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Advanced Drug Delivery Reviews (v.64, #6)
Modification of physicochemical characteristics of active pharmaceutical ingredients and application of supersaturatable dosage forms for improving bioavailability of poorly absorbed drugs
by Kohsaku Kawakami (pp. 480-495).
New chemical entities are required to possess physicochemical characteristics that result in acceptable oral absorption. However, many promising candidates need physicochemical modification or application of special formulation technology. This review discusses strategies for overcoming physicochemical problems during the development at the preformulation and formulation stages with emphasis on overcoming the most typical problem, low solubility. Solubility of active pharmaceutical ingredients can be improved by employing metastable states, salt forms, or cocrystals. Since the usefulness of salt forms is well recognized, it is the normal strategy to select the most suitable salt form through extensive screening in the current developmental study. Promising formulation technologies used to overcome the low solubility problem include liquid-filled capsules, self-emulsifying formulations, solid dispersions, and nanosuspensions. Current knowledge for each formulation is discussed from both theoretical and practical viewpoints, and their advantages and disadvantages are presented.Display Omitted
Keywords: Poorly soluble drug; Dissolution; Bioavailability; Supersaturation; Crystal form; Self-emulsifying formulation; Solid dispersion; Amorphous; Nanosuspension
Microfabrication technologies for oral drug delivery
by Shilpa Sant; Sarah L. Tao; Omar Z. Fisher; Qiaobing Xu; Nicholas A. Peppas; Ali Khademhosseini (pp. 496-507).
Micro-/nanoscale technologies such as lithographic techniques and microfluidics offer promising avenues to revolutionalize the fields of tissue engineering, drug discovery, diagnostics and personalized medicine. Microfabrication techniques are being explored for drug delivery applications due to their ability to combine several features such as precise shape and size into a single drug delivery vehicle. They also offer to create unique asymmetrical features incorporated into single or multiple reservoir systems maximizing contact area with the intestinal lining. Combined with intelligent materials, such microfabricated platforms can be designed to be bioadhesive and stimuli-responsive. Apart from drug delivery devices, microfabrication technologies offer exciting opportunities to create biomimetic gastrointestinal tract models incorporating physiological cell types, flow patterns and brush-border like structures. Here we review the recent developments in this field with a focus on the applications of microfabrication in the development of oral drug delivery devices and biomimetic gastrointestinal tract models that can be used to evaluate the drug delivery efficacy.Display Omitted
Keywords: Microfabrication; Microdevices; Microfluidics; Oral drug delivery; Oral absorption; In vitro models
Oral drug delivery utilizing intestinal OATP transporters
by Ikumi Tamai (pp. 508-514).
Transporters play important roles in tissue distribution and urinary- and biliary-excretion of drugs and transporter molecules involved in those processes have been elucidated well. Furthermore, an involvement of efflux transporters such as P-glycoproteins, multidrug resistance associated protein 2, and breast cancer resistance protein as the intestinal absorption barrier and/or intestinal luminal secretion mechanisms has been demonstrated. However, although there are many suggestions for the contribution of uptake/influx transporters in intestinal absorption of drugs, information on the transporter molecules responsible for the intestinal absorptive process is limited. Among them, most studied absorptive drug transporter is peptide transporter PEPT1. However, utilization of PEPT1 for oral delivery of drugs may not be high due to the chemical structural requirement of PEPT1 limited to peptide-mimetics. Recently, organic anion transporting polypeptide (OATP) family such as OATP1A2 and OATP2B1 has been suggested to mediate intestinal absorption of several drugs. Since OATPs exhibit species difference in expressed tissues and functional properties between human and animals, human studies are essential to clarify the intestinal absorption mechanisms of drugs via OATPs. Recent pharmacogenomic studies demonstrated that OATP2B1 is involved in the drug absorption in human. In addition, information of drug–juice interaction in the intestine also uncovered the contribution of OATP1A2 and OATP2B1 in drug absorption. Since OATP1A2 and OATP2B1 exhibit broader substrate selectivity compared with PEPT1, their potential to be applied for oral delivery should be high. In this review, current understanding of characteristics and contribution as the absorptive transporters of OATPs in small intestine in human is described. Now, it is getting clearer that OATPs have significant roles in intestinal absorption of drugs, therefore, there are higher possibility to utilize OATPs as the tools for oral delivery.Display Omitted
Keywords: Absorption; OATP; Transporter; Drug–fruit juice interaction; Genetic polymorphism
Spiral progression in the development of absorption enhancers based on the biology of tight junctions
by Masuo Kondoh; Azusa Takahashi; Kiyohito Yagi (pp. 515-522).
