检索问题
药品本身具有明显的胃肠道副作用，改良为哪种剂型可降低胃肠道副作用？
为了降低具有明显胃肠道副作用的药物的胃肠道副作用，可以考虑以下几种改良剂型：
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肠溶剂型（Enteric-Coated Formulations）：
- 作用机制：肠溶剂型通过在药片或胶囊外覆盖一层特殊的包衣，使其能够在胃酸环境中保持完整，直到进入肠道碱性环境才崩解并释放药物。这种延迟释放的特性有助于避免药物与胃黏膜的直接接触，从而减轻对胃部的刺激，降低局部不良反应。
- 应用实例：
- 米非司酮（Mycophenolate Mofetil, MMF）和肠溶性霉酚酸钠（Enteric-Coated Mycophenolate Sodium, EC-MPS）：霉酚酸钠是霉酚酸（MPA）的一种肠溶剂型，旨在改善MPA的胃肠道耐受性。尽管一些盲法试验未能证实EC-MPS在胃肠道症状负担方面有显著改善，但多项开放标签研究一致表明，EC-MPS能提高胃肠道耐受性，从而允许恢复最佳的MPA剂量。EC-MPS与MMF具有相同的疗效，可能具有不同的耐受性，为医生和患者，特别是那些经历MMF相关胃肠道症状、糖尿病患者或需要减少MPA剂量的患者提供了选择。
- 碳酸氢钠（Sodium Bicarbonate, NaHCO3）：肠溶剂型的碳酸氢钠胶囊可以减轻摄入后胃肠道副作用。与明胶（GEL）和延迟释放（DEL）胶囊相比，肠溶剂型碳酸氢钠报告的胃肠道症状更少，症状严重程度更低。
- 萘普生（Naproxen）：有研究开发了肠溶剂型萘普生，以应对其局部胃肠道毒性。肠溶剂型萘普生的吸收程度与普通片剂相同，但吸收开始时间因在胃中停留较长时间而延迟，尤其是在随餐服用时。
- 阿司匹林（Aspirin）：虽然肠溶阿司匹林片剂缓冲后可能比普通无包衣阿司匹林刺激性小，但并不能完全预防溃疡。在狗中使用肠溶阿司匹林片剂不被推荐，因为其全身吸收不可预测。
- 优点：减少药物在胃内的局部不良反应，避免药物峰值血药浓度相关的副作用，方便给药，提高患者依从性，减少全天血药浓度波动。
- 缺点：在急性或慢性肠道快速转运障碍（如胃肠炎或肠易激综合征）患者中可能吸收不完全。可能比即释剂型更昂贵。
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缓释剂型或控释剂型（Sustained-Release, Extended-Release, or Time-Release Formulations）：
- 作用机制：这类剂型通过延迟药物释放，或以预定方式一点一点地释放药物，从而延长药物作用时间，维持药物血药浓度稳定，并减少因药物在胃肠道局部浓度过高引起的刺激。
- 应用实例：
- 二甲双胍（Metformin）：二甲双胍即释剂型与缓释剂型相比，胃肠道副作用如腹胀和腹泻的风险更高。缓释剂型有助于减少胃肠道副作用和降低给药频率。
- 神经精神药物：许多精神科药物已被制成缓释剂型，以减少胃肠道局部不良反应，降低与血药浓度峰值相关的副作用，或人为地延长其半衰期。
- 优点：减少胃肠道局部副作用和与血药浓度峰值相关的副作用，延长半衰期，提高给药依从性，减少血药浓度波动。
- 缺点：可能在肠道快速转运的患者中吸收不完全。
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纳米颗粒和微粒剂型（Nanoparticles and Microparticles）：
- 作用机制：通过将药物封装在纳米或微米大小的载体中，可以改变药物的释放模式，改善生物利用度，减少对胃肠道的直接刺激，并实现靶向递送。
- 应用实例：
- 二甲双胍：微粒和纳米颗粒药物递送系统被探索用于优化二甲双胍治疗，以提高生物利用度，减少给药频率，降低胃肠道副作用和毒性。
- 辣椒素（Capsaicin）：辣椒素负载的甲氧基聚（乙二醇）-聚（ε-己内酯）纳米颗粒显著提高了辣椒素的生物利用度，并显著减轻了对大鼠胃黏膜的刺激。
- 米索前列醇（Misoprostol）：研究探索了利用喷雾/振动技术生产用于米索前列醇胃部靶向递送的口服微胶囊，以提高其化学稳定性并减少相关的全身副作用。其中，含有米索前列醇/羟丙基-β-环糊精（HP-β-CD）包合物的微胶囊在模拟胃液中30分钟内释放，并表现出更强的在模拟胃环境中稳定米索前列醇的能力，同时对胃黏膜的黏附最小。
- 优点：提高生物利用度，降低给药频率，减少胃肠道副作用和毒性，可能实现靶向递送。
- 缺点：可能存在复杂性、成本、生物相容性、储存和运输稳定性、载药量、所需技术以及监管审批等挑战。
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宿主-客体包合物（Host-Guest Complexes）：
- 作用机制：通过将药物与宿主分子（如环糊精或葫芦脲）形成包合物，可以改变药物的溶解度、溶解速率和胃肠道黏膜的黏附性，从而减少胃肠道刺激并提高生物利用度。
- 应用实例：
