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Advancing medication with the right DDS: Pulsatile release

What are drug delivery systems?


Various Medication and Injections

Drug delivery systems (DDS) describe various technologies used to deliver or carry drugs through the body to the affected target regions. Methods of delivery may include oral pills or tablets made of specific materials that dissolve at specific rates in the body, topical creams or ointments for a more localized area of effect, or injections of medications into the muscles or veins. 


The right DDS enables the medication to reach its target in the body quickly with minimal degradation so that it has the greatest effect on disease-related symptoms with the least amount of side effects on healthy tissues and organs. Improving DDS technologies can advance the field of medicine by facilitating more targeted and accurate delivery of medications in a way that is most convenient and easiest for the patient to use, while at the same time reducing negative side effects. 


More effective medications with less side effects and easier methods of administration have the potential to improve patient compliance and better their quality of life as a result. Let’s be honest. Who in this world doesn’t want faster, more effective, less harmful, easier-to-administer medications?


What is pulsatile release in drug delivery?


A pulsatile release drug delivery system is defined as “the instant and transient release of a specified number of drug molecules during a brief time immediately after a preset off-release interval, [known as a lag time].  This delivery system is designed to release the drug according to a predetermined schedule, [in other words], at the proper time and site of action.”


So why does it matter? 


Pulsatile release can have a significant impact on improving medication efficacy to treat specific conditions. Some medical conditions depend on the body’s circadian rhythm, which regulates the onset or extent of disease-related symptoms following a certain, predictable pattern or rhythm in relation to time—a characteristic known as chronological pathophysiology. Chronopharmacology is a field of pharmacology that studies a drug’s effects based on biological timing mechanisms to optimize drug delivery and patient benefit. 


Sustained release formulations may not be the most efficient approach to treating medical conditions influenced by the body’s circadian rhythm, including prevalent diseases, such as cancer, diabetes, asthma, and arthritis.


How is pulsatile release applied to different medical conditions?


Cancer


Cancer cells

The circadian rhythm may play a role in tumor development via its regulation of diverse molecular processes that contribute to the pathogenesis of cancer. These metabolic processes may include cellular growth and proliferation, apoptosis, and DNA repair processes. The circadian rhythm also influences the processes involved in the self-renewal of cancer stem cells as well as angiogenesis, or growth of blood vessels promoting the optimal tumor microenvironment. Additionally, widespread mutations and genomic instability affecting the circadian locomotor output cycles kaput (CLOCK) gene may contribute to the immune escape mechanisms that promote the growth of cancer cells.


Pulsatile chemotherapeutic drug delivery profiles carry a significant potential to maximize therapeutic outcomes to treat cancer. For example, inactivity of the drug during the off-release interval or lag-time of the pulsatile release can help minimize off-target side effects as the drug travels through the body to the target site. Pulsatile timing of the drug release can optimize the anticancer toxicity of these medications to target the tumors themselves more effectively, especially if they are in certain locations that the drug must travel a distance to reach in the body, as well as capitalize on disrupting the circadian-dependent molecular processes that promote tumor growth. 


Lastly, pulsatile release drug delivery of cancer treatments may help overcome the challenge of adaptive resistance, in which the body becomes so tolerant to the medication that it no longer responds as well to the medication. Delivering the medication over shorter durations of time for targeted maximal effect will limit the body’s exposure to the medication and hopefully reduce the likelihood of developing adaptive resistance.


Diabetes


Person using a home diabetic blood testing kit

Continuous monitoring and control of blood glucose concentrations is the most critical component to successful treatment of diabetes. Although it is the most convenient and comfortable route of drug delivery for patients, oral delivery of insulin presents with the pharmacological problems of rapid degradation in the body, a short half-life, and poor stability, all of which significantly impact bioavailability of the active drug. 


Many factors influence blood glucose and therefore the need for insulin in the body. Disruption to circadian rhythms has been found to acutely impact glycemic control and increase risk for impaired glucose tolerance, leading to the development of diabetes. Circadian rhythm is controlled by a multi-oscillator system regulated by the central clock, which is located in the hypothalamic suprachiasmatic nucleus (SCN), in addition to peripheral clocks in the organs, tissues, and cells. The SCN responds to light signals conducted through the retinohypothalamic tract by relaying timing signals through nerves or release of hormones to activate other regions of the brain and peripheral organs, such as the pancreas, which produces insulin. 


Other non-photic variables, including exercising and eating also affect blood glucose levels, making effective glucose regulation an incredibly complex process. The challenge arises when insulin concentrations must elevate within minutes following a meal to control blood glucose concentrations. Eating is one of the strongest time cues for metabolic organs like the liver and pancreas.


