Excipient-free nanoporous microparticles of budesonide for pulmonary delivery

The aim of this study was to investigate the application of a spray-drying process for the production of nanoporous microparticles (NPMPs) to budesonide, and to characterise the particles produced in terms of their suitability for pulmonary delivery.Budesonide was spray dried with and without ammonium carbonate from ethanol/water or methanol/water solutions. The solid-state characteristics and micromeritic (particle size, density, surface area) properties of spray dried powders were assessed. In vitro deposition studies were performed to assess aerosol performance.The densities of the NPMPs were significantly lower and the surface areas significantly higher than for non-porous spray dried or micronised material. NPMPs of budesonide demonstrated improved aerosolisation properties compared to spray dried non-porous, micronised material and two budesonide commercial products. All spray dried materials were amorphous in nature. The glass transition temperature (90 °C) was sufficiently high to suggest good physical stability at room temperature. When stored at 25 °C/60% RH NPMPs showed a reduced tendency to recrystallise compared to the equivalent non-porous spray dried powder. The physical stability and amorphous nature of NPMPs was retained, under these storage conditions for at least one year and the in vitro aerosolisation properties were not affected by the storage conditions.Excipient-free porous microparticles, prepared by the novel process described, show good potential for drug delivery by oral inhalation with improved in vitro deposition properties compared to non-porous particles.     

口服结肠靶向给药系统的研究概况

口服结肠靶向给药系统具有很多优点,尤其对肠病的治疗。本文综述了口服结肠靶向蛤药系统的机制、类型的研究概况。     

Pectin-based oral drug delivery to the colon

This review presents an overview of studies concerning oral formulations intended for site-specific drug delivery to the colon with pectin as the main excipient. The biological aspects covered include gastrointestinal transit and the enzymatic degradation of pectin. Scintigraphic methods demonstrating the functionality of pectin formulations are discussed. The main focus is on the various formulations reported, including matrix tablets, multiparticulate formulations as pellets and hydrogel beads, and pectin-based coatings. Also included is an evaluation of common excipients employed to improve colon specificity by crosslinking or increasing the hydrophobicity. Finally, properties of the pectin molecules that are important for successful formulations are examined. The conclusion is that the studies found in the literature provide an excellent platform for the development of pectin-based colon delivery systems.     

Pectin-based oral drug delivery to the colon

This review presents an overview of studies concerning oral formulations intended for site-specific drug delivery to the colon with pectin as the main excipient. The biological aspects covered include gastrointestinal transit and the enzymatic degradation of pectin. Scintigraphic methods demonstrating the functionality of pectin formulations are discussed. The main focus is on the various formulations reported, including matrix tablets, multiparticulate formulations as pellets and hydrogel beads, and pectin-based coatings. Also included is an evaluation of common excipients employed to improve colon specificity by crosslinking or increasing the hydrophobicity. Finally, properties of the pectin molecules that are important for successful formulations are examined. The conclusion is that the studies found in the literature provide an excellent platform for the development of pectin-based colon delivery systems.     

Development of PEGDMA: MAA based hydrogel microparticles for oral insulin delivery

An oral insulin delivery system based on copolymers of poly(ethylene glycol) dimethacrylate and methacrylic acid was developed and its functional activity was tested in non-obese diabetic rats. Poly(ethylene glycol) dimethacrylates (PEGDMA) were synthesized by esterification reaction of different molecular weight poly(ethylene glycol) with methacrylic acid (MAA) in presence of acid catalyst. PEG dimethacrylates of molecular weight ranging from 400 to 4000 and methacrylic acid were further copolymerized by suspension polymerization to obtain pH sensitive hydrogel microparticles. The diameter of poly(PEGDMA:MAA) microparticles increased with increasing the molecular weight of the poly(ethylene glycol) dimethacrylate used for respective microparticle synthesis. Insulin was loaded into the hydrogel microparticles by partitioning from concentrated insulin solution. In vitro release studies of insulin loaded microparticles were performed by simulating the condition of gastrointestinal tract, which showed the minimal insulin leakage (18-25%) at acidic pH (2.5) and significantly higher release at basic pH (7.4). Animal studies were carried out to investigate the abilities of the insulin loaded hydrogel microparticles to influence the blood glucose levels of the diabetic rats. In studies with diabetic rats, the blood glucose level reduced for animals that received the insulin loaded hydrogel microparticles and the effect lasted for 8-10h. It was also observed, two capsules per day of poly(PEGDMA4000:MAA) hydrogel microparticles containing 80 I.U./kg of insulin dose were sufficient to control the blood glucose level of fed diabetic rats between 100 and 300 mg/dl.     