- 吡罗昔康（Piroxicam）：吡罗昔康是常与胃肠道损伤相关的非甾体抗炎药（NSAID）。与β-环糊精（β-CD）相比，葫芦脲（CB）与吡罗昔康的结合常数高约70倍，形成的吡罗昔康@CB包合物在胃液中表现出快速溶解速率，显著提高口服生物利用度和最大浓度，并对胃黏膜的黏附最少，引起的胃部副作用最轻。
- 米索前列醇：米索前列醇与HP-β-CD形成包合物的微胶囊，可以提高米索前列醇的稳定性并减少胃肠道副作用。
- 优点：改善药物溶解度和溶解速率，减少胃肠道黏膜黏附，降低副作用，提高生物利用度。
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磷脂复合物或磷脂酰胆碱（Phosphatidylcholine, PC）结合剂型：
- 作用机制：胃肠道黏膜具有疏水性、不湿润的特性，作为对腔内酸的屏障，而磷脂，特别是磷脂酰胆碱，在维持这种屏障特性中发挥作用。将非甾体抗炎药（NSAIDs）与磷脂酰胆碱结合，可以保护胃黏膜，降低胃肠道毒性。
- 应用实例：
- NSAIDs：开发将NSAIDs与PC结合的脂质基制剂，已在临床前和临床观察中验证了其胃肠道安全性和治疗效果。
- 优点：通过增强胃黏膜屏障特性来减轻胃肠道副作用。
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胃部靶向递送系统（Gastric-Directed Drug Delivery Systems）：
- 作用机制：这类系统旨在将药物直接递送到胃黏膜，从而在局部达到高浓度，提高疗效并减少全身副作用，但前提是药物在胃部发挥作用或减少胃黏膜的刺激。
- 应用实例：
- 米索前列醇：通过喷雾/振动技术生产的微胶囊，旨在实现米索前列醇在胃黏膜的局部递送，以治疗胃十二指肠溃疡，并减少其相关的全身副作用。
- 幽门螺杆菌感染治疗：胃滞留递送系统（如漂浮系统、膨胀或溶胀系统、生物粘附系统）可以增加药物对黏液层的渗透，从而增加作用部位的药物浓度，以治疗幽门螺杆菌感染。
- 优点：实现药物在特定胃部区域的高浓度，提高局部疗效，减少全身副作用。
- 缺点：通常存在非特异性、受黏液更新限制或难以在胃中持续存在的问题。
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透皮给药系统（Transdermal Drug Delivery Systems）：
- 作用机制：透皮给药系统通过皮肤吸收药物，完全避免了口服给药的胃肠道副作用。
- 优点：避免口服给药的主要缺点（如胃肠道副作用、生物利用度低、需要多次给药）和肠外给药的缺点（如侵入性、疼痛、心理压力和针头产生的生物危害废物），从而提高患者的接受度和依从性。
- 应用实例：长效透皮贴剂、微针和分子印迹聚合物系统等。
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阴道给药系统（Vaginal Drug Delivery Systems）：
- 作用机制：对于某些药物，阴道腔作为给药部位可以避免胃肠道副作用的发生率和严重程度。
- 优点：避免胃肠道副作用，无需注射带来的不便（疼痛、组织损伤、感染风险），易于自行插入和移除，可实现与阴道黏膜的长时间接触。
- 缺点：药物递送系统的有效性受生物环境、聚合物和药物性质的影响。
总结： 当药物具有明显的胃肠道副作用时，可以根据药物的性质、作用机制以及目标治疗效果，选择以下改良剂型来降低胃肠道副作用：
- 肠溶剂型：适用于药物在胃酸中不稳定或对胃黏膜有刺激性，但需要在肠道吸收或作用的药物。
- 缓释/控释剂型：适用于需要延长作用时间、减少给药频率、避免血药浓度峰值副作用的药物，并可在一定程度上减少胃肠道刺激。
- 纳米/微粒剂型：提供更精细的药物递送方式，可提高生物利用度，降低副作用，并可能实现靶向递送。
- 宿主-客体包合物：通过分子结合改变药物的理化性质，从而减少胃肠道刺激并提高生物利用度。
- 磷脂酰胆碱结合剂型：特异性地通过增强胃黏膜屏障来保护胃部。
- 胃部靶向递送系统：适用于需要在胃部局部发挥作用的药物，以提高局部疗效并减少全身副作用。
- 透皮给药系统和阴道给药系统：作为非口服给药途径，完全避免了胃肠道的参与，是降低胃肠道副作用的根本性方法，但适用范围受限。
具体选择哪种剂型需要综合考虑药物的理化性质、药代动力学、药效学、患者依从性、成本以及预期的副作用减少效果。例如，非甾体抗炎药（NSAIDs）如吡罗昔康和酮洛芬常导致胃肠道损伤（如消化不良、烧心、炎症、出血、溃疡甚至穿孔），对于这类药物，肠溶剂型、磷脂复合物、宿主-客体包合物或新型递送系统（如水凝胶、前药、共轭药物）都可能有效降低其胃肠道副作用。对于二甲双胍，缓释剂型和微/纳米颗粒剂型已被证明可有效减少胃肠道副作用。
References
1Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: A systematic review, meta-analysis and meta-regression of randomized controlled trials.PubMed
Katarzyna Nabrdalik, Karolina Skonieczna-Żydecka, Krzysztof Irlik, et al.
