only a certain population can afford the novel treatments. A decrease in the cost of novel drug delivery systems will be of great help compared to cheap generic versions for patients with limited resources. Affordable access to the novel medications, the future would demand a series of innovations, joint efforts in drug delivery technologies, and highly automated low-cost manufacturing platforms.
Yogeshwar Bachhav has pursued B.S.(Pharm) from North Maharashtra University (M.S.India). and M.S. (Pharm) and PhD from Institute of Chemical Technology, Mumbai (india) He has around 17 years of Post PhD experience in Europe in the field of Pharmaceutical Development of investigational drugs. Currently he is working as Director (Consultant) at AiCuris Anti-infective Cures AG Germany and responsible for Pharmaceutical Development of investigational drugs in the domain of innovative antiviral and antibacterial drugs. He has also started a consultancy firm called Adex Pharma which deals with solving complex issues in the pharmaceutical development of new and approved drugs since 2016.
