Formulation and optimization of a single-layer coat for targeting budesonide pellets to the descending Colon.

The current budesonide formulations are inadequate for addressing left-sided colitis, and patients might hesitate to use an enema for a prolonged time. This study focuses on developing a single-layer coating for budesonide pellets targeting the descending colon. Pellets containing budesonide (1.5%w/w), PVP K30 (5%w/w), lactose monohydrate (25%w/w) and Avicel pH 102 (68.5%w/w) were prepared using extrusion spheronization technique. Coating formulations were designed using response surface methodology with pH and time-dependent Eudragits. Dissolution tests were conducted at different pH levels (1.2, 6.5, 6.8, and 7.2). Optimal coating formulation, considering coating level and the Eudragit (S + L) ratio to the total coating weight, was determined. Budesonide pellets were coated with the optimized composition and subjected to continuous dissolution testing simulating the gastrointestinal tract. The coating, with 48% S, 12% L, and 40% RS at a 10% coating level, demonstrated superior budesonide delivery to the descending colon. Coated pellets had a spherical shape with a uniform 30 µm thickness coating, exhibiting pH and time-dependent release. Notably, zero-order release kinetics was observed for the last 9 h in colonic conditions. The study suggests that an optimized single-layer coating, incorporating pH and time-dependent polymers, holds promise for consistently delivering budesonide to the descending colon.

Supercritical CO2 versus water as an antisolvent in the crystallization process to enhance dissolution rate of curcumin.

Antisolvent crystallization approach using either water (in conventional crystallization process (WAS)), or supercritical CO2 (in supercritical anti-solvent crystallization (SCAS)), was employed in presence of hydroxypropyl methylcellulose (HPMC) to enhance the dissolution of curcumin. The impact of pressure, temperature and depressurization time on the SCAS process was studied using the Box-Behnken design to achieve the highest saturation solubility. A physical mixture of curcumin-HPMC was prepared for comparison purposes. Saturation solubility, scanning electron microscopy, differential scanning calorimetry, X-ray diffraction analysis and Fourier transform infrared spectroscopy were conducted to characterize the solid-state characteristics of the crystallized samples. Dissolution studies helped in ascertaining the effects of the crystallization techniques on the performance of the formulation. Curcumin crystalized by different antisolvent displayed varied shapes, sizes, saturation solubility's and dissolution properties. In SCAS process, the maximum saturation solubility (2.83 µg/mL) was obtained when the pressure, temperature and depressurization time were 275 bars, 55 °C, and 22 min respectively. The SCAS samples showed the highest dissolution (70%) in 30 min compared to WAS (27%), physical mixture (18%) and unprocessed curcumin (16%). The improved dissolution rate of SCAS sample originates from the development of sponge-like particles with augmented porosity, decreased crystallinity as well as increased solubility of curcumin.

Optimization study of combined enteric and time-dependent polymethacrylates as a coating for colon targeted delivery of 5-ASA pellets in rats with ulcerative colitis.

Formulation design for colon-specific delivery of 5-aminosalicylic acid (5-ASA) could bring some therapeutic benefits in the treatment of ulcerative colitis (UC). In the current study, a 32 full factorial design was used to predict optimum coating composed of two enteric (poly methacrylic acid, methyl methacrylates 1:2 and 1:1) and time-dependent (poly ethyl acrylate, methyl methacrylate, trimethylammonio ethyl methacrylate chloride 1:2:0.1) polymethacrylates for colon-specific delivery of 5-ASA pellets. A unique coating composition and coating level predicted by the model was applied onto either inulin-free 5-ASA pellets or inulin-bearing 5-ASA pellets and the coated pellets were examined by dissolution test in-vitro. The coated pellets were also tested in a rat model of UC and compared with the a commercially available colonic delivery system of 5-ASA. The ratio of the two enteric polymethacrylates and time-dependet polymethacrylate of 16:64:20 w/w at a coating level of 15% was discovered as the optimum coating for delivery of 5-ASA pellets to the colon. In general, the coated pellets offered a better therapeutic outcome compared to commercially available colonic delivery system of 5-ASA and uncoated pellets in terms of colitis activity index and the colon's tissue enzymes of MDA and GSH. It seems that the coating composed of enteric and pH-dependent polymethacrylates could tune up the rate of drug release from 5-ASA-coated pellets and trigger drug release based on pH and time.

Preparation and Characterization of a Novel Multiparticulate Dosage Form Carrying Budesonide-Loaded Chitosan Nanoparticles to Enhance the Efficiency of Pellets in the Colon.