INTRODUCTION: Metformin is the first choice drug in the treatment of type 2 diabetes mellitus but its administration may be linked to gastrointestinal adverse events limiting its use. OBJECTIVES: The objective of this systematic review and meta-analysis was to assess the risk of gastrointestinal adverse events related to metformin use in patients with type 2 diabetes treated with metformin. METHODS: PUB MED/CINAHL/Web of Science/Scopus were searched from database inception until 08.11.2020 for articles in English and randomized controlled trials related to patients with type 2 diabetes treated with metformin were included. RESULTS: From 5315 publications, we identified 199 potentially eligible full-text articles. Finally, 71 randomized controlled trials were included in the meta-analysis. In these studies, metformin use was associated with higher risk of abdominal pain, diarrhea and nausea comparing to control. The risks of abdominal pain and nausea were highest comparing to placebo. Bloating risk was only elevated when metformin treatment was compared to DPP4i. CONCLUSIONS: The risk of gastrointestinal adverse events such as abdominal pain, nausea and diarrhea is higher in type 2 diabetes patients treated with metformin compared to other antidiabetic drugs. There is a higher risk of bloating and diarrhea with metformin immediate-release than with metformin extended release formulation. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289975, identifier CRD42021289975.
2Oral delivery of proteins and peptides: Challenges, status quo and future perspectives.PubMed
Quangang Zhu, Zhongjian Chen, Pijush Kumar Paul, et al.
Proteins and peptides (PPs) have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy, but fewer side effects. Owing to the poor stability and limited permeability through gastrointestinal (GI) tract and epithelia, the therapeutic PPs are usually administered by parenteral route. Given the big demand for oral administration in clinical use, a variety of researches focused on developing new technologies to overcome GI barriers of PPs, such as enteric coating, enzyme inhibitors, permeation enhancers, nanoparticles, as well as intestinal microdevices. Some new technologies have been developed under clinical trials and even on the market. This review summarizes the history, the physiological barriers and the overcoming approaches, current clinical and preclinical technologies, and future prospects of oral delivery of PPs.
3Sustained-release, extended-release, and other time-release formulations in neuropsychiatry.PubMed
Chittaranjan Andrade
Pills and capsules may release their contents within minutes of ingestion; these are immediate-release formulations. Pills and capsules may also release their contents after a time lag, or a little at a time, or in some other predetermined way; these are time-release formulations. Many drugs in psychiatry have been time-release formulated to reduce their local adverse effects in the gastrointestinal tract, to reduce adverse effects associated with peak blood levels, or to artificially extend their half-life. Time-release formulations are associated with the added advantages of convenience of dosing, improved compliance, and less fluctuation in blood levels across the course of the day. A disadvantage of time-release formulations is that they may be incompletely absorbed; this is a serious issue in patients with acute or chronic intestinal hurry disorders, such as gastroenteritis or irritable bowel syndrome. Time-release formulations may also be more expensive than immediate-release formulations.
4Long-acting transdermal drug delivery formulations: Current developments and innovative pharmaceutical approaches.PubMed
Tanvi Karve, Amruta Dandekar, Vivek Agrahari, et al.
Transdermal administration remains an active research and development area as an alternative route for long-acting drug delivery. It avoids major drawbacks of conventional oral (gastrointestinal side effects, low drug bioavailability, and need for multiple dosing) or parenteral routes (invasiveness, pain, and psychological stress and bio-hazardous waste generated from needles), thereby increasing patient appeal and compliance. This review focuses on the current state of long-acting transdermal drug delivery, including adhesive patches, microneedles, and molecularly imprinted polymeric systems. Each subsection describes an approach including key considerations in formulation development, design, and process parameters with schematics. An overview of commercially available conventional (adhesive) patches for long-acting drug delivery (longer than 24 h), the reservoir- and matrix-type systems under preclinical evaluation, as well as the advanced transdermal formulations, such as the core-shell, nanoformulations-incorporated and stimuli-responsive microneedles, and 3D-printed and molecularly imprinted polymers that are in development, is also provided. Finally, we elaborated on translational aspects, challenges in patch formulation development, and future directions for the clinical advancement of new long-acting transdermal products.
