A novel in situ forming drug delivery system for controlled parenteral drug delivery

The objective of this study was to investigate the in vitro drug (diltiazem hydrochloride and buserelin acetate) release from different in situ forming biodegradable drug delivery systems, namely polymer solutions (in situ implants) and in situ microparticle (ISM) systems. The drug release from ISM systems [poly(d,l-lactide) (PLA) or poly(d,l-lactide-co-glycolide) (PLGA)-solution dispersed into an external oil phase] was investigated as a function of the type of solvent and polymer, polymer concentration and internal polymer phase:external oil phase ratio and was compared to the drug release from in situ implant systems and microparticles prepared by conventional methods (solvent evaporation or film grinding). Upon contact with the release medium, the internal polymer phase of the ISM system solidified and formed microparticles. The initial drug release from ISM systems decreased with increasing polymer concentration and decreasing polymer phase:external oil phase ratio. The type of biocompatible solvent also affected the drug release. It decreased in the rank order DMSO>NMP>2-pyrrolidone. In contrast to the release of the low molecular weight diltiazem hydrochloride, the peptide release (buserelin acetate) was strongly dependent on the polymer degradation/erosion. One advantage of the ISM system when compared to in situ implant systems was the significantly reduced burst effect because of the presence of an external oil phase. ISM systems resulted in drug release profiles comparable to the drug release of microparticles prepared by the solvent evaporation method. Therefore, the ISM systems are an attractive alternative to existing complicated microencapsulation methods.     

Light-responsive in situ forming injectable implants for effective drug delivery to the posterior segment of the eye

ABSTRACT

Introduction: Frequent intravitreal injections are currently the preferred treatment method for diseases affecting the posterior segment of the eye. However, these repeated injections have been associated with pain, risk of infection, hemorrhages, retinal detachment and high treatment costs. To overcome these limitations, light-responsive in situ forming injectable implants (ISFIs) may emerge as novel systems providing site-specific controlled drug delivery to the retinal tissues with great accuracy, safety, minimal invasiveness and high cost efficiency.

Area covered: Complex ocular barriers, routes for drug delivery, types of injectable implants, ocular application of light and benefits of light-responsive systems are discussed with regards to challenges and strategies employed for effective drug delivery to the posterior segment of the eye. In particular, we have highlighted photoresponsive moieties, photopolymerization mechanisms and different development strategies with their limitations as well as recent advancements in the field.

Expert opinion: Biodegradable light-responsive ISFIs are promising drug delivery systems that have shown a high degree of biocompatibility with sustained drug release in a number of applications. However, their use in intravitreal drug delivery is still in the very early stages. Issues related to the biocompatibility of the photoinitiator and the elimination of photo-degraded by-products from the ocular tissues need careful consideration, not only from a chemistry standpoint, but also from a biological perspective to improve the suitability of these systems for clinical applications.     

抗肿瘤药物可注射原位凝胶系统的药理学评价

抗肿瘤药物可注射植入型水凝胶是一种用于肿瘤局部用药的新型控释系统。根据凝胶材料的不同以及各个实验室的具体条件,对该系统的药理学评价方法有许多种。这些方法大致分为3类,包括生物相容性(安全性)评价、细胞毒性(药效学)评价和药动学评价。综述该系统药理学评价方法学研究的近况,为进一步研究和应用提供参考。     

Preparation and evaluation of biopolymeric nanoparticles as drug delivery system in effective treatment of rheumatoid arthritis

Purpose

The study purposes to evaluate nanocrystalline biopolymeric nanoparticles encapsulating methotrexate and dexamethasone with high biocompatibility, enhanced therapeutic efficacy and reduced toxicity.

Methods

Chitosan nanoparticles were prepared by ionic gelation, and Methotrexate (MTX) and Dexamethasone (DEX) were loaded during the preparation and screened for their in vitro efficacy in HEK and RAW264.7 cells, ex vivo and in vivo efficacy.

