Development of pulsatile systems for targeted drug delivery of celecoxib for prophylaxis of colorectal cancer

The aim of the present study was to formulate fast release enteric-coated tablets for drug delivery to the colon. Two different approaches were used for the preparation of these tablets. The first included making use of superdisintegrant (SD) in the tablet. The amount of super disintegrant (cross-linked PVP) in the tablet and the coat weight were varied to formulate a suitable time-controlled release system, that would provide colon-specific drug delivery. The second approach consisted of development of osmogen-based tablets for drug delivery into the tracts of the colon. Two different osmogens, sodium chloride and potassium chloride, were used. These also were coated at different coat levels. Celecoxib was used as a model drug. In vitro drug release studies showed that superdisintegrants were more effective in showing burst effect in the tablets and therefore showed a rapid drug release as compared with osmogens, which would show a sustained drug release all through the colon. Osmotic tablets were formulated making use of a high concentration of osmogen sodium chloride (OM-SC) and potassium chloride (OM-KC) were further enteric-coated. These also were found to be useful in providing a sustained delivery of nearly 80-90% of the drug into the colonic region. The coat weight required in these tablets for protection in the upper gastrointestinal conditions varied from 9.69% in OM-KC tablets to 4.65% in OM-SC tablets.     

In vivo evaluation of guargum-based colon-targeted oral drug delivery systems of celecoxib in human volunteers.

The present study involved the in vivo evaluation of orally administered guar gum-based colon-targeted tablet formulations of celecoxib (colon-targeted tablet-20 or colon-targeted tablet-30) as compared with an immediate release capsule in 15 human volunteers. Blood samples were obtained at different time intervals and the plasma concentration of celecoxib was estimated by reversed phase HPLC. The immediate release capsules of celecoxib might have disintegrated very fast in GI tract and absorbed quickly from stomach and small intestine thereby producing peak plasma concentration (Cmax of 478 +/- 57 ng/ml) within 3.8 +/- 0.1 h (Tmax). Though celecoxib could be seen in plasma after oral administration of colon-targeted tablet-20 or colon-targeted tablet-30 between 1 and 2 h, low levels of drug were observed upto 8 h resulting in peak concentration (Cmax) of 78 +/- 6 ng/ml or 88 +/- 15 ng/ml at 10.5 +/- 1.9 h or 13.5 +/- 1.4 h (Tmax) respectively, whereas the immediate release capsules produced peak plasma concentration (Cmax) of 478 +/- 57 ng/ml at 3.8 +/- 0.1 h (Tmax). Colon-targeted tablets showed decreased AUC(0-infinity), Cmax and absorption rate constant, prolonged absorption time (ta), and increased t1/2 in comparison with the immediate release capsules. The results of the study indicated that the guar gum-based colon-targeted tablets of celecoxib did not release the drug significantly in stomach and small intestine, but delivered to the colon resulting in a slow absorption of the drug and making it available for local action in the colon.     

Cutting-edge technologies in colon-targeted drug delivery systems

Oral colon-targeted drug delivery systems have gained enormous attention among researchers in the last two decades. The significance of this site-specific drug delivery system can be measured by its usefulness for delivering a variety of therapeutic agents, both for the treatment of local diseases or for systemic therapies. With the arrival of newer innovations, a large number of breakthrough technologies have emerged for targeting a drug molecule to the colon. Researchers have attempted various approaches in the development of these formulation technologies, such as pH-dependent, time-dependent and microflora-activated systems. Recently, a number of approaches have been proposed that utilize a novel concept of di-dependent drug delivery systems, that is, the systems in which the drug release is controlled by two factors: pH and time, and pH and microflora of the colon. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the formulation technologies that have been developed for attaining colon-specific drug delivery.     

