Oral drug delivery with nanoparticles into the gastrointestinal mucosa

The oral route of protein and peptide drugs has been a popular method of drug delivery in recent years, although it is often a challenge to achieve effective drug release and minimize the barrier functions of the gastrointestinal tract. Gastrointestinal mucosa can capture and remove harmful substances; similarly, it can limit the absorption of drugs. Many drugs are effectively captured by the mucus and rapidly removed, making it difficult to control the release of drugs in the gastrointestinal tract. The use of drug carrier systems can overcome the mucosal barrier and significantly improve bioavailability. Nanoparticle drug carriers can protect the drug from degradation, transporting it to a predetermined location in the gastrointestinal tract to achieve more efficient and sustained drug delivery. It is becoming clearer that the characteristics of nanoparticles, such as particle size, charge, and hydrophobicity, are related to permeability of the mucosal barrier. This review focuses on the latest research progress of nanoparticles to penetrate the mucosal barrier, including the delivery methods of nanoparticles on the surface of gastrointestinal mucosa, and aims to summarize how successful oral nanoparticle delivery systems can overcome this biological barrier in the human body. In addition, the in vitro model based on gastrointestinal mucus is an important tool for drug research and development. Here, we discuss different types of drug delivery systems and their advantages and disadvantages in design and potential applications. Similarly, we reviewed and summarized various methods for evaluating oral nanoparticles in in vitro and in vivo models.     

Effects of Emetic and Cathartic Agents on the Gastrointestinal Tract and the Treatment of Toxic Ingestion

Abstract

Emetic drugs and saline cathartics produce direct or reflex changes in gastrointestinal motility. The changes in gastrointestinal smooth muscle function may be important in the rapid oral or rectal expulsion of gastrointestinal contents, effects which serve as a basis for emetic and cathartic drug use in the treatment of toxic ingestion. Because of difficulties in recording gastrointestinal smooth muscle contractile activity from the intact, unanesthetized animal or man, relatively few studies have attempted to characterize the changes in gastrointestinal motility preceding vomiting. Limited results from past studies and the results of more recent studies employing improved technology suggest that pharmacological activation of the emetic reflex is accompanied by characteristic movements of the stomach and small intestine. The gastric response consists of initial muscle relaxation and an expansion of gastric volume. The intestine responds with a contraction, which begins in the distal ileum and migrates orad over the entire small intestine immediately before active retching. The changes in gastric and intestinal motility may be initiated by structures in the central nervous system and may be an important component of the emetic reflex. This article urges more active research to characterize the gastrointestinal emetic response and to investigate more generally the therapeutic value of emesis in the treatment of toxic ingestion. Emphasis should be placed on the clinically important emetic drugs apomorphine and syrup of ipecac. Studies comparing the efficiency of removal of gastrointestinal contents, resultant blood levels of orally administered drugs with and without emesis, differences in the gastrointestinal emetic response between agents and the pharmacology of the gastrointestinal emetic response should be performed. Studies should also be conducted to determine the pharmacology of the emetic sensory receptors in the gastrointestinal tract and the intraluminal physical-chemical or gastrointestinal physiological factors influencing gastrointestinal emetic sensory receptor activation. The results would demonstrate the value of emesis in various poison cases and help establish criteria for use and selection of emetic drugs. No less experimental attention should be devoted to the cathartic drugs. There are no experimental studies which demonstrate unequivocally that when given alone saline cathartics reduce the extent of oral drug or poison absorption, or that saline cathartics enhance the antidotal effectiveness of activated charcoal. More studies should be performed to evaluate the effectiveness of saline cathartics in limiting drug absorption, while considering their potential to alter the antidotal actions of activated charcoal through chemical means, or by alteration of gastrointestinal physiological function. New procedures to achieve gastrointestinal decontamination or enhance drug elimination should also be evaluated. Whole intestinal lavage with newly developed iso-osmotic solutions that neither induce absorption nor secretion may be of value. High-dose, repeated administration of activated charcoal during the postabsorptive phase of drug or poison ingestion may enhance elimination. Whole intestinal lavage with non-absorbable solutions containing activated charcoal may prove more effective than currently established protocols for saline cathartic drug use in the treatment of toxic ingestion.     

