Strategies to improve oral drug bioavailability

Efforts to improve oral drug bioavailability have grown in parallel with the pharmaceutical industry. As the number and chemical diversity of drugs has increased, new strategies have been required to develop orally active therapeutics. The past two decades have been characterised by an increased understanding of the causes of low bioavailability and a great deal of innovation in oral drug delivery technologies, marked by an unprecedented growth of the drug delivery industry. The advent of biotechnology and consequent proliferation of biopharmaceuticals have brought new challenges to the drug delivery field. In spite of the difficulties associated with developing oral forms of this type of therapeutics, significant progress has been made in the past few years, with some oral proteins, peptides and other macromolecules currently advancing through clinical trials. This article reviews the approaches that have been successfully applied to improve oral drug bioavailability, primarily, prodrug strategies, lead optimisation through medicinal chemistry and formulation design. Specific strategies to improve the oral bioavailability of biopharmaceuticals are also discussed.     

Strategies to improve oral drug bioavailability

Efforts to improve oral drug bioavailability have grown in parallel with the pharmaceutical industry. As the number and chemical diversity of drugs has increased, new strategies have been required to develop orally active therapeutics. The past two decades have been characterised by an increased understanding of the causes of low bioavailability and a great deal of innovation in oral drug delivery technologies, marked by an unprecedented growth of the drug delivery industry. The advent of biotechnology and consequent proliferation of biopharmaceuticals have brought new challenges to the drug delivery field. In spite of the difficulties associated with developing oral forms of this type of therapeutics, significant progress has been made in the past few years, with some oral proteins, peptides and other macromolecules currently advancing through clinical trials. This article reviews the approaches that have been successfully applied to improve oral drug bioavailability, primarily, prodrug strategies, lead optimisation through medicinal chemistry and formulation design. Specific strategies to improve the oral bioavailability of biopharmaceuticals are also discussed.     

Communication strategies to improve drug use evaluation

Successful examples of teams and drug use evaluations explore communication strategies to enhance quality improvement of medication use. Topics highlighted include establishing contacts within key departments, creating committee connections, fostering physician and nurse participation, and increasing visibility and maintaining awareness. Multidisciplinary collaboration and linkage between the hospital and the managed care pharmacy are also reviewed. Medication use can be improved by integrating these communication tactics.     

Formulation studies of a poorly water-soluble drug in solid dispersions to improve bioavailability

To improve the bioavailability of a poorly water-soluble drug, RP 69698 (1), solid dispersion formulations were investigated in beagle dogs. The formulations were prepared by a melting method with water-soluble carriers in which 1 is highly soluble. When incorporated into a solid dispersion formulation composed of polyethylene glycol (PEG) 3350, Transcutol and Labrasol, the bioavailability of 1 was determined to be 11.8%. This represented about 2-fold improvement over 6% bioavailability observed previously with an aqueous suspension of the drug in 0.5% methylcellulose. When the formulation contained only Labrasol, in which 1 was completely solubilized, the bioavailability of 1 was 12.9%. Addition of a surfactant, polysorbate 80, at a strength of 10% to the dispersion with PEG 3350 and Labrasol as carriers increased the bioavailability of 1 from 11.8 to 27.6%. This result was attributed to the ability of the surfactant to increase the wettability and spreadability of the drug in a solubilized state once released in the gastrointestinal medium. Increase in the concentration of the surfactant did not further increase the bioavailability of 1. DSC and powder XRD data demonstrated that the major fraction of drug was dissolved in the carrier. A possible explanation for the maximum achievable bioavailability of about 25% with solid dispersion preparation may be that once released, a significant fraction of drug may precipitate in the GI tract. Re-solubilization of the precipitated drug for the absorption is likely to be difficult due to its very low aqueous solubility.     

Pharmaceutical particle technologies: An approach to improve drug solubility,dissolution and bioavailability

Pharmaceutical particle technology is employed to improve poor aqueous solubility of drug compounds that limits in vivo bioavailability owing to their low dissolution rate in the gastrointestinal fluids following oral administration. The particle technology involves several approaches from the conventional size reduction processes to the newer, novel particle technologies that modify the solubility properties of the drugs and produce solid, powdered form of the drugs that are readily soluble in water and can be easily formulated into various dosage forms. This review highlights the solid particle technologies available for improving solubility, dissolution and bioavailability of drugs with poor aqueous solubility.     

