Effects of alginate coated on PLGA microspheres for delivery tetracycline hydrochloride to periodontal pockets

The effects of alginate coated on tetracycline (Tc) loaded poly (D, L-lactic-co-glycolic acid) (PLGA) microspheres fabricated by double emulsion solvent evaporation technique for local delivery to periodontal pocket were investigated. Alginate coated PLGA microspheres showed smoother surface but enlarged their particle sizes compared with those of uncoated ones. In addition, alginate coated microspheres enhanced Tc encapsulation efficiency (E.E.) from 11.5?±?0.5% of uncoated ones to 17.9?±?0.5%. Moreover, all of the coated PLGA microspheres even fabricated at different conditions could prolong Tc release from 9–12 days with 50% or higher in cumulative release of Tc compared with those of uncoated ones. The swelling ratios of PLGA microspheres for alginate coated or uncoated ones, one of the possible mechanisms for enhancing Tc release for the coated ones, were measured. The results showed that 20% or higher in swelling ratio for the coated microspheres at the earlier stage of hydration (e.g.?≤?24?h) could be an important factor to result in high Tc release compared to the uncoated ones. In conclusion, alginate coated Tc loaded PLGA microspheres could enhance Tc delivery to periodontal pocket by enhancing drug encapsulated efficiency, released quantities and sustained release period compared with uncoated ones.     

Improved bioavailability of orally delivered insulin using Eudragit-L30D coated PLGA microparticles

Large porous microparticles of PLGA entrapping insulin were prepared by solvent evaporation method and evaluated in diabetes induced rat for its efficacy in maintaining blood sugar level from a single oral dose. Incorporation of Eudragit L30D (0.03% w/v) in the external aqueous phase resulted in formation of pH responsive enteric coated polymer particles which release most of the entrapped insulin in alkaline pH. At acidic pH, release of insulin from uncoated PLGA microparticles and Eudragit L30D coated PLGA microparticles was 31.62 +/- 1.8% and 17.5 +/- 1.29%, respectively, for initial 30 min. However, in 24 h, in vitro released insulin from uncoated PLGA and Eudragit coated particles was 96.29 +/- 1.01% and 88.30 +/- 1%, respectively. Released insulin from composite polymer particles were mostly in monomer form without aggregation and was stable for a month at 37 degrees C. Oral administration of insulin loaded PLGA (50 : 50) and Eudragit L30D coated PLGA (50 : 50) microparticles (equivalent to 25 IU insulin/kg of animal weight) in alloxan induced diabetic rats resulted in 37.3 +/- 11% and 62.7 +/- 3.8% reduction in blood glucose level, respectively, in 2 h. This effect continued up to 24 h in the case of Eudragit L30D coated PLGA microparticles. Results demonstrate that use of stabilizers during PLGA particle formulation, large porous particle for quick release of insulin and coating with Eudragit L30D resulted in a novel oral formulation for once a day delivery of insulin.     

Polyelectrolyte-coated alginate microspheres as drug delivery carriers for dexamethasone release

Alginate microspheres loaded with dexamethasone were prepared by the droplet generator technique. Important parameters affecting drug release, including initial drug content, the type of polyelectrolyte coating, and a combination of different ratios of coated and uncoated microspheres were investigated to achieve in vitro dexamethasone delivery with approximately zero order release kinetics, releasing up to 100% of entrapped drug within 1 month, wherein dexamethasone released at a steady rate of 4.83 μg/day after an initial burst release period. These findings imply that these polyelectrolyte-coated alginate microspheres show promise as release systems to improve biocompatibility and prolong lifetime of implantable glucose sensors.     

Compressed biodegradable matrices of spray-dried PLGA microspheres for the modified release of ketoprofen

A spray-drying technique was used to prepare poly(lactide-co-glycolide) (PLGA) drug loaded microspheres. Ketoprofen was chosen as a model NSAID drug. The microspheres were characterized in terms of morphology, drug content and release behaviour. The spray-dried particles were subject to a direct compression process for the preparation of biodegradable matrix tablets. The spray-dried powders were found to have good compaction properties. Tablets were also prepared from a mixture of microspheres and microcrystalline cellulose, mannitol and hydroxypropylmethylcellulose or sodium alginate. The release of ketoprofen in phosphate buffer (pH 7.4) was significantly sustained, indicating the suitability of using tabletted spray-dried PLGA microspheres for controlled drug delivery. The results show that spray-dried PLGA particles have promising properties as direct compression and release controlling excipients in matrix tablets for oral administration.     

