Formulation and Dosage Form Design in Drug-Induced Topical Irritation of the Gastrointestinal Tract

To test drugs for topical effects on gastrointestinal mucosa, a new in situ rabbit colon model was used that permits direct application of drugs in suspensions from gel cups, solutions, or commercially available tablets and capsules onto rabbit colonic mucosa for up to 8 hr. For each agent tested an irritation index was calculated—the product of the area of the mucosa affected by drug exposure and a numerical score for observed effect. Irritation indices ranged from 0 (no effect) to 25.6 (maximal irritation measurable). In general, the immediate release of drug onto tissue elicited the greatest effect, whereas slow or controlled release of drug produced the least response. Topical irritation was found to be a function of (1) the drug, (2) the formulation, (3) the delivery rate, and (4) the concentration. The gastrointestional therapeutic system (GITS) of potassium chloride and of brompheniramine/pseudoephedrine produced far less irritation than current commercial formulations of these drugs. The rabbit colon model is proposed as a useful screening tool during drug development to aid in selecting the formulation of an oral dosage form that will minimize topical irritation.     

硫酸氨基葡萄糖氯化钾的制备及对大鼠骨关节炎模型的治疗作用

目的：制备硫酸氨基葡萄糖氯化钾,考察其对大鼠骨关节炎模型的治疗作用。方法：以甲壳素为原料,经盐酸水解得盐酸氨基葡萄糖,将其与硫酸钾置于水溶液中,通过充分的离子交换反应,并加入作为沉淀剂的有机溶剂,制备硫酸氨基葡萄糖氯化钾;考察反应温度、反应溶液中各离子平衡时间、反应原料配比以及沉淀剂的种类、加入量和加入时间等对最终产物的影响,优化制备工艺。建立木瓜蛋白酶诱导的大鼠骨关节炎模型,并灌胃给予硫酸氨基葡萄糖氯化钾,通过血清中丙二醛和一氧化氮含量测定、关节肿胀度观察和关节软骨病理切片检查,考察硫酸氨基葡萄糖氯化钾对模型大鼠骨关节损伤的保护作用。结果：确立优化的硫酸氨基葡萄糖氯化钾制备工艺：反应温度为45~55℃,离子平衡时间为0.5 h,盐酸氨基葡萄糖与硫酸钾的质量配比为22.5：7.15,作为沉淀剂的乙醇加入浓度约为75%及加入时间为3 h。骨关节炎模型大鼠接受硫酸氨基葡萄糖氯化钾给药后,血清中丙二醛和一氧化氮含量显著降低（P〈0.05或P〈0.01）,关节肿胀度明显减轻（P〈0.01）,且病理切片显示,仅有少许关节软骨细胞轻度变性,软骨未见明显坏死,细胞未见明显增生。结论：优化的硫酸氨基葡萄糖氯化钾制备工艺适用于工业化生产;硫酸氨基葡萄糖氯化钾对骨关节炎损伤具有显著保护作用,且效果好于盐酸氨基葡萄糖。     

Application of a Biomagnetic Measurement System (BMS) to the Evaluation of Gastrointestinal Transit of Intestinal Pressure-Controlled Colon Delivery Capsules (PCDCs) in Human Subjects

Purpose. For determination of the transit time through various partsof the gastrointestinal (GI) tract, we developed a method that providesthe location of disintegration and drug release. This method involves GImagnetomarkergraphy (GIMG) using a 129-channel Shimadzu vectorbiomagnetic measurement system (BMS). Methods. To magnetically label the pressure-controlled colon deliverycapsule (PCDC) containing 75.0 ± 0.5 mg of caffeine as a tracer drug,small capsule caps containing 90 mg of ferric oxide powdered magnetite(Fe₂O₃) were attached to PCDCs. After orally administration to fastedhuman volunteers, saliva samples were collected hourly and salivarycaffeine concentration was measured. At the same time, locations ofthe magnetic PCDC were detected by BMS just after the PCDCs weremagnetized with the coils of a magnetic resonance imaging (MRI)system. The magnetic field distributions were analyzed and theestimated positions were shown on the MRI picture of the same subject'sabdominal structure. Results. We magnetized PCDC with permanent magnets or anelectromagnet before ingestion and the estimated locations of PCDC in the GItract exhibited high estimation error. In order to increase the precision ofestimated localization of PCDCs, PCDCs were magnetized within thecoils of the MRI. As a result, these PCDCs had strong magnetic dipolesthat were parallel to the sensor unit of BMS in every measurement,and therefore the spatial resolution of the PCDC's two-dimensionalpositions in the organs of the GI tract was within a range of severalmillimeters. Conclusions. GIMG is a powerful tool for the study of colon deliveryefficiencies of PCDCs. The main advantage of GIMG is the capabilityto obtain even more detailed knowledge of the behavior and fate ofsolid pharmaceutical formulations during GI passage.     

