Film coated tablets (ColoPulse technology) for targeted delivery in the lower intestinal tract: influence of the core composition on release characteristics

The design of a film coating technology which allows a tablet to deliver the drug in the ileocolonic segment would offer new treatment possibilities. The objective is to develop a platform technology that is suitable for a broad range of drug compounds. We developed a coated tablet with a delayed, pulsatile release profile based on a pH-sensitive coating technology (ColoPulse). The production process was validated, and the effect of core composition on the in vitro release and water uptake investigated. The release profile of the standard tablet core composition, based on the use of cellulose as a filler, was independent of the coat thickness in a range of 9.0-13.2?mg/cm(2). The release profile of a coated tablet was strongly influenced when cellulose was partly replaced by the model substance glucose (loss of sigmoidal release), citric acid (stabilization), sodium bicarbonate (destabilization) or sodium benzoate (destabilization). The film coating takes up water when below the pH-threshold. However, this did not cause early disintegration of the coating. The ColoPulse technology is successfully applied on tablets. The in vitro release characteristics of the coated tablets are influenced by the composition of the core.     

结肠定位释药双氯芬酸钠包衣片体内外相关性

目的研制时间依赖型口服结肠定位释药双氯芬酸钠包衣片。方法用释放度测定法研究双氯芬酸钠包衣片体外释放行为 ,用HPLC法测定包衣片在家犬体内的血药浓度 ,并计算出相关参数 ,进行体内外相关性考察。结果体外平均延迟释放时间为 4～ 5h时 ,体内平均时滞为 3～ 6h ,达到预期结果。结论本文研制的双氯芬酸钠片有进一步开发的价值     

Exploiting gastrointestinal bacteria to target drugs to the colon: an in vitro study using amylose coated tablets

The bacterial substrate amorphous amylose, in the form of a film coating, provides a means of delivering drugs to the colon. This coating has traditionally been applied to multi-unit systems, in part because of the small size and divided nature of this type of dosage form, which provides a large surface area for enzymatic attack and drug release. The present study was conducted to explore the utility of the coating for colonic targeting of single unit tablet systems. Amylose was combined with the water-insoluble polymer ethylcellulose, which acts as a structuring agent, in different proportions to produce film coatings of various thicknesses for application to mesalazine (mesalamine or 5-aminosalicylic acid)-containing tablets. Drug release from the coated products was assessed under pH dissolution conditions resembling the stomach and small intestine, and also in conditions simulating the colon using a batch culture fermenter inoculated with human faecal bacteria. The rate and extent of drug release was related to the ratio of amylose to ethylcellulose in the film and the thickness of the coating. Increasing the proportion of ethylcellulose in the film and/or the thickness of the coating depressed the rate of drug release in the conditions of the upper gastrointestinal tract. Drug release from the coated products was accelerated in the fermentation environment of the colon. This is attributed to bacterial digestion of the amylose component of the film coat producing pores for drug diffusion. This work indicates that amylose coated tablet formulations are promising vehicles for drug delivery to the colon.     

中药结肠靶向给药系统研究进展

目的对结肠靶向给药(CTDD)系统的相关进展全面综述,探讨其今后的发展方向,为研究人员提供参考与依据。方法查阅国内外19种期刊25篇相关文献,并进行分析、归纳。结果中药CTDD系统包括pH依赖型、时间依赖型、微生物酶解型、生物黏附型、压力依赖型、脉冲型和联合应用型。结论中药CTDD具有广阔的应用前景,但中药指标成分、体内评价等方面的研究还需加强。     

Mechanisms of drug release in pH-sensitive micelles for tumour targeted drug delivery system: A review

