Bioadhesive microspheres as a controlled drug delivery system

The concept of controlled drug delivery has been traditionally used to obtain specific release rates or spatial targeting of active ingredients. The phenomenon of bioadhesion, introduced by Park and Robinson [Park, K., Robinson, J.R., 1984. Bioadhesive polymers as platforms for oral controlled drug delivery: method to study bioadhesion. Int. J. Pharm. 198, 107-127], has been studied extensively in the last decade and applied to improve the performance of these drug delivery systems. Recent advances in polymer science and drug carrier technologies have promulgated the development of novel drug carriers such as bioadhesive microspheres that have boosted the use of "bioadhesion" in drug delivery. This article presents the spectrum of potential applications of bioadhesive microspheres in controlled drug delivery ranging from the small molecules, to peptides, and to the macromolecular drugs such as proteins, oligonucleotides and even DNA. The development of mucus or cell-specific bioadhesive polymers and the concepts of cytoadhesion and bioinvasion provide unprecedented opportunities for targeting drugs to specific cells or intracellular compartments. Developments in the techniques for in vitro and in vivo evaluation of bioadhesive microspheres have also been discussed.     

Development of oral drug delivery system using floating microspheres

Floating acrylic resin microspheres with an internal hollow structure were prepared by a solvent diffusion and evaporation method. The yield of microspheres depended on the diffusion rate of ethanol and/or isopropanol in the organic phase. They were successfully produced when amixture of ethanol and isopropanol was used instead of ethanol alone. The mixing ratioof components in the organic phase affected the size and the yield of microspheres and the best results were obtained at the volume ratio of ethanol:isopropanol:dichloromethane (8:2:5). Direct introduction of the organic phase into the aqueous phase through aglass tube alsosignificantly improved the yield by avoiding the contact of organic phase with the surface of water. The optimum rotation speed and temperature were 250rpm and 25 C, respectively. Several different drugs with various physico-chemical properties were used as model drugs for encapsulation and release tests. When a drug had low solubility in dichloromethaneandhighsolubilityin both water and amixture of ethanol/isopropanol, the loading efficiency was the lowest. The release profiles were significantly different depending on the solubility of a drug in the release medium and the physico-chemical properties of an encapsulated drug.     

Development of oral drug delivery system using floating microspheres

Floating acrylic resin microspheres with an internal hollow structure were prepared by a solvent diffusion and evaporation method. The yield of microspheres depended on the diffusion rate of ethanol and/or isopropanol in the organic phase. They were successfully produced when a mixture of ethanol and isopropanol was used instead of ethanol alone. The mixing ratio of components in the organic phase affected the size and the yield of microspheres and the best results were obtained at the volume ratio of ethanol:isopropanol:dichloromethane (8:2:5). Direct introduction of the organic phase into the aqueous phase through a glass tube also significantly improved the yield by avoiding the contact of organic phase with the surface of water. The optimum rotation speed and temperature were 250 rpm and 25 degrees C, respectively. Several different drugs with various physico-chemical properties were used as model drugs for encapsulation and release tests. When a drug had low solubility in dichloromethane and high solubility in both water and a mixture of ethanol/isopropanol, the loading efficiency was the lowest. The release profiles were significantly different depending on the solubility of a drug in the release medium and the physico-chemical properties of an encapsulated drug.     

Dextran cross-linked gelatin microspheres as a drug delivery system.

This paper describes the use of oxidized dextran as a cross-linker for the preparation of gelatin microspheres. Microspheres were obtained by a thermal gelation method and their dissolution kinetic was examined. In order to find evidence of sugar mediated cross-linking, swelling tests and gelatin microspheres dissolution experiments were performed. The obtained results indicated that oxidized dextran can form a cross-linked gelatin network which can reduce the dissolution of gelatin. More interestingly, gelatin microspheres treated by both native and oxidized dextran slow down, even if to a different extent, the release of the antitumor drug TAPP-Br used as a model compound. Taken together, our results suggest that oxidized dextran could be an interesting means to cross-link gelatin microspheres allowing the use of this delivery formulation for controlled release of drugs.     