Epithelium covers the body and, therefore, separates the inner body from the outside environment. Passage across the epithelium is the first step in drug absorption. Tight junctions (TJs) seal the space between adjacent epithelial cells and prevent the free movement of solutes through the paracellular space. Modulation of the epithelial barrier is the most important strategy for enhancing drug absorption. Development of the strategy has accelerated with progress in understanding of the biology of the TJ seal. The first-generation absorption enhancers were screened on the basis of their absorption-enhancing activity in vivo. However, TJs were not well understood initially. The identification of TJ components, including those based on occludin and claudins, has led to the development of new strategies for drug absorption. Accumulation of knowledge of claudins has provided new insights into the paracellular transport of drugs. This review examines the relationship between advances in understanding of TJ biology and paracellular transport of drugs and discusses progress in the development of mucosal absorption enhancers.Display Omitted
Keywords: Abbreviations; TJ; tight junction; EDTA; ethylenediaminetetraacetic acid; AJ; adherens junction; DS; desmosome; GP; gap junction; CPE; Clostridium perfringens; enterotoxinTight junction; Absorption enhancer; Occludin; Claudin; Paracellular transport
Gut-associated lymphoid tissues for the development of oral vaccines
by Jun Kunisawa; Yosuke Kurashima; Hiroshi Kiyono (pp. 523-530).
Oral vaccine has been considered to be a prospective vaccine against many pathogens especially invading across gastrointestinal tracts. One key element of oral vaccine is targeting efficient delivery of antigen to gut-associated lymphoid tissue (GALT), the inductive site in the intestine where antigen-specific immune responses are initiated. Various chemical and biological antigen delivery systems have been developed and some are in clinical trials. In this review, we describe the immunological features of GALT and the current status of antigen delivery system candidates for successful oral vaccine.Display Omitted
Keywords: Mucosal vaccine; Peyer's patch; GALT; M cells
Oral biodrug delivery using cell-penetrating peptide
by El-Sayed Khafagy; Mariko Morishita (pp. 531-539).
During the past few decades, the novel biotherapeutic agents such as peptides and proteins have been contributed to the treatment of several diseases. However, their oral absorption is significantly limited due to their poor delivery through the intestinal mucosa. Therefore, the feasible approaches are needed for improving the oral bioavailability of biodrugs. Recently, cell-penetrating peptides (CPPs) such as HIV-1 Tat, penetratin and oligoarginine are considered as a useful tool for the intracellular delivery of therapeutic macromolecules. Hence, it was expected that the ability of CPPs may be applicable to enhance the absorption of biodrugs through intestinal epithelial membrane. CPPs are likely to become powerful tools for overcoming the low permeability of therapeutic peptides and proteins through the intestinal membrane, the major barrier to their oral delivery. Further advantage of this promising strategy is that this successful intestinal absorption could be achieved by more convenient methodology, coadministration of CPP with drugs via intermolecular interaction among them. Hereafter, the further establishment of delivery system based on CPPs is required to realize the development of the oral forms of therapeutic peptides and proteins. The aim here is to introduce our vision focusing on oral biodrug delivery by the use of CPPs as potential peptide carrier in order to provide new information in the design and development of new oral delivery systems for novel biotherapeutics.Display Omitted
Keywords: Cell-penetrating peptides; Biodrugs; Therapeutic peptides and proteins; Non-invasive; Oral delivery; Intestinal absorption; Molecular and biological factors; Pharmaceutical strategy; Perspectives
Oral colon delivery of insulin with the aid of functional adjuvants
by Alessandra Maroni; Lucia Zema; Maria Dorly Del Curto; Anastasia Foppoli; Andrea Gazzaniga (pp. 540-556).
Oral colon delivery is currently considered of importance not only for the treatment of local pathologies, such as primarily inflammatory bowel disease (IBD), but also as a means of accomplishing systemic therapeutic goals. Although the large bowel fails to be ideally suited for absorption processes, it may indeed offer a number of advantages over the small intestine, including a long transit time, lower levels of peptidases and higher responsiveness to permeation enhancers. Accordingly, it has been under extensive investigation as a possible strategy to improve the oral bioavailability of peptide and protein drugs. Because of a strong underlying rationale, most of these studies have focused on insulin. In the present review, the impact of key anatomical and physiological characteristics of the colon on its viability as a protein release site is discussed. Moreover, the main formulation approaches to oral colon targeting are outlined along with the design features and performance of insulin-based devices.Display Omitted
Keywords: Abbreviations; IBD; inflammatory bowel disease; GI; gastrointestinal; GALT; gut-associated lymphoid tissue; CFU; colony-forming unit; SITT; small intestinal transit time; SE; standard error; HPMC; hydroxypropylmethylcellulose; HEC; hydroxyethylcellulose; HPC; hydroxypropylcellulose; CTDC; Colon-Targeted Delivery Capsule; IDE; insulin-degrading enzyme; CYP450; cytochrome P450; ACE; angiotensin-converting enzyme; MW; molecular weight; RIA; radioimmunoassay; HEMA; hydroxyethylmethacrylate; PA; pharmacological availability; Na; 2; EDTA; disodium ethylenediaminetetraacetate; HPMCAS; hydroxypropylmethylcellulose acetate succinate; W/O/W; water-in-oil-in-water; EPA; eicosapentaenoic acid; DHA; docosahexaenoic acid; LDH; lactate dehydrogenase; GRAS; generally regarded as safeOral colon delivery; Formulation; Protein; Peptide; Insulin; Bioavailabilty
Oral drug delivery with polymeric nanoparticles: The gastrointestinal mucus barriers
by Laura M. Ensign; Richard Cone; Justin Hanes (pp. 557-570).