Converting peptides into drug leads by lipidation

Lipidation is a posttranslational modification of proteins that has also found its use in designing peptide drugs. The presence of a lipid group in peptides modulates their hydrophobicity, secondary structures and self-assembling propensities while retaining their abilities to bind to target receptors. Lipidation improves peptides' metabolic stability, membrane permeability, bioavailability, and changes peptides' pharmacokinetic and pharmacodynamic properties. Herein, we review the applications of various lipidation strategies in peptide drug design, the effects of the chain length and anchor position of fatty acids in peptide lipidation, the physicochemical and biological properties of selected lipidated peptides and the synthesis strategies for peptide lipidation.     

Novel functionalization strategies to improve drug delivery from polymers

Introduction: The utility of controlled and sustained release of drugs from polymeric systems, both bulk (hydrogels) and colloids (nanoparticles), is a key point that should be addressed. Unfortunately, classic delivery systems are essentially driven by diffusion, which is very quick due to the high concentration gradient present in the body.

Area covered: This review provides an overview of functionalization strategies which have been used to reduce release rates by taking advantage of post-polymerization functionalization of polymers. This paradigm is extremely useful in the pharmacological treatment of several diseases, particularly multifactorial diseases, which may require a variety of release kinetics for different drugs from a single device.

Expert opinion: Polymer chains can be functionalized with several post-polymerization strategies in order to link, with a cleavable bond, drug molecules to reactive points of the polymeric network. Following this strategy, the main mechanism related to drug release is the breakage of the link that could be opportunely chosen depending on the medical needs: the weaker the bond, the higher the release rate.     

Transdermal iontophoresis: combination strategies to improve transdermal iontophoretic drug delivery.

For several decades, there has been interest in using the skin as a port of entry into the body for the systemic delivery of therapeutic agents. However, the upper layer of the skin, the stratum corneum, poses a barrier to the entry of many therapeutic entities. Given a compound, passive delivery rate is often dependent on two major physicochemical properties: the partition coefficient and solubility. The use of chemical enhancers and modifications of the thermodynamic activity of the applied drug are two frequently employed strategies to improve transdermal permeation. Chemical enhancers are known to enhance drug permeation by several mechanisms which include disrupting the organized intercellular lipid structure of the stratum corneum , 'fluidizing' the stratum corneum lipids , altering cellular proteins, and in some cases, extracting intercellular lipids . However, the resulting increase in drug permeation using these techniques is rather modest especially for hydrophilic drugs. A number of other physical approaches such as iontophoresis, sonophoresis, ultrasound and the use of microneedles are now being studied to improve permeation of hydrophilic as well as lipophilic drugs. This article presents an overview of the use of iontophoresis alone and in conjunction with other approaches such as chemical enhancement, electroporation, sonophoresis, and use of microneedles and ion-exchange materials.     

Intestinal OCTN2- and MCT1-targeted drug delivery to improve oral bioavailability

Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.     

Cyclization strategies in peptide derived drug design

The choice of peptides as prototype modulators of biological function, is justified on the grounds that peptides are natural constituents of living systems. They exist as hormones, biochemical inhibitors, antigens, growth factors, transmembrane carriers and, indeed they are comprised of the building blocks of all proteins. As such, the natural and mutated analogs of these functional entities provide a rich variety of pharmacophore models for further development. Peptidomimetic modification of active peptides can provide biostable analogs. Moreover, cyclization of linear peptides is frequently used as an attractive venue to provide both conformationally more restricted as well as more biostable analogs. The objective of this review is to report an updated summary of the more recently developed methodologies for the design and synthesis of cyclized peptides, citing selected examples of the effect of cyclization on both proteolytic stability and biological activity.     