Effects of Dissolution Medium pH and Simulated Gastrointestinal Contraction on Drug Release From Nifedipine Extended-Release Tablets*

In contrast to nifedipine matrix-based extended-release dosage forms, the osmotic pump drug delivery systems have a zero-order drug release independent of external variables such as pH, agitation rate, and dissolution media. The objective of this study focuses on the in vitro evaluation of the mechanical properties of osmotic pump and polymer matrix-based formulations in dissolution media, and the potential impacts that media pH and simulated gastrointestinal contraction have on drug release. Two strengths of osmotic pump product A and polymer matrix-based product B were used in this study. An in-house system was developed with the capability of applying mechanical compression and monitoring mechanical properties of sample during dissolution testing. A United States Pharmacopeia or an in-house apparatus was used for dissolution testing under various conditions. Compared to the product A, the mechanical properties of the product B change significantly at various pHs and mechanical compressions. The results suggest that polymer matrix-based products bear a risk of formulation-related interactions with the gastrointestinal tract during in vivo drug dissolution, especially in the case of concomitant pH and gastric contractile changes. Modified dissolution testing devices may help formulation scientists in product development and provide regulatory agencies with an additional metric for quality assurance of drug products.     

Impact of Acid-Reducing Agents on Gastrointestinal Physiology and Design of Biorelevant Dissolution Tests to Reflect These Changes

BackgroundOf the various drug therapies that influence gastrointestinal (GI) physiology, one of the most important are the acid-reducing agents (ARAs). Because changes in GI physiology often influence the pharmacokinetics of drugs given orally, there is a need to identify in vitro methods with which such effects can be elucidated.ObjectiveLiterature concerning the effects of ARAs (antacids, H₂-receptor antagonists, and proton pump inhibitors [PPIs]) on GI physiology are reviewed with the aim of identifying conditions under which drugs are released after oral administration in the fasted state. In vitro dissolution tests to mimic the effects in the stomach were designed for H₂-receptor antagonists and PPIs.ConclusionsThe impact of ARAs on GI physiology depends on the type, duration, and amount of ARA administered as well as the location in the GI tract, with greatest impact on gastric physiology. While ARAs have a high impact on the gastric fluid pH and composition, changes in volume, viscosity, surface tension, and gastric emptying appear to be less profound. The proposed dissolution tests enable a ready comparison between dosage form performance in healthy adults and those receiving PPIs or H₂-receptor antagonists.     

山楂叶总黄酮对大鼠血管环的作用及其机制探讨

<正>山楂叶总黄酮(hawthorn leaves flavonoids,HLF)是从花期山楂的叶子中提取的黄酮类化合物的总称,具有资源广泛、有效成分含量高等特点,现已应用于冠心病、心绞痛、高     

FDA的“评估简化新药申请的仿制透皮和局部给药系统可能的刺激性和致敏性的供企业用的指导原则草案”介绍

美国食品药品监督管理局（FDA）于2023年4月发布了“评估简化新药申请仿制透皮和局部给药系统可能的刺激性和致敏性的供企业用的指导原则草案”,全面而又具体地阐明FDA对仿制透皮和局部给药系统（TDS）可能的刺激性和致敏性人体内研究的设计和实施的建议。其中包括一般原则（一般考虑）、研究设计和实施、统计分析（刺激性分析和致敏性分析）、辅料TDS和阳性对照TDS以及部分（切割）TDS等。而中国目前还没有类似的指导原则,详细介绍FDA该指导原则主要内容,期望对中国仿制TDS刺激性和致敏性人体内研究与监管有所裨益。     

鬼针草总黄酮对免疫性肝纤维化大鼠胶原代谢的影响及机制

目的探讨鬼针草总黄酮(TFB)对免疫性肝纤维化大鼠胶原代谢的影响及机制。方法 SD大鼠随机分为正常组、模型组、TFB大、中、小剂量组和秋水仙碱阳性药对照组,采用腹腔注射猪血清诱导肝纤维化模型,造模后灌服相应的受试药物。ELISA法测定大鼠血清Ⅲ型前胶原酶(PCⅢ)、Ⅳ型胶原酶(CⅣ)含量;免疫组化法测定肝组织中Ⅰ型胶原蛋白的表达;RT-PCR技术检测肝组织中Ⅰ型胶原、α-SMA、TGF-β1 mRNA的表达情况;Western blot检测肝组织中Smad2蛋白的表达。结果与模型组相比,TFB能明显降低肝纤维化大鼠血清中PCⅢ、CⅣ含量,抑制肝组织中Ⅰ型胶原、α-SMA、TGF-β1 mRNA及Ⅰ型胶原、Smad2蛋白的表达。结论 TFB能明显降低免疫性大鼠肝纤维化胶原含量,其机制可能与降低TGF-β1表达进而抑制肝星状细胞活化减少胶原生成有关。     

Effects of N6-cyclohexyladenosine (CHA) on responses to adrenergic and cholinergic nerve stimulation in the peripheral autonomic nervous system