Cutting-edge technologies in colon-targeted drug delivery systems

Oral colon-targeted drug delivery systems have gained enormous attention among researchers in the last two decades. The significance of this site-specific drug delivery system can be measured by its usefulness for delivering a variety of therapeutic agents, both for the treatment of local diseases or for systemic therapies. With the arrival of newer innovations, a large number of breakthrough technologies have emerged for targeting a drug molecule to the colon. Researchers have attempted various approaches in the development of these formulation technologies, such as pH-dependent, time-dependent and microflora-activated systems. Recently, a number of approaches have been proposed that utilize a novel concept of di-dependent drug delivery systems, that is, the systems in which the drug release is controlled by two factors: pH and time, and pH and microflora of the colon. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the formulation technologies that have been developed for attaining colon-specific drug delivery.     

Advances in colon-targeted nano-drug delivery systems: challenges and solutions

Archives of Pharmacal Research - Nano-drug delivery systems (NDDS) for colon-targeted drug delivery are an active area of research on local diseases affecting the colon, such as ulcerative colitis,...     

Luminal delivery and dosing considerations of local celecoxib administration to colorectal cancer.

The purpose of this study was to develop a biodegradable drug platform composed of chitosan and guar gum and to explore the possibility of using it for local adjuvant or neoadjuvant therapy of colorectal cancer. Celecoxib (Cx), a chemopreventative drug for familial adenomatous polyposis (FAP) and under trial for reducing post surgical colorectal malignancies, was selected as a model drug for this topical system because of the contraindications that are associated with its systemic administration. Films made of chitosan (Ct) and guar gum (GG) were prepared, characterized for equilibrium swelling, mucoadhesion, in vitro and in vivo degradation and loaded with Cx. Short term dosing studies in vitro were performed in the HT-29 colon carcinoma cell line that was incubated with Cx using the MTT test to assess IC50. The impact of a single high dose was evaluated and compared with a repeating low-dose regimen. In vivo dosing experiments with Cx were performed in the perfused intestine of the anaesthetized rat. Measuring tissue LDH assessed epithelium injury. Mechanical, mucoadhesion and in vitro degradation of the polysaccharide films were dictated by manipulating the ratios of Ct and GG. The addition of rat cecal contents to the dissolution medium increased the total Cx released from those films containing high amounts of GG. MTT reduction, a measure of cell proliferation, diminished as a function of increasing drug concentration and exposure time in the HT-29 cell line studies. Local high concentrations of Cx were shown to impede the proliferation of cancer cells directly, while chemoprevention has been demonstrated with low Cx doses. Healthy cells were shown to be sensitive to high Cx doses. Maximum therapeutic efficiency in the context of minimal healthy tissue exposure would thus be predicted utilizing a local delivery system such as the proposed adhesive, biodegradable polysaccharide composites.     

Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer

Hyaluronic acid–coupled chitosan nanoparticles bearing oxaliplatin (L-OHP) encapsulated in Eudragit S100–coated pellets were developed for effective delivery to colon tumors. The in vitro drug release was investigated using a USP dissolution rate test paddle-type apparatus in different simulated gastrointestinal tract fluids. In therapeutic experiments the pellets of free drug, and hyaluronic acid–coupled and uncoupled chitosan nanoparticles bearing L-OHP were administered orally at the dose of 10 mg L-OHP/kg body weight to tumor-bearing Balb/c mice. In vivo data showed that hyaluronic acid–coupled chitosan nanoparticles delivered 1.99 ± 0.82 and 9.36 ± 1.10 μg of L-OHP/g of tissue in the colon and tumor, respectively after 12 hours, reflecting its targeting potential to the colon and tumor. These drug delivery systems show relatively high local drug concentration in the colonic milieu and colonic tumors with prolonged exposure time, which provides a potential to enhance antitumor efficacy with low systemic toxicity for the treatment of colon cancer.From the Clinical EditorIn this study, a nanoparticle system was developed to deliver oxaliplatin to colorectal tumors. In murine models, the drug delivery system showed relatively high local drug concentration in colonic tumors with prolonged exposure time, which provides a potential for enhanced antitumor efficacy with low systematic toxicity.     

