Drug delivery systems
Introduction:
Drug delivery systems describe technologies that carry drugs into or throughout the body. These technologies include the method of delivery, such as a pill that you swallow or a vaccine that is injected. Drug delivery systems can also describe the way that drugs are ‘packaged’—like a micelle or a nanoparticle—that protects the drug from degradation and allows it to travel wherever it needs to go in the body. The field of drug delivery has advanced dramatically in the past few decades, and even greater innovations are anticipated in the coming years. Biomedical engineers have contributed substantially to our understanding of the physiological barriers to efficient drug delivery and have also contributed to the development of several new modes of drug delivery that have entered clinical practice.
Yet, with all of this progress, many disease treatments still have unacceptable side effects. Side effects occur because drugs interact with healthy organs or tissues, and this can limit our ability to treat many diseases such as cancer, neurodegenerative diseases, and infectious diseases. Continuing advances in this space will help to facilitate the targeted delivery of drugs while also mitigating their side effects.
Drug delivery methods
Drugs can be introduced into the body via several different routes. These routes are generally classified by their “starting point” – the location at which the drug is administered. Each route has its own advantages and disadvantages.
Buccal drug delivery
Buccal drug delivery describes the administration of a drug through the buccal mucosa (lining of the cheek). Whilst this route of delivery avoids first-pass effects (rapid drug uptake and metabolism into inactive compounds by the liver), it presents as a “challenging” barrier to drug absorption, especially for larger biopharmaceuticals – delivery is currently limited to small molecule drugs with lipophilic properties as they can readily cross the membrane.
As the buccal route is often used for extended-release drug delivery (whereby the drug is released in a controlled way over an extended time period), formulations that can attach to the mucosa are typically preferred. A variety of formulations have been developed for buccal delivery including; tablets, gels, lozenges and patches.
Nasal drug delivery
Nasal drug delivery involves the delivery of a drug via the nasal cavity of the nose. Nasal spray medications are usually used for the treatment of local diseases affecting the upper respiratory tract (e.g., nasal congestion, allergic rhinitis). However, in some circumstances (where for example rapid onset is required) this delivery approach can be exploited for systemic delivery of small molecule drugs – e.g., the migraine medication olmatriptan.
The thin nasal mucosa is heavily vascularized meaning transfer to the systemic blood circulation is rapid, and similarly to buccal administration, first-pass metabolism can be avoided. Liquid and (less frequently) powder formulations can be used for nasal drug delivery.
Ocular drug delivery
Ocular drug delivery has been somewhat of a difficult task for drug delivery scientists, due to the eye’s unique anatomy and physiology – both static, dynamic and metabolic ocular barriers impede the absorption of drugs through the eye.
There are several different administration routes for the delivery of drugs to specific parts of the eye. Researchers have been able to partially combat the challenges of delivering drugs to ocular tissues through identifying specific efflux and influx transporters in the eye and modifying drugs to target these transporters.
Oral drug delivery
Oral drug delivery is by far the most well-known and often the preferred route of drug administration due to its non-invasive nature, ease-of-use, cost-effectiveness, and the highly absorptive properties of the gastrointestinal (GI) tract.
For oral drug delivery to be successful, the aqueous solubility of the drug compound in the GI system should be assessed to determine if modifications are required to improve bioavailability.
Oral drug delivery does however have drawbacks when it comes to its suitability for certain patient populations including; pediatric, geriatric and those with cognitive impairment.
Pulmonary drug delivery
Pulmonary drug delivery describes the administration of a drug via inhalation through the mouth and into the airways. Inhaled medications are an effective means for treating local disease of the lungs.
More recently, pulmonary drug delivery has also been studied as a potential route of administration for systemic diseases due to the vast absorptive surface area and highly permeable membrane of the alveolar region. Pulmonary delivery is unaffected by dietary complications and interpatient metabolic variation, two additional advantages.
Sublingual drug delivery
Sublingual drug delivery is the term used for administration of a drug under the tongue, which is then absorbed into the bloodstream via the tongue’s ventral surface and the floor of the mouth.
Sublingual absorption is rapid, therefore onset of action can be achieved quickly. This route of delivery also avoids hepatic first‐pass metabolism. It does, however, disrupt talking, eating and drinking which is disadvantageous.
In addition, absorption and consequently efficacy of the drug is reduced by smoking due to vasoconstriction of the vessels, therefore use in smokers is not recommended.
