Challenges in oral drug delivery of antiretrovirals and the innovative strategies to overcome them☆
Graphical abstract
Introduction
Due to remarkable advantages such as minimal invasiveness, painfulness, ease-of-use (no need of trained personnel), cost-effectiveness, reproducibility of the administration and feasibility in the whole range of patient ages, the oral route is the most patient compliant. In addition, since the gastrointestinal transit takes place along several hours, slow-release formulations may be tuned to prolong the duration of the action. Moreover, drugs can be formulated in such a way that they are released in the stomach or different portions of the small intestine and/or the colon to tune the absorption site or attain localized activity (e.g., inflammatory bowel disease). On the other hand, oral drug delivery must overcome numerous challenges, including the acidic gastric environment, the poor aqueous solubility and chemical stability of many drugs and the presence of digestive enzymes [1]. The mucus barrier is another hurdle because it can prevent timeous penetration and absorption of the released drug, making the oral bioavailability often unpredictable. Further, it is unsuitable in patients who are uncooperative, strictly “nil by mouth”, vomiting profusely or have ileus. Finally, upon intestinal absorption, many of them undergo extensive first-pass metabolism in the liver, a pathway that decreases the oral bioavailability. Regardless of the difficulty to ensure high bioavailability and plasma concentrations within the therapeutic window, the advantages of oral drug delivery are more prominent than the disadvantages, and thus it remains the preferred option in patients affected by chronic diseases.
Even though countless efforts have and are being made to eradicate the HIV from the host, to date, the cure is not possible and a chronic combined antiretroviral (ARV) therapy is required to ensure viral suppression and reduce the rate of progression from the infection to the active phase of the disease, the acquired immunodeficiency syndrome (AIDS). In addition, effective therapeutic strategies must be adopted to target HIV reservoirs such as those at the central nervous system (CNS) and lymphatic cells, to reduce the gradual deterioration of the host tissues and systems and to improve the quality of life of patients [2].
The current clinical therapy, known as ‘high activity antiretroviral therapy’ or HAART, is one of the most significant advances in the field. Since the middle of 1990s, HAART has made a remarkable contribution towards reducing the patient mortality and, as more recently demonstrated, the transmission rates among high-risk individuals [3]. ARVs are classified into different families based on the stage of the HIV life cycle where they act on. Presently, there are five different classes of approved ARVs: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) [4], non-nucleoside reverse transcriptase inhibitors (NNRTIs) [5], protease inhibitors (PIs) [6], entry/fusion inhibitors [7] and integrase inhibitors [8]. A gold-standard cocktail comprises a minimum of three ARVs from two classes, while in the case of PIs they are co-administered with the ARV ritonavir (used in sub-therapeutic dose) as boosting agent. All the ARVs, with the exception of the subcutaneous oligopeptide enfuvirtide, are administered at least once a day by the oral route [9]. Rilpivirine, a second-generation NNRTI, is currently being clinically trialed in a long-acting injectable formulation [10], [11].
Patient compliance represents one of the greatest challenges to achieve therapeutic success [12]; due to pill burden and/or complicated administration schedules patients tend to cease the therapy, a phenomenon that results in viral rebound and favors the development of resistance. The use of fixed-dose combinations (FDCs), namely formulations that contain more than one ARV in one single administration unit (e.g., pill) and at a fixed dose and drug ratio, has made the administration regimens simpler and more patient compliant. However, FDCs are still conventional oral drug delivery systems (DDS) and they do not address the relevant biopharmaceutical and pharmacokinetic (PK) drawbacks of the approved ARVs [13]. In this scenario, to improve the oral bioavailability of ARVs, the design and development of advanced oral DDS are called for [14], [15]. The present review describes the state-of-the-art pharmaceutical products for the therapy of HIV and highlights innovative microtechnology and nanotechnology research strategies adopted to overcome the most relevant limitations of the present treatment regimens and hence, to enhance the efficacy of the oral ARV therapy against HIV. It is worth remarking that a detailed description of the first-line treatment regimens is out of the scope and it could be found in the review by Sued et al. (16, current theme issue).
Section snippets
Challenges in oral delivery of ARVs
The design of conventional and advanced oral delivery systems in general and for ARVs in particular demands a deep understanding of the conditions to which the active pharmaceutical ingredient (API) will be exposed during its transit from the mouth to the absorption site, usually the small intestine and the obstacles that exist to reach the systemic circulation (Fig. 1). In this section, the main challenges in the oral delivery of ARVs will be overviewed in sequential manner, from the mouth
Short residence time in the intestine and half-life in plasma—the high administration frequency and pill burden issues
Owing to the relatively short systemic half-life, ARVs are administered in high dose and, at least, once a day and often twice a day. For example, indinavir displays a half-life of approximately 1 h. Hence, it was initially administered t.i.d., a frequency that was reduced to b.i.d when boosted with ritonavir. Clinicians refer this phenomenon as one of the most challenging aspects of the therapy today because patients tend to abandon the treatment or miss doses, especially in very
Pending challenges
The oral route of drug administration provides many advantages for the delivery of ARVs for extended times. Approaches to effectively protect the ARV from harsh acidic environment of stomach, using various polymeric particles and coatings came up with success stories. Importantly, if ARV nanoformulations with better bioavailability and hence, requiring lower drug doses, become available globally, treatments will turn into more cost-effective since the API accounts for the major proportion of
Acknowledgements
This work was funded by the European Union's—Seventh Framework Program under grant agreement #612675-MC-NANOTAR and the Phyllis and Joseph Gurwin Fund for Scientific Advancement (Technion grant #2020855). RA thanks the Israel Council for Higher Education for a postdoctoral scholarship.
References (190)
- et al.
Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers
Adv. Drug Deliv. Rev.