Pharmacologic therapy for bronchial asthma

Many drugs with which to treat reversible obstructive airway disease are available. Beta-adrenergic aerosols are the first line of defense; these are followed, when necessary, by either timed-release theophylline or oral beta-adrenergics. Often, a combination of these drugs must be used to achieve effective relief of symptoms. Once-daily theophylline preparations can be extremely effective in patients who need regular medication and in whom gastrointestinal upset or compliance is a problem. In patients who have frequent setbacks, occasional courses of tapered doses of steroid are necessary. When oral steroids are necessary regularly, the physician should consider using an aerosol corticosteroid, cromolyn sodium, or both. These drugs can be used daily with relative safety. However, only a small amount (ie, no more than 12%) of an inhaled medication reaches the lungs. In selected patients, regular doses of cromolyn sodium are used for prophylaxis and may preclude the need for theophylline or oral beta-adrenergics, which can have deleterious effects in adults and children. Cromolyn sodium is most effective if used before exercise or exposure to animals. Research is continuing on more effective and longer-acting beta-adrenergic aerosols and oral preparations.     

Mechanisms and perspectives in clinical chronopharmacokinetics

The pharmacokinetic parameters of drugs vary largely and predictably as a function of their dosing time along the 24-hr scale (and also the year and the menstrual cycle) in Man. Such chronopharmacokinetics have been described following single or repeated doses via the oral or the venous route, and whether drug halflife is short or long. Moreover continuous infusion of a drug at a constant rate cannot maintain constant plasma levels. Such phenomena are accounted for by circadian (and other) rhythms which characterize absorption, protein binding, transmembrane flux, as well as liver and kidney metabolism and biliary and urinary excretions. It is anticipated that the knowledge of the physical and chemical properties of a drug and that of the circadian organization of the main physiologic functions involved into its bioavailability will allow to predict its chronopharmacokinetics.     

Drug permeation enhancement via buccal route: possibilities and limitations.

Over the last decade, there has been a particular interest in delivering drugs, especially peptides and proteins via the buccal route. It provides direct entry into the systemic circulation thus avoiding the hepatic first-pass effect and degradation in the gastrointestinal tract, ease of administration, and the ability to terminate delivery when required. However membrane permeation can be a limiting factor for many drugs administered via the buccal route, and the epithelium that lines the oral mucosa is a very effective barrier to the absorption of drugs. In order to deliver broader classes of drugs across the buccal mucosa, reversible methods of reducing the barrier potential of this tissue must be employed. This requisite has fostered the study of penetration enhancers that will safely alter the permeability restrictions of the buccal mucosa. It has been shown that buccal penetration can be improved by using various classes of transmucosal and transdermal penetration enhancers such as bile salts, surfactants, fatty acids and derivatives, chelators, cyclodextrins and chitosan. Among these chemicals used for the drug permeation enhancement, bile salts are most common. The first part of this paper focuses on work related to the elucidation of mechanisms of action of bile salts in buccal permeation enhancement of various drugs and mucosal irritation. In the second part, results showing the enhancing effect of chitosan on buccal permeation of hydrocortisone, a commonly used topical oral anti-inflammatory agent, and transforming growth factor beta (TGF-beta), which is a bioactive peptide to which the oral mucosa is relatively impermeable is presented.     

Safety Considerations in Prescription of NSAIDs for Musculoskeletal Pain: A Narrative Review

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for the treatment of painful musculoskeletal conditions. When prescribing oral NSAIDs, clinicians must consider coexisting cardiovascular, cerebrovascular, gastrointestinal, and renal disease because oral NSAIDs are associated with a broad spectrum of adverse effects on these systems. The different safety profiles of NSAIDs can be attributed to differences in the extent to which the drug inhibits cyclo-oxygenase-1 vs -2 and their potential for drug-drug interactions. This narrative review intends to guide the clinician in prescribing oral NSAIDs while taking into consideration these comorbid conditions and drug interactions.

Effect of administration site in the gastrointestinal tract on bioavailability of poorly absorbed drugs taken after a meal.

