Influence of polymers on the bioavailability of microencapsulated celecoxib

Celecoxib, a selective COX-2 inhibitor, primarily used in treatment of osteoarthritis, rheumatoid arthritis and acute pain was encapsulated in microparticles composed of various polyesters, polymethacrylates or cellulose derivatives used alone or blended. The influence of polymers on microparticle mean diameter, encapsulation efficiency and in vitro and in vivo celecoxib release was investigated. Microparticles were in the size range 11–37?µm. Encapsulation efficiency was optimal due to poor aqueous solubility of celecoxib. Considering in vitro release, microparticles could be divided into drug delivery systems with fast and slow release profiles. Microparticles prepared with poly-ε-caprolactone, Eudragit® RS and low viscosity ethylcellulose, together with physical mixture of celecoxib with lactose and Celebrex®, were tested in vivo. Relative bioavailability of celecoxib was below 20% in all cases and was probably the consequence of a slow in vivo release of celecoxib from microparticles or low wettability in the case of Celebrex® and physical mixture.     

In vitro and in vivo evaluation of carbamazepine-loaded enteric microparticles

The objective of the study was to prepare and evaluate carbamazepine-loaded enteric microparticles produced by a novel coacervation method. An aqueous polymeric stabilizer solution was added to an organic carbamazepine/Eudragit L100-55 solution. Water, which is a non-solvent for the drug and the enteric polymer, caused phase separation and the formation of coacervate droplets. These droplets hardened into microparticles upon further addition of the aqueous phase. The microparticles were characterized with respect to particle size distribution, morphology, encapsulation efficiency, yield, physical state and physical stability of the drug, wettability, in vitro release and in vivo bioavailability. Microparticles with a smooth surface and dense structure were obtained with high encapsulation efficiency (>85%) and yield (>90%). The drug was in a non-crystalline state in the matrix and physically stable for 5 months at room temperature. Under sink conditions, the drug dissolution rate from the microparticles was significantly enhanced compared to the physical mixture and to the pure drug; the release profile of the microparticles was stable after 5 months. Under non-sink conditions, an unstable supersaturated solution of carbamazepine was obtained from microparticles with the subsequent formation of needle-shaped crystals. The high surface area and good wettability of the microparticles, the non-crystalline state of the drug in the matrix and the fast dissolution rate contributed to a significantly enhanced oral bioavailability from the microparticles when compared to the physical mixture.     

Preparation of naproxen–ethyl cellulose microparticles by spray-drying technique and their application to textile materials

Abstract

The objective of this study is to develop a new textile-based drug delivery system containing naproxen (NAP) microparticles and to evaluate the potential of the system as the carrier of NAP for topical delivery. Microparticles were prepared by spray-drying using an aqueous ethyl cellulose dispersion. The drug content and entrapment efficiency, particle size and distribution, particle morphology and in vitro drug release characteristics of microparticles were optimized for the application of microparticles onto the textile fabrics. Microparticles had spherical shape in the range of 10–15?μm and a narrow particle size distribution. NAP encapsulated in microparticles was in the amorphous or partially crystalline nature. Microparticles were tightly fixed onto the textile fabrics. In vitro drug release exhibited biphasic release profile with an initial burst followed by a very slow release. Skin permeation profiles were observed to follow near zero-order release kinetics.     

Anticoagulant activity of heparin following oral administration of heparin-loaded microparticles in rabbits

Heparin-loaded microparticles, prepared according to the double emulsion method with biodegradable (PCL and PLGA) and nonbiodegradable (Eudragit RS and RL) polymers used alone or in combination, with or without gelatin, were characterized in vitro and in vivo after oral administration in rabbits. The entrapment efficiency and the release of heparin were determined by a colorimetric method with Azure II. The antifactor Xa activity of heparin released in vitro after 24 h was assessed. After oral administration of heparin-loaded microparticles in rabbits, the time course of modification of the clotting time estimated by the activated partial thromboplastin time (APTT) was followed over 24 h. Microparticles with a size ranging from 80 to 280 microm were obtained. Heparin entrapment efficiency as well as heparin release depended on both the nature of the polymers and the presence of gelatin. The Eudragit polymers increased the drug loading but slowed down the heparin release, whereas gelatin accelerated the release. No change in clotting time was observed after oral administration of gelatin microparticles. Heparin-loaded microparticles prepared with blends of PLGA and Eudragit displayed a prolonged duration of action characterized by a twofold increase in APTT and a enhancement of absorption. This study demonstrated the feasibility of encapsulating heparin within polymeric particles, and the significant increase in APTT confirmed the oral absorption of heparin released from polymeric microparticles.     