结构修饰策略改善药物血脑屏障通透性

如何使药物有效地穿越血脑屏障并发挥药效,是治疗中枢神经系统疾病的一大难题。通过结构修饰,可以改善小分子药物的理化性质,使其可由被动扩散的方式到达脑部;另外,可将药物修饰成能借助载体或受体介导的转运系统运输的结构,经由载/受体转运进入脑部。这两种手段是目前常用的改善药物血脑屏障通透性的化学方法。本文简要介绍了药物传送到脑部的主要途径,并重点阐述基于传送途径对小分子药物利用化学手段进行结构修饰以改善药物血脑屏障通透性的方法。     

Microemulsions as drug delivery systems to improve the solubility and the bioavailability of poorly water-soluble drugs

Importance of the field: Microemulsions have been studied extensively as potential drug delivery vehicles for poorly water-soluble drugs. An understanding of the physicochemical and biopharmaceutical characteristics of the microemulsions according to administration routes will provide guidance for designing the formulations of microemulsions.

Areas covered in this review: In this paper, the use and the characteristics of microemulsions as drug delivery vehicles are reviewed. As the formulations of the microemulsion always include a great amount of surfactant and co-surfactant, which may cause hemolysis or histopathological alterations of the tissue, the potential toxicity or the irritancy of microemulsions is also discussed in this paper.

What the reader will gain: Developments of microemulsions for poorly water-soluble drugs in recent years are included in this review. Several factors limiting the commercial or clinical use of microemulsions are also discussed.

Take home message: Considering the potential in enhanced drug uptake/permeation and facing the limitations, their unique properties make microemulsions a promising vehicle for poorly water-soluble drugs.     

Development of a nanofiltration process to improve the stability of a novel anti-MRSA carbapenem drug candidate

The benzenesulfonate salt of an anti-methicillin-resistant Staphylococcus aureus carbapenem antibiotic studied is a crystalline, nonhygroscopic powder which is stable at room temperature, making it an ideal compound for long-term storage. However, the limited aqueous solubility of this salt prohibits parenteral administration. Conversely, the chloride salt of this carbapenem demonstrates opposing characteristics; it is quantitatively soluble in water, however is amorphous and subject to significant hydrolytic degradation in the solid state. Given two such extreme alternatives for pharmaceutical salt selection, a common approach taken is to develop the bioavailable salt and devise manufacturing and storage conditions that minimize degradation. This report describes a different approach to this manufacturing dilemma via the application of a simple and efficient nanofiltration process to convert the benzenesulfonate salt (storage entity) to the chloride salt (formulated drug product). Such an approach combines the positive attributes of these two salt forms into a single scalable process that reduces processing cycle times via elimination of redundant unit operations, increases the flexibility in manufacturing schedule, and improves overall product quality.     

Cell-penetrating TAT peptide in drug delivery systems: Proteolytic stability requirements

The stability and activity of the HIV cell-penetrating TAT peptide (TATp) on the surface of TATp-modified micelles and liposomes in relation to its proteolytic cleavage was investigated. TATp moieties were attached to the surface of these nanocarriers using TATp modified with a conjugate of phosphatidyl ethanolamine with a ‘short’ PEG (PEG-PE). Following pre-incubation with trypsin, elastase, or collagenase, the proteolytic stability of TATp on the surface of these modified carriers was studied by HPLC with fluorescence detection using fluorenylmethyl chloroformate (FMOC) labeling. All tested enzymes produced a dose-dependent cleavage of TATp as shown by the presence of TATp Arg-Arg fragments. Inhibition of TATp cleavage occurred when these TATp-micelles were modified by the addition of longer PEG-PE blocks, indicating an effective shielding of TATp from proteolysis by these blocks. TATp-modified carriers were also tested for their ability to accumulate in EL-4, HeLa, and B16-F10 cells. Trypsin treatment of TATp-modified liposomes and micelles resulted in decreased uptake and cell interaction, as measured by fluorescence microscopy and fluorescence-activated cell sorting techniques. Furthermore, a decrease in the cytotoxicity of TATp-modified liposomes loaded with doxorubicin (Doxil) was observed following trypsin treatment. In conclusion, steric shielding of TATp is essential to ensure its in vivo therapeutic function.     

