Elsevier

Advanced Drug Delivery Reviews

Volume 103, 1 August 2016, Pages 105-120
Advanced Drug Delivery Reviews

Challenges in oral drug delivery of antiretrovirals and the innovative strategies to overcome them

https://doi.org/10.1016/j.addr.2015.12.022Get rights and content

Abstract

Development of novel drug delivery systems (DDS) represents a promising opportunity to overcome the various bottlenecks associated with the chronic antiretroviral (ARV) therapy of the human immunodeficiency virus (HIV) infection. Oral drug delivery is the most convenient and simplest route of drug administration that involves the swallowing of a pharmaceutical compound with the intention of releasing it into the gastrointestinal tract. In oral delivery, drugs can be formulated in such a way that they are protected from digestive enzymes, acids, etc. and released in different regions of the small intestine and/or the colon. Not surprisingly, with the exception of the subcutaneous enfuvirtide, all the marketed ARVs are administered orally. However, conventional (marketed) and innovative (under investigation) oral delivery systems must overcome numerous challenges, including the acidic gastric environment, and the poor aqueous solubility and physicochemical instability of many of the approved ARVs. In addition, the mucus barrier can prevent penetration and subsequent absorption of the released drug, a phenomenon that leads to lower oral bioavailability and therapeutic concentration in plasma. Moreover, the frequent administration of the cocktail (ARVs are administered at least once a day) favors treatment interruption. To improve the oral performance of ARVs, the design and development of more efficient oral drug delivery systems are called for. The present review highlights various innovative research strategies adopted to overcome the limitations of the present treatment regimens and to enhance the efficacy of the oral ARV therapy in HIV.

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.

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