Results

FTIR confirmed the involvement of phosphoric group of sTPP with amine groups of chitosan and also role of hydrogen bonding involved in the preparation of MTXCHNP and DEXCHNP. Controlled release patterns coupled with diffusion of drug were observed in two different buffers (PBS) at pH 7.4 and pH 5.8. The IC50 for MTXCHNP for HEK was 26.1 μg/ml and 7.7 μg/ml for RAW 264.7 cells. In DEXCHNP, the IC50 was 20.12 μg/ml for HEK and 7.37 μg/ml for RAW264.7 cells. Enhanced uptake of FITC-CHNP by RAW cells indicated internalization of nanoparticles by phagocytosis. The enhanced release of drug at lower pH justified increased cytotoxicity. Negligible ex-vivo hemolysis indicated the higher biocompatibility of the nanoparticles. ^99mTc-CHNP exhibited maximum absorption in blood circulation in 3 h, followed by hepatic metabolism and renal clearance. Higher in-vivo anti-arthritic activity and antioxidant activity was observed post-intraperitoneal (i.p.) injections by both MTXCHNP and DEXCHNP when compared to MTX (0.75 mg/Kg by i.p. route) and DEX (0.2 mg/Kg/i.p./daily) per se.

Conclusion

The nanocrystalline biopolymeric nanoparticles were stable, biocompatible and have potential to be administered through i.p. route with minimal toxicity and high efficacy.

     

注射用缓控释给药系统的研究进展

注射用缓控释给药系统因可延长药物的作用时间、减少注射次数、改善患者的顺应性而成为当前药剂研究的一大热点。现根据给药途径的不同，介绍了近年来注射用缓控释给药系统在静脉、肌内、皮下、鞘内及靶部位给药方面的研究状况，涉及微球、脂质体、纳米粒及原位凝胶等剂型，评价了该类制剂开发中存在的问题和潜在的医疗风险。     

Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects,and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems(TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treat...     

Myotoxicity studies of injectable biodegradable in-situ forming drug delivery systems

The objective of the study was to investigate the potential in-vitro and in-vivo myotoxicity of different in-situ forming biodegradable drug delivery systems, namely in-situ Microparticle (ISM) systems and polymer solutions (in-situ implant systems). The acute myotoxicity was evaluated in-vitro using the isolated rodent skeletal muscle model by measuring the cumulative creatine kinase (CK) efflux. For the in-vivo study, following intramuscular injection (i.m.) into male Sprague Dawley rats, the area under the plasma CK-curve was used to evaluate muscle damage. The formulations included ISM-systems [a poly (lactide)-solvent phase dispersed into an external oil phase] and poly (lactide) solutions (in-situ implant systems). Phenytoin and normal saline served as positive and negative controls, respectively. Poly (lactide) in different solvents (in-situ implant systems) resulted in 14.4-24.3 times higher CK-values compared to normal saline, indicating a high myotoxic potential. With the ISM-system, the CK-release was significantly lower, decreased with a lower polymer phase: oil phase ratio, and approached the values of normal saline at a ratio of 1:4. Bupivacaine HCl- and Buserelin acetate- containing ISM-systems resulted in significantly lower CK-levels when compared to the corresponding drug formulation in normal saline. The in-vivo studies confirmed the in-vitro data and showed good muscle compatibility of the ISM-systems.     

In situ forming parenteral drug delivery systems: an overview.

Biodegradable injectable in situ forming drug delivery systems represent an attractive alternative to microspheres and implants as parenteral depot systems. Their importance will grow as numerous proteins will lose their patent protection in the near future. These devices may offer attractive opportunities for protein delivery and could possibly extend the patent life of protein drugs. The controlled release of bioactive macromolecules via (semi-) solid in situ forming systems has a number of advantages, such as ease of administration, less complicated fabrication, and less stressful manufacturing conditions for sensitive drug molecules. For these reasons, a number of polymeric drug delivery systems with the ability to form a drug reservoir at the injection site are under investigation. Here, we review various strategies used for the preparation of in situ forming parenteral drug depots and their potential benefits/draw-backs, especially with regard to the delivery of protein drug candidates.     

