Advancements in Controlled-Release Formulations: A Pharmaceutic Revolution

*Rahul Rawat, ¹Asha Joshi
*Research Scholar, MotherHood University, Roorkee
¹Research Scholar, MotherHood University, Roorkee

Expand for Article Information

Authors: Rahul Rawat, Asha Joshi

Journal: Pexacy International Journal of Pharmaceutical Science

Volume and Issue: Volume 2, Issue 3

Page Numbers: 53-66

Publication Date: 19/03/2023

Corresponding Author: rawatrahul9@gmail.com

Abstract

Controlled-release formulations have emerged as a transformative approach in drug delivery, offering significant advantages in terms of therapeutic efficacy, patient compliance, and reduced side effects. This review explores the advancements in controlled-release formulations across various medical conditions, including diabetes, cancer, and neurodegenerative diseases. Utilizing nanotechnology, multiparticulate systems, and microencapsulation techniques, these formulations have revolutionized the field of pharmacotherapy. The review also delves into the future trends and challenges in the development of controlled-release formulations, emphasizing the need for ongoing research to optimize drug release profiles and enhance clinical outcomes.

Keywords- Controlled-release formulations, Drug delivery, Therapeutic efficacy, Patient compliance, Nanotechnology, Multiparticulate systems, Microencapsulation, Pharmacotherapy, Future trends, Chronic conditions.

Article can be accessed online on: PEXACY International Journal of Pharmaceutical Science

*Corresponding Author- rawatrahul9@gmail.com

Update: Received on 09/02/2023; Accepted; 12/02/2023, Published on; 19/03/2023

INTRODUCTION

The pharmaceutical industry has been undergoing a transformative shift with the advent of controlled-release formulations. These formulations have revolutionized drug delivery by offering a more sustained and targeted release of active pharmaceutical ingredients (APIs), thereby enhancing therapeutic outcomes and patient compliance. The concept of controlled-release formulations is not new; however, recent advancements in this field have opened up new avenues for drug delivery, particularly in the treatment of chronic conditions that require long-term medication (Patel et al., 2022).

Gastric Floating Systems

One of the most promising advancements in controlled-release formulations is the development of gastric floating drug delivery systems. These systems are designed to float on the gastric fluid, thereby prolonging the gastric residence time of the drug and ensuring a more controlled release (Rashid Iqbal, 2022).

Dissolution Testing

The efficacy of controlled-release formulations is highly dependent on their dissolution characteristics. Recent advancements in dissolution testing have provided more accurate and reliable methods for evaluating the release profiles of both oral and non-oral formulations (Klein, 2019).

Drug Delivery to the Lungs

Controlled drug delivery to the lungs has also seen significant advancements, particularly in the development of innovative formulations that overcome the technical and toxicological challenges associated with pulmonary drug delivery (Aragao-Santiago et al., 2016).

Food Bioactive Ingredients

The application of controlled-release formulations is not limited to pharmaceuticals. The food industry has also benefited from these advancements, particularly in the delivery of bioactive ingredients. Modeling techniques have been developed to predict the release of these ingredients from various carriers and nanocarriers (Malekjani & Jafari, 2021).

Colon-Specific Drug Delivery

Novel approaches in colon-specific drug delivery have also been developed, offering more targeted treatment options for diseases like inflammatory bowel disease and colorectal cancer (Tyagi, 2022).

Immediate/Sustained-Release Formulations

The development of immediate/sustained-release formulations, such as the combination of acetaminophen and ibuprofen, has shown promise in treating conditions like severe nocturia associated with overactive bladder (Wein, 2019).

4D Printed Systems

The future of controlled-release formulations looks even more promising with the advent of 4D printed intravesical drug delivery systems, which offer both safety and versatility (Uboldi et al., 2023).

Controlled-Release Formulations in Chronic Diseases

Extended Release Drug Delivery Systems

The management of chronic diseases often necessitates long-term medication, making patient compliance a significant concern. Extended-release drug delivery systems have emerged as a solution to this issue by reducing the frequency of drug administration. These systems work by prolonging the release of the drug, thereby maintaining therapeutic levels in the bloodstream for an extended period. This not only improves patient compliance but also enhances the overall therapeutic efficacy of the treatment (Sugandini & Reddy, 2023).