Transdermal drug delivery
Transdermal drug delivery is a method of delivering a drug systemically by applying a formulation onto intact skin. Initially the drug penetrates the stratum corneum and then progresses through the deeper epidermis and dermis where it is finally systemically absorbed via the dermal microcirculation. The fact that it is non-invasive and suitable for unconscious or vomiting patients are two key advantages.
Vaginal/anal drug delivery
Vaginal/anal drug delivery routes have a faster onset of action compared to the oral route and a higher bioavailability. Rectal medications can be used to exhibit local effects (e.g., laxative) or systemic effects (e.g., analgesics when other routes are contraindicated).
Vaginal drug administration avoids first-pass metabolism and is unaffected by gastrointestinal disturbances. The vaginal route is often considered for administration of hormones and to address women’s health issues. Numerous vaginal formulation options are available including; hydrogels, tablets, pessaries or suppositories.
Drug delivery vehicles
Drug molecules that exhibit low bioavailability require protection from degradation (enzymatic and acid-catalyzed) once inside the body15 – ~40 % of novel active pharmaceutical ingredients (APIs) are rejected by the pharmaceutical industry due to low bioavailability. To address this, carrier systems have been developed to increase bioavailability and defend drug molecules against degradation. Here, we look at three types of carrier-based delivery.
Nanoparticles
Nanoparticles are typically 100–500 nm in size. By modifying their properties, it is possible to optimize bioavailability, decrease clearance, and increase stability, making them ideal “carriers” for delivering a particular drug to its specific target-tissue.
Nanoparticles have good solubility and consequently increased bioavailability due to their small size and larger surface area. Their appeal as drug carriers is enhanced by their ability to:
1. cross the blood–brain barrier (BBB)
2. enter the pulmonary system
3. pass through the tight junctions of endothelial cells
Nanoparticles can enter the body via three main routes; injection, inhalation, or taken orally. To develop the “ideal” nanoparticle-based delivery system you must first determine how the body will handle exogenous particulate matter. If the body detects a nanoparticle as “foreign”, the body’s natural immune response will result in it being cleared from the body – this issue can be addressed by changing the surface properties of the particle. By incorporating polymer complexes into the surface, binding of plasma proteins (which typically increase clearance) is prevented.
Nanoparticles have been explored as carriers for drugs to treat numerous conditions including cancer, neurological disorders and acquired immune deficiency syndrome (AIDS).
Liposomes
Liposomes are spherical vesicles consisting of one (or more) phospholipid bilayers. These vesicles present themselves as an attractive delivery system due to them possessing flexible biochemical and physiochemical properties allowing them to be easily manipulated.
Liposomes have a unique ability to encase lipophilic and hydrophilic compounds, making them suitable carriers for a range of drugs. Other advantages include their capacity to self-assemble, ability to carry large drug-loads and their biocompatibility. Being composed of natural phospholipids makes them “pharmacologically inactive”, meaning they display minimal toxicity. Liposomes can be categorized into four main types:
a. Conventional
b. Theranostic
c. PEGylated
d. Ligand-targeted
It is worth noting that whilst liposomes can be easily manipulated and modified – with modification comes increased chances of detection and clearance.
Microspheres
Microspheres are small (1–1000 µm) spherical particles,19 that are typically prepared from linear polymers and are described as “free flowing powdered drug delivery systems”.
When it comes to their use as a drug delivery system, they possess numerous advantageous properties including being; biodegradable, biocompatible and easily administered.
They can be used for both localized and targeted delivery of drugs. The drug is dispersed throughout the polymer matrix of the microsphere. Microspheres can be prepared using either natural polymers or synthetic polymers.
Synthetic polymers can be further classified depending on whether they are biodegradable or non-biodegradable. The persistence of non-biodegradable microspheres in the body can increase the risk of toxicity over longer time periods. Biodegradable polymers, however, do not pose the same risk, making them better suited to parenteral applications.
Other carrier-based methods include resealed erythrocytes, niosomes and monoclonal antibodies.
Current Scenario:
Clinicians historically have attempted to administer interventions to areas of the body directly affected by disease. Instead of delivering drugs systemically, which affects the whole body, some drugs can be administered locally, which can decrease side effects and drug toxicity while maximizing a treatment’s impact.