During the past decades, chemotherapy has been regarded as the most effective method for tumor therapy, but still faces significant challenges, such as poor tumor selectivity and multidrug resistance. The development of targeted drug delivery systems brings certain dramatic advantages for reducing the side effects and improving the therapeutic efficacy. Coupling a specific stimuli-triggered drug release mechanism with these delivery systems is one of the most prevalent approaches for targeted therapy. Among these approaches, pH-sensitive micelles are regarded as the most general strategy with advantages of increasing solubility of water-insoluble drugs, pH-sensitive release, high drug loading, etc.This review will focus on the potential of pH-sensitive micelles in tumor therapy, analyze four types of drug-loaded micelles and mechanisms of drug release and give an exhaustive collection of recent investigations. Sufficient understanding of these mechanisms will help us to design more efficient pH-sensitive drug delivery system to address the challenges encountered in targeted drug delivery systems for tumor therapy.     

Influence of various lipid core on characteristics of SLNs designed for topical delivery of fluconazole against cutaneous candidiasis

Dermal delivery of fluconazole (FLZ) is still a major limitation due to problems relating to control drug release and achieving therapeutic efficacy. Recently, solid lipid nanoparticles (SLNs) were explored for their potential of topical delivery, possible skin compartments targeting and controlled release in the skin strata. The retention and accumulation of drug in skin is affected by composition of SLNs. Hence, the aim of this study was to develop FLZ nanoparticles consisted of various lipid cores in order to optimize the drug retention in skin. SLNs were prepared by solvent diffusion method and characterized for various in vitro and in vivo parameters. The results indicate that the SLNs composed of compritol 888 ATO (CA) have highest drug encapsulation efficiency (75.7?±?4.94%) with lower particle size (178.9?±?3.8?nm). The in vitro release and skin permeation data suggest that drug release followed sustained fashion over 24?h. The antifungal activity shows that SLNs made up of CA lipid could noticeably improve the dermal localization. In conclusion, CA lipid based SLNs are represents a promising carrier means for the topical treatment of skin fungal infection as an alternative to the systemic delivery of FLZ.     

Assessment of the in‐vivo drug release from pellets film‐coated with a dispersion of high amylose starch and ethylcellulose for potential colon delivery

Objectives The aim of this study was to test the ability of a colon targeting system comprising pellets film‐coated with a dispersion of high amylose starch (Hylon VII) and ethylcellulose (Surelease) (1 : 2 w/w) to deliver a model drug (5‐aminosalicylic acid; 5‐ASA) in vivo into the colon of rabbits. An uncoated pellet formulation was used as a control. Methods Six New Zealand female rabbits, approximately 2 kg, were randomly divided into two groups. Pellet formulations containing 50 mg/kg of 5‐ASA were filled into hard gelatin capsules size 4, and were administered orally using a cannula. The rabbits were fasted for 12 h before, and throughout, the study but had free access to water. Blood samples were collected, through a catheter inserted into the marginal vein of the ear, at pre‐determined times and the plasma analysed by a validated HPLC method with fluorescence detection. Results Analysis of the 5‐ASA plasma levels following administration of the uncoated pellets showed a C_max of 2.38 ± 0.49 μg/ml at 2 h post administration confirming that this system released the drug at an unspecific site, most likely in the rabbits' stomach and proximal small intestine. On the other hand, the coated formulation showed a delayed drug absorption (C_max 0.22 ± 0.19 μg/ml and t_max of 8 h), suggesting that the coating is able to prevent drug release in the stomach and small intestine, but allowing drug release in the colon. The coated pellets were retrieved from the rabbits' faeces after the 24‐h study. They had a drug content of < 40%, suggesting that the film‐coating had been digested by the bacterial amylases of the colon and the drug was released specifically in the colon of the rabbits. Conclusions Results from this study showed that the proposed drug delivery system has the potential to deliver drugs specifically into the colon.     

Development of a mucoadhesive nanoparticulate drug delivery system for a targeted drug release in the bladder

Purpose

Purpose of the present study was the development of a mucoadhesive nanoparticulate drug delivery system for local use in intravesical therapy of interstitial cystitis, since only a small fraction of drug actually reaches the affected site by conventional treatment of bladder diseases via systemic administration.