Studies on the development of colon targeted oral drug delivery systems for ornidazole in the treatment of amoebiasis

The aim of the present study is to develop colon-targeted drug delivery sytems for ornidazole using guar gum as a carrier. The core formulation containing ornidazole was directly compressed. Compression-coated tablets of ornidazole containing various proportions of guar gum in the coat were prepared. All the formulations were evaluated for hardness and drug content uniformity and were subjected to in vitro drug release studies. The amount of ornidazole released from tablets at different time intervals was estimated by the HPLC method. The compression-coated formulations released less than 8% of ornidazole in the physiological environment of stomach and small intestine. The compression-coated tablets with 85%, 75%, and 65% of guar gum coat released about 21%, 38%, and 73% of ornidazole, respectively, in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that compression-coated ornidazole tablets with either 65% (OLV-65) or 75% (OLV-75) of guar gum coat are most likely to provide targeting of ornidazole for local action in the colon owing to its minimal release of the drug in the first 5 hr. The ornidazole compression-coated tablets showed no change in physical appearance, drug content, or in dissolution pattern after storage at 40°C/75% relative humidity for 6 months.     

Pharmacokinetic evaluation of guar gum-based colon-targeted drug delivery systems of tinidazole in healthy human volunteers

The aim of the present investigation was to determine the in vivo availability of guar gum-based colon-targeted tablets of tinidazole in comparison with immediate release tablets of tinidazole in human volunteers. Six healthy volunteers participated in the study, and a cross-over design was used. The plasma concentration of tinidazole was estimated by HPLC. The pharmacokinetic parameters were calculated from the plasma concentration of tinidazole versus time data. The immediate release tablets of tinidazole produced a peak plasma concentration (C_max of 3239 ± 428 ng/ml) at 1.04 ± 0.32 hr (T_max), whereas colon-targeted tablets produced peak plasma concentration (C_max of 2158 ± 78 ng/ml) at 14.9 ± 1.6 hr. The delayed T_max, decreased C_max, and K_a, and unaltered bioavailability and elimination half-life of tinidazole from guar gum-based colon-targeted tinidazole tablets, in comparison with the immediate tablets, indicated that the drug was not released in the stomach and small intestine but delivered to the colon. Slow absorption of the drug from the less absorptive colon might result in the availability of the drug for local action in the colon. The guar gum-based colon-targeted tablets of tinidazole may be useful in providing an effective and safe therapy of intestinal amoebiasis.     

低剂量阿司匹林预防结直肠癌的研究进展

阿司匹林是一种水杨酸类非甾体抗炎药,临床上主要用于急性冠脉综合征(ACS)的一级预防。近年来,越来越多研究显示,阿司匹林能够降低多种恶性肿瘤的发生风险甚至显著减低病人的死亡率。美国预防服务工作组(USPSTF)发布一项建议,将低剂量阿司匹林列为成人结直肠癌等多种肿瘤的二级预防措施。该文旨在对阿司匹林预防结直肠癌及其作用机制的研究进行综述。     

Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib

Celecoxib is a hydrophobic and highly permeable drug belonging to class II of biopharmaceutics classification system. Low aqueous solubility of celecoxib leads to high variability in absorption after oral administration. Cohesiveness, low bulk density and compressibility, and poor flow properties of celecoxib impart complications in it's processing into solid dosage forms. To improve the solubility and bioavailability and to get faster onset of action of celecoxib, the self-microemulsifying drug delivery system (SMEDDS) was developed. Composition of SMEDDS was optimized using simplex lattice mixture design. Dissolution efficiency, t(85%), absorbance of diluted SMEDDS formulation and solubility of celecoxib in diluted formulation were chosen as response variables. The SMEDDS formulation optimized via mixture design consisted of 49.5% PEG-8 caprylic/capric glycerides, 40.5% mixture of Tween20 and Propylene glycol monocaprylic ester (3:1) and 10% celecoxib, which showed significantly higher rate and extent of absorption than conventional capsule. The relative bioavailability of the SMEDDS formulation to the conventional capsule was 132%. The present study demonstrated the suitability of mixture design to optimize the compositions for SMEDDS. The developed SMEDDS formulations have the potential to minimize the variability in absorption and to provide rapid onset of action of celecoxib.     

