Preparation and evaluation of alpha-mangostin solid self-emulsifying drug delivery system

Alpha-mangostin(AMG),a natural xanthone extracted from Garcinia mangostana Linn,has a variety of pharmacological therapeutic effects such as antioxidant activity,antibacterial activity,anticancer,and anti-inflammatory[1].However,it has poor aqueous-solubility and dissolution,which results in low bioavailability.Solid self-emulsifying drug delivery system(solid-SEDDS),an effective pharmaceutical strategy,offers the potential for enhancing the oral bioavailability of poorly water-soluble drugs[2].Therefore,solid-SEDDS is of interest as a potential method for enhancing the solubility and dissolution of AMG.

Milk-derived exosomes as a promising vehicle for oral delivery of hydrophilic biomacromolecule drugs

Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.

From oral formulations to drug-eluting implants:using 3D and 4D printing to develop drug delivery systems and personalized medicine

Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical treatment that is tuned to the individual.One possible way to realize personalized medicine is 3D printing.When using materials that can be tuned upon stimulation,4D printing is established.In recent years,many studies have been exploring a new field that combines 3D and 4D printing with therapeutics.This has resulted in many concepts of pharmaceutical devices and formulations that can be printed and,possibly,tailored to an individual.Moreover,the first 3D printed drug,Spritam®,has already found its way to the clinic.This review gives an overview of various 3D and 4D printing techniques and their applications in the pharmaceutical field as drug delivery systems and personalized medicine.

Preparation of Ionic Liquid Functionalized Silica Nanoparticles for Oral Drug Delivery

The objective of this study is to utilize the pH sensitivity of modified silica nanoparticles (SNIL) by imidazole-based ionic liquid for oral delivery of insulin. In the first time, the imidazole was covalently attached to the 3-trimethoxysily-lpropyl chloride with replacement of all the chlorine atoms. Then, a silica nanoparticle was modified by N-(3-trimeth-oxysilylpropyl) imidazole. The nanocapsule (NCIL) was achieved after the etching of the modified silica nanoparticle template with hydrofluoric acid. The nanoparticles connected through an ionic liquid-like network were characterized by FTIR and SEM. Insulin was entrapped in these carriers and the in vitro release profiles were established separately in both enzyme-free simulated gastric and intestinal fluids (SGF, pH 1) and (SIF, pH 7.4), respectively. When these drug-loaded nanoparticles was placed in physiological buffer solution (pH 7.4), a partial negative surface charge on the modified silica nanoparticle was generated due to the deprotonation of silanol groups, and the strong electrostatic repulsion triggered a sustained release of the loaded molecules.

UNIQUE ORAL DRUG DELIVERY SYSTEM

An oral drug delivery system using proteinoid microspheres is discussed with respect to itsunique dependence on pH. It has been found that certain drugs such as insulin and heparin canbe encapsulated in proteinoid spheres at stomach pH's (1--3). These spheres also dissemble atintestinal pH's (6--7) releasing the drug for absorption. Using this technique low molecularweight heparin and human growth hormone have been orally delivered successfully to severalanimal species. Future work has been proposed to study the interaction and binding of thespecific drugs with synthesized oligopeptides.

Metal-organic frameworks in oral drug delivery

Metal-organic frameworks(MOFs)offer innovative solutions to the limitations of traditional oral drug delivery systems through their unique combination of metal ions and organic ligands.This review systematically examines the structural properties and principles of MOFs,setting the stage for their application in drug delivery.It discusses various classes of MOFs,including those based on zirconium,iron,zinc,copper,titanium,aluminum,potassium,and magnesium,assessing their drug-loading capacities,biocompatibility,and controlled release mechanisms.The effectiveness of MOFs is illustrated through case studies that highlight their capabilities in enhancing drug solubility,providing protection against the harsh gastrointestinal environment,and enabling precise drug release.The review addresses potential challenges,particularly the toxicity concerns associated with MOFs,and calls for further research into their biocompatibility and interactions with biological systems.It concludes by emphasizing the potential of MOFs in revolutionizing oral drug delivery,highlighting the critical need for comprehensive research to harness their full potential in clinical applications.