Methods

Chitosan-thioglycolic acid (chitosan-TGA) nanoparticles (NP) and unmodified chitosan NP were formed via ionic gelation with tripolyphosphate (TPP). Trimethoprim (TMP) was incorporated during the preparation process of NP. Thereafter, the mucoadhesive properties of NP were determined in porcine urinary bladders and the release of TMP among simulated conditions with artificial urine was evaluated.

Results

The particles size ranged from 183 nm to 266 nm with a positive zeta potential of +7 to +13 mV. Under optimized conditions the encapsulation efficiency of TMP was 37%. The adhesion of prehydrated chitosan-TGA NP on the urinary bladder mucosa under continuous urine voiding was 14-fold higher in comparison to unmodified chitosan NP. Release studies indicated a more sustained TMP release from covalently cross linked particles in comparison to unmodified chitosan-TPP NP over a period of 3 h in artificial urine at 37 °C.

Conclusion

Utilizing the method described here, chitosan-TGA NP might be a useful tool for local intravesical drug delivery in the urinary bladder.     

Polymeric nanocarriers as stimuli-responsive systems for targeted tumor (cancer) therapy: Recent advances in drug delivery

In the last decade, considerable attention has been devoted to the use of biodegradable polymeric materials as potential drug delivery carriers. However, bioavailability and drug release at the disease site remain uncontrollable even with the use of polymeric nanocarriers. To address this issue, successful methodologies have been developed to synthesize polymeric nanocarriers incorporated with regions exhibiting a response to stimuli such as redox potential, temperature, pH, and light. The resultant stimuli-responsive polymeric nanocarriers have shown tremendous promise in drug delivery applications, owing to their ability to enhance the bioavailability of drugs at the disease site. In such systems, drug release is controlled in response to specific stimuli, either exogenous or endogenous. This review reports recent advances in the design of stimuli-responsive nanocarriers for drug delivery in cancer therapy. In particular, the synthetic methodologies investigated to date to introduce different types of stimuli-responsive elements within the biomaterials are described. The sufficient understanding of these stimuli-responsive nanocarriers will allow the development of a better drug delivery system that will allow us to solve the challenges encountered in targeted cancer therapy.     

Peroral delivery systems based on superporous hydrogel polymers: release characteristics for the peptide drugs buserelin, octreotide and insulin

Novel peroral peptide drug delivery systems based on superporous hydrogel (SPH) and SPH composite (SPHC) have recently been developed in our laboratory. In this report the following issues were studied: release of the peptide drugs buserelin, octreotide and insulin from SPH and SPHC polymers and the developed delivery systems, stability of these peptides during the release and the integrity of insulin in the polymeric matrix of SPHC. Release studies from SPH and SPHC polymers revealed that buserelin, octreotide and insulin were released almost completely from the polymers. Peptide release rates from SPH were faster than from SPHC, due to the more porous structure of SPH polymer. All peptides studied in contact with SPHC polymer were stable under different environmental conditions (ambient temperature, 37 °C, light and darkness and at pH values 3.2 and 7.2). FTIR studies demonstrated that no covalent binding occurred between insulin and the polymeric SPHC matrix. Release profiles of all peptides from the developed delivery systems showed a time-controlled release profile: after a short lag time of 10–15 min, a burst release of peptides occurred during which more than 80% of peptide was released within 30–45 min. In conclusion, the present delivery systems based on SPH and SPHC show appropriate in vitro properties for application in peroral peptide drug delivery of buserelin, octreotide and insulin, and are therefore promising for further in vivo evaluation.     