Mucoadhesive Hydrogels in Buccal Diseases

Chronic buccal diseases like oral lichen planus and recurrent aphthous stomatitis often require sustained drug delivery for effective management. Mucoadhesive poloxamer-based hydrogels have shown promise in this regard. These hydrogels are designed to adhere to the mucosal surface, thereby providing a controlled release of drugs like dexamethasone. The use of hydroxypropyl-beta-cyclodextrin (HP-β-CD) as a complexing agent further enhances the solubility and stability of the drug, making it a viable option for the treatment of chronic buccal diseases (Diaz-Salmeron et al., 2021).

Parenteral Formulations in Psychiatry

The treatment of psychiatric disorders like schizophrenia and bipolar disorder often involves the use of antipsychotic drugs, which can have severe side effects when administered in high doses. Controlled parenteral formulations have been developed to address this issue. These formulations offer a more controlled release of antipsychotic drugs, thereby reducing the risk of side effects and improving patient compliance. The use of biodegradable polymers in these formulations further enhances their safety profile (Gupta et al., 2020).

Inhalational Therapy for Respiratory Diseases

Chronic respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD) require long-term medication for effective management. Recent advancements in inhalational therapy have led to the development of novel modified-release drug delivery systems. These systems are designed to provide a more controlled release of drugs, thereby maintaining therapeutic levels in the lungs for an extended period. The use of lipid-based carriers and polymeric nanoparticles in these formulations further enhances their efficacy and safety (Hye et al., 2023).

Controlled-Release Formulations in Cardiovascular Diseases

Propranolol Release Mechanisms

Cardiovascular diseases remain a leading cause of mortality globally, necessitating innovative therapeutic approaches for effective management. One such advancement is in the controlled release of beta-blockers like propranolol. Traditional immediate-release formulations require multiple daily doses, leading to fluctuations in plasma drug concentrations. Controlled-release formulations have been developed to mitigate this issue, providing a more stable plasma drug profile and thereby potentially reducing side effects (Conceição et al., 2018).

Supercritical Fluid Technologies

The application of supercritical fluid technologies in drug formulation has opened new avenues for cardiovascular drug delivery. These technologies allow for the incorporation of both synthetic and natural active compounds into materials, offering a more controlled and targeted release. This is particularly beneficial in the treatment of conditions like hypertension and atherosclerosis, where a sustained release of the drug can significantly improve therapeutic outcomes (Kravanja et al., 2022).

Chronopharmacology in Cardiovascular Diseases

Chronopharmacology, the study of how biological rhythms affect drug pharmacokinetics and pharmacodynamics, has significant implications for cardiovascular diseases. Controlled-release formulations that align with the body’s circadian rhythms can offer more effective treatment options. For instance, the release of antihypertensive drugs can be timed to coincide with the early morning surge in blood pressure, thereby providing a more targeted therapy (Lemmer, 2005).

Metoprolol in Heart Failure

Metoprolol, a commonly used beta-blocker for treating heart failure, has seen advancements in its controlled-release formulations. These formulations offer a more sustained release of the drug, thereby maintaining therapeutic levels in the bloodstream for an extended period. This not only improves patient compliance but also enhances the overall therapeutic efficacy of the treatment (Benfield et al., 1986).

Floating Pulsatile Release Systems

Another innovative approach in cardiovascular drug delivery is the development of floating pulsatile release systems. These systems are designed to float on the gastric fluid, thereby prolonging the gastric residence time of the drug and ensuring a more controlled release. This is particularly beneficial for drugs like antihypertensives, where a sustained release can significantly improve therapeutic outcomes (Dalvadi et al., 2011).

Controlled-Release Formulations in Diabetes Management

Nanoparticle-Based Insulin Delivery

Diabetes management has been a focal point of research in controlled-release formulations, given the chronic nature of the disease and the need for consistent insulin levels. Nanoparticle-based insulin delivery systems have shown promise in this regard. These systems are designed to encapsulate insulin and release it in a controlled manner, thereby maintaining stable blood glucose levels. This approach has the potential to significantly improve patient compliance and overall therapeutic outcomes (Samavati et al., 2022).

Glyburide Controlled Release Tablets

Oral antidiabetic agents like glyburide have also seen advancements in controlled-release formulations. Trilayer matrix tablets using natural gums have been developed to provide a more sustained release of glyburide. This not only improves the drug’s bioavailability but also minimizes the risk of hypoglycemia, a common side effect associated with antidiabetic medications (Ram Prasad & Bhikshapathi, 2018).