Microparticles prepared by grinding of polymeric films

Microparticles were prepared by a film grinding method, whereby thin drug-containing ethylcellulose films were cryogenically ground into microparticles. The particle size and shape of the microparticles could be controlled by the thickness of the films and by the milling time. The encapsulation efficiency as well as the in vitro drug release depended on the physical state of the drug in the ethylcellulose matrix (dispersed vs dissolved). Increased drug loadings and decreased particle size and film thickness increased the drug release. Microparticles prepared from cast films were more dense and had a slower drug release compared to microparticles prepared from sprayed films or from films prepared from an aqueous colloidal ethylcellulose dispersion, Aquacoat ECD. Lamination of the drug-containing film with a drug-free polymer layer on both sides resulted in a reduced drug release. Hydrophilic plasticizers acted as pore-formers and accelerated drug release, while lipophilic plasticizers reduced the drug release. The solubility of the drug in the organic polymer solution was one of the main parameters to achieve high encapsulation efficiencies and extended drug release, while dispersed drug was released much faster. The drug release from microparticles prepared by film grinding was faster than from microparticles prepared by the solvent evaporation method. The faster release was attributed to the fractured surface of the ground particles. Grinding of microparticles, which were prepared by the solvent evaporation, also resulted in a faster release.     

Development of HPMC and Eudragit S100 blended microparticles containing sodium pantoprazole

Pantoprazole is used in the treatment of acid related disorders and Helicobacter pylori infections. It is activated inside gastric parietal cells binding irreversibly to the H+/K(+)-ATPase. In this way, pantoprazole must be absorbed intact in gastro-intestinal tract, indicating that enteric delivery systems are required. The purpose of this study was to prepare pantoprazole-loaded microparticles by spray-drying using a blend of Eudragit S100 and HPMC, which can provide gastro-resistance and controlled release. Microparticles presented acceptable drug loading (120.4 mgg(-1)), encapsulation efficiency (92.3%), surface area (49.0 m2g(-1)), and particle size (11.3 microm). DSC analyses showed that the drug is molecularly dispersed in the microparticles, and in vivo anti-ulcer evaluation demonstrated that microparticles were effective in protecting stomach against ulceration. Microparticles were successfully tabletted using magnesium stearate. In vitro gastro-resistance study showed that microparticles stabilized pantoprazole in 62.0% and tablets in 97.5% and provided a controlled release of the drug.     

Preparation and characterization of chitosan-treated alginate microparticles incorporating all-trans retinoic acid

Chitosan treated alginate microparticles were prepared with the purpose of incorporating all-trans retinoic acid (ATRA) using an inexpensive, simple and fast method, enhancing dermal localization and sustaining the release of ATRA into the skin. Microparticles characterization, drug-polymer interaction, release profile and in vitro skin retention were investigated. Microparticles presented spherical shape and drug loading capacity of 47%. The drug content of these microparticles was affected by ATRA concentration and by the solvent used and it was more weakly affected by chitosan concentration. The release of ATRA was also affected by chitosan concentration. Microparticles prepared with 0.4% chitosan (w/w) resulted in drug release with a more sustained profile. The results of in vitro retention studies showed that chitosan treated alginate microparticles decreased the drug retention in the stratum corneum (SC), where occur the skin irritation, but maintained the ATRA concentration in the deeper skin layers, where occur the pathologies treated with ATRA. Then, the microparticles developed in this work can be a good candidate to improve the topical therapy with retinoid.     