An attempt was made to conquer the limitation of orally administered nanoparticles for the delivery of budesonide to the colon. The ionic gelation technique was used to load budesonide on chitosan nanoparticles. The nanoparticles were investigated in terms of size, zeta potential, encapsulation efficiency, shape and drug release. Then, nanoparticles were pelletized using the extrusion-spheronization method and were investigated for their size, mechanical properties, and drug release. Pellets were subsequently coated with a polymeric solution composed of two enteric (eudragit L and S) and time-dependent polymers (eudragit RS) for colon-specific delivery. All formulations were examined for their anti-inflammatory effect in rats with induced colitis and the relapse of the colitis after discontinuation of treatment was also followed. The size of nanoparticles ranged between 288 ± 7.5 and 566 ± 7.7 nm and zeta potential verified their positive charged surface. The drug release from nanoparticles showed an initial burst release followed by a continuous release. Pelletized nanoparticles showed proper mechanical properties and faster drug release in acidic pH compared with alkaline pH. It was interesting to note that pelletized budesonide nanoparticles released the drug throughout the GIT in a sustained fashion, and had long-lasting anti-inflammatory effects while rapid relapse was observed for those treated with conventional budesonide pellets. It seems that there is a synergistic effect of nanoformulation of budesonide and the encapsulation of pelletized nanoparticles in a proper coating system for colon delivery that could result in a significant and long-lasting anti-inflammatory effect.

The Effect of Thermal-Treating on Drug Release from Sustained Release Alginate-Eudragit RS Matrices.

Purpose: The main objective of the present study was to develop the colonic delivery system for 5-aminosalicylic acid (5-ASA) as an anti-inflammatory drug. Methods: Matrix pellets containing various proportions of alginate, calcium and Eudragit® RS were prepared by extrusion-spheronization technique. Thermal treatment was used to investigate the effect of the curing process on the surface morphology, mechanical and physicochemical properties and in vitro drug release profile of pellets. Based on the obtained results optimal formulations were selected to coating by the Eudragit® RS and subjected to a subsequent continuous dissolution test. Results: Image analysis and also scanning electron microscopy results proved acceptable morphology of the pellets. The fourier transform infrared spectroscopy and differential scanning calorimetry studies ruled out any interactions between the formulation's components. Curing process did not alter the mechanical properties of pellets. The release rate of the drug from matrices was prolonged due to the decreased porosity of cured pellets. Furthermore, selected cured pellets which coated with Eudragit® RS, prevented undesired premature drug release. Conclusion: Formulation containing 17.5% calcium, 17.5% alginate, and a coating level of 10% demonstrated enhanced drug release so that provided resistance to acidic conditions, allowing complete drug release in alkaline pH, mimicking colonic environment. The slow and consistent drug release from this formulation could be used for treatment of a broader range of Inflammatory bowel disease (IBD) patients especially in whom colonic pH levels have been measured at lower than pH 7.0.

Application of inulin/Eudragit RS in 5-ASA pellet coating with tuned, sustained-release feature in an animal model of ulcerative colitis.

A tunable release of 5-aminosalicylic acid (5-ASA) could bring therapeutic benefits in the treatment of inflammatory bowel disease (IBD). A 32 factorial design was used to achieve a tuned delivery of 5-ASA pellets in the small and large intestine using a coating composed of inulin/Eudragit RS (RS). The ratio of inulin/RS and coating level were independent variables while the dependent variables were the percent of drug release at pH 1.2 in 2 h and total release of drug in 10 h at pH 6.8. 5-ASA release from pellets was examined at different pH levels and the therapeutic efficacy of the optimum pellets was compared to 5-ASA pellets of Pentasa in rats with ulcerative colitis. The inulin/RS of 18/82 at a coating level of 16% was found to be the optimum for delivery of the drug to the small and large intestine. The coated pellets offered a superior therapeutic outcome compared to uncoated pellets and Pentasa in terms of colitis activity index (CAI), and the colon's tissue enzymes of GSH and MDA. The optimum coating composed of inulin and RS could offer a tuned sustained release of 5-ASA throughout the small and large intestine with the sensitivity of drug release to microbial degradation.

Screening of different polysaccharides in a composite film based on Eudragit RS for subsequent use as a coating for delivery of 5-ASA to colon.