Prolonged-Release Metformin

Metformin, another widely used antidiabetic drug, has been formulated into new prolonged-release versions to improve gastrointestinal tolerability. These formulations offer a more controlled release of the drug, thereby reducing gastrointestinal side effects, which are a common concern with traditional metformin tablets (Davidson & Howlett, 2004).

Biopharmaceutical Formulations

Recent advancements in biopharmaceutical formulations have also contributed to improved diabetes management. These formulations are engineered to provide a more targeted and controlled release of antidiabetic agents, thereby enhancing their therapeutic efficacy. This is particularly beneficial for patients who require multiple daily injections, as it reduces the frequency of administration (Maikawa et al., 2021).

Depot-Based Drug Delivery for Depression in Diabetes

Depression is a common comorbidity in diabetes patients, and its management often requires long-term medication. Depot-based drug delivery systems have been developed for the controlled release of antidepressants, offering a more effective treatment option for patients with both diabetes and depression (Pilaniya et al., 2011).

Controlled-Release Formulations in Cancer Therapy

Opioid Analgesics in Cancer Pain Management

Cancer pain management is a critical aspect of oncology care, and opioid analgesics remain the cornerstone for treating moderate to severe pain. Controlled-release formulations of opioids like morphine and oxycodone have been compared with transdermal formulations of buprenorphine and fentanyl. These controlled-release formulations have shown to be effective in managing severe pain in cancer patients, thereby improving their quality of life (Nosek et al., 2017).

pH-Responsive Nanoparticles for Gastric Cancer

The development of pH-responsive nanoparticles has opened new avenues for targeted drug delivery in cancer therapy. Specifically, PEGylated niosomal nanoparticles have been employed as an active-targeting cyclophosphamide delivery system for gastric cancer. These nanoparticles are designed to release the drug in a controlled manner in response to the acidic tumor microenvironment, thereby enhancing the therapeutic efficacy (Khodabakhsh et al., 2022).

Laser-Induced Thermal Response in Nanocarriers

Laser-induced thermal response has been explored as a mechanism for controlled drug release from polymeric nanocarriers loaded with copper oxide nanoparticles. This approach allows for the spatiotemporal control of drug release, which is particularly beneficial for localized cancer therapy (Maor et al., 2021).

Nanoparticles in Lung Cancer

Nanoparticles have also been extensively studied for lung cancer therapy. Various formulations have been developed to improve the pharmacodynamics of anticancer drugs, thereby enhancing their therapeutic index. These nanoparticles offer a more controlled and targeted drug delivery, which is crucial for minimizing systemic toxicity (Zheng et al., 2018).

Dynamic Covalent Bonds in Drug Conjugates

Dynamic covalent bonds have been employed in drug conjugates for cancer therapy. These bonds offer a reversible linkage between the drug and the carrier, allowing for a more controlled release of the drug. This approach has been particularly useful in the delivery of chemotherapeutic agents, enhancing their therapeutic efficacy while minimizing side effects (Theodosis-Nobelos et al., 2020).

Controlled-Release Formulations in Neurodegenerative Diseases

PLGA Nanoparticles for Brain Penetration

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s present unique challenges for drug delivery, primarily due to the blood-brain barrier. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles have been employed to improve the brain penetration of small molecules like S14. These nanoparticles offer a controlled release mechanism, thereby enhancing the therapeutic efficacy of the drug in neurodegenerative conditions (Nozal et al., 2021).

Microparticulate Systems in Ocular Diseases

Ocular neurodegenerative diseases like glaucoma and age-related macular degeneration also benefit from controlled-release formulations. Microparticulate drug delivery systems have been developed to protect retinal cells in ocular excitotoxicity diseases. These systems offer a more targeted and controlled drug release, thereby improving therapeutic outcomes (Rodríguez Villanueva et al., 2020).

Polyphenol Nano-Formulations in Neurotherapy

Polyphenols have shown promise in the treatment of neurodegenerative diseases due to their antioxidant properties. Nano-formulations of polyphenols have been rationalized for use in neurotherapy. These formulations offer a more controlled release of polyphenols, thereby enhancing their bioavailability and therapeutic efficacy (Kumari et al., 2022).