The adenosine derivative N⁶-cyclohexyladenosine (CHA), was studied in various cardiovascular and autonomic experiments. In hemodynamic studies in dogs, CHA 0.5 mg/kg, i.v., caused moderate hypotension and bradycardia. Additional studies in dogs showed that a portion of the bradycardia was the result of an inhibitory effect on the sympathetic nerves to the heart since the chronotropic reponses to cardioaccelerator nerve stimulation were inhibited while the responses to isoproterenol were slightly potentiated. CHA was more potent than adenosine in this experiment and caffeine, 3 mg/kg, i.v., antagonized the effects of CHA. CHA was also found to inhibit the pressor effects of lumbar sympathetic nerve stimulation in rats while responses to intraarterial norepinephrine(NE) were potentiated. In the isolated stimulated guinea pig ileum, both CHA and adenosine inhibited the stimulation-evoked twitches, with CHA being the more potent. Caffeine, 0.1 mM, antagonized the inhibitory effects of both compounds. CHA had no significant effect on the negative chronotropic responses to vagus nerve stimulation in dogs. These findings indicate that CHA is qualitatively similar to adenosine but is more potent and longer lasting. CHA, like adenosine, appears to alter reponses to both adrenergic and cholinergic nerve stimulation.     

Effects of perinatal combined exposure to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) and tributyltin (TBT) on rat female reproductive system

1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p′-DDE) is the most prevalent metabolite of DDT used as a pesticide before and tributyltin (TBT) compounds are used primarily as antifouling agents on vessels, ships, and aqua culture facilities, as they exert biocidal actions. Currently, p,p′-DDE and TBT are ubiquitously distributed in the environment and bio-accumulated in marine products, especially fish or shellfish. Thus, oral p,p′-DDE and TBT intake through marine products is demonstrated to be rather high in Japan. Consequently, the fetus and neonate will be exposed to p,p′-DDE and TBT via mother. Therefore, effects of perinatal combined exposure to p,p′-DDE and TBT on the female reproductive system after maturation have been investigated in rat female offspring of dams ingesting 125 ppm p,p′-DDE (approximately 10 mg/kg) and 25 ppm TBT (approximately 2 mg/kg) during the perinatal period from gestation to lactation. In the present study, no deleterious reproductive outcomes were recognized in p,p′-DDE and/or TBT-treated dams. In contrast, growth retardation had developed in rat female offspring following perinatal exposure to TBT and sustained even after cessation of exposures. Further, reduced ovarian weights with elevated serum follicle-stimulating hormone (FSH) concentrations were observed in the reproductive system of matured female offspring following perinatal exposure to TBT. At present, biological relevance of these alterations remains unknown, but there is a possibility that these alterations lead to reproductive malfunctions in matured female offspring.     

Effects of enhancing mitochondrial oxidative phosphorylation with reducing equivalents and ubiquinone on 1-methyl-4-phenylpyridinium toxicity and complex I-IV damage in neuroblastoma cells

The effects of increasing mitochondrial oxidative phosphorylation (OXPHOS), by enhancing electron transport chain components, were evaluated on 1-methyl-4-phenylpyridinium (MPP+) toxicity in brain neuroblastoma cells. Although glucose is a direct energy source, ultimately nicotinamide and flavin reducing equivalents fuel ATP produced through OXPHOS. The findings indicate that cell respiration/mitochondrial O(2) consumption (MOC) (in cells not treated with MPP+) is not controlled by the supply of glucose, coenzyme Q(10) (Co-Q(10)), NADH+, NAD or nicotinic acid. In contrast, MOC in whole cells is highly regulated by the supply of flavins: riboflavin, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), where cell respiration reached up to 410% of controls. In isolated mitochondria, FAD and FMN drastically increased complex I rate of reaction (1300%) and (450%), respectively, having no effects on complex II or III. MPP+ reduced MOC in whole cells in a dose-dependent manner. In isolated mitochondria, MPP+ exerted mild inhibition at complex I, negligible effects on complexes II-III, and extensive inhibition of complex IV. Kinetic analysis of complex I revealed that MPP+ was competitive with NADH, and partially reversible by FAD and FMN. Co-Q(10) potentiated complex II ( approximately 200%), but not complex I or III. Despite positive influence of flavins and Co-Q(10) on complexes I-II function, neither protected against MPP+ toxicity, indicating inhibition of complex IV as the predominant target. The nicotinamides and glucose prevented MPP+ toxicity by fueling anaerobic glycolysis, evident by accumulation of lactate in the absence of MOC. The data also define a clear anomaly of neuroblastoma, indicating a preference for anaerobic conditions, and an adverse response to aerobic. An increase in CO(2), CO(2)/O(2) ratio, mitochondrial inhibition or O(2) deprivation was not directly toxic, but activated metabolism through glycolysis prompting depletion of glucose and starvation. In conclusion, the results of this study indicate that the mechanism of action for MPP+, involves the inhibition of complex I and and more specifically complex IV, leading to impaired OXPHOS and MOC. Moreover, flavin dervatives control the rate of complex I/cellular respiration and Co-Q10 augments complex II [corrected].