In vitro characterization of polyorthoester microparticles containing bupivacaine

Laboratory-scale spray-congealing equipment was utilized to fabricate injectable microparticles consisting of polyorthoester and bupivacaine. Operating conditions for the spray-congealing process were optimized to produce microparticles with the desired shape and particle size to yield acceptable syringeability and injectability. Characterizations were performed to determine the chemico-physical properties of polyorthoester before and after microparticle fabrication. Microparticles with different drug loadings and comparable particle sizes were produced, and their in vitro drug-release profiles were determined. The in vitro drug release of microparticles with a high drug loading was markedly faster than those with a low drug loading. This is partially attributed to a more significant initial burst-drug release of the microparticles with a high drug loading. The microparticles have demonstrated the potential to be used for long-acting postsurgery pain management by local injection.     

Chitosan and poly(methyl vinyl ether-co-maleic anhydride) microparticles as nasal sustained delivery systems

An original dosage form for nasal delivery based on the encapsulation of hydrophilic drug in chitosan-poly(methyl vinyl ether-co-maleic anhydride) (CH-PVM/MA) microparticles prepared by spray-drying technique was developed. Microparticles were characterized in terms of morphology, size, swelling properties, encapsulation efficiency and drug release. The physical state of the drug and the polymer was determined by scanning electron microscopy (SEM) and infrared spectroscopy (IR). Propranolol hydrochloride (PH) was a β-blocker, used for the treatment of hypertension and was chosen as a model of hydrophilic drug. SEM studies showed spherical particles with smooth surfaces for chitosan hydrochloride (CH-HCl), whereas rather gross surface defects resulted from the incorporation of poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA). In vitro release studies revealed a sustained release of propranolol HCl from microparticles and in particular chitosan hydrochloride provided the lowest release of drug.     

Chitosan and poly(methyl vinyl ether-co-maleic anhydride) microparticles as nasal sustained delivery systems.

An original dosage form for nasal delivery based on the encapsulation of hydrophilic drug in chitosan-poly(methyl vinyl ether-co-maleic anhydride) (CH-PVM/MA) microparticles prepared by spray-drying technique was developed. Microparticles were characterized in terms of morphology, size, swelling properties, encapsulation efficiency and drug release. The physical state of the drug and the polymer was determined by scanning electron microscopy (SEM) and infrared spectroscopy (IR). Propranolol hydrochloride (PH) was a beta-blocker, used for the treatment of hypertension and was chosen as a model of hydrophilic drug. SEM studies showed spherical particles with smooth surfaces for chitosan hydrochloride (CH-HCl), whereas rather gross surface defects resulted from the incorporation of poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA). In vitro release studies revealed a sustained release of propranolol HCl from microparticles and in particular chitosan hydrochloride provided the lowest release of drug.     

Development of microparticles prepared by spray-drying as a vaccine delivery system against brucellosis

The antigenic extract Hot Saline from Brucella ovis was microencapsulated by the spray-drying technique with different polyesters (poly-lactide-co-glycolide RG502H [PLGA], and blends with poly- epsilon -caprolactone [PEC]) in order to obtain microparticles smaller than 5 microm. Microparticles were tested for encapsulation efficiency, release studies, acidification of the in vitro release medium, and in vitro J744-macrophage experiments (phagocytosis and toxicity of the preparations) to determine the optimal formulation for vaccination purposes. Formulation containing no PCL showed the highest encapsulation efficiency, although the differences were not significant. The in vitro release kinetics were characterized by a high burst effect after 1 h of incubation, followed by a slow and continuous release. For the formulation based on PLGA, the pH of the medium during release dropped from 7.4 to 3.5 while the presence of PEC attenuated the pH drop. All formulations showed light toxicity by the MTT assay, but differences were observed in terms of phagocytosis, as particles prepared with PEC showed the higher uptake by J744-macrophages and cell respiratory burst, determined by oxygen peroxide release. All these characteristics suggest that the microparticulated antigenic formulation containing the higher ratio of PEC is susceptible to be used in animal vaccination studies.     