Mucoadhesive microspheres for controlled drug delivery

Mucoadhesion is a topic of current interest in the design of drug delivery systems. Mucoadhesive micro-spheres exhibit a prolonged residence time at the site of application or absorption and facilitate an intimate contact with the underlying absorption surface and thus contribute to improved and/or better therapeutic performance of drugs. In recent years such mucoadhesive microspheres have been developed for oral, buccal, nasal, ocular, rectal and vaginal routes for either systemic or local effects. The objective of this article is review the principles underlying the development and evaluation of mucoadhesive microspheres and the research work carried out on these systems.     

Gelatin-methotrexate conjugate microspheres as a potential drug delivery system

Gelatin-methotrexate microspheres for intra-tumor administration have possibilities for minimizing systemic toxicities of methotrexate (MTX) and overcoming its resistance. Gelatin-MTX conjugates prepared by a carbodiimide reaction were crosslinked with glutaraldehyde to form microspheres (MTX:gelatin molar ratios of 2:1, 15:1, and 21:1). Microspheres were evaluated under in vitro tumor conditions at pH 6.5 and 37 degrees C with and without Cathepsin B (Cat B). Some microspheres were capped with an ethanolamine/cyanoborohydride procedure. SEM of broken microspheres revealed a hollow shell structure. Superficial Cat B degradation influenced some free MTX release but produced no conjugate fragment release. HPLC measured release of fragments (<10 kDa) was very little and release of free MTX was small. However, higher drug load microspheres released less free MTX than lower drug load, a substantial lag phase of free MTX release from capped microspheres changed to an initial rapid release in uncapped microspheres, and fragments were only released from uncapped microspheres. Opened unstable Schiff base crosslinks in uncapped microspheres may allow enzyme to produce conjugate fragments not observed in capped microspheres. Free MTX release may occur from dissolved uncrosslinked conjugate within the hollow microspheres. Important relationships and observations are described that will be useful for gelatin and perhaps other proteinaceous microspheres.     

Bioadhesive microspheres as a potential nasal drug delivery system

The rapid mucociliary clearance mechanism in the nasal cavity can be considered as an important factor when low bioavailabilities are obtained for drugs given intranasally. A nasal delivery system in the form of bioadhesive microspheres has been developed. Studies in human volunteers using gamma scintigraphy showed great differences in clearance times between 3 microsphere systems and two controls. The half life of clearance for starch microspheres was found to be in the order of 240 min as compared to 15 min for the liquid and powder control formulations. The microspheres form a gel-like layer in contact with the nasal mucosa that is cleared slowly from the nasal cavity. In vitro studies using model compounds (cromoglycate and Rose bengal) showed high degrees of loading capacities for the various microsphere systems. Using various physical and chemical approaches, it was possible to a certain degree to control the release of the compounds from the microsphere systems.     

Poly(palmitoyl-l-hydroxyproline ester) microspheres as potential oral controlled drug delivery system

A new type of carrier using poly(palmitoyl-l-hydroxyproline ester) (PPH) [IUPAC name: poly((1-palmitoyl-4,2-pyrrolidinediyl)carbonyloxy)], a poly(amino acid) is described. The polymer is synthesized by conventional method and the microspheres were prepared by solvent evaporation technique for application in drug delivery system. Microspheres with different sizes were prepared by varying certain formulation and technological parameters and their distributive stabilities under physiological conditions were studied. The microspheres were characterized by DSC, optical and laser particle size analysis. A model drug, rifampicin (antituberculosis drug) was entrapped in the microspheres and the in vitro release studies were performed in pH 7.4 and pH 1.5 buffer media. The pH value seemed to have some influence on the dissolution rate of the rifampicin-containing microspheres. Dissolution experiments using rifampicin indicated the possibility of using PPH microspheres with other hydrophobic drugs.     