Periodontal delivery of ipriflavone: new chitosan/PLGA film delivery system for a lipophilic drug

The aim of the present work was to design a film dosage form for sustained delivery of ipriflavone into the periodontal pocket.For this purpose, monolayer composite systems made of ipriflavone loaded poly(D,L-lactide-co-glycolide) (PLGA) micromatrices in a chitosan film form, were obtained by emulsification/casting/evaporation technique. Multilayer films, made of three layers of polymers (chitosan/PLGA/chitosan), were also prepared and compared to monolayer films for their "in vitro" characteristics. Morphology and physico-chemical properties of the different systems were evaluated. The influence of pH, ionic strength and enzymatic activity on film degradation, was also investigated. Significant differences in swelling, degradation and drug release were highlighted, depending on film structure and composition. In vitro experiments demonstrated that the composite micromatricial films represent a suitable dosage form to prolong ipriflavone release for 20 days.     

Different ratios of lactide and glycolide in PLGA affect the surface property and protein delivery characteristics of the PLGA microspheres with hydrophobic additives

This study investigated whether the surface quantities of the additives and protein delivery characteristics for protein-loaded PLGA 85 (85:15), PLGA75 (75:25) and PLGA 50 (50:50) microspheres with hydrophobic additives, phosphatidylcholine (PC) as a model, are affected by the different ratios of lactide and glycolide in PLGA polymers. By applying phospholipids analysis, surface PC quantities of the microspheres are 2.1 +/- 1.2, 1.2 +/- 0.3 and 1.0 +/- 0.7 Pg (n = 3) per mg of PLGA 85, PLGA 75 and PLGA 50 microspheres with PC addition, respectively, that are affected by the ratio of lactide and glycolide in PLGA. The addition of PC causes the decreased encapsulation efficiency (E.E.) of albumin of the microspheres and the decreased percentages of E.E. are negative correspondent to ratio of lactide and glycolide in PLGA (e.g. -13.5, -20.2 and -24.5% for PLGA 85, PLGA 75 and PLGA 50, respectively) compared with those without addition. The cumulative releases of albumin were influenced by the ratio of lactide and glycolide in PLGA for both PC addition and non-addition microspheres. Moreover, the additions of PC reduce the initial burst and cumulative releases of albumin of the microspheres compared with those of non-added ones. Further investigation suggests that resistant water uptake of PC added microspheres may play a role on affecting those reduced protein release behaviours. In conclusion, the different ratios of lactide and glycolide in PLGA affect the surface quantities of PC, E.E. and cumulative release profiles of albumin for the PLGA microspheres with PC addition. The results of the study may help the better practical applications for protein delivery of the microspheres with hydrophobic additives.     

Fabrication of microparticle protein delivery systems based on calcium alginate

Microparticle protein delivery systems based on calcium alginate were fabricated using a very convenient method, i.e. directly shredding the protein-loaded calcium alginate beads into microparticles in a commercial food processor for 3 min. Bovine serum albumin (BSA) as a model protein was encapsulated in the calcium alginate microparticles. The obtained protein-loaded microparticles were then coated with chitosan. This fabrication method offered high encapsulation efficiency and a high particle yield. Compared with beads, the microparticles exhibited a faster release rate in the initial release stage. By comparing the release profiles of uncoated beads/microparticles and chitosan-coated beads/microparticles, it was found that the releases from chitosan-coated beads/microparticles were slower. To examine whether the loaded protein denatured during the microparticle fabrication, trypsin was encapsulated in the calcium alginate microparticles and the bioactivity of trypsin released from the microparticles was measured.     