Food-drug interactions may reduce the bioavailability of drugs taken after meals (negative food effect). In order to develop pharmaceutical technologies that overcome this problem, the effect of administration site within the gastrointestinal tract on the bioavailability of several model drugs was examined in rats. Bioavailability after oral administration to fed animals was one-fifth to one-tenth of that in the fasted animals because of interactions between drugs and large amounts of food components remaining in the stomach. This strong negative food effect was reduced when drugs were administered directly into any site of the small intestine. Bioavailability was maximized when the drug administration site was the middle small intestine. On the other hand, intracolonic administration did not result in the reduction of the negative food effect. Site-specific drug delivery to the middle small intestine could be a useful approach for reducing the negative food effect on drug absorption with maximized bioavailability.     

静脉剂型马利兰在造血干细胞移植中的应用和观察

目的 研究评价造血干细胞移植预处理方案中静脉剂型马利兰的应用和疗效。方法22例患者预处理方案采用静脉剂型马利兰，30例患者采用口服剂型马利兰，观察两组的疗效及相关毒性。结果静脉剂型马利兰在胃肠道反应（22．7％）、口腔黏膜炎（18．2％）发生率低于口服剂型马利兰组（66．6％）及（83．8％）。无需补充给药，血药浓度稳定。结论预处理方案中应用静脉剂型马利兰，毒副作用少，疗效确切，比口服马利兰更有优势。     

Formulation aspects in the development of osmotically controlled oral drug delivery systems.

Osmotically controlled oral drug delivery systems utilize osmotic pressure for controlled delivery of active agent(s). Drug delivery from these systems, to a large extent, is independent of the physiological factors of the gastrointestinal tract and these systems can be utilized for systemic as well as targeted delivery of drugs. The release of drug(s) from osmotic systems is governed by various formulation factors such as solubility and osmotic pressure of the core component(s), size of the delivery orifice, and nature of the rate-controlling membrane. By optimizing formulation and processing factors, it is possible to develop osmotic systems to deliver drugs of diverse nature at a pre-programmed rate. In the present review, different types of oral osmotic systems, various aspects governing drug release from these systems, and critical formulation factors are discussed.     

Dose-dependent effects of oral dronedarone on the circadian variation of RR and QT intervals in healthy subjects: implications for antiarrhythmic actions

Dronedarone, a non-iodinated benzofuran derivative, was developed as a potentially less toxic alternative to amiodarone. This study describes Holter data of dronedarone in humans. Five groups of healthy subjects were given 1 of 5 oral doses of dronedarone in a twice-daily regimen or placebo. Holter recordings of circadian rhythmicity of RR and QT intervals were evaluated. Dronedarone prolonged RR and QT intervals as a function of dose, without effect on circadian patterns. The relative prolongation of QT, QTc, and RR by dronedarone was significant. The QTc interval did not exhibit a clearly recognizable circadian pattern, suggesting that the circadian pattern of the QT interval was mostly a reflection of circadian changes in the RR interval in the study population. Dronedarone resembled amiodarone in class III and sympatholytic effects, indicating its potential as a unique antiarrhythmic compound seemingly devoid of the side effects mediated by iodine in amiodarone.     

Reduction of peristaltic artifacts on magnetic resonance imaging of the abdomen: a comparative evaluation of three drugs

Background: Peristaltic motion is an omnipresent source of degradation in abdominal magnetic resonance (MR) imaging by blurring images and producing ghost artifacts that can mask or mimic lesions. The objective of this study was to select an effective and easy-to-administer drug to provide consistent reduction of peristaltic motion artifacts on MR images. Methods: One hundred forty-eight adult patients with MR examinations of the abdomen were enrolled in a prospective, single-blind comparative study. Four groups were defined: (a) no-drug control group (n = 35), (b) 1 mg of intravenous (IV) glucagon (n = 19), (c) 20 mg of IV butylscopolamine (n = 28), and (d) 20 mg of oral dicyclomine (n = 66). All patients received high-density barium sulphate as a negative oral contrast medium. Quantitative image analysis was performed with operator-defined region-of-interest measurements of signal intensity. Gastrointestinal noise was measured outside the patient at the posterior part of the left hemiabdomen along the phase-encoding direction on a short inversion time inversion recovery (STIR) sequence. Results: Treatment groups showed reduced gastrointestinal noise (p < 0.01). When compared with the control group, IV butylscopolamine (p < 0.05) and oral dicyclomine (p < 0.05) significantly reduced gastrointestinal noise, whereas glucagon did not. Conclusion: Anticholinergic drugs significantly reduced the intensity of ghost artifacts on MR imaging of the abdomen. Twenty milligrams of oral dicyclomine is an effective and safe alternative to more expensive and parenterally administered drugs such as glucagon and butylscopolamine. Received: 22 November 1994/Accepted after revision: 14 March 1995     