5Cucurbit[7]uril-based host-guest complexes for improving bioavailability and reducing side effects of piroxicam.PubMed
Yan Wang, Xiaodi Yang, Jianguo Luo, et al.
Piroxicam (PX) is a nonsteroidal anti-inflammatory drug (NSAID) commonly associated with gastrointestinal (GI) injuries, including dyspepsia, heartburn, inflammation, bleeding, ulceration, and life-threatening perforation. The β-cyclodextrin (β-CD)-based PX formulation (PX@CD) has been shown to reduce gastric side effects by improving PX's solubility and dissolution rates. However, the solubility of PX can only be increased to a limited extent by β-CD, due to the low binding constant between PX and β-CD (∼100 M). As a result, adverse reactions such as epigastric pain and pyrosis are still commonly reported. Cucurbit[7]uril (CB[7]) is a synthetic macrocyclic host compound that binds strongly to various drugs. In this study, we demonstrated that CB[7] forms complexes with PX in the gastric acid environment with a binding constant approximately 70 times higher than that between β-CD and PX. The PX@CB[7] inclusion complexes exhibited rapid dissolution rates in the gastric environment. In addition, PX@CB[7] showed significantly higher oral bioavailability and maximum concentration (C) compared to PX and PX@CD (1:2.5), resulting in improved anti-inflammatory effects in both mouse and rat models. Moreover, PX@CB[7] (1:2.5) had the least adhesion to the gastric mucosa and caused the mildest gastric side effects in rat models when compared to PX, PX@CD (1:2.5), and PX@CB[7] (1:1). Lastly, CB[7] demonstrated good oral biocompatibility in a subacute toxicity evaluation study. These findings indicate that CB[7] could be used as an excipient to improve treatment effectiveness and decrease adverse reactions in orally administered formulations with a favorable safety profile.
6Enteric-Coated Sodium Bicarbonate Attenuates Gastrointestinal Side-Effects.PubMed
Nathan Philip Hilton, Nicholas Keith Leach, Melissa May Craig, et al.
Enteric-formulated capsules can mitigate gastrointestinal (GI) side effects following sodium bicarbonate (NaHCO3) ingestion; however, it remains unclear how encapsulation alters postingestion symptoms and acid-base balance. The current study aimed to identify the optimal ingestion form to mitigate GI distress following NaHCO3 ingestion. Trained males (n = 14) ingested 300 mg/kg body mass of NaHCO3 in gelatin (GEL), delayed-release (DEL), and enteric-coated (ENT) capsules or a placebo in a randomized cross-over design. Blood bicarbonate anion concentration, potential hydrogen, and GI symptoms were measured pre- and postingestion for 3 hr. Fewer GI symptoms were reported with ENT NaHCO3 than with GEL (p = .012), but not with DEL (p = .106) in the postingestion phase. Symptom severity decreased with DEL (4.6 ± 2.8 arbitrary units) compared with GEL (7.0 ± 2.6 arbitrary units; p = .001) and was lower with ENT (2.8 ± 1.9 arbitrary units) compared with both GEL (p < .0005) and DEL (p = .044) NaHCO3. Blood bicarbonate anion concentration increased in all NaHCO3 conditions compared with the placebo (p < .0005), although this was lower with ENT than with GEL (p = .001) and DEL (p < .0005) NaHCO3. Changes in blood potential hydrogen were reduced with ENT compared with GEL (p = .047) and DEL (p = .047) NaHCO3, with no other differences between the conditions. Ingestion of ENT NaHCO3 attenuates GI disturbances for up to 3 hr postingestion. Therefore, ENT ingestion forms may be favorable for those who report GI disturbances with NaHCO3 supplementation or for those who have previously been deterred from its use altogether.
7Enteric-coated mycophenolate sodium.PubMed
Klemens Budde, Michael Dürr, Lutz Liefeldt, et al.
IMPORTANCE OF THE FIELD: Mycophenolic acid (MPA) therapy is a fundamental component of most post-transplant immunosuppressive regimens. Side effects, however, are common and frequently necessitate dose reductions or discontinuations. AREAS COVERED IN THIS REVIEW: Enteric-coated mycophenolate sodium (EC-MPS) is designed to improve the gastrointestinal (GI) tolerability of MPA. This review assesses the pharmacology, efficacy and safety of EC-MPS. WHAT THE READER WILL GAIN: An understanding of the use of EC-MPS in solid organ transplantation and the key trials examining the GI impact of EC-MPS versus the immediate-release mycophenolate mofetil (MMF) formulation. The article also addresses the possible impact of proton pump inhibitor therapy, and the optimal MPA dose with different concomitant immunosuppressants. TAKE HOME MESSAGE: Evidence from blinded trials using standard reporting measures or patient-reported outcomes has not confirmed a significant improvement in the GI symptom burden using EC-MPS. Several open-label studies, however, have consistently shown an improvement in GI tolerability with EC-MPS, which can permit restoration of the optimal MPA dose. EC-MPS has equal efficacy and possibly a different tolerability profile to MMF, thus offering a choice to physicians and their patients, particularly those experiencing MMF-related GI symptoms, diabetic patients or those in whom an MPA dose reduction is required.