(2012) - et al.
HIV-1 reverse transcriptase and antiviral drug resistance. Part 1
Curr. Opin. Virol.
(2013) - et al.
HIV integrase inhibitors: 20-year landmark and challenges
Adv. Pharmacol.
(2013) - et al.
Drug delivery systems in HIV pharmacotherapy: what has been done and the challenges standing ahead
J. Control. Release
(2009) - et al.
Pure drug and polymer based nanotechnologies for the improved solubility, stability, bioavailability and targeting of anti-HIV drugs
Adv. Drug Deliv. Rev.
(2010) - et al.
Depressive symptoms, neurocognitive impairment, and adherence to highly active antiretroviral therapy among HIV-infected persons
Psychosomatics
(2004) - et al.
Milk as a medium for pediatric formulations: experimental findings and regulatory aspects
Int. J. Pharm.
(2015) - et al.
Oral pharmacokinetics of the anti-HIV efavirenz encapsulated within polymeric micelles
Biomaterials
(2011) - et al.
Polycarboxylic acid ion-exchange resin adsorbates for taste coverage in chewable tablets
J. Pharm. Sci.
(1971) - et al.
Controlled-release liquid suspensions based on ion-exchange particles within acrylic microcapsules
Int. J. Pharm.
(2000)
Elimination of bitter, disgusting tastes of drugs and foods by cyclodextrins
Eur. J. Pharm. Biopharm.
Taste masking microspheres for orally disintegrating tablets
Int. J. Pharm.
Film coatings for taste masking and moisture protection
Int. J. Pharm.
The complexities of antiretroviral drug–drug interactions: role of ABC and SLC transporters
Trends Pharmacol. Sci.
Self-assembled drug delivery systems: part 3. In vitro/in vivo studies of the self-assembled nanoparticulates of cholesteryl acyl didanosine
Int. J. Pharm.
Didanosine polymorphism in a supercritical antisolvent process
J. Pharm. Sci.
Preparation of gastro-resistant pellets containing chitosan microspheres for improvement of oral didanosine bioavailability
J. Pharm. Anal.
Spray-dried didanosine-loaded polymeric particles for enhanced oral bioavailability
Colloids Surf. B: Biointerfaces
Statistical investigation of simulated intestinal fluid composition on the equilibrium solubility of biopharmaceutics classification system class II drugs
Eur. J. Pharm. Sci.
Enhancing intestinal drug solubilisation using lipid-based delivery systems
Adv. Drug Deliv. Rev.
Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q 10: formulation development and bioavailability assessment
Int. J. Pharm.
Novel protease inhibitor-loaded nanoparticle-in-microparticle delivery system leads to a dramatic improvement of the oral pharmacokinetics in dogs
Biomaterials
Salt formation to improve drug solubility
Adv. Drug Deliv. Rev.
Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates
Adv. Drug Deliv. Rev.
Pharmaceutical cocrystals and poorly soluble drugs
Int. J. Pharm.
Exploring the use of novel drug delivery systems for antiretroviral drugs
Eur. J. Pharm. Biopharm.
Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs
Int. J. Pharm.
Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amorphous formulation approaches
Int. J. Pharm.
An overview on in situ micronization technique—an emerging novel concept in advanced drug delivery
Saudi Pharm. J.
Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs
Asian J. Pharm. Sci.
Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug delivery
Int. J. Pharm.
Influence of high pressure homogenisation equipment on nanodispersions characteristics
Int. J. Pharm.
Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation
Eur. J. Pharm. Biopharm.
Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers
Adv. Colloid Interf. Sci.
Preparation of stable nitrendipine nanosuspensions using the precipitation–ultrasonication method for enhancement of dissolution and oral bioavailability
Eur. J. Pharm. Sci.
Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs
J. Pharm. Sci.
Ritonavir–PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations
J. Pharm. Sci.
Inhibition of indomethacin crystallization in poly (vinylpyrrolidone) coprecipitates
J. Pharm. Sci.
Cyclodextrins as pharmaceutical solubilizers
Adv. Drug Deliv. Rev.
Cyclodextrins and their pharmaceutical applications
Int. J. Pharm.
Antiviral activity of novel 1-indanone thiosemicarbazones and their inclusion complexes with hydroxypropyl-β-cyclodextrin against the hepatitis C virus (HCV)
Eur. J. Pharm. Sci.
Antiretrovirals: need for an effective drug delivery
Indian J. Pharm. Sci.
Expansion of HAART coverage is associated with sustained decreases in HIV/AIDS morbidity, mortality and HIV transmission: the “HIV treatment as prevention” experience in a Canadian setting
PLoS One
Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability
J. Int. AIDS Soc.
HIV protease inhibitors: a review of molecular selectivity and toxicity
HIV AIDS (Auckl)
Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket
Amino Acids
Nanoparticulate delivery systems for antiviral drugs
Antivir. Chem. Chemother.
Pharmacokinetics and disposition of rilpivirine (TMC278) nanosuspension as a long-acting injectable antiretroviral formulation
Antimicrob. Agents Chemother.
Long-acting injectable antiretrovirals for HIV treatment and prevention
Curr. Opin. HIV AIDS
Adherence to protease inhibitor therapy and outcomes in patients with HIV infection
Ann. Intern. Med.
Cited by (89)
Polymersomes for protein drug delivery across intestinal mucosa
2023, International Journal of PharmaceuticsOral drug delivery platforms for biomedical applications
2023, Materials TodayCurrent status of dolutegravir delivery systems for the treatment of HIV-1 infection
2022, Journal of Drug Delivery Science and Technology
- ☆
This review is part of the Advanced Drug Delivery Reviews theme issue on “HIV/AIDS_dasNeves_Sarmento_Sosnik”.