Chitosan-based mucoadhesive microspheres of clarithromycin as a delivery system for antibiotic to stomach

The objective of the present study was to develop chitosan-based mucoadhesive microspheres of clarithromycin to provide prolonged contact time for drug delivery of antibiotics to treat stomach ulcers. Microspheres based mucoadhesive formulation were extensively evaluated and characterized for in vitro performance followed by investigation of in vivo pharmacokinetics in rats. Microspheres were prepared by emulsification technique using glutaraldehyde as a crosslinking agent. Formulation conditions were optimized for percent drug entrapment and mucoadhesion, by varying different formulation and process parameters like drug to polymer ratio, concentration of crosslinking agent and time of crosslinking. Prepared microspheres were evaluated extensively for particle size, percent drug entrapment, swelling kinetics, in vitro mucoadhesion using rat stomach membrane and in vitro drug release studies. In vitro permeation studies across rat stomach membrane were carried out to determine diffusion parameters and drug retention in the stomach membrane of the formulation and the plain drug. Finally in vivo performance of microsphere formulation in comparison to plain drug was evaluated by pharmacokinetic studies in albino rats. Drug entrapment upto 74% was obtained. Swelling studies indicated that with an increase in cross-linking, the swelling ability decreased. The in vitro drug release and in vitro mucoadhesion studies showed a dependence on the extent of cross-linking and concentration of chitosan. Extent of cross-linking exhibited an inverse relation to drug release rate as well as mucoadhesion, whereas polymer concentration exhibited an inverse correlation with drug release while linear relationship with mucoadhesion (up to 86%). In vitro permeation studies across stomach tissue showed higher accumulation of drug in the stomach tissue with microspheres formulation as compared to that of free drug. This is evident from higher value of K (partition coefficient) and Qm/Csf values for microspheres (68.34 and 106.42X10(3), respectively) as compared to that of free drug (1.86 and 173.00, respectively). These findings when analyzed showed an increase in the bioavailability of clarithromycin from microsphere formulation as compared to plain drug suspension in vivo, with AUC 0-->alpha being 91.7 (microg h/ml)and 24.9 (microg h/ml) respectively. Results of the study demonstrated good mucoadhesion of the microspheres with the stomach mucosa as well as higher accumulation of drug in the stomach membrane. Microspheres also exhibited sustained release of drug. Thus chitosan microspheres appear, technically, promising mucoadhesive drug delivery systems for delivering clarithromycin to treat stomach ulcers.     

Collagen-coated polycaprolactone microparticles as a controlled drug delivery system

OBJECTIVE: Polycaprolactone (PCL) microparticles coated with acetylated collagen have been assessed for use as a controlled drug delivery system. METHOD: The surface morphology, drug encapsulation and release profile of PCL microparticles and collagen-coated PCL microparticles containing doxycycline hydrochloride (DH) have been investigated in order to develop a controlled release system which would in addition act as a scaffold for cell attachment. PCL microparticles were prepared by emulsion solvent evaporation technique and loaded with DH. Since the encapsulation was found to be low, PCL microparticles were coated with acetylated collagen containing DH, to increase the drug availability. Collagen was modified by acetylation to shift its isoelectric point and to have acetylated collagen solution at pH 7.0. The microparticles were characterized using a scanning electron microscope (SEM) and the in vitro drug release profile was determined using HPLC. RESULTS: Uniform sized (approximately 1000 nm) PCL microparticles were prepared using 4% PVA in the external water phase. Acetylated collagen at pH 7.0 was coated onto the PCL microparticles. This resulted in microparticles of uniform size at neutral pH. PCL acts as a support for collagen which acts as a scaffold for cell attachment. In vitro drug release studies show that collagen-coated PCL microparticle is a promising candidate for controlled drug delivery system having release duration of over 10 days. In vitro fibroblast culture studies reveal that collagen is a good substrate for cell attachment and would provide a stable environment for cell proliferation and regeneration. Thus, this system would be ideal for a short-term drug delivery to create an aseptic environment where cells can adhere and proliferate to regenerate the site.     

漂浮药物传递系统的新进展——中空微球

目的介绍漂浮药物传递系统的新进展———中空微球,就胃排空的机理、中空微球的制备及体内外表征作一综述。方法查阅相关文献,进行整理和归纳。结果该剂型可以延长药物在胃内的滞留时间,改善药物吸收,从而提高生物利用度。结论中空微球作为漂浮药物传递系统的一种新剂型,具有广阔的发展前景     

Collagen-coated polycaprolactone microparticles as a controlled drug delivery system

Objective: Polycaprolactone (PCL) microparticles coated with acetylated collagen have been assessed for use as a controlled drug delivery system.