8Advances in metformin-delivery systems for diabetes and obesity management.PubMed
Mehrnaz Abbasi, Braeden Heath, Lauren McGinness
Metformin is a medication that is commonly prescribed to manage type 2 diabetes. It has been used for more than 60 years and is highly effective in lowering blood glucose levels. Recent studies indicate that metformin may have additional medical benefits beyond treating diabetes, revealing its potential therapeutic uses. Oral medication is commonly used to administer metformin because of its convenience and cost-effectiveness. However, there are challenges in optimizing its effectiveness. Gastrointestinal side effects and limitations in bioavailability have led to the underutilization of metformin. Innovative drug-delivery systems such as fast-dissolving tablets, micro/nanoparticle formulations, hydrogel and microneedles have been explored to optimize metformin therapy. These strategies enhance metformin dosage, targeting, bioavailability and stability, and provide personalized treatment options for improved glucose homeostasis, antiobesity and metabolic health benefits. Developing new delivery systems for metformin shows potential for improving therapeutic outcomes, broadening its applications beyond diabetes management and addressing unmet medical needs in various clinical settings. However, it is important to improve drug-delivery systems, addressing issues such as complexity, cost, biocompatibility, stability during storage and transportation, loading capacity, required technologies and biomaterials, targeting precision and regulatory approval. Addressing these limitations is crucial for effective, safe and accessible drug delivery in clinical practice. In this review, recent advances in the development and application of metformin-delivery systems for diabetes and obesity are discussed.
9Investigating the prilling/vibration technique to produce gastric-directed drug delivery systems for misoprostol.PubMed
Vita D'Amico, Nunzio Denora, Marianna Ivone, et al.
Prilling/vibration technique to produce oral microcapsules was explored to achieve local delivery of misoprostol (MIS), a prostaglandin E1 analogue indicated for the treatment of gastric-duodenal ulcers, at the gastric mucosa. To improve MIS chemical stability and reduce its associated systemic side effects, drug delivery systems were designed and developed as microcapsules consisting of a core of sunflower oil and MIS (F and F) or a MIS complex with hydroxypropyl-beta-cyclodextrin (HP-β-CD) (F), confirmed by specific studies, and a polymeric shell. The produced microcapsules showed high encapsulation efficiencies for those with MIS solubilized in sunflower oil (>59.86 %) and for the microcapsules with MIS/HP-β-CD (97.61 %). To demonstrate the ability of these systems to deliver MIS into the stomach, swelling and drug release experiments were also conducted in simulated gastric fluid. Among the three formulations, F showed gastric release within 30 min and was the most advantageous formulation because the presence of the MIS/HP-β-CD inclusion complex ensured a greater ability to stabilise MIS in the simulated gastric environment. In addition, these new systems have a small size (<540 µm), and good flow properties and the dose of the drug could be easily adapted using different amounts of microcapsules (flexibility), making them a passepartout for different age population groups.
10Mycophenolates in transplantation.PubMed
Hans W Sollinger
The discovery of mycophenolic acid (MPA) as a potent immunosuppressant, able to inhibit B- and T-cell proliferation by blocking production of guanosine nucleotides required for DNA synthesis, allowed its potential in the field of transplantation to be realized. Mycophenolate mofetil (MMF), an MPA prodrug, has been shown to be an effective immunosuppressant in transplant therapy. Clinical trials in renal, heart, and liver transplant recipients have demonstrated that, in combination with cyclosporine and steroids, MMF therapy can reduce the incidence and severity of acute rejection episodes and improve graft and patient survival as well as graft function. Although MMF is generally well tolerated, optimal therapy may be limited by associated side effects, in particular gastrointestinal (GI) toxicity, which may occur in over 40% of patients. Dose changes resulting from GI side effects may potentially lead to sub-therapeutic dosing and impaired clinical outcomes. An enteric-coated formulation delivering MPA - enteric-coated mycophenolate sodium (EC-MPS) has been developed to improve MPA-related upper GI adverse events. EC-MPS delays the release of MPA, consistent with a functional enteric-coating. Recent clinical trials have demonstrated that EC-MPS is as effective and safe as MMF in both de novo and maintenance renal transplant patients.