Biodegradable microparticulate system of captopril

Albumin microparticles have found many applications in diagnosis and treatment in recent years and more than 100 diagnostic agents and drugs have been incorporated into albumin microparticles. In the present study, bovine serum albumin (BSA) based microparticles bearing captopril were prepared by an emulsification-heat stabilization technique. Four batches of microparticles with varying ratio of drug and polymer were prepared. The prepared microparticles were studied for drug loading, particle size distribution, in vitro release characteristics, in vivo tissue distribution study and stability studies. The microparticles had mean diameter between 2 and 11 microm of which more than 70% were below 5 microm and incorporation efficiency of 41-63% was obtained. In vitro release profile for formulations containing captopril-loaded albumin microparticles with heat stabilizing technique shows slow controlled release up to 24 h. The in vivo result of drug-loaded microparticles showed preferential drug targeting to liver followed by lungs, kidneys and spleen. Stability studies showed that maximum drug content and closest in vitro release to initial data were found in the formulation stored at 4 degrees C. In the present study, captopril-loaded BSA microparticles were prepared and targeted to various organs to a satisfactory level and were found to be stable at 4 degrees C.     

Preparation of prolonged release clarithromycin microparticles for oral use and theirin vitro evaluation

Prolonged release microparticles of clarithromycin (CL) were prepared using Eudragit RL 100 and RS 100 by spray-drying and casting-drying techniques. For the characterization of those microparticles, preparation yield, particle size distribution, X-ray diffraction, thermal behavior, active agent content and in vitro dissolution from the microparticles were performed. HPLC was used for the assay of clarithromycin and the assay method was validated. All the formulations obtained showed prolonged release when compared to pure clarithromycin. Microparticles prepared by spray-drying method had a slower release compared to those of casting-drying method. Spray-drying method seems to be a more suitable method to prepare microparticles for prolongation in release.     

Methacrylate micro/nano particles prepared by spray drying: a preliminary in vitro/in vivo study

Delivery systems controlling drug release only in the colon holds great promises since they improve utilization of drug and decrease the dosing times comparison with conventional forms. The aim of the present study was to prepare polymeric microparticles on the basis of Ciprofloxacin via oral route for the treatment of inflammatory bowel disease. Ciprofloxacin was selected because of its extensive coverage for intestinal flora, relatively favorable side-effect profile and preliminary data suggesting its efficacy in the treatment of active Crohn's Disease. Microparticles were prepared using different acrylic compounds, namely Eudragit® RL (PO) and RS (PO) and a mixture of both. Spray-drying was used as a preparation method of Ciprofloxacin/Eudragit® microparticles using a Mini Spray Dryer B-290 (Büchi, Postfach, Switzerland). In vitro dissolution studies were performed to choose the best formulation and selected microparticles were characterized by size and morphology by environmental scanning electron microscopy. Yield and encapsulation efficiency were calculated and in vivo/ex vivo experiments were investigated both of which suggest that selected microparticles can be used for colon targeting of drugs increasing residence time of the drug in the affected area.     

Highly loaded, sustained-release microparticles of curcumin for chemoprevention

Curcumin, a dietary polyphenol, has preventive and therapeutic potential against several diseases. Because of the chronic nature of many of these diseases, sustained-release dosage forms of curcumin could be of significant clinical value. However, extreme lipophilicity and instability of curcumin are significant challenges in its formulation development. The objectives of this study were to fabricate an injectable microparticle formulation that can sustain curcumin release over a 1-month period and to determine its chemopreventive activity in a mouse model. Microparticles were fabricated using poly(D, L-lactide-co-glycolide) polymer. Conventional emulsion solvent evaporation method of preparing microparticles resulted in crystallization of curcumin outside of microparticles and poor entrapment (～1%, w/w loading). Rapid solvent removal using vacuum dramatically increased drug entrapment (～38%, w/w loading; 76% encapsulation efficiency). Microparticles sustained curcumin release over 4 weeks in vitro, and drug release rate could be modulated by varying the polymer molecular weight and/or composition. A single subcutaneous dose of microparticles sustained curcumin liver concentration for nearly a month in mice. Hepatic glutathione-s-transferase and cyclooxygenase-2 activities, biomarkers for chemoprevention, were altered following treatment with curcumin microparticles. The results of these studies suggest that sustained-release microparticles of curcumin could be a novel and effective approach for cancer chemoprevention.     

Effect of solvent composition during preparations on the characteristics of enoxacin microparticles.