Extracellular Vesicles in Drug Delivery

Extracellular vesicles have emerged as a novel approach for drug delivery in neurodegenerative diseases. These vesicles can encapsulate therapeutic agents and offer a more targeted and controlled release. This approach has been particularly useful in overcoming the challenges posed by the blood-brain barrier (Kumar et al., 2020).

Mosquito-Repellent Formulations in Neuroinfectious Diseases

While not directly related to neurodegenerative diseases, it’s worth noting that controlled-release formulations have also been employed in mosquito-repellent products to combat neuroinfectious diseases like malaria. These formulations offer a prolonged release of the repellent, thereby enhancing its efficacy (Mapossa et al., 2021).

Conclusion

The landscape of controlled-release formulations has undergone significant transformations over the past few decades, with advancements in nanotechnology, materials science, and pharmacology driving this evolution. The utility of controlled-release formulations extends across a myriad of medical conditions, ranging from cardiovascular diseases and diabetes to cancer and neurodegenerative disorders. These formulations offer the advantage of improved therapeutic outcomes, reduced side effects, and enhanced patient compliance, thereby revolutionizing the field of drug delivery (Mukherjee et al., 2015).

Multiparticulate drug delivery systems have emerged as a versatile platform for controlled release, offering the flexibility to tailor drug release profiles to specific therapeutic needs. These systems have been particularly effective in the management of chronic conditions that require sustained drug release over extended periods (Dey et al., 2008).

Oral multiunit pellet extended-release dosage forms have also gained attention for their ability to provide a more uniform drug release, thereby minimizing peak-to-trough fluctuations in plasma drug concentrations. This is particularly beneficial in conditions that require a steady state of the drug for optimal therapeutic efficacy (Sachdeva et al., 2013).

Recent research has also delved into the microencapsulation of bacteriophages for pH-triggered controlled release, expanding the scope of controlled-release formulations beyond small molecules to include biological entities. This opens up new avenues for the treatment of bacterial infections and other conditions that may benefit from a targeted release of biological agents (Richards & Malik, 2021).

Moreover, the integration of pharmacokinetic-pharmacodynamic modeling in the development of controlled-release formulations has provided valuable insights into optimizing drug release profiles. This has been particularly useful in the case of opioid analgesics, where controlled-release formulations have been shown to offer a more stable and effective pain management strategy (Ladebo et al., 2020).

Lastly, the trends in the uptake of new formulations, particularly in the case of controlled-release oxycodone in Canada, indicate a growing acceptance and reliance on these advanced drug delivery systems. This not only underscores the clinical relevance of controlled-release formulations but also highlights the need for ongoing research and development in this domain (Gomes et al., 2018).