11Vaginal mucoadhesive drug delivery systems.PubMed
Raphaela Regina de Araújo Pereira, Marcos Luciano Bruschi
BACKGROUND: The vaginal mucosal cavity is a feasible, safe, very attractive site for drug delivery and highly dynamic with respect to absorption of drugs, their metabolism and their elimination. Compared with other mucosal application sites, the vagina has the following advantages as, a fall in the incidence and severity of gastrointestinal side effects, avoidance of the inconvenience caused by pain, tissue damage and risk of infections which are associated with parenteral routes, ease of self-insertion and removal of the dosage form is possible. In addition, a prolonged contact of a delivery system with the vaginal mucosa may be achieved more easily than at other absorption sites like rectum or intestinal mucosa. Mucoadhesive systems provide intimate contact between a dosage form and the vaginal mucosa, which may result in high concentration in a local area and hence high drug flux through the vaginal mucosa. The efficacy of vaginal mucoadhesive drug delivery systems (DDS) is affected by the biological environment and the properties of the polymer and the drug. OBJECTIVE: This article reviews systematically some relevant citations regarding the environment, strategies for vaginal drug delivery, evaluation, and utilization of the main polymers. CONCLUSION: We provide a review of several vaginal mucoadhesive DDS currently in developmental stages or available in the market, immunization via the vagina and special emphasis on the challenges and difficulties associated with delivery of drugs via the vaginal route.
12Future prospects of ketoprofen in improving the safety of the gastric mucosa.PubMed
Joanna Kuczyńska, Barbara Nieradko-Iwanicka
INTRODUCTION: Ketoprofen (K) was synthesized in 1968. K belongs to nonsteroidal anti-inflammatory drugs (NSAIDs) and has analgesic, anti-inflammatory and antipyretic properties. K is commonly used due to rapid absorption, simple metabolism, high antinociceptive activity and fast blood brain barrier crossing. However, this substance causes various side effects which are the major factors affecting its' popularity. Many researchers have modified this drug to discover an improved and safe NSAID. AIM: The aim of the review was to find in recent publications data bout future prospects of K of improved safety for the gastric mucosa after oral administration. METHOD: Systematic literature review was conducted in March 2021 (2015 onwards). We selected 22 articles from PubMed, Google Scholar, Medline Complete databases. RESULTS AND DISCUSSION: Many studies aimed at obtaining K with lower ulcerogenic properties. This article describes K with lysine, new K delivery systems, K in form of hydrogels, prodrugs and codrugs of K, K as ATB-352, K with zinc, K encapsulated as proliposomal powders and several substances that reduce the gastric side effects of K described after 2015. CONCLUSION: Our review confirms that modifications of K maintain its' desirable actions and decrease ulcer producing side effect. Some new forms of K were also found to have better activity profile compared to the parent drug.
13Antiulcer therapy.PubMed
M G Papich
Perhaps older drugs to treat ulcers, such as antacids, are just as effective as the newer drugs, but veterinarians have all but abandoned these drugs in favor of H2-receptor antagonists, sucralfate, and omeprazole. For most patients, one of the H2-receptor antagonists or sucralfate is probably the initial drug of choice. For patients refractory to these drugs or for which once-a-day dosing is desirable, omeprazole has an advantage. The doses for these drugs are listed in Table 1. Patients presented with acute bleeding ulcers should be managed with emergency therapy. Fluid therapy and blood transfusions are the essential elements of the initial therapy. Surgical resection of the ulcers may be necessary, and most patients should be administered H2-receptor antagonists or sucralfate while they recuperate. Longer term therapy with antiulcer drugs will depend on the predisposing factors that initiated the ulcers. The practice of lavage of the stomach with iced saline or epinephrine to stop bleeding from gastric ulcers is not effective. A common cause of ulcers in small animals is the administration of NSAIDs. Ulcers caused by these agents should be managed like any other ulcers. Fortunately, if ulcers are diagnosed early, they usually heal once the NSAID is discontinued. Unfortunately, many NSAID-induced ulcers identified postmortem did not produce clinical signs, and the ulcers may not be apparent until severe bleeding occurs. In cases in which patients are at risk for developing ulcers from NSAIDs, there may be an advantage in administering the synthetic prostaglandin misoprostol. In many patients that are sensitive to the GI irritation of NSAIDs, switching from one NSAID to another may alleviate some of the signs. Buffered aspirin may be somewhat less irritating than plain uncoated aspirin but will not completely prevent ulcers. The administration of enteric-coated aspirin tablets to dogs is discouraged, because systemic absorption from these tablets is unpredictable.