Feasibility, stability and release performance of a time-dependent insulin delivery system intended for oral colon release

The aim of the present work was to evaluate the viability of a time-dependent delivery platform (Chronotopic^TM) in preparing an insulin-based system intended for oral colon delivery. The main objectives were to assess the influence of the manufacturing process and storage conditions on the protein stability. Insulin-loaded cores were manufactured by direct compression and were subsequently coated with hydroxypropyl methylcellulose (HPMC) in a top-spray fluid bed up to increasing weight gains, namely 20%, 60% and 100%. In order to evaluate the impact the operating conditions may have on the protein integrity, insulin and its main degradation products (A21-desamido insulin - A21, Other Insulin-Related Compounds - OIRCs, and High-Molecular Weight Proteins - HMWPs) were assayed on samples collected after each process step by chromatographic methods. Furthermore, long-term (4 °C) and accelerated (25 °C-60% RH) stability studies were carried out on tablet cores and coated systems by assessing insulin, A21, OIRC and HMWP percentages throughout a one-year storage period. In addition, the in vitro release behaviour was investigated during the same study period. The overall results indicated that the manufacturing process is not detrimental for insulin integrity and that 4 °C storage temperature alters neither the protein content nor the release performances of the device.It was therefore concluded that insulin-containing systems intended for oral colon delivery can be obtained by the Chronotopic^TM technology.     

Chitosan coated Ca-alginate microparticles loaded with budesonide for delivery to the inflamed colonic mucosa.

Using a novel one-step spray-drying process uncoated and Eudragit S 100 coated chitosan-Ca-alginate microparticles efficiently loaded with budesonide (BDS), with bioadhesive and controlled release properties in GIT, were prepared. Microparticles were spherical with mean particle size of 4.05-5.36 microm, narrow unimodal distribution and positive surface charge. A greater extent of calcium chloride limited the swelling ratio of beads, while swelling behaviour of coated beads was mainly determined by properties of enteric coating. Comparing the release profiles of formulations, under different pH conditions, influence of polymer properties and concentration of cross-linker on the rate and extent of drug release was evident. Coating has successfully sustained release of BDS in buffers at pH 2.0 and 6.8, while providing potential for efficient release of BDS at pH 7.4. Release data kinetics indicated influence of erosion and biodegradation of polymer matrix on drug release from microparticles. Prepared formulations were stable for 12 months period at controlled ambient conditions. In conclusion coated microparticles prepared by one-step spray-drying procedure could be suitable candidates for oral delivery of BDS with controlled release properties for local treatment of inflammatory bowel diseases.     

Polymeric nano- and microparticles for the oral delivery of peptides and peptidomimetics

Due to recent advances, numerous bioactive peptides are now available in large quantities. Administering these substances by the oral route appears as a formidable challenge due to their insufficient stability in the gastrointestinal tract and their poor absorption pattern. Several approaches have been investigated to improve their oral bioavailability. Among them, the use of polymeric particulate delivery systems (microparticles and nanoparticles) represents a promising concept. Encapsulating or incorporating peptides in particles should at least protect these substances against degradation and, in some cases, also enhance their absorption. The aim of this paper is to review the principal studies where peptide-loaded particles were administered by the oral route. The preparation methods and in vitro trials are presented and in vivo results are discussed with emphasis placed on the peptide blood levels reached or on the biological effects observed. Whether or not intact particles can be taken up and translocated to the systemic circulation is not the aim of this review.     