In vitro release characteristics and cellular uptake of poly(D,L-lactic-co-glycolic acid) nanoparticles for topical delivery of antisense oligodeoxynucleotides

The efficacy of antisense oligodeoxynucleotides (AsODNs) is compromised by their poor stability in biological fluids and the inefficient cellular uptake due to their size and negative charge. Since chemical modifications of these molecules have resulted in a number of non-antisense activities, incorporation into particulate delivery systems has offered a promising alternative. The aim of this study was to evaluate various poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles for AsODN entrapment and delivery. PLGA nanoparticles were prepared using the double emulsion solvent evaporation method. The influence of formulation parameters such as PLGA concentration and volume ratio of internal aqueous phase volume (Va1) to organic phase volume (Vo) to external aqueous phase volume (Va2) on particle size, polydispersity index (PDI) and zeta potential (ZP) was investigated using a full factorial study. The particle size increased with increasing PLGA concentrations and volume ratios, with an interaction detectable between the two factors. AsODN entrapment efficiencies ranged between 49.97% and 54.95% with no significant difference between various formulations. By fitting the in vitro release profiles to a dual first order release model it was shown that the AsODN release occurred via two processes: a diffusion controlled process in the early phase (25 to 32% within one day) and a PLGA degradation process in the latter (39 to 70% after 14 days). Cellular uptake studies using primary corneal epithelial cells suggested active transport of nanoparticles via endocytosis. PLGA nanoparticles therefore show potential to successfully entrap AsODNs, transport them into cells and release them over time due to polymer erosion.     

Influence of the primary emulsification procedure on the characteristics of small protein-loaded PLGA microparticles for antigen delivery

Microparticles prepared from poly(lactic-co-glycolic acid) (PLGA) using a W₁/O/W₂ double emulsion solvent evaporation method are suitable vehicles for the delivery of proteins to antigen presenting cells, e.g. dendritic cells. In this study, the influence of different techniques for the preparation of the primary W₁/O emulsion was investigated with respect to the protein localization within the microparticles, morphological characteristics of these particles, protein burst release and the native state of the released protein. Bovine serum albumin bearing fluorescein isothiocyanate (FITC-BSA) was used as model protein. A static micromixer was applied for the preparation of the W₁/O/W₂ double emulsion. Employing a rotor-stator homogenizer (Ultra-Turrax®) for primary emulsification, microcapsules with a high burst release were produced, because nearly all FITC-BSA was attached to the outside of the particle wall. Using a high pressure homogenizer or an ultrasonic procedure resulted in the formation of microspheres with homogeneous protein distribution and a reduced burst release.     

Influence of the coating thickness and type of oral delivery system (tablets, pellets) on the stability towards degradation by neutron irradiation: Validation of neutron activation III

Enteric coated dexchlorpheniramine maleate (DCPA) tablets and pellets with varying coating thickness were subjected to several in vitro tests after irradiation by thermal neutrons in a flux of 1.1×10¹³ n cm⁻² s⁻¹ for 2, 4 or 15 min. The appearance of the tablet formulation changed extensively after exposure of the tablets to pile radiation. The irradiation caused the film to loosen from the surface of the core, indicating the generation of gases during the irradiation process. Already after irradiating the tablets for 2 min the disintegration and dissolution behaviour were significantly changed. The extent of tablet damage increased with increasing time of exposure and increasing thickness of the coating. Compared with the tablet formulation, the cores could resist a larger amount of irradiation since dissolution behaviour of the cores was only affected after 15 min of irradiation. This indicates that the irradiation procedure initially affects the coating of the formulation. Although the dissolution behaviour of the pellet formulations changed significantly after the irradiation procedure, the changes were too small to be attributed exclusively to radiation damage.     

The influence of the degree of esterification on the release characteristics of in situ gelling pectin formulations for oral sustained delivery of paracetamol

The aim of this study was to examine the effect of a change of the degree of esterification of pectin on the in situ gelation and release characteristics of 1.5% (w/v) pectin solutions over a wide pH range. Formulations of pectin with degrees of esterification of 9% (DE9) and 31% (DE31) containing complexed calcium ions formed gels in vitro at pH 1.2 as a consequence of cross-linking of the pectin chains by free calcium ions released from the complex. In vitro release of paracetamol from these gels was diffusion controlled. A sustained release of paracetamol was observed following oral administration of pectin DE9 and DE31 formulations to gastric acidity-controlled rats at pH 2.5 but only with DE9 formulations at pH 5.5. Examination of the stomach contents confirmed effective in situ gelation of pectin DE9 formulations at a gastric pH of 6 but there was no evidence of the gelation of pectin DE31 formulations at this pH.     