Vesicular drug delivery systems for oral absorption enhancement

Oral administration is the most acceptable route of drug delivery at this stage due to its convenience,safety,and non-invasiveness.However,drugs given orally are exposed to a complex gastrointestinal environment,causing a tremendous challenge for their successful absorption into the circulation.Over the past decades,researchers have developed various novel pharmaceutical technologies to improve oral absorption,among which the vesicular drug delivery system(like liposomes,niosomes and transfersomes)has received extensive attention.Encouragingly,there have been several investigations confirming the improved effect of vesicular drug delivery systems on oral drug absorption.Nevertheless,the clinical translation of oral vesicular drug delivery systems has been less impressive than implied by the positive results,and few vesicular formulations for oral use have been marketed yet.Against this background,this article provides an overview of the current applications and challenges associated with the vesicular delivery systems available for oral drug delivery,specifically liposomes,niosomes,transfersomes,chitosomes and bilosomes.The composition,formation mechanism,drug delivery advantages and application cases of these carriers in oral drug delivery are summarized.The possible mechanisms by which vesicular carriers enhance oral drug absorption are analyzed in terms of the in vivo process of oral drugs.Further,the challenges that oral vesicular carriers now face,such as safety,undefined in vivo fate,and scale-up production,are summarized,while possible strategies to deal with them are indicated.By reviewing the aforementioned,it can facilitate a more comprehensive knowledge of vesicular systems that can be used for oral drug delivery,providing a theoretical basis and reference for the design of oral formulations.

Oral administration microrobots for drug delivery

Oral administration is the most simple, noninvasive, convenient treatment. With the increasing demands on thetargeted drug delivery, the traditional oral treatment now is facing some challenges: 1) biologics how toimplement the oral treatment and ensure the bioavailability is not lower than the subcutaneous injections;2)How to achieve targeted therapy of some drugs in the gastrointestinal tract? Based on these two issues, drugdelivery microrobots have shown great application prospect in oral drug delivery due to their characteristics offlexible locomotion or driven ability. Therefore, this paper summarizes various drug delivery microrobotsdeveloped in recent years and divides them into four categories according to different driving modes: magneticcontrolleddrug delivery microrobots, anchored drug delivery microrobots, self-propelled drug delivery microrobotsand biohybrid drug delivery microrobots. As oral drug delivery microrobots involve disciplines such asmaterials science, mechanical engineering, medicine, and control systems, this paper begins by introducing thegastrointestinal barriers that oral drug delivery must overcome. Subsequently, it provides an overview of typicalmaterials involved in the design process of oral drug delivery microrobots. To enhance readers’ understanding ofthe working principles and design process of oral drug delivery microrobots, we present a guideline for designingsuch microrobots. Furthermore, the current development status of various types of oral drug delivery microrobotsis reviewed, summarizing their respective advantages and limitations. Finally, considering the significantconcerns regarding safety and clinical translation, we discuss the challenges and prospections of clinical translationfor various oral drug delivery microrobots presented in this paper, providing corresponding suggestions foraddressing some existing challenges.

口服液体缓控释制剂技术的研究进展

目的针对各类口服液体缓控释技术的释药机理、应用特点及局限性进行综述,为此类制剂的开发提供参考。方法查阅国内外相关文献,对口服液体缓控释技术进行整理归纳。结果目前已有基于离子交换树脂和微囊技术的口服液体缓控释制剂上市,此外,微球、固体脂质纳米粒、原位凝胶等技术也应用于口服液体缓控释制剂领域。结论口服液体缓控释给药系统相比于传统固体缓控释制剂,因其口服可接受性良好,剂量调整灵活,给药依从性优势明显,具有良好的开发应用前景。

活性氧响应型鬼臼毒素聚合物前药胶束的制备及其抗口腔癌活性

目的制备基于透明质酸(HA)活性氧(ROS)响应型鬼臼毒素(POD)聚合物前药胶束(HTP-M),并考察其抑制口腔鳞状细胞癌(OSCC)效果。方法采用两步酯化法合成基于HA的ROS响应型POD聚合物前药HA-TK-POD,采用透析法制备聚合物前药胶束HTP-M,并对其形态特征、粒径、电位和载药量进行表征,同时考察ROS响应性药物释放。以SCC-9细胞和荷瘤小鼠为模型,考察HTP-M体内外抗肿瘤效果。结果磁共振氢谱(^(1)H-NMR)证实HA-TK-POD聚合物前药成功合成。所得HTP-M胶束呈类球形,粒径(126.1±3.5)nm,分布均一,Zeta电位(-26.8±1.9)mV。HTP-M载药量(12.3±0.8)%,具有良好ROS响应性。HTP-M可特异性靶向CD44高表达的SCC-9细胞,具有良好的体内外抗肿瘤效果。结论制备了一种基于HA的ROS响应型POD聚合物前药胶束HTP-M,其具有良好的ROS响应性,并可有效抑制OSCC,为临床OSCC的治疗提供了新策略。