Time-controlled oral delivery systems for colon targeting

In recent years, many research efforts have been spent in the achievement of selective delivery of drugs into the colon following oral administration. Indeed, colonic release is regarded as a beneficial approach to the pharmacological treatment or prevention of widespread large bowel pathologies, such as inflammatory bowel disease and adenocarcinoma. In addition, it is extensively explored as a potential means of enhancing the oral bioavailability of peptides, proteins and other biotechnological molecules, which are known to be less prone to enzymatic degradation in the large, rather than in the small, intestine. Based on these premises, several formulation strategies have been attempted in pursuit of colonic release, chiefly including microflora-, pH-, pressure- and time-dependent delivery technologies. In particular, this review is focused on the main design features and release performances of time-controlled devices, which rely on the relative constancy that is observed in the small intestinal transit time of dosage forms.     

Cyclodextrin multicomponent complexation and controlled release delivery strategies to optimize the oral bioavailability of vinpocetine

In the present work, to maintain a suitable blood level of vinpocetine (VP) for a long period of time, VP-cyclodextrin-tartaric acid multicomponent complexes were prepared and formulated in hydroxypropylmethylcellulose matrix tablets. In vitro and in vivo performances of these formulations were investigated over a VP immediate release dosage form. Solubility studies were performed to evaluate the drug pH solubilization profile and to assess the effect of multicomponent complexation on VP solubility. The drug release process was investigated using United States Pharmacopeia apparatus 3 and a comparative oral pharmacokinetic study was subsequently undertaken in rabbits. Solubility studies denoted the pH-solubility dependence of VP and solubility improvement attained by complexation. Dissolution results showed controlled and almost complete release behavior of VP over a 12-h period from complex hydroxypropylmethylcellulose-based formulations. A clear difference between the pharmacokinetic patterns of VP immediate release and VP complex-based formulations was revealed. The area under the plasma concentration-time curve after oral administration of complex-based formulations was 2.1-2.9 times higher than that for VP immediate release formulation. Furthermore, significant differences found for mean residence time, elimination half-life, and elimination rate constant values corroborated prolonged release of VP from complex-based formulations. These results suggest that the oral bioavailability of VP was significantly improved by both multicomponent complexation and controlled release delivery strategies.     

Time-controlled oral delivery systems for colon targeting

In recent years, many research efforts have been spent in the achievement of selective delivery of drugs into the colon following oral administration. Indeed, colonic release is regarded as a beneficial approach to the pharmacological treatment or prevention of widespread large bowel pathologies, such as inflammatory bowel disease and adenocarcinoma. In addition, it is extensively explored as a potential means of enhancing the oral bioavailability of peptides, proteins and other biotechnological molecules, which are known to be less prone to enzymatic degradation in the large, rather than in the small, intestine. Based on these premises, several formulation strategies have been attempted in pursuit of colonic release, chiefly including microflora-, pH-, pressure- and time-dependent delivery technologies. In particular, this review is focused on the main design features and release performances of time-controlled devices, which rely on the relative constancy that is observed in the small intestinal transit time of dosage forms.     

pH- and ion-sensitive polymers for drug delivery

Introduction: Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body.

Areas covered: Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations.

Expert opinion: Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.     

Preparation and evaluation of an oral delivery system for time-dependent colon release of insulin and selected protease inhibitor and absorption enhancer compounds

The aim of this work was to prepare and evaluate an oral dosage form intended for time-dependent colon delivery of insulin along with a selected protease inhibitor (camostat mesilate) and absorption enhancer (sodium glycocholate). A previously described release platform, which had proven potentially suitable for the protein delivery, was exploited. Insulin compatibility with the above-mentioned adjuvants was preliminarily evaluated. For this purpose, the drug and its main degradation products were assayed by HPLC in insulin powder mixtures with camostat mesilate and/or sodium glycocholate stored 12 months at 4°C. No significant decrease in protein content or increase in degradation product percentages beyond Eur. Ph. 6th Ed. limits was highlighted. Moreover, calorimetric studies performed on physical and compacted binary insulin mixtures with camostat mesilate and sodium glycocholate showed that the thermal behavior of both adjuvants was unchanged. Subsequently, tablet cores with differing compositions were prepared and spray-coated with an aqueous HPMC solution in order to obtain pulsatile delivery systems. The coated units were demonstrated to concurrently release the drug and the adjuvants in a prompt and quantitative mode after consistent lag times. Based on these results, the device was proven a potential candidate for colon delivery of insulin and the selected adjuvants. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4661–4669, 2009     