Researchers are developing innovative technologies incorporating the concept of pulsatile release drug delivery systems to treat patients with diabetes more effectively. One novel drug delivery device uses focused ultrasound to externally (visually) control the pulsatile release of insulin from polyacrylic acid nanobubbles. Another chronomodulated oral medication was formulated for first optimal release timed around breakfast, 30 minutes following consumption, with a second pulse delivering a sustained release of the drug to manage glucose concentrations for the remainder of the day. Yet another strategic treatment approach involves encapsulating insulin within liposomes, microspheres, microemulsion, and nanoparticles to prevent premature degradation of the insulin within the digestive tract. These oral encapsulations of insulin are designed to release the medication once blood glucose concentrations reach a certain threshold. Release of insulin from these encapsulated carriers occurs according to their hydrogen ion (H+) response indicative of pH level, which determines blood glucose concentrations. These are just some approaches that manipulate drug delivery systems using pulsatile release that capitalize on the influence that circadian rhythms and timing of drug administration and release have on effective diabetes control. 


Asthma


Two inhalers

Asthma demonstrates a strong circadian rhythm influence with nocturnal symptoms and overnight decline in lung function manifesting as common characteristics of the condition.


Around 40% of individuals with asthma experience nocturnal symptoms, including cough and dyspnea, due to circadian variations in airway inflammation, functional changes in the hypothalamic-pituitary-adrenal axis and other important receptors, and potential influences of melatonin. Nocturnal symptoms also increase the risk of asthma-related mortality due to respiratory arrest and sudden death between midnight and 8:00 in the morning.


Treatment strategies using pulsatile DDS can be released while individuals with asthma are asleep to treat symptoms that occur at night and reduce the likelihood of nocturnal mortality.


Arthritis


Person holding arthritic knee in pain

Arthritis is another medical condition that has strong circadian rhythm influences. Rheumatoid arthritis (RA) is an autoimmune condition that symmetrically affects the joints, resulting in decreased mobility, increased pain, and chronic joint inflammation. These symptoms also are associated with poorer quality sleep, altering the circadian rhythms of affected individuals. When the circadian rhythm is disrupted, it negatively impacts the hypothalamic-pituitary-adrenal axis and impairs proper cortisol release (typically higher in the morning), further triggering a pro-inflammatory state and perpetuating the whole cycle. 


Osteoarthritis (OA), the most common type of arthritis, may result from dysfunctional secretion of circadian clock-regulated hormones, including melatonin, thyroid-stimulating hormone (TSH), and cortisol. Impaired regulation of these hormones increases the expression of pro-inflammatory cytokines and enzymes that break down articular cartilage, contributing to the progression of OA. 


Chronotherapy approaches using pulsatile DDS can optimally time the release of RA or OA medications to break this cycle of pain and inflammation leading to poor sleep and impaired hormone regulation by effectively controlling symptoms at night. Arthritis medications can be programmed with specific lag time intervals followed by rapid release of the medications in pulses so that the active pharmaceutical ingredients are available at the site of action at the right time in the right amount. 


Advantages and challenges of pulsatile release in DDS


Pulsatile release in DDS has garnered much attention over the past several decades. Application of technologies to enhance pulsatile release of medications leads to several pharmacological advantages , including:

  • More precise release of targeted therapy as close to the affected body region as possible

  • Less systemic side effects of medications due to decreased dose frequency and quantity

  • Timing of release of medication for optimal impact and efficacy when disease-related symptoms are most active, and the medication is most needed

  • Improved patient compliance due to increased efficacy, decreased side effects, and improved cost-effectiveness

  • Use for extended daytime or nighttime drug activity/release

  • Adaptability to circadian rhythms that influence symptom onset and severity in several medical conditions

  • Circumventing the effects of first-pass metabolism in oral formulations


However, pulsatile DDS face many challenges as well, including:

  • The complexities and multiple steps involved in researching, developing, and manufacturing such precise medications

  • The need for patient-specific variations of the medications as each individual may respond differently to the same drug

  • The barriers associated with standardization and regulation of drug development 

  • Low drug loading capacity 

  • Potential incomplete release of the drug in vivo


Technological innovations promoting pulsatile release in DDS 


One emerging technological solution that can overcome many of the challenges facing pulsatile release in DDS is three-dimensional (3D) printing applied to the manufacturing of complex pharmaceuticals. This innovative technology is well-suited to the development and production of time-controlled and pulsatile release DDS by manipulating multiphase release properties, printer parameters, and various manufacturing materials to promote more precise drug delivery. The additive manufacturing principles supported by computer-aided design in 3D printing promotes the development and manufacturing of patient-centric, personalized drug formulations


Mohapatra and colleagues affirmed the potential for 3D printing to promote pulsatile DDS, stating: 

Snehamayee Mohapatra
“Apart from the wide application in designing different formulations, various recent signs of progress on customized drug delivery have been found in 3D printing technology. Personalized drug dosing, complex drug-release profiles, personalized topical treatment devices are becoming more popular because the key benefits behind [3D printing] are patient-centric design (tailored manufacturing), real-time analysis of dosage form simplified logistics, and reducing wastage.”

The combination of technological innovations and pharmacological advancements in understanding the chronological pathophysiology of certain diseases can lead to improved patient outcomes and quality of life. The future of patient-centric medicine looks quite promising in the context of 3D printing of pulsatile release drug delivery systems.

 
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Laxxon Medical is dedicated to engineering patented 3D pharmaceutical solutions that optimize products and benefit patients. Our goal is to establish SPID®-Technology as a manufacturing process with the individual and the pharmaceutical partner in mind.




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