5-氨基水杨酸口服制剂及联合中药在炎症性肠病治疗中的应用

5-氨基水杨酸(5-ASA)是1种从中药柳树皮中分离提纯得到的天然抗炎活性成分水杨酸的衍生物,别名阿米诺水杨酸、美沙拉嗪,是临床治疗炎症性肠病(IBD)并预防其复发的一线药物。尽管目前莎尔福(Salofalk)、亚沙可(Asacol)和潘他沙(Pentasa)等5-ASA口服结肠靶向制剂已广泛用于IBD的临床治疗,但仍存在在小肠提前释药和受胃肠道生理状态影响显著等制剂缺陷、对克罗恩病和重度溃疡性结肠炎(UC)治疗效果不佳等临床未满足的需求,以及减少UC患者黏膜菌群多样性、长期使用增加用药风险和降低患者服药依从性等问题。开发硅胶纳米粒、水凝胶等新型递药载体,基于pH依赖、时滞控制和菌群/酶触发等多机制结合释药原理设计新型口服结肠靶向制剂从而解决制剂缺陷问题,提高5-ASA疗效和患者服药耐受性、依从性是目前制剂研究的重点。此外,5-ASA口服制剂联合中药保留灌肠、中药口服制剂和注射液等治疗IBD可发挥协同抗炎作用,实现增效减毒目的。对5-ASA口服制剂品种、近年来新型制剂和递药载体的研究进展,以及与中药联用的临床应用和研究现状等进行综述,为5-ASA口服制剂的剂型改造、载体材料研究和临床用药等提供参考。

Adapting liposomes for oral drug delivery

Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes,oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract,difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.

吞咽困难患者新型口服抗肿瘤药物的替代给药方法

目的为吞咽困难的患者提供新型口服抗肿瘤药物的替代给药方法。方法根据“新型抗肿瘤药物临床应用指导原则(2022年版)”药品目录确定检索范围,通过查阅说明书,检索PubMed、Micromedex、UpToDate等数据库获得药品临时液体制剂的制备、稳定性、储存和相关临床信息。结果70种口服抗肿瘤药物被纳入文献检索,其中33种药物有相关的文献或数据支持替代给药方法,8种在说明书中有替代给药的相关信息,其他药物的证据水平各不相同。结论大部分药物临时液体制剂的证据水平较低,医疗团队在使用说明书以外的用法时应充分考虑利弊,谨慎使用。

Single small molecule-assembled nanoparticles mediate efficient oral drug delivery

Oral drug delivery,which requires surviving the harsh environment in the gastrointestinal(Gl)tract and penetrating the intestinal epithelium,has not bee n achieved using simple formulatio n nan oparticles(NPs).Medici nal natural products(MNPs)have bee n widely used in traditi onal medicine for disease management through oral consumption.However,most pharmacologically active compounds within MNPs do not have the properties suitable for oral applicatio ns.We hypothesize that some MNPs contain n atural nano materials that can convert those compounds into oral formulations by forming NPs.After screening 66 MNPs,we identified five classes of small molecules that form NPs,many of which are capable of efficient drug encapsulation and Gl penetration.We show that one of them,dehydrotrametenolic acid(DTA),is capable of mediating oral delivery for effective disease treatment.We determined that DTA NPs assemble through hydrogen bonding and penetra怕the Gl tract via apical sodium-depe ndent bile acid tran sporter.Our study reveals a no vel class of single comp orient,small molecule-assembled NPs for oral drug delivery,and suggests a n ovel approach to modernizi ng MNPs through nano material discovery.

An update on oral drug delivery via intestinal lymphatic transport

Orally administered drug entities have to survive the harsh gastrointestinal environment,penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation.Whereas the gastrointestinal stability can be well maintained by taking proper measures,hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism.The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway.Intestinal lymphatic transport is emerging as a promising pathway to this end.In this review,we intend to provide an updated overview on the rationale,strategies,factors and applications involved in intestinal lymphatic transport.There are mainly two pathways for peroral lymphatic transportdthe chylomicron and the microfold cell pathways.The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.

The intragastrointestinal fate of paclitaxel-loaded micelles:Implications on oral drug delivery

The goal of the present study is to elucidate the intragastrointestinal fate of micellar delivery systems by monitoring fluorescently labeled different micelles and the model drug paclitaxel(PTX).Both in vitro and ex vivo leakage studies showed fast PTX release in fluids while micelles remained intact,except in fedstate simulated intestinal fluid and fasted-state pig intestinal fluid,thus referring to the intact absorption of micelles and PTX leakage in the gastrointestinal tract with D-a-tocopherol polyethylene glycol 1000 succinate(TPGS)micelles showing higher stability than other micelles.All groups of micelles were absorbed intact in Caco-2 and Caco-2/HT29-MTX cell models and the absorption of TPGS micelles was found to be higher than other micelles.The transport of the micelles across Caco-2/Raji(1.6%-3.5%),Caco-2(0.8%-1%),and Caco-2/HT29-MTX(0.58%-1%)cell monolayers further verified the absorption of micelles and their subsequent transport;however,more TPGS micelles transported across cell monolayers than other groups.Moreover,the histological examination also confirmed that micelles ente red the enterocytes and were transported to basolateral tissues and TPGS showed the stronger ability of penetration than other groups.Thus,these results are succinctly presenting the absorption of intact micelles in GIT confirmed by imaging evidence with prior leakage of the drug,upta ke by enterocytes and the transport of micelles that survive the digestion by enterocytes and mainly by microfold cells in material nature dependent way with TPGS showing better results than other groups.In conclusion,these results identify the mechanism by which the gastrointestinal tract processes micelles and point to the likely use of this approach in the design of micelles-based therapies.