萘丁美酮和吲哚美辛分别与甲氨喋呤合用治疗类风湿关节炎的不良反应

目的：比较非甾体抗炎免疫药（NSAIDS）与慢作用抗风湿病药（SAARDs)合用治疗类风湿关节炎（RA）的不良反应发生情况。方法：对萘丁美酮（NAB）＋甲氨喋呤MTX）和吲哚美辛（IND）＋MTX两组病人采用问卷方式进行调查，同时查阅病人的病历和各种化验单，资料采用Epi info软件进行统计分析。结果：两组病人治疗后的不良反应出现率除恶心和纳差的差异有显著意义外（P＜0．05），其余的不良反应出现率之间的差异均无显著意义（P＞0．05），结论：在RA治疗上常采用的NSAIDs与SAARDs合并用药中，选择性COX－2抑制剂NAB合用MTX在胃肠道的不良反应方面少于IND合用MTX。     

Drug delivery systems for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a severe immune-mediated disease characterized by chronically progressive inflammation and destruction of joints and associated structures. Significant advances in our understanding of its pathophysiology and early diagnosis have led to improved therapy and better outcome. Nevertheless, a number of details in the pathogenesis of RA are still unknown and thus the disease cannot be cured at present. Therefore, current therapy aims at accomplishing complete and long-lasting remission. However, this goal is only achieved in a small proportion of patients, and partial remission and frequent relapses are a common problem. A significant number of patients still do not respond at all to available treatments. In addition, all antirheumatic and immune-modulating drugs developed so far carry a considerable risk of adverse effects, some of which can be severe or even life threatening. This is due, at least in part, to a lack of specificity of most drugs for the target tissue, and to a high volume of distribution for systemic application, which, together with rapid clearance of most drugs, requires frequent application of high dosages. Targeted drug delivery and prolongation of bioavailability would alleviate this issue significantly. This article, therefore, reviews a selection of studies that report promising strategies for joint specific delivery of antiarthritic drugs.     

Drug delivery systems for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a severe immune-mediated disease characterized by chronically progressive inflammation and destruction of joints and associated structures. Significant advances in our understanding of its pathophysiology and early diagnosis have led to improved therapy and better outcome. Nevertheless, a number of details in the pathogenesis of RA are still unknown and thus the disease cannot be cured at present. Therefore, current therapy aims at accomplishing complete and long-lasting remission. However, this goal is only achieved in a small proportion of patients, and partial remission and frequent relapses are a common problem. A significant number of patients still do not respond at all to available treatments. In addition, all antirheumatic and immune-modulating drugs developed so far carry a considerable risk of adverse effects, some of which can be severe or even life threatening. This is due, at least in part, to a lack of specificity of most drugs for the target tissue, and to a high volume of distribution for systemic application, which, together with rapid clearance of most drugs, requires frequent application of high dosages. Targeted drug delivery and prolongation of bioavailability would alleviate this issue significantly. This article, therefore, reviews a selection of studies that report promising strategies for joint specific delivery of antiarthritic drugs.     

Emulsion forming drug delivery system for lipophilic drugs

In the recent years, there is a growing interest in the lipid-based formulations for delivery of lipophilic drugs. Due to their potential as therapeutic agents, preferably these lipid soluble drugs are incorporated into inert lipid carriers such as oils, surfactant dispersions, emulsions, liposomes etc. Among them, emulsion forming drug delivery systems appear to be a unique and industrially feasible approach to overcome the problem of low oral bioavailability associated with the BCS class II drugs. Self-emulsifying formulations are ideally isotropic mixtures of oils, surfactants and co-solvents that emulsify to form fine oil in water emulsions when introduced in aqueous media. Fine oil droplets would pass rapidly from stomach and promote wide distribution of drug throughout the GI tract, thereby overcome the slow dissolution step typically observed with solid dosage forms. Recent advances in drug carrier technologies have promulgated the development of novel drug carriers such as control release self-emulsifying pellets, microspheres, tablets, capsules etc. that have boosted the use of "self-emulsification" in drug delivery. This article reviews the different types of formulations and excipients used in emulsion forming drug delivery system to enhance the bioavailability of lipophilic drugs.     