Spray-dried microparticles: a potential vehicle for oral delivery of vaccines

This study aims to formulate a microparticle-based system that protects the protein from the harsh gastric conditions and also provides appropriate uptake via M cells for desired immune response upon oral administration. The formulation was derived using a valid statistical model, analysed by JMP? (SAS). The average size and charge of the resulting microparticles were 1.51?±?0.125?μm and?+?15.7?±?2.5?mV, respectively. Moreover, the particles provided a prolonged release over a period of 8?hrs which ensures M-cell uptake of intact particle with antigen (Kunisawa et?al., 2011). This was further supported with in?vivo studies where particle uptake was found in Peyer's patches of small intestine when observed for 8?h. Thus, these microparticles can be used as an efficient vaccine delivery vehicle upon oral administration.     

Targeted delivery, safety, and efficacy of oral enteric-coated formulations of budesonide

Budesonide is a potent corticosteroid with a high first-pass metabolism rate. Two commercially available enteric-coated pH-dependent release formulations (Entocort EC and Budenofalk) deliver budesonide to the ileum and proximal colon, regions most commonly affected in Crohn's disease. The drug's effectiveness in this disease has been proven in multiple, placebo-controlled trials, where it has been shown to be superior to mesalamine and placebo, and equivalent to prednisolone for the control of mild to moderately active right-sided Crohn's disease. This beneficial therapeutic effect comes with less adrenal suppression and a small improvement in the clinical adverse effect profile, as compared to prednisolone. However, budesonide provides no benefit over conventional therapy for left-sided colonic disease, and it is less effective for treatment of more severe disease activity and more distal colonic disease. Continuous budesonide does not prolong remission and is, therefore, best used in an intermittent fashion to treat acute exacerbations.     

Evaluation of Eudragit-coated chitosan microparticles as an oral immune delivery system

Chitosan microparticles containing ovalbumin (OVA), OVA-containing chitosan microparticles (Chi-OVA), were prepared, coated with Eudragit L100 (ER), and evaluated as oral vaccine. Chi-OVA with an OVA content of 34.4% (w/w) and a mean particle size of 2.3 microm were used for experiments in vitro and in vivo. ER-coated Chi-OVA (ER-Chi-OVA) contained 3.6-20.5% (w/w) OVA and had a particle size of 47.9-161.1 microm. Chi-OVA dissolved readily in JP 14 first fluid, but not in JP 14 second fluid. The release of OVA from Chi-OVA was suppressed extensively in JP 14 second fluid. ER-Chi-OVA did not dissolve in JP 14 first fluid, and the release of OVA was suppressed greatly in JP 14 first and second fluids. OVA solution, Chi-OVA and ER-Chi-OVA (200 and 800 microg OVA/mouse) were administered to Balb/C mice twice at a 1-week interval. At 7 d after the second administration, plasma OVA-specific IgG and fecal OVA-specific IgA levels were measured. OVA-specific IgG tended to be enhanced in Chi-OVA and ER-Chi-OVA, but was the highest in OVA solution. OVA-specific IgA was induced significantly more efficiently by ER-Chi-OVA than the others. These suggested that ER-Chi-OVA should be possibly useful to induce an intestinal mucosal immune response.     

Spray-dried microparticles: a potential vehicle for oral delivery of vaccines

This study aims to formulate a microparticle-based system that protects the protein from the harsh gastric conditions and also provides appropriate uptake via M cells for desired immune response upon oral administration. The formulation was derived using a valid statistical model, analysed by JMP® (SAS). The average size and charge of the resulting microparticles were 1.51?±?0.125?µm and?+?15.7?±?2.5?mV, respectively. Moreover, the particles provided a prolonged release over a period of 8?hrs which ensures M-cell uptake of intact particle with antigen (Kunisawa et al., 2011). This was further supported with in vivo studies where particle uptake was found in Peyer's patches of small intestine when observed for 8?h. Thus, these microparticles can be used as an efficient vaccine delivery vehicle upon oral administration.     