This study aims at identifying the more suitable polysaccharide in a composite film based on Eudragit RS for 5-ASA delivery to the colon. Different polysaccharides (pectin, chitosan, guar, inulin, and dextran) were examined. The mechanical properties, swelling index, loss of film mass and permeability of films to 5-ASA were recorded at simulating gastric (SGF), intestinal (SIF) and colonic fluids (SCF). Films containing inulin or dextran were more flexible and showed better mechanical properties. Films containing chitosan, pectin or guar exhibited extensive swelling in SGF and SIF. Loss of film mass and drug permeation was more pronounced in SCF than SIF for all samples indicating their sensitivity to colonic bacteria. However, films containing inulin or dextran showed minimum swelling index in SGF and SIF and the highest ratio of permeability in SCF to SIF. Accordingly, inulin and dextran are suggested as appropriate polysaccharides in a film based on Eudragit RS for colon delivery of 5-ASA.

Synergistic effect of polyethylene glycol and superdisintegrant on dissolution rate enhancement of simvastatin in pellet formulation.

Slow dissolution is a major drawback for poorly water-soluble drugs when they are extruded-spheronized with microcrystalline cellulose (MCC). Therefore, the aim of the current study was to explore excipients to enhance the dissolution of simvastatin without compromising the extrudability and sphericity of pellets. Pellets containing simvastatin, MCC and polyethylene glycols (PEGs) or superdisintegrants were prepared by extrusion-spheronization and their micromeritics and mechanical properties, drug release and solid state of simvastatin were studied. All formulations produced pellets with reasonable size and sphericity. Generally, the inclusion of PEG and superdisintegrants decreased crushing strength and elastic modulus of pellets and increased the dissolution rate of simvastatin. A substantial increase in dissolution rate was observed when a combination of PEG and superdisintegrant was used due to the formation of more porous matrix, faster disintegration and remarkable reduction in drug crystallinity. It was interesting to note that the use of PEG and superdisintegrant had a synergistic effect on the dissolution enhancement of simvastatin in pellet formulation. The results of this study confirmed that a simple method of extrusion-spheronization can be employed to enhance the dissolution of simvastatin in multi particulates dosage form which can also be employed for other poorly water-soluble drugs.

A review on 5-aminosalicylic acid colon-targeted oral drug delivery systems.

Site-specific colon drug delivery is a practical approach for the treatment of local diseases of the colon with several advantages such as rapid onset of action and reduction of the dosage of the drug as well as minimization of harmful side effects. 5-aminosalicylic acid (5-ASA) is a drug of choice in the treatment of inflammatory bowel disease and colitis. For the efficient delivery of this drug, it is vital to prevent 5-ASA release in the upper part of the gastrointestinal tract and to promote its release in the proximal colon. Different approaches including chemical manipulation of drug molecule for production of prodrugs or modification of drug delivery systems using pH-dependent, time-dependent and/or bacterially biodegradable materials have been tried to optimize 5-ASA delivery to the colon. In the current review, the different strategies utilized in the design and development of an oral colonic delivery dosage form of 5-ASA are presented and discussed.

Peculiar effect of polyethylene glycol in comparison with triethyl citrate or diethyl phthalate on properties of ethyl cellulose microcapsules containing propranolol hydrochloride in process of emulsion-solvent evaporation.

Plasticizers play a crucial role in various process of microencapsulation. In this study, the effect of incorporation of plasticizer in process of emulsion solvent evaporation was investigated on properties of ethyl cellulose (EC) microcapsules containing propranolol hydrochloride. The effect of plasticizer type and concentration were investigated on characteristics of microcapsules prepared from different viscosity grades of EC. Product yield, encapsulation efficiency, mean particle size, shape, surface characteristics, solid state of drug, and drug release profiles were evaluated. Product yield and encapsulation efficiency were not dependent on plasticizer type and concentration. However, encapsulation efficiency decreased with increase in EC viscosity grade in the most of the cases. The mean particle size was in the range of 724-797 µm and was not dependent on plasticizer type. Microcapsules formed in the presence of PEG had a very smooth surface with few pores. XRD and DSC studies revealed a reduction of drug crystallinity after microencapsulation especially in presence of PEG. The results showed that the presence of TEC and DEP with different concentrations had no marked effect on drug release from microcapsules containing different viscosity grades of EC. This was not the case when PEG was used, and despite its water solubility it reduced the drug release rate noticeably. The reduction in the drug release in the presence of PEG was concentration-dependent. The use of PEG as a plasticizer in process of emulsion solvent evaporation highly improved the EC microcapsule structure and retarded the drug release rate and therefore is recommended.

Indomethacin electrospun nanofibers for colonic drug delivery: In vitro dissolution studies.