REFERENCES

1. Patel, K., Shah, S., & Patel, J. (2022). Solid dispersion technology as a formulation strategy for the fabrication of modified release dosage forms: A comprehensive review. Daru: Journal of Faculty of Pharmacy, Tehran University of Medical Sciences, 30(1), 165–189.
2. Rashid Iqbal, M. (2022). Gastric Floating Drug Delivery Systems: A promising carriers for the delivery of controlled release drugs. International Journal of Life Science and Pharma Research, P127–P136.
3. Klein, S. (2019). Advancements in dissolution testing of oral and non-oral formulations. AAPS PharmSciTech, 20(7), 266.
4. Aragao-Santiago, L., Bohr, A., Delaval, M., Dalla-Bona, A. C., Gessler, T., Seeger, W., & Beck-Broichsitter, M. (2016). Innovative formulations for controlled drug delivery to the lungs and the technical and toxicological challenges to overcome(.). Current Pharmaceutical Design, 22(9), 1147–1160.
5. Malekjani, N., & Jafari, S. M. (2021). Modeling the release of food bioactive ingredients from carriers/nanocarriers by the empirical, semiempirical, and mechanistic models. Comprehensive Reviews in Food Science and Food Safety, 20(1), 3–47.
6. Tyagi, S. (2022). Novel approaches for colon site-specific drug delivery: An overview of recent advancements. Journal of Pharmaceutical Negative Results, 4479–4495.
7. Wein, A. J. (2019). Re: Novel immediate/sustained-release formulation of acetaminophen-ibuprofen combination (paxerol®) for severe nocturia associated with overactive bladder: A multi-center, randomized, double blinded, placebo-controlled, 4-arm trial [Review of Re: Novel immediate/sustained-release formulation of acetaminophen-ibuprofen combination (paxerol®) for severe nocturia associated with overactive bladder: A multi-center, randomized, double blinded, placebo-controlled, 4-arm trial]. The Journal of Urology, 202(2), 217–218.
8. Uboldi, M., Perrotta, C., Moscheni, C., Zecchini, S., Napoli, A., Castiglioni, C., Gazzaniga, A., Melocchi, A., & Zema, L. (2023). Insights into the safety and versatility of 4D printed intravesical drug delivery systems. Pharmaceutics, 15(3), 757.
9. Sugandini, G., & Reddy, M. S. (2023). An overview on classification, mechanism of extended release drug delivery of oral formulations. Journal of Drug Discovery and Therapeutics, 11(3), 06–17.
10. Diaz-Salmeron, R., Toussaint, B., Huang, N., Bourgeois Ducournau, E., Alviset, G., Goulay Dufaÿ, S., Hillaireau, H., Dufaÿ Wojcicki, A., & Boudy, V. (2021). Mucoadhesive poloxamer-based hydrogels for the release of HP-β-CD-complexed dexamethasone in the treatment of buccal diseases. Pharmaceutics, 13(1), 117.
11. Gupta, H., Panchal, R., Acharya, N., & Mehta, P. J. (2020). Controlled parenteral formulations: An efficacious and favourable way to deliver the anti-psychotic drugs. Current Psychiatry Research and Reviews, 16(1), 42–59.
12. Hye, T., Moinuddin, S. M., Sarkar, T., Nguyen, T., Saha, D., & Ahsan, F. (2023). An evolving perspective on novel modified release drug delivery systems for inhalational therapy. Expert Opinion on Drug Delivery, 20(3), 335–348.
13. Conceição, A. P., Sá, R. R., da Silva, V. C., Ferreira, M. da S., Cazedey, E. C. L., Magalhães, H. I. F., & Santos Júnior, A. de F. (2018). A comparative study of propranolol release by in vitro dissolution profiles in pharmaceutical formulations. Dissolution Technologies, 25(4), 54–61.
14. Kravanja, K. A., Finšgar, M., Knez, Ž., & Knez Marevci, M. (2022). Supercritical fluid technologies for the incorporation of synthetic and natural active compounds into materials for drug formulation and delivery. Pharmaceutics, 14(8), 1670.
15. Lemmer, B. (2005). Chronopharmacology and controlled drug release. Expert Opinion on Drug Delivery, 2(4), 667–681.
16. Benfield, P., Clissold, S. P., & Brogden, R. N. (1986). Metoprolol. Drugs, 31(5), 376–429.
17. Dalvadi, H. P., Patel, J. K., & Shah, D. P. (2011). Time and/or site specific drug delivery of floating pulsatile release delivery system. Systematic Reviews in Pharmacy, 2(1), 59.
18. Samavati, S. S., Kashanian, S., Derakhshankhah, H., & Rabiei, M. (2022). Nanoparticle application in diabetes drug delivery. Journal of Nanoparticle Research: An Interdisciplinary Forum for Nanoscale Science and Technology, 24(9).
19. Ram Prasad, B., & Bhikshapathi, D. V. R. N. (2018). Design and in vitro evaluation of glyburide controlled release trilayer matrix tablets using natural gums. American Journal of PharmTech Research, 8(4), 23–37.
20. Davidson, J., & Howlett, H. (2004). New prolonged-release metformin improves gastrointestinal tolerability. The British Journal of Diabetes & Vascular Disease, 4(4), 273–277.