Evaluation of Mucoadhesive PLGA Microparticles for Nasal Immunization

In this study, hepatitis B surface antigen (HBsAg) loaded poly(lactic-co-glycolic acid) (PLGA) microparticles were prepared and coated with chitosan and trimethyl chitosan (TMC) to evaluate the effect of coating material for nasal vaccine delivery. The developed formulations were characterized for size, zeta potential, entrapment efficiency, and mucin adsorption ability. Plain PLGA microparticles demonstrated negative zeta potential. However, coated microparticles showed higher positive zeta potential. Results indicated that TMC microparticles demonstrated substantially higher mucin adsorption when compared to chitosan-coated microparticles and plain PLGA microparticles. The coated and uncoated microparticles showed deposition in nasal-associated lymphoid tissue under fluorescence microscopy. The coated and uncoated microparticles were then administered intranasally to mice. Immune-adjuvant effect was determined on the basis of specific antibody titer observed in serum and secretions using enzyme-linked immunosorbent assay. It was observed that coated particles showed a markedly increased anti-HBsAg titer as compared to plain PLGA microparticles, but the results were more pronounced with the TMC-coated PLGA microparticles.     

Improved bioavailability of orally delivered insulin using Eudragit-L30D coated PLGA microparticles

Large porous microparticles of PLGA entrapping insulin were prepared by solvent evaporation method and evaluated in diabetes induced rat for its efficacy in maintaining blood sugar level from a single oral dose. Incorporation of Eudragit L30D (0.03% w/v) in the external aqueous phase resulted in formation of pH responsive enteric coated polymer particles which release most of the entrapped insulin in alkaline pH. At acidic pH, release of insulin from uncoated PLGA microparticles and Eudragit L30D coated PLGA microparticles was 31.62?±?1.8% and 17.5?±?1.29%, respectively, for initial 30 min. However, in 24 h, in vitro released insulin from uncoated PLGA and Eudragit coated particles was 96.29?±?1.01% and 88.30?±?1%, respectively. Released insulin from composite polymer particles were mostly in monomer form without aggregation and was stable for a month at 37°C. Oral administration of insulin loaded PLGA (50 : 50) and Eudragit L30D coated PLGA (50 : 50) microparticles (equivalent to 25 IU insulin/kg of animal weight) in alloxan induced diabetic rats resulted in 37.3?±?11% and 62.7?±?3.8% reduction in blood glucose level, respectively, in 2 h. This effect continued up to 24 h in the case of Eudragit L30D coated PLGA microparticles. Results demonstrate that use of stabilizers during PLGA particle formulation, large porous particle for quick release of insulin and coating with Eudragit L30D resulted in a novel oral formulation for once a day delivery of insulin.     

海藻酸-壳聚糖-聚乳酸羟乙醇酸复合微球的制备及其对蛋白释放的调节

目的制备蛋白的海藻酸-壳聚糖-聚乳酸羟乙醇酸(PLGA)复合微球，以增加蛋白药物的包封率、减少突释和不完全释放。方法以牛血清白蛋白为模型药物采用修饰的乳化、醇洗法制备小粒径海藻酸微囊，再以壳聚糖孵育制得海藻酸-壳聚糖双层微囊，并进一步用PLGA包裹制得复合微球。采用微量BCA试剂盒测定蛋白浓度，考察其包封率及释放行为，改变各种制备因素调节微球的释放特性。结果复合微球粒径约30 μm，形态圆整。与单纯PLGA微球相比，包封率由60%-70%上升至80%以上。复合微球在磷酸盐缓冲液的1 h突释量由40%-50%下降至25%以下，在生理盐水中则进一步下降至5%以下。结论海藻酸-壳聚糖-PLGA复合微球提高了蛋白药物的包封率，减少了药物的突释，并可通过调节PLGA比例调节药物的释放。     

Microencapsulation of hemoglobin in chitosan-coated alginate microspheres prepared by emulsification/internal gelation