Generally, although the conventional drug delivery systems, such as using only pH-dependent polymers or time-dependent release systems are popular, the individuals' variations of physiological conditions usually lead to premature or imperfect drug release from each of these systems. Therefore, a combination of pH- and time-dependent polymers could be more reliable for delivering drugs to the lower GI tract such as colon. To this end, electrospinning method was used as a fabrication approach for preparing electrospun nanofibers of indomethacin aimed for colon delivery. Formulations were prepared based on a 32 full factorial design. Independent variables were the drug:polymer ratio (with the levels of 3:5, 4.5:5 and 6:5w/w) and Eudragit S:Eudragit RS w/w ratio (20:80, 60:40 and 100:0). The evaluated responses were drug release at pH 1.2, 6.4, 6.8 and 7.4. Combinations of Eudragit S (ES), Eudragit RS (ERS) and drug based on factorial design were loaded in 10ml syringes. Electrospinning method was used to prepare electrospun nanofibers from electrospinning solutions. Conductivity and the viscosity of the solutions were analyzed prior to electrospinning. After collection, the nanofibers were evaluated in terms of morphology and drug release. It was shown that the ratio of drug:polymer and polymer:polymer were pivotal factors to control the drug release from nanofibers. A formulation containing Eudragit S:Eudragit RS (60:40) and drug:polymer ratio of 3:5 exhibited the most appropriate drug release as a colon delivery system with a minor release at pH 1.2, 6.4 and 6.8 and major release at pH 7.4. Nanofibers resulted from this formulation were also more uniform and contained fewer amounts of beads. It was demonstrated that the electrospinning could be regarded as a modern approach for the preparation of colon drug delivery systems leading to marketable products.

Preparation and characterization of celecoxib dispersions in soluplus(®): comparison of spray drying and conventional methods.

The present study deals with characterization of dispersions of a poorly water-soluble drug, celecoxib (CLX) in polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus(®) (SOL)) prepared by different techniques. Dispersions of CLX in SOL at different ratios (2:1, 1:1, 1:2, 1:4 and 1:6) were prepared by spray drying, conventional solvent evaporation and melting methods. The solid states of samples were characterized using particle size measurements, optical and scanning electron microscopy, XRPD, DSC and FT-IR. The Gordon-Taylor equation was used to predict the Tg of samples and the possibility of interaction between CLX and SOL. The solubility and dissolution rate of all samples were determined. Stability of samples was studied at ambient conditions for a period of 12 months. DSC and XRPD analyses confirmed amorphous state of drug in samples. Surprisingly dispersions of CLX:SOL with the ratio of 2:1 and 1:1 showed slower dissolution rate than CLX while other samples showed higher dissolution rate. At 1:2 ratio the spray dried samples exhibited higher dissolution rate than corresponding samples prepared by other methods. However at higher SOL content (1:4 and 1:6), samples prepared by different methods showed similar dissolution profiles. The stability studies showed that there were no remarkable changes in the dissolution profiles and solid state of the drug after 12 months storage at ambient conditions. It was concluded that SOL was a proper carrier to enhance the dissolution rate of CLX. At high SOL ratios the method of preparation of dispersed samples had no effect on dissolution rate, whilst at low SOL content spray drying was more efficient method.

Surelease as granulating liquid in preparation of sustained release matrices of ethylcellulose and theophylline.

OBJECTIVES: Use of Surelease as a granulation liquid in preparation of granules and matrices of theophylline and ethylcellulose was evaluated. MATERIALS AND METHODS: Physical mixtures (at 1:1 or 1:1.5 drug:polymer) were granulated using water, Surelease or diluted Surelease as granulating liquid. The granule characteristics (shape, size, flow rate, mechanical properties, friability and release profile) were studied. Afterwards, matrices were manufactured and their crushing strengths, friability and release profiles were determined. RESULTS: Granulation produced agglomerated particles with better flowability than physical mixtures. Change of granulation liquid from water to Surelease or diluted Surelease led to the marginal increase in size of granules at 1:1 drug:polymer, however, the flow rate and Carr's index were considerably improved. The hardness, elastic modulus, friability and rate of drug release were not affected by granulation liquid. Increase in polymer content resulted in reduction in size of granules, flow rate, elastic modulus and rate of drug release. However hardness of the granules was unaffected. Granulation process and granulation liquid did not affect the hardness, and dissolution rate of matrices at 1:1 drug:polymer, while the use of Surelease or diluted Surelease as a granulating liquid, increased the hardness and decreased drug release rate at 1:1.5 drug:polymer. Matrices prepared from Surelease or diluted Surelease showed similar characteristics. CONCLUSIONS: Surelease is a suitable granulating liquid for preparation of ethylcellulose matrices especially when high amount of polymer is used and could not only improve the flow and compatibility of the granules, but also help in reducing the rate of drug release.