口服缓释、控释制剂的常用技术及临床应用

背景：新型缓释、控释制剂加速药物制剂的研究速度,使得药物剂型及制剂质量不断提高。目的：分析了目前临床上常用的口服缓释、控释制剂的常用技术及临床应用情况。方法：以＂缓释,控释,生物制药,药物载体,高分子材料＂或＂delayed release,drug delivery carrier,polymer material;controlled release＂为检索词,应用计算机检索CNKI和PubMed数据库中2000-02/2011-04关于口服缓释、控释药物的相关文章。选入文章内容与高分子药用材料及缓释、控释药物制剂技术及和临床应用有关,排除重复研究。结果与结论：理想的剂型是指药物对靶部位选择性高,且能推迟必要的药效时间,迅速而完全地排泄,尽量不对其他脏器与组织产生不良反应。在缓释制剂的设计中,需要充分考虑药物的水溶性、油水分配系数、化学稳定性以及蛋白结合率等理化性质和生物学性质对缓释制剂释药行为的控制;生理因素对缓释制剂的设计,如给药部位、胃肠蠕动、首过效应、血流供应、患者疾病状态、药物作用的靶器官等也需考虑。     

Endoscopic evaluation of the effects of indobufen and aspirin in healthy volunteers

This is an outcomes pharmacodynamic study using Nonsteroidal antiinflammatory agents, particularly acetylsalicylic acid (ASA), have been shown useful in various cardiovascular disorders, but they can be a major cause of iatrogenic gastrointestinal injury. Newer NSAIDs such as indobufen, an inhibitor of platelet aggregation that acts by reversibly inhibiting the platelet cyclooxygenase enzyme, have proven to be as effective as the older NSAIDs and appear to have a better gastrointestinal tolerability profile. When the gastroduodenal tolerability of 10 days of oral treatment with indobufen or ASA was assessed in healthy adult volunteers using endoscopic evaluation and the modified score scale of Lanza, only 1 of 18 (6%) volunteers who received indobufen had an increased erosion score at the completion of therapy, compared with 6 of 18 volunteers who received ASA (33%). Overall, both drugs were well tolerated. These results suggest that indobufen has a lower incidence of gastrointestinal effects than other NSAIDs and should be useful in the management of patients with cardiovascular disease.     

An enteric-coated dry emulsion formulation for oral insulin delivery.

A novel oral dosage formulation of insulin consisting of a surfactant, a vegetable oil, and a pH-responsive polymer has been developed. First, a solid-in-oil (S/O) suspension containing a surfactant-insulin complex was prepared. Solid-in-oil-in-water (S/O/W) emulsions were obtained by homogenizing the S/O suspension and the aqueous solution of hydroxypropylmethylcellulose phthalate (HPMCP). A microparticulate solid emulsion formulation was successfully prepared from the S/O/W emulsions by extruding them to an acidic aqueous solution, followed by lyophilization. The insulin release from the resultant dry emulsion responded to the change in external environment simulated by gastrointestinal conditions, suggesting that the new enteric-coated dry emulsion formulation is potentially applicable for the oral delivery of peptide and protein drugs.     

口服阿司匹林致上消化道出血的危险因素分析

目的探讨口服阿司匹林致上消化道出血的相关危险因素及引起消化道大出血的相关机制。方法收集本院2010年3月至2013年4月仅口服阿司匹林一种非甾体抗炎药200例患者,用药过程中未发生消化道出血的102例患者作为对照组,引发上消化道出血的98例患者作为观察组,采集两组患者吸烟史、现病史、既往史,行凝血常规、幽门螺杆菌（Hp）检测及胃镜检查,经单因素统计分析筛选出阿司匹林引发上消化道出血的危险因素;通过多元 Logistic回归分析得出阿司匹林引发上消化道出血的独立危险因素。结果年龄＞60岁、吸烟、糖尿病、Hp感染、既往溃疡病史的患者在观察组所占比例明显高于对照组,差异具有统计学意义（P＜0.05）;经多元 Logistic回归后表明年龄＞60岁、糖尿病、Hp 感染、既往溃疡病史和阿司匹林引发上消化道出血的 OR值有统计学差异（P＜0.05）。结论年龄＞60岁、糖尿病、Hp感染、溃疡病史是阿司匹林引发上消化道出血的4个独立危险因素。     