Oral delivery is the most common method for drug administration. However, poor solubility, stability, and bioavailability of many drugs make achieving therapeutic levels via the gastrointestinal (GI) tract challenging. Drug delivery must overcome numerous hurdles, including the acidic gastric environment and the continuous secretion of mucus that protects the GI tract. Nanoparticle drug carriers that can shield drugs from degradation and deliver them to intended sites within the GI tract may enable more efficient and sustained drug delivery. However, the rapid secretion and shedding of GI tract mucus can significantly limit the effectiveness of nanoparticle drug delivery systems. Many types of nanoparticles are efficiently trapped in and rapidly removed by mucus, making controlled release in the GI tract difficult. This review addresses the protective barrier properties of mucus secretions, how mucus affects the fate of orally administered nanoparticles, and recent developments in nanoparticles engineered to penetrate the mucus barrier.Display Omitted
Keywords: Oral delivery; Mucus barrier; Mucoadhesion; Mucus penetrating particles
Transepithelial transport and toxicity of PAMAM dendrimers: Implications for oral drug delivery
by S. Sadekar; H. Ghandehari (pp. 571-588).
This article summarizes efforts to evaluate poly(amido amine) (PAMAM) dendrimers as carriers for oral drug delivery. Specifically, the effect of PAMAM generation, surface charge and surface modification on toxicity, cellular uptake and transepithelial transport is discussed. Studies on Caco-2 monolayers, as models of intestinal epithelial barrier, show that by engineering surface chemistry of PAMAM dendrimers, it is possible to minimize toxicity while maximizing transepithelial transport. It has been demonstrated that PAMAM dendrimers are transported by a combination of paracellular and transcellular routes. Depending on surface chemistry, PAMAM dendrimers can open the tight junctions of epithelial barriers. This tight junction opening is in part mediated by internalization of the dendrimers. Transcellular transport of PAMAM dendrimers is mediated by a variety of endocytic mechanisms. Attachment or complexation of cytotoxic agents to PAMAM dendrimers enhances the transport of such drugs across epithelial barriers. A remaining challenge is the design and development of linker chemistries that are stable in the gastrointestinal tract (GIT) and the blood stream, but amenable to cleavage at the target site of action. Recent efforts have focused on the use of PAMAM dendrimers as penetration enhancers. Detailed in vivo oral bioavailability of PAMAM dendrimer–drug conjugates, as a function of physicochemical properties will further need to be assessed.Display Omitted
Keywords: Abbreviations; AB; Apical to basolateral; BA; Basolateral to apical; CF; 5(6)-carboxyfluorescein; CPT-11; Irinotecan hydrochloride; CsA; Cyclosporin A; DAPI; 4V,6-diamidino-2-phenylindole; DIC; Disseminated intravascular coagulation; EEA-1; Early endosome antigen-1; EPR; Enhanced permeability and retention; FD; Fluorescein isothiocyanate-labeled dextrans; FDP; Fibrin degradation product; FITC; Fluorescein isothiocyanate; GIT; Gastrointestinal tract; GX.0-NH; 2; Amine-terminated PAMAM dendrimer generation X.0; GX.0-OH; Hydroxyl-terminated PAMAM dendrimer generation X.0; GX.5-COOH; Carboxyl-terminated PAMAM dendrimer generation X.5; G3.5-gly-SN38; SN38 conjugated with G3.5-COOH via a glycine spacer; G3.5-βala-SN38; SN38 conjugated with G3.5-COOH via a β-alanine spacer; GXLY; Amine-terminated PAMAM dendrimer of generation X.0 modified with Y moles of lauric acid per mole of PAMAM; G0-lact-NAP; Naproxen conjugated to G0.0 via a lactic acid spacer; G0-deg-NAP; Naproxen conjugated to G0.0 via a diethyleneglycol spacer; GX.0-NH; 2; -FITC; Fluorescein isothiocyanate- labeled amine terminated PAMAM dendrimer of generation X.0; LAMP-1; Lysosome-associated membrane protein 1; LDH; Lactate dehydrogenase; MDCK; Madin-Darby canine kidney; MTT; (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide); PAMAM-NH; 2; Amine-terminated PAMAM dendrimer; PAMAM-COOH; Carboxyl-terminated PAMAM dendrimer; PAMAM-OH; Hydroxyl-terminated PAMAM dendrimer; P; app; Apparent permeability coefficient; P-gp; P-glycoprotein; PAMAM; Poly(amido amine); PAT; Polyamine transport; PBS; Phosphate Buffer Saline; PEG; Poly(ethylene glycol); SGF; Simulated gastric fluid; SIF; Simulated intestinal fluid; SN-38; 7-ethyl-10-hydroxy-camptothecin; TEER; Transepithelial electrical resistance; TEM; Transmission electron microscopy; TES; N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid; WST-1; (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate)Poly(amido amine) (PAMAM) dendrimers; Oral drug delivery; Transepithelial transport; Polymers
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