21. Maikawa, C. L., d’Aquino, A. I., Lal, R. A., Buckingham, B. A., & Appel, E. A. (2021). Engineering biopharmaceutical formulations to improve diabetes management. Science Translational Medicine, 13(578), eabd6726.
22. Pilaniya, U., Khatri, K., & Patil, U. K. (2011). Depot based drug delivery system for the management of depression. Current Drug Delivery, 8(5), 483–493.
23. Nosek, K., Leppert, W., Nosek, H., Wordliczek, J., & Onichimowski, D. (2017). A comparison of oral controlled-release morphine and oxycodone with transdermal formulations of buprenorphine and fentanyl in the treatment of severe pain in cancer patients. Drug Design, Development and Therapy, 11, 2409–2419.
24. Khodabakhsh, F., Bourbour, M., Yaraki, M. T., Bazzazan, S., Bakhshandeh, H., Ahangari Cohan, R., & Tan, Y. N. (2022). PH-responsive PEGylated niosomal nanoparticles as an active-targeting cyclophosphamide delivery system for gastric cancer therapy. Molecules (Basel, Switzerland), 27(17), 5418.
25. Maor, I., Asadi, S., Korganbayev, S., Dahis, D., Shamay, Y., Schena, E., Azhari, H., Saccomandi, P., & Weitz, I. S. (2021). Laser-induced thermal response and controlled release of copper oxide nanoparticles from multifunctional polymeric nanocarriers. Science and Technology of Advanced Materials, 22(1), 218–233.
26. Zheng, D., Wang, J., Guo, S., Zhao, Z., & Wang, F. (2018). Formulations, pharmacodynamic and clinical studies of nanoparticles for lung cancer therapy-an overview. Current Drug Metabolism, 19(9), 759–767.
27. Theodosis-Nobelos, P., Charalambous, D., Triantis, C., & Rikkou-Kalourkoti, M. (2020). Drug conjugates using different dynamic covalent bonds and their application in cancer therapy. Current Drug Delivery, 17(7), 542–557.
28. Nozal, V., Rojas-Prats, E., Maestro, I., Gil, C., Perez, D. I., & Martinez, A. (2021). Improved controlled release and brain penetration of the small molecule S14 using PLGA nanoparticles. International Journal of Molecular Sciences, 22(6), 3206.
29. Rodríguez Villanueva, J., Martín Esteban, J., & Rodríguez Villanueva, L. J. (2020). Retinal cell protection in ocular excitotoxicity diseases. Possible alternatives offered by microparticulate drug delivery systems and future prospects. Pharmaceutics, 12(2), 94.
30. Kumari, N., Daram, N., Alam, M. S., & Verma, A. K. (2022). Rationalizing the use of polyphenol nano-formulations in the therapy of neurodegenerative diseases. CNS & Neurological Disorders Drug Targets, 21(10), 966–976.
31. Kumar, A., Zhou, L., Zhi, K., Raji, B., Pernell, S., Tadrous, E., Kodidela, S., Nookala, A., Kochat, H., & Kumar, S. (2020). Challenges in biomaterial-based drug delivery approach for the treatment of neurodegenerative diseases: Opportunities for extracellular vesicles. International Journal of Molecular Sciences, 22(1), 138.
32. Mapossa, A. B., Focke, W. W., Tewo, R. K., Androsch, R., & Kruger, T. (2021). Mosquito-repellent controlled-release formulations for fighting infectious diseases. Malaria Journal, 20(1), 165.
33. Mukherjee, B., Dutta, L., Mondal, L., Dey, N. S., Chakraborty, S., Maji, R., & Shaw, T. K. (2015). Nanoscale formulations and diagnostics with their recent trends: A major focus of future nanotechnology. Current Pharmaceutical Design, 21(36), 5172–5186.
34. Dey, N. S., Majumdar, S., & Rao, M. E. B. (2008). Multiparticulate drug delivery systems for controlled release. Tropical Journal of Pharmaceutical Research: TJPR, 7(3).
35. Sachdeva, V., Alam, M. S., Kumar, R., & Kataria, M. K. (2013). Oral multiunit pellet extended release dosage form: A review. International Current Pharmaceutical Journal, 2(10), 177–184.
36. Richards, K., & Malik, D. J. (2021). Microencapsulation of bacteriophages using membrane emulsification in different pH-triggered controlled release formulations for oral administration. Pharmaceuticals (Basel, Switzerland), 14(5).
37. Ladebo, L., Foster, D. J. R., Abuhelwa, A. Y., Upton, R. N., Kongstad, K. T., Drewes, A. M., Christrup, L. L., & Olesen, A. E. (2020). Population pharmacokinetic-pharmacodynamic modelling of liquid and controlled-release formulations of oxycodone in healthy volunteers. Basic & Clinical Pharmacology & Toxicology, 126(3), 263–276.
38. Gomes, T., Jain, S., Paterson, J. M., Sketris, I., Caetano, P., Henry, D., & Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. (2018). Trends and uptake of new formulations of controlled-release oxycodone in Canada. Pharmacoepidemiology and Drug Safety, 27(5), 520–525.