Chitosan-coated alginate microspheres prepared by emulsification/internal gelation were chosen as carriers for a model protein, hemoglobin (Hb), owing to nontoxicity of the polymers and mild conditions of the method. The influence of process variables related to the emulsification step and microsphere recovering and formulation variables, such as alginate gelation and chitosan coating, on the size distribution and encapsulation efficiency was studied. The effect of microsphere coating as well its drying procedure on the Hb release profile was also evaluated. Chitosan coating was applied by either a continuous microencapsulation procedure or a 2-stage coating process. Microspheres with a mean diameter of less than 30 microm and an encapsulation efficiency above 90% were obtained. Calcium alginate cross-linking was optimized by using an acid/CaCO(3) molar ratio of 2.5, and microsphere-recovery with acetate buffer led to higher encapsulation efficiency. Hb release in gastric fluid was minimal for air-dried microspheres. Coating effect revealed a total release of 27% for 2-stage coated wet microspheres, while other formulations showed an Hb release above 50%. Lyophilized microspheres behaved similar to wet microspheres, although a higher total protein release was obtained with 2-stage coating. At pH 6.8, uncoated microspheres dissolved in less than 1 hour; however, Hb release from air-dried microspheres was incomplete. Chitosan coating decreased the release rate of Hb, but an incomplete release was obtained. The 2-stage coated microspheres showed no burst effect, whereas the 1-stage coated microspheres permitted a higher protein release.     

Preparation and characterization of poly(D,L-lactic-co-glycolic Acid) microspheres containing flurbiprofen sodium

This study aimed to prepare biodegradable microspheres containing flurbiprofen sodium, a nonsteroidal anti-inflammatory drug (NSAID), as the drug delivery system to the periodontal pocket. Microspheres were prepared from biodegradable copolymers of poly (D,L-lactic-co-glycolic acid) (PLGA) using solvent evaporation method. The effects of the different copolymers and amounts of polyvinyl alcohol (PVA) as a dispersing agent on characteristics of the microspheres were evaluated. Although there was no correlation between microsphere size and amount of PVA, an optimum PVA concentration was essential to achieve narrower size distributions of microspheres. As the concentration of PVA increased, the drug loading of the microspheres increased. The effect of PVA on drug loading was found to be statistically significant for those microspheres prepared from PLGA 50:50 (p < 0.05). Regarding copolymer composition, PLGA 85:15 provided higher drug loading into the microspheres than PLGA 50:50 (p < 0.05). The recoveries of microspheres (60-80%) were affected neither by different PVA concentrations nor by copolymer compositions (p > 0.05). According to the first-order release rate constants of the microspheres, the microspheres of PLGA 50:50 released the drug at the highest rate consistently, with the highest hydrophilicity of this copolymer.     

Polysaccharide coated niosomes for oral drug delivery: formulation and in vitro stability studies

Non-ionic surfactant vesicles (niosomes) were prepared and appended with a polysaccharide cap using hydrophobic anchors. Hydrophobized polysaccharides, O-palmitoyl pullulan (OPPu) and cholesteroyl pullulan (CHPu) were anchored onto propranolol.HCL containing preformed niosomes. The coated niosomes were characterized for average vesicle size, size distribution, shape, encapsulation efficiency and in vitro release profile and were compared with their uncoated counterparts. No significant difference was observed in % encapsulation (P > 0.05 in a rank sum test) of polysaccharide coated and uncoated vesicles. In vitro release studies however, revealed a significant lowering (P < 0.01) of drug release for the coated systems in simulated gastric and intestinal fluids with a biphasic release profile. The influence of the hydrophobized polysaccharide cap on niosomal membrane integrity and stabilization against harsh bio-environment conditions was also investigated. The parameters investigated include detergent and bile (bile salts and fresh-pooled rat bile) challenge, freeze-thaw cycling, osmotic stress, and long term and shelf stability studies. It was seen that at higher bile salt concentrations and detergent content, uncoated niosomes underwent bilayer solubilization into intermediate micellar structures, whereas coated niosomes were able to maintain their structural integrity as reflected from their higher % latency for the entrapped water soluble agent. Similarly, freeze-thaw cycling could not bring any fusion or collapse of the niosomal membrane (unlike uncoated ones). Furthermore, the exceptional shelf stability of the coated vesicles both at 37 +/- 1 degrees and at 4 +/- 1 degrees C establishes the potential of polysaccharide coated niosomes as an oral delivery system for water-soluble agents. Results from OPPu and CHPu coated niosomal systems for their oral stability potential are compared.     

Microencapsulation of lipophilic drugs in chitosan-coated alginate microspheres.