Chronotherapy for cancer

Cancer chronotherapy is attracting attention as a novel and logical therapy in which anti-cancer drugs are administered with optimal timing according to circadian rhythms of anti-cancer action and those of adverse effects on normal cells. Advances in chronobiology have identified the suprachiasmatic nucleus (SCN) as the center of biological rhythms and the area in which clock genes such as PER1, PER2, PER3, CLOCK, BMAL1, TIM, CRY1, CRY2, tau act to generate and coordinate biological rhythms. These findings have led to the development of chronotherapy. Clinically, patients with advanced gastrointestinal cancer have been treated by chronomodulated chemotherapy with good response. For colorectal cancer patients with unresectable liver metastases, chronotherapy with ℓ-OHP + 5–FU + FA (folinic acid) has been reported to allow complete surgical resection of liver metastases, resulting in 39–50% 5–year survival. Many believe that chronotherapy will become accepted as a refined and advantageous therapeutic option for not only cancer but also for other diseases, due to its universally applicable principles.     

Diagnosis and treatment in circadian rhythm sleep disorders

Circadian rhythm sleep disorders (CRSD) are characterized by misalignment between major sleep episode and desired sleep phase, or symptoms associated with internal desynchronization between endogenous circadian rhythm and overt sleep-wake rhythm. Endogenous circadian rhythm is mainly regulated by master circadian clock located in the suprachiasmatic nucleus. Light entrains the circadian clock according to a phase-response curve. Furthermore, social time cue affects human sleep-wake rhythm. Instructions concerning sleep hygiene including light environment play fundamental role for the treatment in CRSD. In addition, light therapy and oral melatonin administration have application to delayed sleep phase type. Diagnostic classification and treatment in each types of CRSD are reviewed in this article.     

Adherence to imatinib therapy in gastrointestinal stromal tumors and chronic myeloid leukemia

The number of anticancer drugs available in oral formulation has risen sharply in the past few years and this is expected to continue to increase over the next several decades. For patients, the convenience of self-administration constitutes a major benefit associated with oral therapy. For clinicians, however, the transition from parenteral to oral therapy has resulted in concerns about adherence to therapy, its monitoring, and its effects on clinical outcomes. Several studies have demonstrated that imatinib is effective at improving overall survival and/or recurrence-free survival in patients with gastrointestinal stromal tumors and chronic myeloid leukemia (primary and metastatic disease). Despite the survival benefit and the favorable toxicity profile of imatinib, however, adherence to imatinib remains poor. Herein, we review the evidence showing the effects of nonadherence on patient outcomes as well as data indicating that adherence to imatinib (and oral anticancer therapy in general) is suboptimal. We also highlight factors that may contribute to nonadherence and suggest key steps that can be implemented by the multidisciplinary medical team to overcome the daily challenges of adherence. Improving adherence to imatinib depends on open communication and comprehensive patient education. All of this is essential to maximize benefits from therapy and improve clinical outcomes for our patients.     

Pharmaceutical design of a novel colon-targeted delivery system using two-layer-coated tablets of three different pharmaceutical formulations, supported by clinical evidence in humans.

Drug delivery systems to the colon are being actively investigated in order to develop oral preparations of peptides and treat local colonic diseases. However, it is difficult to ensure that an oral preparation disintegrates specifically in the human colon. To make a colonic delivery system practical for medical use, in vitro testing methods need to be established in order to determine the specifications of the preparations. To achieve this objective, three pharmaceutical preparations, designed to have different tablet disintegration times, were used to examine three buffers in seven combinations intended to simulate pH changes in the stomach, small intestine, and colon of humans. To validate the in vitro methodology, furthermore, the fate of all the formulations was examined in the gastrointestinal (GI) tract of healthy volunteers. A three-way crossover trial by scintigraphy revealed that the three formulations--in spite of presenting different in vitro tablet disintegration profiles--have comparable transit profiles and excellent colon-targeting properties in the human gastrointestinal tract regardless of gender and age. These facts strongly suggest that this novel delivery system may be useful for the delivery of drugs to the human colon.