Challenges to improve the biopharmaceutical properties of poorly water-soluble drugs and the application of the solid dispersion technology

The oral solid dosage forms are extremely relevant to drug therapy and responsible for much of the pharmaceutical industry turnover worldwide. However, the development of medicines in solid form involves significant challenges, including obtaining formulations with appropriate bioavailability for low aqueous solubility drugs (classes II and IV of the Biopharmaceutics Classification System). One of the most effective strategies to overcome poor dissolution rate and low absorption of drugs is the solid dispersion technique, however, although it has been the focus of much research in recent decades, there are relatively few commercially available products based on such technology. This is mainly due to problems related to production scale-up and physicochemical instability and creates opportunities for new studies to explore the full potential of the technology. This review presents an overall approach to the factors affecting the dissolution rate and oral bioavailability of BCS-classes II and IV drugs and a brief review of the state-of-theart of solid dispersion technology.

1. INTRODUCTION

The oral route is the most commonly used for drug administration due to significant inherent advantages compared to other routes, such as safety, non-invasive nature, convenience and comfort to the patient, possibility of self-administration and systemic distribution of the drug. Among all types of oral dosage forms, the solid ones, such as tablets and capsules, are the most used in therapy, because they offer many benefits, such as simplicity and low cost of production, high stability, convenience of the presentation in unit doses, portability, ease of administration and masking the unpleasant taste of many drugs [1,2].

A major obstacle to the development and large-scale production of oral solid dosage forms is the low solubility of many drugs, given the negative effect that this property has on drug absorption and bioavailability. Concern about drug solubility in the pharmaceutical industry has intensified from the 90s, when the use of techniques, such as combinatorial chemistry and high throughput screening (HTS), increased the achievement of new chemical entities with high molecular weight and high lipophilicity [3, 4]. Recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling the rate and the extent of drug absorption grounded the proposition of the Biopharmaceutical Classification System (BCS) for correlating drug product in vitro dissolution and in vivo bioavailability, in which classes II and IV encompass drugs with low solubility [5, 6, 7].

The need for effective formulations for BCS-classes II and IV drugs led to the progress of knowledge in the area of drug delivery systems for oral administration, over the years, and to the development of various technological strategies to remedy unsatisfactory biopharmaceutical properties, for example, micronization [8], formation of complexes with cyclodextrins [9], self-emulsifying drug delivery systems (SEDDS) [10], liquisolid systems [11, 12] and solid dispersions [13, 14].

Large investments in research and development of solid dispersions brought good results for the pharmaceutical industry, with the emergence of products based on this technology on the market. Nevertheless, there is still plenty of room for improvement, aiming to overcome some limitations of the solid dispersion technology. Additional studies for development and improvement are still needed regarding the production processes, carrier materials and stabilization strategies, so that the full potential of solid dispersions is explored, thus resulting in increased number of commercially available products [13,15]. This review presents an overall approach to the factors affecting the dissolution and oral bioavailability of BCS-classes II and IV drugs and a brief review of the state-of-the-art of solid dispersion technology.

2. ORAL ADMINISTRATION OF POORLY WATER-SOLUBLE DRUGS

For producing the desired pharmacological response after oral administration, as shown in Figure 1, a dosage form must release the drug in the gastrointestinal tract to be absorbed, reach the systemic circulation, and be distributed in the site of action in the body at sufficient rate and extent [16, 17]. The term bioavailability refers to the rate and extent at which the active drug reaches the systemic circulation [17, 18, 19]. Many factors may influence the bioavailability of drugs, which may be related to the dosage form, the manufacturing process and the drug itself [20, 21, 22, 23].

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