Method: The surface morphology, drug encapsulation and release profile of PCL microparticles and collagen-coated PCL microparticles containing doxycycline hydrochloride (DH) have been investigated in order to develop a controlled release system which would in addition act as a scaffold for cell attachment. PCL microparticles were prepared by emulsion solvent evaporation technique and loaded with DH. Since the encapsulation was found to be low, PCL microparticles were coated with acetylated collagen containing DH, to increase the drug availability. Collagen was modified by acetylation to shift its isoelectric point and to have acetylated collagen solution at pH 7.0. The microparticles were characterized using a scanning electron microscope (SEM) and the in vitro drug release profile was determined using HPLC.

Results: Uniform sized (～1000 nm) PCL microparticles were prepared using 4% PVA in the external water phase. Acetylated collagen at pH 7.0 was coated onto the PCL microparticles. This resulted in microparticles of uniform size at neutral pH. PCL acts as a support for collagen which acts as a scaffold for cell attachment. In vitro drug release studies show that collagen-coated PCL microparticle is a promising candidate for controlled drug delivery system having release duration of over 10 days. In vitro fibroblast culture studies reveal that collagen is a good substrate for cell attachment and would provide a stable environment for cell proliferation and regeneration. Thus, this system would be ideal for a short-term drug delivery to create an aseptic environment where cells can adhere and proliferate to regenerate the site.     

Floating microspheres as drug delivery system: newer approaches

A controlled drug delivery system with prolonged residence time in the stomach can be of great practical importance for drugs with an absorption window in the upper small intestine. The main limitations are attributed to the inter- and intra-subject variability of gastro-intestinal (GI) transit time and the non-uniformity of drug absorption throughout the alimentary canal. Floating drug delivery systems (FDDSs) are expected to remain buoyant in a lasting way upon the gastric contents and consequently to enhance the bioavailability of drugs. The various buoyant preparations include hollow microspheres, granules, powders, tablets, capsules, pills and laminated films. Floating microspheres are specially gaining attention due to their wide applicability in the targeting of drugs to stomach. These floating microspheres have the advantage that they remain buoyant and distributed uniformly over the gastric fluid to avoid the vagaries of gastric emptying and release the drug for prolonged period of time. A major drawback of low-density floating drug delivery systems is that their performance is strongly dependent upon the gastric emptying process of stomach. Multiparticulate low-density particles can successfully prolong the gastric retention time of drugs. This article is a review of two important approaches utilized to prepare and improve the performance of floating microspheres.     

Stomach-specific drug delivery of 5-Fluorouracil using ethylcellulose floating microspheres

A multiple-unit-type oral floating dosage form (FDF) of 5-Fluorouracil (5-FU) was developed to prolong gastric residence time for the treatment of stomach cancer. The floating microspheres were prepared by solvent evaporation method. The prepared microspheres were characterized for their micromeretic properties, floating behavior and entrapment efficiency; as well by Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), thin layer chromatography (TLC) and scanning electron microscopy (SEM). The in vitro release studies and floating behavior were performed in HCl buffer pH 1.2, Phosphate buffer pH 4.5 and in Simulated Gastric Fluid (SGF). The best fit release kinetics was achieved with Higuchi plot. The yields of preparation were very high and low entrapment efficiencies were noticed with larger particle size for all the formulations. Mean particle size, entrapment efficiency and production yield were highly influenced by polymer concentration. It was concluded from the present investigation that porous Ethylcellulose microspheres are promising controlled release as well as stomach targeted carriers for 5-FU.     