Preparation and evaluation of mucinated sodium alginate microparticles for oral delivery of insulin

Effective oral insulin delivery remains a challenge to the pharmaceutical industry. In this study, insulin-loaded microparticles for oral delivery were prepared with mucin and sodium alginate combined at different ratios using a novel method based on polymer coacervation and diffusion filling. Some physical characteristics of the various insulin-loaded microparticles such as particle size, morphology and compressibility indices were determined. The microparticles were filled into hard gelatin capsules and the in vitro insulin release as well as the blood glucose reduction after oral administration to diabetic rabbits were determined. The microparticles formed were generally multi-particulate, discrete and free flowing. Before insulin loading, microparticles were round and smooth, becoming fluffier, less spherical and larger with rough and pitted surface after insulin loading. The insulin content of the microparticles increased with increase in their sodium alginate content. The various insulin-loaded microparticles prepared with the mucinated sodium alginate when encapsulated exhibited lag time before insulin release. The time taken to reach maximum insulin release from the various formulations varied with the mucin–sodium alginate ratio mix. The mean dissolution time of insulin from the microparticles prepared with sodium alginate, mucin, sodium alginate: mucin ratios of 1:1, 3:1 and 1:3 was 11.21 ± 0.75, 3.3 ± 0.42, 6.69 ± 023, 8.52 ± 0.95 and 3.48 ± 0.65 (min.), respectively. The percentage blood glucose reduction for the subcutaneously administered insulin was significantly (p < 0.001) higher than for the formulations. The blood glucose reduction effect produced by the orally administered insulin-loaded microparticles prepared with three parts of sodium alginate and one part of mucin after 5 h was, however, equal to that produced by the subcutaneously administered insulin solution, an indication that it is an effective alternative for the delivery of insulin.     

Preparation and evaluation of mucinated sodium alginate microparticles for oral delivery of insulin

Effective oral insulin delivery remains a challenge to the pharmaceutical industry. In this study, insulin-loaded microparticles for oral delivery were prepared with mucin and sodium alginate combined at different ratios using a novel method based on polymer coacervation and diffusion filling. Some physical characteristics of the various insulin-loaded microparticles such as particle size, morphology and compressibility indices were determined. The microparticles were filled into hard gelatin capsules and the in vitro insulin release as well as the blood glucose reduction after oral administration to diabetic rabbits were determined. The microparticles formed were generally multi-particulate, discrete and free flowing. Before insulin loading, microparticles were round and smooth, becoming fluffier, less spherical and larger with rough and pitted surface after insulin loading. The insulin content of the microparticles increased with increase in their sodium alginate content. The various insulin-loaded microparticles prepared with the mucinated sodium alginate when encapsulated exhibited lag time before insulin release. The time taken to reach maximum insulin release from the various formulations varied with the mucin–sodium alginate ratio mix. The mean dissolution time of insulin from the microparticles prepared with sodium alginate, mucin, sodium alginate: mucin ratios of 1:1, 3:1 and 1:3 was 11.21 ± 0.75, 3.3 ± 0.42, 6.69 ± 023, 8.52 ± 0.95 and 3.48 ± 0.65 (min.), respectively. The percentage blood glucose reduction for the subcutaneously administered insulin was significantly (p < 0.001) higher than for the formulations. The blood glucose reduction effect produced by the orally administered insulin-loaded microparticles prepared with three parts of sodium alginate and one part of mucin after 5 h was, however, equal to that produced by the subcutaneously administered insulin solution, an indication that it is an effective alternative for the delivery of insulin.     

Poly(N-vinylcaprolactam-co-methacrylic acid) hydrogel microparticles for oral insulin delivery

pH-sensitive copolymeric hydrogels prepared from N-vinylcaprolactam and methacrylic acid monomers by free radical polymerization offered 52% encapsulation efficiency and evaluated for oral delivery of human insulin. The in vitro experiments performed on insulin-loaded microparticles in pH 1.2 media (stomach condition) demonstrated no release of insulin in the first 2?h, but almost 100% insulin was released in pH 7.4 media (intestinal condition) in 6?h. The carrier was characterized by Fourier transform infrared, differential scanning calorimeter, thermogravimetry and nuclear magnetic resonance techniques to confirm the formation of copolymer, while scanning electron microscopy was used to assess the morphology of hydrogel microparticles. The in vivo experiments on alloxan-induced diabetic rats showed the biological inhibition up to 50% and glucose tolerance tests exhibited 44% inhibition. The formulations of this study are the promising carriers for oral delivery of insulin.