Surelease or organic solution of ethylcellulose in preparation of sustained release theophylline micromatrices or matrices using spray drying technique.

This study evaluated ethylcellulose (EC) in two forms in preparation of sustained release theophylline microparticles using spray drying. Spray dried (SD) samples at different drug:polymer ratios were prepared using Surelease (SDaq) or organic solutions of ethylcellulose (SDor). Properties of particles (yield, particle morphology, size distribution and release profiles) were examined. Differential scanning calorimetry (DSC) and infrared spectroscopy (IR) studies were performed to track polymorphic changes and/or drug polymer interactions. SD samples were compressed and crushing strengths and release profiles were determined. The yields were in the range of 55-70%. The SD samples were nearly spherical with numerous fine particles attached to their surfaces. The SDor samples showed the smallest particle size. No polymorphism or drug-polymer interaction was observed. Uncompressed SDaq samples showed inadequate sustained release of drug compared to SDor samples. Surelease content did not affect drug release from SDaq samples. Tablets prepared from SDaq were softer and showed some plasticity, while those prepared from SDor exhibited higher crushing strengths. Tablets prepared from SDaq showed sustained release properties while the release of drug from compressed SDor samples were too slow. Overall Surelease was unable to sustain release of theophylline from SDaq microparticles, however, in compacted form showed more appropriate drug release than compacted SDor.

Promising dissolution enhancement effect of soluplus on crystallized celecoxib obtained through antisolvent precipitation and high pressure homogenization techniques.

Poor solubility and dissolution of hydrophobic drugs have become a major challenge in pharmaceutical development. Drug nanoparticles have been widely accepted to overcome this problem. The aim of this study was to manufacture celecoxib nanoparticles using antisolvent precipitation and high pressure homogenization techniques in the presence of varying concentrations of soluplus(®) as a hydrophilic stabilizer. Antisolvent crystallization followed by freeze drying (CRS-FD) and antisolvent crystallization followed by high pressure homogenization and freeze drying (HPH-FD) were used to obtain celecoxib nanoparticles. The obtained nanoparticles were analyzed in terms of particle size, saturation solubility, morphology (optical and scanning electron microscopy), solid state (DSC, XRPD and FT-IR) and dissolution behavior. The results showed that celecoxib nanoparticle can be obtained when soluplus was added to the crystallization medium. In addition, the results showed that the concentration of soluplus and the method used to prepare nanoparticles can control the size and dissolution of celecoxib. Samples obtained in the presence of 5% soluplus through HPH technique showed an excellent dissolution (90%) within 4min. It is interesting to note that celecoxib samples with high crystallinity showed better dissolution than those celecoxib samples with high amorphous content, although they had the same concentration of soluplus. DSC and XRPD proved that samples obtained via HPH technique are more crystalline than the samples obtained through only antisolvent crystallization technique.

Improvement of Physico-mechanical Properties of Partially Amorphous Acetaminophen Developed from Hydroalcoholic Solution Using Spray Drying Technique.

OBJECTIVE(S): This study was performed aiming to investigate the effect of particle engineering via spray drying of hydroalcoholic solution on solid states and physico-mechanical properties of acetaminophen. MATERIALS AND METHODS: Spray drying of hydroalcoholic solution (25% v/v ethanol/water) of acetaminophen (5% w/v) in the presence of small amounts of polyninylpyrrolidone K30 (PVP) (0, 1.25, 2.5 and 5% w/w based on acetaminophen weight) was carried out. The properties of spray dried particles namely morphology, surface characteristics, particle size, crystallinity, dissolution rate and compactibility were evaluated. RESULTS: Spray drying process significantly changed the morphology of acetaminophen crystals from acicular (rod shape) to spherical microparticle. Differential scanning calorimetery (DSC) and x-ray powder diffraction (XRPD) studies ruled out any polymorphism in spray dried samples, however, a major reduction in crystallinity up to 65%, especially for those containing 5% w/w PVP was observed. Spray dried acetaminophen particles especially those obtained in the presence of PVP exhibited an obvious improvement of the dissolution and compaction properties. Tablets produced from spray dried samples exhibited excellent crushing strengths and no tendency to cap. CONCLUSIONS: The findings of this study revealed that spray drying of acetaminophen from hydroalcoholic solution in the presence of small amount of PVP produced partially amorphous particles with improved dissolution and excellent compaction properties.