In vivo evaluation of guar gum-based colon-targeted drug delivery systems of ornidazole in healthy human volunteers

The aim of the present study was to find the in vivo performance of guar gum-based colon-targeted tablets of ornidazole (dose 250 mg) in comparison with an immediate release tablet of ornidazole (250 mg) in human volunteers. Six healthy volunteers participated in the study, and a cross over design was followed. The plasma concentration of ornidazole was estimated by HPLC. The immediate release tablets of ornidazole produced peak plasma concentration (Cmax of 2171.33+/-278.15 ng/ml) at 2.91+/-0.14 h (Tmax) whereas colon-targeted tablets produced peak plasma concentration (Cmax of 1716.66+/-125.83 ng/ml) at 11.91+/-0.14 h. The delayed Tmax, decreased Cmax, and decreased ka of ornidazole from guar gum-based colon-targeted ornidazole tablets, in comparison with the immediate tablets, indicated that the drug was not released in stomach and small intestine, but targeted to colon. Slow absorption of ornidazole from the less absorptive colon might result in the availability of drug for local action in the colon.     

Preparation and characterization of nanocapsules for colon-targeted drug delivery system

Context: Nanoparticles for colon-specific drug delivery system are known for their specific accumulation in the inflamed tissue in the colon and may therefore allow a selective delivery to the site of inflammation for the treatment of inflammatory bowel disease (IBD).

Objective: The objective of this study was to formulate and evaluate nanocapsules (NC), an oral system designed to achieve site-specific and instant drug release in colon for effective treatment of IBD.

Materials and methods: Prednisolone (PD), a typical glucocorticoid, has been widely used for the treatment of IBD. In this study, nanoprecipitation method was used to prepare polymeric NC of PD with pH responsive polymer Eudragit S100. The effect of several formulation variables such as surfactant, oil, and polymer on the PD-NC properties (average size, drug release rate, and drug entrapment) was investigated. In vitro drug release study was done by changing pH method and an in vivo study on rat was done to ascertain efficiency of PD-NC to release drug specifically in colon.

Results and discussion: The optimized formulations lead to the preparation of PD-NC with a mean size of 567.87?nm, high encapsulation efficiency of 90.21%. In vitro studies reveal that NC releases the drug after 4.5-h lag time corresponding to time to reach colonic region, and in vivo studies show that NC release drug after 3-h lag time in rat corresponds to arrival in colon.

Conclusion: The above NC formulation of PD is the targeted drug to the colon and may provide effective way of treatment of colonic disease.     

Pharmacokinetic evaluation of guar gum-based colon-targeted oral drug delivery systems of metronidazole in healthy volunteers.

The present study was carried out to find the in vivo performance of guar gum-based colon-targeted tablets of metronidazole as compared to an immediate release tablets in human volunteers. Six healthy volunteers participated in the study and a crossover design was used. Blood samples were obtained at different time intervals and the plasma concentration of metronidazole was estimated by reverse phase HPLC. The immediate release tablets of metronidazole produced peak plasma concentration (Cmax of 2990 +/- 574.6 ng/mL) within 2.8 +/- 0.6 h. On oral administration of colon-targeted tablets, metronidazole started appearing in the plasma between 5 h and 8 h, and reached the peak concentration (Cmax of 1940.0 +/- 528.4 ng/mL) at 11.1 +/- 2.1 h (Tmax). The AUC(0-infinity) and t(1/2) of metronidazole were unaltered on administering the drug as a colon-targeted tablet indicating that the extent of absorption and elimination were not affected by targeting the drug to the colon. However, colon-targeted tablets showed delayed tmax and absorption time (ta), decreased Cmax and decreased absorption rate constant as compared to immediate release tablets. This in turn indicated that metronidazole was delivered to the colon resulting in a slow absorption of the drug and making it available for local action in the colon.     