Solid self-nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of glimepiride: development and antidiabetic activity in albino rabbits

Abstract

Context: This study presents novel self-nanoemulsifying drug delivery system potential of oral delivering which leads poorly aqueous soluble drug glimepiride.

Objective: The objective of this study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS) for the improved oral delivery of glimepiride and to evaluate its therapeutic efficacy in albino rabbits.

Results and discussion: The droplet size analyses revealed a droplet size of less than 200?nm. The solid state characterization of S-SNEDDS by scanning electron microscopy (SEM), X-ray powder diffraction and differential scanning calorimetry (DSC) revealed the absence of crystalline glimepiride in the S-SNEDDS. The in vitro dissolution studies revealed that the significant improvement in glimepiride release characteristics. The effect of S-SNEDDS on therapeutic efficacy of glimepride was assessed in albino rabbits by monitoring blood glucose levels and compared with free drug suspension, L-SNEDDS. The S-SNEDDS showed significant (p?<?0.05) increase in in vitro drug release and therapeutic efficacy as compared with free drug.

Conclusion: This study demonstrated that S-SNEDDS is a promising novel drug delivery system of glimepride to enhance oral delivery.     

Polymeric micelle nanocarriers for targeted epidermal delivery of the hedgehog pathway inhibitor vismodegib: formulation development and cutaneous biodistribution in human skin

Background: The aim was to investigate cutaneous delivery and biodistribution of the hedgehog pathway inhibitor, vismodegib (VSD), indicated for basal cell carcinoma (BCC), from polymeric micelle formulations under infinite/finite dose conditions.

Methods: VSD-loaded micelles were characterized for drug content, particle size, and shape; a micelle gel was characterized for its rheological behavior. Cutaneous deposition and biodistribution of VSD were determined using porcine and human skin in vitro with quantification by UHPLC-MS/MS.

Results: The optimal micelle solution (Z_av 20–30 nm) increased the aqueous solubility of VSD by >8000-fold; drug content was stable after 4 weeks at 4°C. Application of micelle solution and micelle gel (0.086% w/v) to human skin for 12 h under infinite dose conditions resulted in statistically equivalent VSD deposition (0.62 ± 0.11 and 0.67 ± 0.14 μg/cm², respectively). Cutaneous biodistribution in human skin under infinite (micelle solution and gel) and finite (micelle gel) dose conditions showed that the VSD concentrations obtained in the basal epidermis, at depths of 120–200 μm, were ?3800- and ?2300-fold greater than the IC₅₀ reported for hedgehog signaling pathway inhibition in vitro.

Conclusion: Cutaneous delivery of VSD from micelle-based formulations might enable targeted, topical treatment of superficial BCC with minimal risk of systemic exposure.     

A novel method to prepare magnetite chitosan microspheres conjugated with methotrexate (MTX) for the controlled release of MTX as a magnetic targeting drug delivery system

The purpose of the present study is to develop a new method to prepare magnetite chitosan microspheres conjugated with methotrexate (MTX) for the controlled release of MTX as a magnetic targeting drug delivery system. MTX was first conjugated to the chitosan chain via a peptide bond and then a suspension cross-linking technique was used for the production of magnetic chitosan microspheres with glutaraldehyde as the cross-linker. The MTX-loading capacity of the magnetic chitosan microspheres was determined and drug release experiments were also carried out to discuss the MTX release behavior. All the data support that the magnetic chitosan-MTX microspheres prepared in this method would have great potential application in magnetic targeting drug delivery technology.