A topical (used on the skin) antibacterial ointment for the treatment of a localized infection or a cortisone injection to relieve pain in a joint can avoid some of the systemic side effects of these medications. There are other ways to achieve targeted drug delivery, but some medications can only be given systemically.
Another example of a drug delivery system includes the components of a vaccine that helps it to travel inside the body. Vaccines work by providing our immune system with instructions to recognize and attack a pathogen.
These ‘instructions’—such as mRNA, in the case of some COVID-19 vaccines—must be packaged so that it is not degraded by the body and can reach its target. The packaging used for COVID-19 mRNA vaccines are lipid nanoparticles, which protects the fragile mRNA cargo and facilitates its delivery into cells.
Technologies to deliver the drugs:
Current research on drug delivery systems can be described in two broad categories: routes of delivery and delivery vehicles.
Routes of Delivery
Medications can be taken in a variety of ways—by swallowing, by inhalation, by absorption through the skin, or by injection. Each method has advantages and disadvantages, and not all methods can be used for every medication. Improving current delivery methods or designing new ones can enhance the use of existing medications.
Microneedle patch for painless vaccinations:
Microneedle arrays are one example of a new method to deliver medications through the skin. In these arrays, dozens of microscopic needles, each far thinner than a strand of human hair, can be fabricated to contain a medicine. The needles are so small that, although they penetrate the skin, they don’t reach the nerves and can deliver medications painlessly.
Scientists are developing such a patch with an array of dissolvable microneedles for vaccine delivery. These patches are easy to use and do not require refrigeration or special disposal methods, so they could be used by patients at home. This technology could be especially helpful in low-resource communities that may not have many health care providers or adequate storage facilities for traditional, refrigerated medicines.
Robotic pill for oral drug delivery of complex drugs:
Self-injections are used to manage some diseases, such as diabetes and Crohn’s disease. Medications for these conditions may require an injection because the drugs used are often complex and easily degradable, and therefore can’t be taken orally. However, self-injection can represent burdens for patients, including the frequency of the injections and the potential for needle stick injuries.
Scientists are developing an alternative method for self-injection: a robotic pill that can be loaded with complex, liquid drugs. Once swallowed, this pill makes its way to the stomach, where the drug is injected into the stomach tissue. The pill is then excreted through the gastrointestinal tract. While these robotic pills have only been evaluated in animal models so far, they could potentially offer an alternative to self-injection across a range of conditions.
Delivery Vehicles
Drug delivery vehicles represent different ways that medications can be packaged so that the drug can safely travel within the body. Some common examples of drug delivery vehicles include micelles, liposomes, or nanoparticles.
Different drug delivery vehicles can improve the targeting of the drug by helping the medication travel exactly where it needs to go. Additionally, research in this space allows for the development of new ways to package hard-to-use drugs, for reasons like size or fragility.
These improvements in biotechnology are leading to improved medications that can target diseases more effectively and precisely.
Nanoparticle carriers for the treatment of eye disorders:
Gene transfer therapies—where genetic material that codes for therapeutic proteins is introduced into cells—represent a promising way to treat a variety of eye disorders, including macular degeneration. Current delivery methods have limitations, such as the size of the genetic material that they can hold, and their tendency to initiate an immune response.
Scientists are developing a nanoparticle to carry genetic material that overcomes these limitations. These nanoparticles are not readily detected by the immune system and can hold larger genes than current methods. In a mouse model of macular degeneration, the researchers found that injection with their gene-loaded nanoparticles resulted in a 60% reduction in abnormal blood vessels (a characteristic of the disease that causes vision impairments) compared with controls. While still in the early stages, this research could lead to better treatments for eye disorders.
Mimicking immune cells to combat inflammation:
While inflammation is an essential part of our immune response to harmful substances, excessive inflammation in the vascular system can ultimately cause tissue injury, notably in the lungs. Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by sudden and severe damage in the lungs which can cause low blood oxygen levels. Treatments typically include mechanical ventilation, but there are no recommended pharmacological interventions. Mortality rates for ARDS are high, ranging from 35-46%.
Part of the vascular inflammation process includes the migration and adhesion of neutrophils, a type of immune cell, into the lungs, where they bind to endothelial cells. Taking advantage of this behavior, NIBIB-funded researchers are designing nanovesicles that mimic neutrophils, which could be loaded with anti-inflammatory drugs that then deposit their therapeutic cargo in the lungs. This new drug delivery system, inspired by biology, is still early in development.