14Microparticulate and nanoparticulate drug delivery systems for metformin hydrochloride.PubMed
Meltem Cetin, Selma Sahin
CONTEXT: Metformin hydrochloride is a biguanide derivative widely used for the treatment of type 2 diabetes, prescribed nearly to 120 million people worldwide. Metformin has a relatively low oral bioavailability (about 50-60%). Although the major effect of metformin is to decrease hepatic glucose output as an antihyperglycemic agent, its inhibitory effects on the proliferation of some cancer cells (e.g. prostate, breast, glioma cells) have been demonstrated in the cell culture studies. Development of novel formulation (e.g. microparticles, nanoparticles) strategies for metformin might be useful to improve its bioavailability, to reduce the dosing frequency, to decrease gastrointestinal side effects and toxicity and to be helpful for effective use of metformin in cancer treatment. OBJECTIVE: The main aim of this review is to summarize metformin HCl-loaded micro- and nanoparticulate drug delivery systems. METHOD: The literature was rewieved with regard to the physicochemical, pharmacological properties of metformin, and also its mechanism of action in type 2 diabetes and cancer. In addition, micro- and nanoparticulate drug delivery systems developed for metformin were gathered from the literature and the results were discussed. CONCLUSION: Metformin is an oral antihyperglycemic agent and also has potential antitumorigenic effects. The repeated applications of high doses of metformin (as immediate release formulations) are needed for an effective treatment due to its low oral bioavailability and short biological half-life. Drug delivery systems are very useful systems to overcome the difficulties associated with conventional dosage forms of metformin and also for its effective use in cancer treatment.
15Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity.PubMed
Lenard M Lichtenberger, Melisa Barron, Upendra Marathi
Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective drugs that inhibit pain and inflammation, and perhaps due to the role of inflammation in the underlying etiology, NSAIDs have also demonstrated efficacy in reducing a patient's risk of developing a number of cancers and neurological diseases (e.g. Alzheimer's disease). The utility of these powerful drugs is limited due to their gastrointestinal (GI) side-effects, notably peptic ulceration and GI bleeding which is briefly reviewed here. We also describe the barrier property of the GI mucosa and how it is affected by NSAIDs, as it is our position that disruption of the surface barrier is an important component in the drugs' pathogenesis, in addition to selective inhibition of COX-2, which has proven to be problematic. We also discuss current alternative approaches being taken to mitigate the GI side-effects of NSAIDs, including developing combination drugs where NSAIDs are packaged with inhibitors of HCl secretion such as proton pump inhibitors or H2-receptor antagonists. We then present the rationale for the development of the PC associated NSAID technology which came out of our observation that the mammalian gastric mucosa has hydrophobic, nonwettable properties that provides a barrier to luminal acid, and the role of phospholipids and specifically phosphatidylcholine (PC) in this barrier property. In the last section we review the development of our current lipid-based PC-NSAID formulations and our encouraging preclinical and clinical observations validating their GI safety and therapeutic efficacy.
16Opioids: a two-faced Janus.PubMed
Karsten Ahlbeck
BACKGROUND: Long-term pain is a debilitating condition that is costly to treat and has a significant impact on patient quality of life. Classical opioids have been used for the treatment of pain for centuries and are one of the most effective drug classes available for acute severe pain and long-term pain. However, concerns regarding adverse effects, tolerance to analgesic effects and the potential for addiction have resulted in a reluctance to prescribe and use opioids for the management of long-term non-cancer pain. Adverse events, including gastrointestinal side effects such as constipation, nausea and vomiting, and central nervous system side effects such as sedation are responsible for as many as one in five patients discontinuing opioid treatment, often leading to inadequate pain relief and poor patient quality of life. Therefore, new analgesic therapies are needed that are associated with fewer adverse effects, whilst providing sustainable pain relief for patients with long-term pain. OBJECTIVE AND METHODS: To provide an overview of the historical development, uses, mechanisms of action, receptor affinities and side-effect profiles of classical opioids. In addition, recent developments and novel approaches for long-term, severe pain treatment are also reviewed. RESULTS: A number of treatment strategies were identified: co-administration with opioid-sparing analgesics to reduce side effects and/or risk of dependence, the use of peripheral opioid antagonists and novel delivery mechanisms to reduce side effects, the development of non-opioid agents that reduce side effects and enhance analgesia such as glial cell modulators, and the development of novel agents with combined µ-receptor and monoaminergic activity within the same molecule. CONCLUSIONS: Despite these recent advances, there have been very few completely novel drug developments. Hence, there remains a continuing need for innovative therapeutic strategies for the treatment of long-term pain. The most promising alternatives appear to be the use of traditional opioids together with peripheral opioid antagonists, combining opioids with glial cell modulators, and the use of novel agents with µ-receptor agonist and noradrenaline reuptake inhibitor activity within the same molecule (MOR-NRI compounds).