来氟米特和甲氨蝶呤联合治疗类风湿关节炎(英文)

目的 :观察小剂量来氟米特和甲氨蝶呤联合应用治疗类风湿关节炎的疗效和安全性。方法 :64例类风湿关节炎病人随机分入 2组 ,各 32例。 2组病人于治疗前 1wk停用非甾体类抗炎镇痛药。试验开始时来氟米特 +甲氨蝶呤组 (Lef +MTX)给予来氟米特 2 0mg ,po ,qd +甲氨蝶呤 (MTX) 7.5mg po ,qw ,服 4wk后来氟米特 10mg ,po ,qd +MTX 7.5mg ,po ,qw ;MTX组服甲氨蝶呤 15mg ,po ,qw ,2组均以 2 4wk为一个疗程。治疗前、治疗后wk 12 ,2 4均做体检及实验室检查 ;治疗前后摄双手正位片。结果 :Lef +MTX组显效 88%( 2 8/32例 ) ,MTX组 38%( 12 /32例 )。Lef +MTX组不良反应 4例占 12 %,主要为皮疹、恶心 ;MTX组 14例占 4 3%,主要为恶心、呕吐、口腔溃疡、脱发、ALT升高、心悸、月经不调等。结论 :来氟米特与甲氨蝶呤联合治疗起效快、疗效佳、不良反应率低。     

A novel, simple method to simulate gelling process of injectable biodegradable in situ forming drug delivery system based on determination of electrical conductivity

The purpose of the present study was to develop a novel, simple and determination-of-electrical-conductivity-based method to trace the gelling process of injectable biodegradable in situ forming organogels after administration. The electrical conductivity of pH 7.4 PBS solution with different amount of N-methyl-2-pyrrolodone (NMP) and drug-free organogel formulation contained 0.6mL NMP were determined at 37 °C, respectively. The electrical conductivity of PBS solution was linearly proportional to the amount of NMP. Organogel contained 0.6 mL NMP in PBS solution showed a descending of electrical conductivity as time runs, while the value of electrical conductivity was almost a constant at 7.58 ms/cm after 110 min, which was nearly equaled to the electrical conductivity of 0.6 mL NMP in PBS solution (7.59 ms/cm). This data indicated that the diffusion of NMP caused the descending of system electrical conductivity and NMP completely diffused from organogel after 110 min, which led to the constant electrical conductivity. Meanwhile, photographs of organogel showed that the gel formed from periphery to center gradually, and totally formed after 110 min. The diffusion terminal point of NMP from organogel could be perfectly anticipated and controlled by this method. Consequently, this electrochemical method had visually simulated the gelling process and located gelling time of organogel in medium solution by measuring variation of electrical conductivity.     

Antitumor effect of an injectable in-situ forming drug delivery system composed of a novel tissue adhesive containing doxorubicin hydrochloride.

Our group has developed a novel tissue adhesive composed of biomacromolecules and organic acid derivatives which have good biocompatibility and exhibit high bonding strength to living tissues. We propose to use this tissue adhesive for in-situ forming drug delivery system (DDS) for cancer chemotherapy. In a previous work, we had prepared a novel in-situ forming DDS composed of human serum albumin (HSA) and tartaric acid derivative (TAD) containing doxorubicin hydrochloride (DOX), and we had demonstrated an in vitro release profile of DOX from HSA-TAD gel for approximately up to 100h. Here, we report on antitumor effect of this injectable in-situ forming DDS. Local injection of DOX by the HSA-TAD was administered to human colon carcinoma (WiDr) implanted subcutaneously onto the immunodeficient mouse. The results of the in vivo experiments showed that the presence of DOX in blood of mice was detectable for up to 3days, and that the tumor volume was effectively minimized with injection of HSA-TAD containing DOX. The in-situ forming DDS with the novel tissue adhesive containing DOX, therefore, is a useful technique for cancer chemotherapy.     

托珠单抗联合甲氨蝶呤治疗类风湿关节炎血液系统不良反应信号检测

目的检测托珠单抗联合甲氨蝶呤治疗类风湿关节炎导致的血液系统不良反应信号,以期为临床联合用药提供参考。方法用基线模型对美国食品和药物管理局不良事件报告系统数据库进行挖掘,并采用SAS9.1.3软件对可疑信号进行统计学检验,以确定信号是否有统计学意义。结果在进行分析的3 109 420份不良反应报告中,加法模型检测到托珠单抗联合甲氨蝶呤致白细胞减少的发生率增加的信号,未发现红细胞和血小板减少的风险信号;乘法模型的检测结果均为阴性。经统计学检验,"托珠单抗-甲氨蝶呤-白细胞减少"组合无统计学意义(加法模型P=0.538 6,乘法模型P=0.419 3)。结论采用基线模型未挖掘出药物正性交互作用的风险信号,提示与单药相比,联合应用托珠单抗和甲氨蝶呤不会增加血液系统的安全风险。     