Cell-penetrating TAT peptide in drug delivery systems: proteolytic stability requirements

The stability and activity of the HIV cell-penetrating TAT peptide (TATp) on the surface of TATp-modified micelles and liposomes in relation to its proteolytic cleavage was investigated. TATp moieties were attached to the surface of these nanocarriers using TATp modified with a conjugate of phosphatidyl ethanolamine with a 'short' PEG (PEG-PE). Following pre-incubation with trypsin, elastase, or collagenase, the proteolytic stability of TATp on the surface of these modified carriers was studied by HPLC with fluorescence detection using fluorenylmethyl chloroformate (FMOC) labeling. All tested enzymes produced a dose-dependent cleavage of TATp as shown by the presence of TATp Arg-Arg fragments. Inhibition of TATp cleavage occurred when these TATp-micelles were modified by the addition of longer PEG-PE blocks, indicating an effective shielding of TATp from proteolysis by these blocks. TATp-modified carriers were also tested for their ability to accumulate in EL-4, HeLa, and B16-F10 cells. Trypsin treatment of TATp-modified liposomes and micelles resulted in decreased uptake and cell interaction, as measured by fluorescence microscopy and fluorescence-activated cell sorting techniques. Furthermore, a decrease in the cytotoxicity of TATp-modified liposomes loaded with doxorubicin (Doxil) was observed following trypsin treatment. In conclusion, steric shielding of TATp is essential to ensure its in vivo therapeutic function.     

Andrographolide-loaded PLGA-PEG-PLGA micelles to improve its bioavailability and anticancer efficacy

Background: Andrographolide (ADG) isolated from Andrographis paniculata exhibits anti-inflammatory and anticancer activities, but high hydrophobicity and poor bioavailability greatly restricts its clinical application.

Objectives: In this study, ADG was encapsulated in a micelle formulation based on poly (D,L-lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly (D,L-lactide-co-glycolide) (PLGA-PEG-PLGA) amphiphilic triblock copolymers, in order to enhance the anticancer efficacy and bioavailability in vivo.

Methods: The physicochemical properties of the ADG-loaded PLGA-PEG-PLGA micelles were investigated for encapsulation efficiency, particle size, zeta potential and critical micelle concentration. These micelles were further evaluated for in vitro cytotoxicity, including proliferation inhibition, cell cycle arrest and pro-apoptosis effects against human breast cancer MAD-MB-231 cells, cellular uptake and pharmacokinetics study in rat.

Results: ADG-loaded PLGA-PEG-PLGA micelles had a high encapsulation and loading efficiency of about 92 and 8.4% (w/w), respectively, and a stable particle size of 124.3 ± 6.4 nm. In vitro cytotoxicity testing demonstrated that ADG-loaded PLGA-PEG-PLGA micelles exhibited higher proliferation inhibition, cell cycle arrest at the G2/M phase and pro-apoptosis effects in MAD-MB-231 cells, which would be contributed to higher efficiency of cellular uptake and intracellular transport. Further, the plasma AUC_{(0 – ∞)} and mean resident time of ADG-loaded PLGA-PEG-PLGA micelles were increased by 2.7- and 2.5-fold, respectively, when compared to the raw suspension.

Conclusion: All of these investigations suggest that PLGA-PEG-PLGA micelles may be a potential drug delivery strategy for improving ADG bioavailability and efficacy in cancer therapy.     

N,N'-dihydroxyamidines: a new prodrug principle to improve the oral bioavailability of amidines

N, N'-dihydroxybenzamdine represents a model compound for a new prodrug principle to improve the oral bioavailability of drugs containing amidine functions. The activation of the prodrug could be demonstrated in vitro by porcine and human subcellular enzyme fractions, the mitochondrial benzamidoxime reducing system, and porcine hepatocytes. In vivo, the bioavailability of benzamidine after oral application of N, N'-dihydroxybenzamidine was about 91% and exceeded that of benzamidine after oral application of benzamidoxime, being about 74% (Liu, L.; Ling, Y.; Havel, C.; Bashnick, L.; Young, W.; Rai, R.; Vijaykumar, D.; Riggs, J. R.; Ton, T.; Shaghafi, M.; Graupe, D.; Mordenti, J.; Sukbuntherng, J. Species comparison of in vitro and in vivo conversion of five N-hydroxyamidine prodrugs of fVIIA inhibitors to their corresponding active amidines. Presented at the 13th North America ISSX Meeting, Maui, HI, 2005).