We have studied the effect of the solvent system during preparation on the morphology, encapsulation efficiency, and release characteristics of enoxacin microparticles intended for localized delivery to the bone for the treatment of bone infections. Microparticles of enoxacin were formulated using poly(glycolic acid-co-DL-lactic acid) (PGLA) of different viscosity grades by the solvent-evaporation technique. Microparticles prepared with pure dichloromethane had smoother surfaces and less tendency to aggregate than microparticles prepared with dichloromethane-acetone solvent mixtures, which had porous surfaces. Approximately 65% of the microparticles prepared with pure dichloromethane were < 125 microm in diameter compared with 16% (approx.) of microparticles prepared with dichloromethane-acetone mixtures. Increasing the proportion of acetone from dichloromethane-acetone, 10:0, to dichloromethane-acetone, 1:1, resulted in an increase in encapsulation efficiency from 25 to 37%, and an increase in the yield of microparticles harvested from 39 to 51%. Although a further increase in the amount of acetone to dichloromethane-acetone, 1:9, had no significant effect on the yield, aggregation, or fraction of microparticles below 125 microm in diameter, the encapsulation efficiency increased to 56%. Approximately 55% of enoxacin was released in 24 h for microparticles prepared with dichloromethane-acetone, 1:9, compared with 100% release in 10h and 2h for microparticles of the same size range prepared with dichloromethane-acetone, 1:1, and dichloromethane-acetone, 10:0, respectively. The results suggest that the composition of the dichloromethane-acetone solvent system significantly influences the encapsulation efficiency and the rate of release of enoxacin from microparticles. This is important for the formulation of sustained-release enoxacin microparticles for the localized treatment of osteomyelitis.     

Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model

We have previously reported that repeated oral doses of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, reduced diabetes-induced retinal vascular endothelial growth factor (VEGF) expression [Ayalasomayajula, S.P., Kompella, U.B., 2003. Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model. Eur J Pharmacol 458, 283-289] and that retinal celecoxib delivery can be improved by several-fold following subconjunctival administration [Ayalasomayajula, S.P., Kompella, U.B., 2004. Retinal delivery of celecoxib is several-fold higher following subconjunctival administration compared to systemic administration. Pharm Res 21, 1797-1804]. The objective of the current study was to determine whether polymeric microparticles of celecoxib sustain retinal drug levels following subconjunctival administration and alleviate diabetes-induced oxidative stress in a streptozotocin-induced diabetic rat model. Biodegradable poly (lactide-co-glycolide) (PLGA; 85:15) microparticles of celecoxib were prepared using solvent evaporation method and characterized for their size, morphology, encapsulation efficiencies, and in vitro release. The celecoxib-PLGA microparticles or solution containing 75 microg of celecoxib was administered subconjunctivally to one eye (ipsilateral) of Sprague Dawley rats and drug levels in the retina, vitreous, lens, and cornea of ipsilateral and contralateral eyes were determined on 1, 7, and 14 days using high-performance liquid chromatography (HPLC). The effect of subconjunctivally administered celecoxib-PLGA microparticles on oxidative stress in day 14 diabetic rat retinas was determined by measuring the retinal glutathione (reduced (GSH) and oxidized (GSSG)), thiobarbituric acid reactive substances, and 4-hydroxynonenal levels using spectrofluorometric and colorimetric methods. Solvent evaporation method produced spherical celecoxib-PLGA microparticles with mean diameters of 3.9+/-0.6 microm and 68.5% loading efficiency. These microparticles sustained celecoxib release during the 49-day in vitro release study. Subconjunctivally administered celecoxib-PLGA microparticles sustained retinal and other ocular tissue drug levels during the 14-day study in rats. No detectable celecoxib levels were observed in the contralateral eye. The celecoxib-PLGA microparticles significantly inhibited the diabetes-induced increases in thiobarbituric acid reactive substance (P=0.012) and 4-hydroxynonenal levels (P=0.029). The particles also inhibited the GSH depletion and the increase in GSSH/GSH ratio associated with diabetes but the effects were not statistically significant (P=0.12). Thus, following subconjunctival administration, celecoxib-PLGA microparticles sustained retinal celecoxib delivery and inhibited diabetes-induced retinal oxidative damage, indicating their potential usefulness in treating diabetes-induced retinal abnormalities.     