Chitosan-coated alginate microspheres containing a lipophilic marker dissolved in an edible oil, were prepared by emulsification/internal gelation and the potential use as an oral controlled release system investigated. Microsphere formation involved dispersing a lipophilic marker dissolved in soybean oil into an alginate solution containing insoluble calcium carbonate microcrystals. The dispersion was then emulsified in silicone oil to form an O/W/O multiple phase emulsion. Addition of an oil soluble acid released calcium from carbonate complex for gelation of the alginate. Chitosan was then applied as a membrane coat to increase the mechanical strength and stabilize the microspheres in simulated intestinal media. Parameters studied included encapsulation yield, alginate concentration, chitosan molecular weight and membrane formation time. Mean diameters ranging from 500 to 800 micron and encapsulation yields ranging from 60 to 80% were obtained. Minimal marker release was observed under simulated gastric conditions, and rapid release was triggered by transfer into simulated intestinal fluid. Higher overall levels of release were obtained with uncoated microspheres, possibly due to binding of marker to the chitosan membrane coat. However the slower rate of release from coated microspheres was felt better suited as a delivery vehicle for oil soluble drugs.     

Preparation and characterization of alginate microspheres containing a model antigen

The goal of this study was to evaluate the technological feasibility of delivering antigen using alginate microspheres. The microspheres were prepared by an emulsification technique and fully characterized as antigen delivery system. Selection of appropriate parameters enabled the preparation of alginate microspheres with a mean diameter of 8 μm. The encapsulation efficiency of bovine serum albumin (BSA), chosen as model antigen, as well as the BSA loading were very high (>90% and 10% w/w, respectively). The process of encapsulation did not affect the molecular weight or the antigenicity of the entrapped antigen. The in vitro release profile showed a fast release rate of encapsulated BSA, particularly in phosphate buffered saline solution. However, a decrease of the release rate was observed when alginate microspheres were coated with poly(l-lysine) or prepared with higher alginate molecular weight. Therefore, alginate microspheres appear, technologically, a promising antigen delivery system.     

5-Fluorouracil-loaded chitosan coated polylactic acid microspheres as biodegradable drug carriers for cerebral tumours

The development of injectable microspheres for anticancer drug delivery into the brain is a major challenge. The possibility of entrapping 5-fluorouracil (5-FU) in chitosan coated monodisperse biodegradable microspheres with a mean diameter of 10-25 um was demonstrated. An emulsion of 5-FU (in water) and polylactic acid (PLA) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of chitosan (or poly-vinyl alcohol) with stirring using a high-speed homogenizer, for the formation of microspheres. 5-FU recovery in microspheres ranged from 44-66% depending on the polymer and emulsification systems used for the preparation. Scanning electron microscopy revealed that the chitosan coated microspheres had less surface micropores compared to PVA based preparations. The drug release behaviour from microspheres suspended in phosphate buffered saline exhibited a biphasic pattern. The amount of drug release was much higher initially (approximately 25%), followed by a constant slow release profile for a 30 days period of study. This chitosan coated PLA/PLGA microsphere formulation may have potential for the targeted delivery of 5-FU to treat cerebral tumours.     

Formulation and preliminary in vivo dog studies of a novel drug delivery system for the treatment of periodontitis

A novel drug delivery system for the treatment of periodontitis was developed using two components. The first was tetracycline base loaded into the microtubular excipient halloysite, which was coated with chitosan to further retard drug release. Encapsulation efficiencies of 32.5% were achieved with the loading procedure, with tetracycline base showing in vitro release for up to 50 days in simulated gingival crevicular fluid. The second component developed was a vehicle for the drug loaded coated halloysite, which was primarily based on the thermoresponsive polymer, poloxamer 407. A concentration of 20% was chosen with the thermoresponsivity of the system modified using PEG 20,000 so that the mobile product at room temperature would gel by temperature rise following syringing into a periodontal pocket. Retention of the overall system in the pocket was further improved by the addition of octyl cyanoacrylate (OCA). The thermoresponsivity of the poloxamer 407 system proved to be sensitive to the presence of added excipients with the levels of PEG 20,000 and OCA requiring modification in the presence of the halloysite component. A final formulation was developed which consisted of 200 mg of halloysite double loaded with tetracycline base and coated with chitosan, suspended in 1 ml of poloxamer 407 20% (w/w), PEG 20,000 0.5% (w/w), OCA 1.0% (w/w), water to 100%, adjusted to pH 4. The syringeability of this formulation at various temperatures was evaluated to ensure ease of delivery to the periodontal pocket. A stability study was performed to examine the change in thermoresponsivity over time, with the final formulation found to be stable for at least 9 months when stored at room temperature (approximately 20 degrees C). This formulation offered ease of delivery to the periodontal pocket and sustained release of the antibiotic for up to 6 weeks. The formulation had preliminary in vivo testing performed in dogs to determine levels of drug release, antimicrobial activity and retentive ability of the product. A wound pocket creation model was developed for the purposes of the trial. The product was easy to deliver to the pockets with application times of less than 1 min. Results showed the product was retained in the pocket for up to 6 weeks with effective tetracycline levels released locally over this time period, which achieved good antibacterial activity.     