17Drug delivery strategies for the treatment of Helicobacter pylori infections.PubMed
B R Conway
Helicobacter pylori is one of the most common pathogenic bacterial infections, colonising an estimated half of all humans. It is associated with the development of serious gastroduodenal disease - including peptic ulcers, gastric lymphoma and acute chronic gastritis. Current recommended regimes are not wholly effective and patient compliance, side-effects and bacterial resistance can be problematic. Drug delivery to the site of residence in the gastric mucosa may improve efficacy of the current and emerging treatments. Gastric retentive delivery systems potentially allow increased penetration of the mucus layer and therefore increased drug concentration at the site of action. Proposed gastric retentive systems for the enhancement of local drug delivery include floating systems, expandable or swellable systems and bioadhesive systems. Generally, problems with these formulations are lack of specificity, limited to mucus turnover or failure to persist in the stomach. Gastric mucoadhesive systems are hailed as a promising technology to address this issue, penetrating the mucus layer and prolonging activity at the mucus-epithelial interface. This review appraises gastroretentive delivery strategies specifically with regard to their application as a delivery system to target Helicobacter. As drug-resistant strains emerge, the development of a vaccine to eradicate and prevent reinfection is an attractive proposition. Proposed prophylactic and therapeutic vaccines have been delivered using a number of mucosal routes using viral and non-viral vectors. The delivery form, inclusion of adjuvants, and delivery regime will influence the immune response generated.
18Enteric coated naproxen tablets.PubMed
O N Gamst
It is postulated that the gastroduodenal mucosal side effects of naproxen are partly based on topical toxicity. With enteric coated aspirin tablets as a model product, enteric coated naproxen formulations have been developed. The extent of absorption is the same for enteric coated and plain tablets. The onset of absorption is delayed as a result of retention of larger particles in the stomach and more so when taken along with food. The gastric emptying of enteric coated naproxen granules is less influenced by food intake, but so far without any verified reduction of gastroscopic findings. The gastro-intestinal transmit has been studied by use of gamma scintigraphy.
19Advanced drug delivery approaches against periodontitis.PubMed
Deeksha Joshi, Tarun Garg, Amit K Goyal, et al.
Periodontitis is an inflammatory disease of gums involving the degeneration of periodontal ligaments, creation of periodontal pocket and resorption of alveolar bone, resulting in the disruption of the support structure of teeth. According to WHO, 10-15% of the global population suffers from severe periodontitis. The disease results from the growth of a diverse microflora (especially anaerobes) in the pockets and release of toxins, enzymes and stimulation of body's immune response. Various local or systemic approaches were used for an effective treatment of periodontitis. Currently, controlled local drug delivery approach is more favorable as compared to systemic approach because it mainly focuses on improving the therapeutic outcomes by achieving factors like site-specific delivery, low dose requirement, bypass of first-pass metabolism, reduction in gastrointestinal side effects and decrease in dosing frequency. Overall it provides a safe and effective mode of treatment, which enhances patient compliance. Complete eradication of the organisms from the sites was not achieved by using various surgical and mechanical treatments. So a number of polymer-based delivery systems like fibers, films, chips, strips, microparticles, nanoparticles and nanofibers made from a variety of natural and synthetic materials have been successfully tested to deliver a variety of drugs. These systems are biocompatible and biodegradable, completely fill the pockets, and have strong retention on the target site due to excellent mucoadhesion properties. The review summarizes various available and recently developing targeted delivery devices for the treatment of periodontitis.
20Oral delivery of capsaicin using MPEG-PCL nanoparticles.PubMed
Wei Peng, Xin-yi Jiang, Yuan Zhu, et al.
AIM: To prepare a biodegradable polymeric carrier for oral delivery of a water-insoluble drug capsaicin (CAP) and evaluate its quality. METHODS: CAP-loaded methoxy poly (ethylene glycol)-poly(ε-caprolactone) nanoparticles (CAP/NPs) were prepared using a modified emulsification solvent diffusion technique. The quality of CAP/NPs were evaluated using transmission electron microscopy, powder X-ray diffraction, differential scanning calorimetry and Fourier transform infrared techniques. A dialysis method was used to analyze the in vitro release profile of CAP from the CAP/NPs. Adult male rats were orally administered CAP/NPs (35 mg/kg), and the plasma concentrations of CAP were measured with a validated HPLC method. The morphology of rat gastric mucosa was studied with HE staining. RESULTS: CAP/NPs had an average diameter of 82.54 ± 0.51 nm, high drug-loading capacity of 14.0% ± 0.13% and high stability. CAP/NPs showed a biphasic release profile in vitro: the burst release was less than 25% of the loaded drug within 12 h followed by a more sustained release for 60 h. The pharmacokinetics study showed that the mean maximum plasma concentration was observed 4 h after oral administered of CAP/NPs, and approximately 90 ng/mL of CAP was detected in serum after 36 h. The area under the curve for the CAP/NPs group was approximately 6-fold higher than that for raw CAP suspension. Histological studies showed that CAP/NPs markedly reduced CAP-caused gastric mucosa irritation. CONCLUSION: CAP/NPs significantly enhance the bioavailability of CAP and markedly reduce gastric mucosa irritation in rats.