Optimization of topical cidofovir penetration using microparticles

Cidofovir is a new class of antiviral agent with potent in vitro and in vivo activity against a broad spectrum of herpes viruses. The aim of this work was to obtain a prolonged therapeutic effect of cidofovir in the basal epidermis after its topical application. For this purpose, poly(lactide-co-glycolide) (PLGA) microparticles were prepared by solvent evaporation and spray-drying methods. Microparticles prepared by spray-drying showed a encapsulation efficiency of 80%. Conversely, for all the microspheres prepared by the W/O/W solvent evaporation method the encapsulation efficiency was low. Also, microparticles prepared by spray-drying showed a higher burst release. Skin penetration and distribution experiments were carried out with cidofovir-loaded microparticles prepared by spray-drying, since these carriers presented the best characteristics in terms of size and encapsulation efficiency. A cidofovir solution in 0.2% PVA served for comparison. Penetration experiments were carried out in Franz type diffusion cells with an available diffusion area of 1.76 cm(2), using porcine skin. The results obtained showed that the amount of cidofovir penetrated, over a 24 h time period, was higher with the drug solution than with microparticles. Cidofovir distribution in porcine skin, after topical application of microparticles and drug solution for 24 h, was determined by horizontal slicing of the skin. The profiles obtained for the two formulations showed that the quantity of cidofovir retained in the skin decreased with the depth. Besides the amount of cidofovir found in the basal epidermis (120-150 microm) was much higher with microparticles than with the control solution. These data showed that cidofovir-loaded microparticles could improve cidofovir topical therapy since these vehicles increased drug retention in the basal epidermis and decreased its penetration through the skin.     

Development and characterization of lipid microparticles as a drug carrier for somatostatin

Somatostatin, a therapeutic peptide with a high therapeutical potential but a very short biological half-live was encapsulated within microparticles by a modified solvent evaporation method and a melt dispersion method without the use of organic solvent. As the use of synthetic polymer matrix materials often goes along with detrimental effects on incorporated peptides, we investigated the potential of physiological lipids such as glyceryl tripalmitate (Dynasan 116) as an alternative matrix material. The two preparation methods were evaluated with respect to surface topography, particle size distribution, encapsulation efficiency, in-vitro release behavior and modification of the resulting microparticles. Microparticles with a suitable particle size distribution for i.m. or s.c. injection could be prepared with both methods. The encapsulation efficiency of the peptide into glyceryl tripalmitate microparticles was substantially influenced by the preparation method and the physical state of the peptide to be incorporated. The melt dispersion technique and the incorporation of the drug as an aqueous solution gave the best results with actual drug loadings up to 9% and an encapsulation efficiency of approximately 90%. Microparticles prepared by the melt dispersion technique crystallized in the unstable alpha-modification. The peptide was released almost continuously over 10 days with no burst effect, 20-30% of the incorporated somatostatin was not released in the monitored time period.     

Polyester Microparticles as a Vaccine Delivery System for Brucellosis: Influence of the Polymer on Release,Phagocytosis and Toxicity

Microparticles, containing an antigenic complex from Brucella ovis (HS), were evaluated for vaccine purposes against brucellosis. They were prepared by the double emulsion solvent evaporation method using two different polyesters, poly-lactide- co -glycolide acid (75:25; RG 756) and poly- ε -caprolactone. The encapsulation efficiency and release of HS from the microparticles, their capacity to be phagocytosed and also their toxicity on murine monocytes J774.2 were investigated. Both polymers lead to smooth and spherical sub-5 μ m particles, with approximately 30% of the antigen initial dose encapsulated. SDS-PAGE and immunoblot of extracted antigens confirmed that the apparent molecular weight and antigenicity remained unaltered after the encapsulation procedure. However, the in vitro release of the antigens differed among them. The release profile for PLGA microparticles was continuous, whereas PEC ones released the antigens in a triphasic release pattern. Phagocytosis was clearly influenced by the hydrophobicity of the polymer, increasing in the case of PEC microparticles. Toxicity assay showed that both types of microparticles induced similar levels of mitochondrial damage. In conclusion, HS-PEC microparticles could be used as an effective vaccine against brucellosis, as the antigen is released in boosters and they are greatly phagocytosed by macrophages.