Characterisation of halloysite for use as a microtubular drug delivery system

Halloysite supplied from New Zealand was shown by electron microscopy to be composed mainly of hollow microtubules having typical dimensions of 2-3 microm long and 0.3/0.1 microm outer/inner diameter. Aggregates of microtubules, double tubules and occasional split or partially unrolled tubules were observed. Energy dispersive analysis showed the mineral to be composed mainly of aluminium, oxygen and silicon, with a low content of iron. The dehydrated state of the mineral was confirmed by XRD analysis, which was partially reversible using a rehydration procedure with subsequent exchange of the intercalated water gained by glycerol, but larger molecules including the drug, diltiazem HCl, failed to exchange. The surface charge was predominantly negative over most of the physiologically relevant pH range (> 2) and the specific surface area of the material was very large (approximately 57 m(2)/g), indicating that the material has significant potential for extensive binding of cationic drugs. Removal of allophanc present by a hot alkali treatment had little effect on luminal porosity, which prior to treatment was estimated to be approximately 0.25 ml/g by a mercury intrusion technique and consequently should be the major site for drug loading. Halloysite also extruded and spheronised well to form smooth round pellets as an aid to further formulation development, which rapidly disintegrated in water unless prevented by sintering at 200 degrees C.     

Albumin microspheres as a drug delivery system for dexamethasone: pharmaceutical and pharmacokinetic aspects

Abstract— Four types of albumin microspheres containing dexamethasone prepared by varying cross-linking time—30, 60, 120 and 180 min—were tested to examine the influence of heat cross-linking degree on the in-vitro drug release. Release rate of dexamethasone associated with the microspheres was slower for samples with a longer time of high temperature denaturation. Encapsulation in neat-stabilized albumin microspheres for 60 min at 100°C significantly retards the in-vivo release of dexamethasone and hence retards absorption from the injection site.     

凝集素修饰透黏膜微粒给药系统

通过对近年来相关文献的检索,本文介绍了凝集素修饰的微球、纳米粒和脂质体,以及凝集素对不同微粒系统的修饰机制,综述凝集素修饰微粒给药系统在透黏膜给药中的应用,认为凝集素修饰微粒给药系统有较好的应用前景。     

Biodegradable microspheres for vitreoretinal drug delivery.

Vitreoretinal disorders are one of the major causes of blindness in the developed world. Treatments of these pathologies often include repeated intravitreous injections to achieve intraocular drug levels within the therapeutical range. However, the risks of complications increase with the frequency of intravitreous injections. Controlled drug delivery formulations, offer an excellent alternative to multiple administrations. These systems are capable of delivering drugs over longer time periods than conventional formulations. Currently, several kinds of polymer devices for drug delivery to the posterior segment of the eye are under clinical use, or under investigation. Among these devices, microparticulates, such as microspheres, provide an alternative to multiple injections to obtain sustained release of the drug with a single administration. Among the polymers used to make the injectable microparticles, the most commonly used are poly(lactic acid), poly(glycolic acid) and copolymers of lactic and glycolic acids because they are biocompatible and degrade to metabolic products that are easily eliminated from the body. This article reviews the literature of biodegradable polymeric microspheres loaded with drugs, that have been investigated for delivery by intravitreous injection to treat diverse vitreoretinal diseases.     

In vitro and in vivo evaluation of riboflavin-containing microballoons for a floating controlled drug delivery system in healthy humans

Microballoons (MB) possessing a spherical cavity enclosed within a hard polymer shell have been developed as a dosage form characterized by excellent buoyancy in the stomach. MB were prepared by the emulsion solvent diffusion method using enteric acrylic polymers dissolved in a mixture of dichloromethane and ethanol. Riboflavin-containing MB were administered orally to each of three healthy volunteers. The pharmacokinetics of riboflavin was investigated by analysis of the urinary excretion. Prolongation of the urinary excretion of riboflavin could be obtained by ingestion of water as well as "fed" conditions. This phenomenon was attributable to the buoyancy properties of MB in the stomach and an increase in the gastric residence time (GRT). The excretion half-life time (t(1/2)) following administration of MB (particle size: 500-1000 microm) exhibiting high buoyancy was longer than that of MB (particle size: <500 microm) displaying low buoyancy. Therefore, the intragastric floating properties of MB are potentially beneficial as far as a sustained pharmacological action is concerned. MB prepared by mixing it with hydroxypropylmethylcellulose (HPMC) in different ratio, results in improved riboflavin-release properties. These MB were evaluated in vivo by analysis of the urinary excretion of riboflavin. As a result, strong correlations were observed between the buoyancy and excretion half-life (t(1/2)) and between the riboflavin release from the MB and total urinary excretion.