5-Fluorouracil-loaded chitosan coated polylactic acid microspheres as biodegradable drug carriers for cerebral tumours

The development of injectable microspheres for anticancer drug delivery into the brain is a major challenge. The possibility of entrapping 5-fluorouracil (5-FU) in chitosan coated monodisperse biodegradable microspheres with a mean diameter of 10-25um was demonstrated. An emulsion of 5-FU (in water) and polylactic acid (PLA) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of chitosan (or poly-vinyl alcohol) with stirring using a high-speed homogenizer, for the formation of microspheres. 5-FU recovery in microspheres ranged from 44-66% depending on the polymer and emulsification systems used for the preparation. Scanning electron microscopy revealed that the chitosan coated microspheres had less surface micropores compared to PVA based preparations. The drug release behaviour from microspheres suspended in phosphate buffered saline exhibited a biphasic pattern. The amount of drug release was much higher initially (25%),followed by a constant slow release profile for a 30 days period of study. This chitosan coated PLA/PLGA microsphere formulation may have potential for the targeted delivery of 5-FU to treat cerebral tumours.     

Alginate coated chitosan nanoparticles are an effective subcutaneous adjuvant for hepatitis B surface antigen

We recently described a delivery system that is composed of a chitosan core to which the hepatitis B surface antigen (HBsAg) was adsorbed and subsequently coated with sodium alginate. In this present work, alginate coated chitosan nanoparticles were evaluated as a subcutaneous adjuvant for HBsAg. HBsAg loaded, alginate coated or uncoated chitosan nanoparticles, associated or not with CpGODN were subcutaneously administered to mice and several immunological parameters were evaluated. A high anti-HBsAg IgG titer (2271+/-120 mIU/ml), with the majority of antibodies being of Th2 type, was observed within group I, vaccinated with HBsAg loaded onto coated nanoparticles. However, regarding cellular immune response, no significant differences were observed for antigen-specific splenocyte proliferation or for the secretion of IFN-gamma and IL-4, when compared to the control group. The co-delivery of antigen-loaded nanoparticles in the presence of the immunopotentiator, CpG ODN 1826, resulted in an increase of anti-HBsAg IgG titers that was not statistically different from the first group; however, an increase of the IgG2a/IgG1 ratio from 0.1 to 1.0 and an increase (p<0.01) of the IFN-gamma production by the splenocytes stimulated with the HBV antigen was observed. The enhancement of the immune response observed with the antigen-loaded nanoparticles demonstrated that chitosan is a promising platform for parenteral HBsAg delivery and, when co-administered with the CpG ODN, resulted in a mixed Th1/Th2 type immune response.     

Alternate polyelectrolyte coating of chitosan beads for extending drug release

In the present study, we addressed the factors modifying ciprofloxacin release from multiple coated beads. Beads were prepared by simple ionic cross-linking with sodium tripolyphoshate and coated with alginate and/or chitosan to prepare single, double, or multilayered beads. The water uptake capacity depended on the nature of beads (coated or uncoated) and pH of test medium. The number of coatings given to the beads influenced ciprofloxacin release rate. The coating significantly decreased the drug release from the beads in comparison to uncoated beads (p < 0.001). When the beads were given three coatings, viz., alginate, chitosan, and again alginate, the drug release appeared to follow the pattern exhibited by colon-targeted drug delivery systems with time dependent release behavior. The increase in coating formed a barrier for easy ingress of dissolution medium into the bead matrix, reducing the diffusion of drug.