Formulation and evaluation of an in situ gel forming system for controlled delivery of triptorelin acetate

The novel physical hydrogels composed of chitosan or its water soluble derivatives such as carboxymethyl chitosan (CMCh) and sodium carboxymethyl chitosan (NaCMCh) and opened ring polyvinyl pyrrolidone (OP-PVP) were used as a controlled delivery system for triptorelin acetate, a luteinizing-releasing hormone agonist. The in situ gel forming system designed according to physical interactions such as chains entanglements and hydrophilic attractions especially h-bonds of chitosan and/or NaCMCh and OR-PVP. In order to increase in situ gel forming rate the chitosan microspheres prepared through spray drying technique. The chitosan or NaCMCh/OR-PVP blends prepared at different ratios (0.05, 0.10, 0.12, 0.16, 0.20 and 0.24) and suspended in sesame oil as non-aqueous vehicle at different solid content (10-30%). The suitable ratio of polymers with faster in situ gel forming rate was selected for in vivo studies. The gel formation and drug release from the system was evaluated both in vitro and in vivo. In vitro and in vivo results were compared with Diphereline SR 3.75mg, a commercially available controlled delivery system of triptorelin. In vitro release studies showed a sustained release profile for about 192h with first order kinetics. In vivo studies on male rats by determination of serum testosterone were confirmed the acceptable performance of in situ gel forming system compared with Diphereline SR in decreasing the serum testosterone level for 35days, demonstrating the potential of the novel in situ gel forming system for controlled delivery of peptides.     

Direct gene delivery strategies for the treatment of rheumatoid arthritis

Gene therapy offers a novel and innovative approach to the delivery of therapeutic proteins to the joints of patients with arthritis. Several viral vectors, including adenovirus, adeno-associated virus, retrovirus and herpes simplex virus, are capable of delivering exogenous cDNAs to the synovial lining, enabling effective levels of intra-articular transgene expression following direct injection to the joint. The expression of certain gene products has proven to be sufficient to inhibit the progression of disease in animals with experimental arthritis. Non-viral methods of gene transfer, however, are less satisfactory, and are limited by toxicity and transience of expression. Although the principle of direct gene delivery to the joint has been demonstrated, maintaining persistent intra-articular transgene expression remains a challenge.     

Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis

Methotrexate administered weekly in low doses is a mainstay in the therapy of rheumatoid arthritis. Although originally developed as a folate antagonist for the treatment of cancer, its mechanism of action in the therapy of rheumatoid arthritis remains less clear. Several mechanisms have been proposed including inhibition of T cell proliferation via its effects on purine and pyrimidine metabolism, inhibition of transmethylation reactions required for the prevention of T cell cytotoxicity, interference with glutathione metabolism leading to alterations in recruitment of monocytes and other cells to the inflamed joint, and promotion of the release of the endogenous anti-inflammatory mediator adenosine. These mechanisms of action and the role of methotrexate in the suppression of rheumatoid arthritis are reviewed.     

In situ forming hydrogels based on chitosan for drug delivery and tissue regeneration

In situ forming hydrogels with simple sol–gel transition are more practicable as injectable hydrogels for drug delivery and tissue regeneration. State-of-the-art in situ gelling systems can easily and efficiently be formed by different mechanisms in situ. Chitosan is a kind of natural polysaccharide that is widely exploited for biomedical applications due to its good biocompatibility, low immunogenicity and specific biological activities. Chitosan-based in situ gelling systems have already gained much attention as smart biomaterials in the development of several biomedical applications, such as for drug delivery systems and regeneration medicine. Herein, we review the typical in situ gelling systems based on chitosan and mechanisms involved in hydrogel forming, and report advances of chitosan-based in situ gels for the applications in drug delivery and tissue regeneration. Finally, development prospects of in situ forming hydrogels based on chitosan are also discussed in brief.