Ferroptosis-based nano delivery systems targeted therapy for colorectal cancer: Insights and future perspectives

There are limited options for patients who develop liver metastasis from colorectal cancer (CRC), the leading cause of cancer-related mortality worldwide. Emerging evidence has provided insights into iron deficiency and excess in CRC. Ferroptosis is an iron-dependent form of programmed cell death characterized by aberrant iron and lipid metabolism, which play crucial roles in tumorigenesis, tumor progression, and treatment options. A better understanding of the underlying molecular mechanism of ferroptosis has shed light on the current findings of ferroptosis-based nanodrug targeting strategies, such as driving ferroptosis in tumor cells and the tumor microenvironment, emerging combination therapy and against multidrug resistance. Furthermore, this review highlights the challenge and perspective of a ferroptosis-driven nanodrug delivery system for CRC-targeted therapy.     

Effects of absorption promoters on insulin absorption through colon-targeted delivery

The aim of this study were to investigate the effect of sodium glycocholate (GC-Na) as an absorption promoter and the effects of the co-administration of GC-Na and various absorption promoters on orally administered insulin absorption utilizing a colon-targeted delivery system. The system containing insulin and GC-Na (CDS) was administered to dogs, and plasma glucose and insulin levels were then measured at 24h after administration. For CDS, the C(max) in plasma glucose level was significantly higher than a reference formulation without GC-Na. The pharmacological availability for CDS was not significantly higher than the reference formulation. In contrast, CDS with poly(ethylene oxide) as a gelling agent (CDSP) showed prolonged hypoglycemia effects. The pharmacological availability was 5.5% and significantly different from the reference formulation. The absolute bioavailability for CDS was 0.25%, and for CDSP it was 0.42%. Consequently, the results of this study demonstrated that colon-specific delivery of insulin with GC-Na was more effective in increasing hypoglycemic effects after oral administration, and the combination of GC-Na and poly(ethylene oxide) tended to prolong the colonic absorption of insulin and might be more effective for improvement of orally administered insulin absorption utilizing the colon-targeted delivery system.     

Nanoparticle-based vaginal drug delivery systems for HIV prevention

Importance of the Field: Several strategies are being investigated for the prevention of heterosexual transmission of HIV. Of these, topical vaginal drug delivery systems, microbicides, are being actively pursued. HIV prevention by means of a topical microbicide has several drug delivery challenges. These challenges include the vaginal mucosal barriers and potential degradation of the drugs in the vaginal lumen due to pH and enzymes present. Also, new drugs being evaluated as microbicides have specific mechanisms of action, which in some cases require drug targeting to a specific site of action. Nanoparticles provide a delivery strategy for targeted or controlled delivery to the vagina which can be applied in the field of HIV prevention.

Areas covered in the review: This review summarizes nanoparticulate systems and their use in mucosal delivery to date. The sexual transmission of HIV along with the various targets to prevent transmission are discussed as well as the potential opportunities, challenges and advantages in using a nanoparticle-based approach for microbicidal drug delivery.

What the reader will gain: This review provides a general understanding of vaginal drug delivery, its challenges, and nanoparticulate delivery systems. Additionally, insight will be gained as to the limited existing application of this technology to the field of HIV prevention.

Take home message: To date, few studies have been published that exploit nanoparticle-based microbicidal delivery to the vagina. The use of nanoparticles for vaginal drug delivery provides an approach to overcome the existing barriers to success.     

siRNA delivery systems for cancer treatment

With increasing knowledge on the molecular mechanisms of endogenous RNA interference, small interfering RNAs (siRNAs) have been emerging as innovative nucleic acid medicines for treatment of incurable diseases such as cancers. Although several siRNA candidates for the treatment of ocular and respiratory diseases are undergoing clinical trials, there are challenges inherent in the further development of siRNAs for anti-cancer therapeutics, because systemic administration will be required in most cases. In addition to nonspecific off-target and immune stimulation problems, appropriate delivery remains a major hurdle. The technologies developed for delivery of nucleic acid medicines such as plasmid DNA and antisense oligonucleotides have paved the way to rapid progress for in vivo delivery of siRNAs. Here, we review various in vivo delivery strategies including chemical modification, conjugation, lipid-based techniques, polymer-based nanosystems, and physical methods. Moreover, the current progress in siRNA delivery systems for gynecologic, liver, lung, and prostate cancers is discussed.