Milk-derived exosomes exhibit versatile effects for improved oral drug delivery

As endogenous courier vesicles,exosomes play crucial roles in macromolecule transmission and intercellular communication.Therefore,exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the past few years.However,few studies have investigated the encapsulation of peptide/protein drugs into exosomes for oral administration.Additionally,the mechanisms underlying their biomimetic properties as oral delivery vehicles remain unknown.Herein,insulin-loaded milk-derived exosomes(EXO@INS)were fabricated and the in vivo hypoglycemic effect was investigated on type I diabetic rats.Surprisingly,EXO@INS(50 and 30 IU/kg)elicited a more superior and more sustained hypoglycemic effect compared with that obtained with subcutaneously injected insulin.Further mechanism studies indicated that the origin of excellent oral-performance of milk-derived exosomes combined active multi-targeting uptake,pH adaptation during gastrointestinal transit,nutrient assimilation related ERK1/2 and p38 MAPK signal pathway activation and intestinal mucus penetration.This study provides the first demonstration that multifunctional milk-derived exosomes offer solutions to many of the challenges arising from oral drug delivery and thus provide new insights into developing naturally-equipped nanovehicles for oral drug administration.

Cisplatin-based miRNA delivery strategy inspired by the circCPNE1/miR-330-3p pathway for oral squamous cell carcinoma

Circular RNAs(circRNAs)are ideal biomarkers of oral squamous cell carcinoma(OSCC)because of their highly stable closed-loop structure,and they can act as microRNA(miRNA)sponges to regulate OSCC progression.By analyzing clinical samples,we identified circCPNE1,a dysregulated circRNA in OSCC,and its expression level was negatively correlated with the clinical stage of OSCC patients.Gain-of-function assays revealed the tumor-suppressive effect of circCPNE1,which was then identified as a miR-330-3p sponge.MiR-330-3p was recognized as a tumor promoter in multiple studies,consistent with our finding that it could promote the proliferation,migration,and invasion of OSCC cells.These results indicated that selective inhibition of miR-330-3p could be an effective strategy to inhibit OSCC progression.Therefore,we designed cationic polylysine-cisplatin prodrugs to deliver antagomiR-330-3p(a miRNA inhibitory analog)via electrostatic interactions to form PP@miR nanoparticles(NPs).Paratumoral administration results revealed that PP@miR NPs effectively inhibited subcutaneous tumor progression and achieved partial tumor elimination(2/5),which confirmed the critical role of miR-330-3p in OSCC development.These findings provide a new perspective for the development of OSCC treatments.

Rational design of oral drugs targeting mucosa delivery with gut organoid platforms

Effective oral drugs and vaccines require high delivery efficiency across the gastrointestinal epithelia and protection of medically effective payloads(i.e.,immunogens)against gastric damage.In this study,hollowed nanocarriers(NCs:silica nanospheres and gold nanocages)with poly-l-lysine(PLL)coating and mammalian orthoreovirus cell attachment proteinσ1 functionalization(NC-PLL-σ1)were explored as functional oral drug delivery vehicles(ODDVs).The transport of these ODDVs to mucosal lymphoid tissues could be facilitated by microfold cells(M-cells)mediated transcytosis(viaσ1-α2–3-linked sialic acids adherence)across gastrointestinal epithelia.PLL coating provided protection and slow-release of rhodamine 6 G(R6G),a model payload.The transport effectiveness of these ODDVs was tested on intestinal organoid monolayers in vitro.When compared with other experimental groups,the fully functionalized ODDV system(with PLL-σ1)demonstrated two significant advantages:a significantly higher transport efficiency(198%over blank control at 48 h);and protection of payloads which led to both better transport efficiency and extended-release of payloads(61%over uncoated carriers at 48 h).In addition,it was shown that the M cell presence in intestinal organoid monolayers(modulated by Rank L stimulation)was a determining factor on the transport efficiency of the ODDVs:more M-cells(induced by higher Rank L)in the organoid monolayers led to higher transport efficiency for ODDV-delivered model payload(R6G).The fully functionalized ODDVs showed great potential as effective oral delivery vehicles for drugs and vaccines.

The feasibility of oral targeted drug delivery: Gut immune to particulates?

Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration(oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.