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Polymeric micelles, which form through the self-assembly of poly(ethylene glycol)-poly(amino acid) block copolymers, are systemic nanocarriers in targeted cancer therapy. These micelles can encapsulate therapeutic compounds, such as lipophilic substances, charged compounds, and metal complexes, that have characteristics of increased solubility, sustained release, and improved tissue distribution. However, few studies have been conducted on the local distribution of polymeric micelles. Thus, we evaluated the skin penetration pattern of hydrophobic drugs in polymeric micelles. We revealed that improved water solubility by the encapsulation of the hydrophobic drugs indomethacin and resveratrol in polymeric micelles significantly increased the amount of drugs penetrating into the skin. Moreover, polymeric micelles did not enhance the permeability of drugs. Furthermore, although the polymers remained on or in the stratum corneum, the encapsulated drugs gradually moved deeper into the skin. These results indicate that encapsulated hydrophobic drugs in polymeric micelles can penetrate the living cell layer of the skin without bringing about unexpected side effects associated with other ingredients in the formulation. Thus, polymeric micelles for encapsulating hydrophobic drugs can be used for skin applications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The present studies were designed to evaluate inhalatory microparticles carrying indomethacin (IN) for potential local (specific and non-specific bronchial inflammatory asthma responses) and systemic treatments (joint inflammation, rheumatoid arthritis and osteoarthritis pain) by optimizing microparticle properties, characterizing their lung deposition, drug release, evaluating cytotoxicity and also pharmacological effect in vitro. The acidic groups of IN were complexed with the cationic groups of the polyelectrolyte polylysine in order to increase the drug water compatibility. The polylysine/indomethacin ratio was fixed and the pH was adjusted in different formulations. Microparticles were obtained by spray drying using a relatively high atomization air flowrate (742 L/min) and a high-performance cyclone in order to optimize the production of microparticles with adequate attributes for inhalatory delivery. The produced microparticles exhibited high process yield and IN loading, volumetric mean diameters smaller than 5 μm and narrow particle size distributions. According to demonstrated aerosolization performance, the powders were suitable for inhalatory indomethacin local and systemic treatments. Emitted fraction was higher than 90%, the MMAD was around 3 μm and the GSD lower than 3. The respirable fraction for particles with aerodynamic diameters smaller than 5 μm was around 29% while for particles with aerodynamic diameters smaller than 3 μm the value was around 17%. The addition of lactose as carrier worsened the aerodynamic performance of the microparticles. The developed powdered systems got wet and dissolved quickly and presented higher release rates respect to pure IN in simulated lung physiological conditions. Furthermore, the assays performed in RAW 264.7 cell line showed that the microparticles exhibited the same anti-inflammatory capability as the pure drug. The developed particles did not affect the RAW 264.7 cell viability. In conclusion, a promising powder formulation for DPIs has been developed to treat, locally and systemically, inflammatory diseases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Solid dispersions (SDs) hold a proven potential in formulating poorly water-soluble drugs. The present paper investigates the interfacial phenomena associated with the bulk powder flow, water sorption, wetting and dissolution of the SDs prepared by a modified melt and quench-cooling (QC) method. Poorly water-soluble indomethacin (IND) was QC molten with solubilizing graft copolymer (Soluplus®) or polyol sugar alcohol (xylitol, XYL). The interfacial interactions of SDs with air/water were found to be reliant on the type (amorphous/crystalline) and amount of the carrier material used. The final SDs were composed of fused agglomerates (SOL) or large jagged particles (XYL) with good wetting and powder flow properties. The initial dissolution of IND was accelerated by both carrier materials studied. The QC molten SDs with amorphous Soluplus® significantly improved the dissolution rate of IND at pH 6.8 (79.9 ± 0.2% at 30 min) compared to that of pure crystalline drug. The substantial improvement in the dissolution rate of IND was in connection with the amorphous state of the drug being stabilized by Soluplus® in the QC molten SDs. However, it is evident that a strong H-bond formation between the components in some regions of the QC molten SDs can limit the dissolution of IND. The QC molten two-phase SDs with a polyol carrier (XYL) showed rapid and continuous drug release without reaching a plateau., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The limited solubility of BCS class II drugs diminishes their dissolution and thus reduces their bioavailability. Our aim in this study was to develop and optimize a spray dried emulsion containing indomethacin as a model for Class II drugs, Labrasol®/Transuctol® mixture as the oily phase, and maltodextrin as a solid carrier. The optimization was carried out using a 2(3) full factorial design based on two independent variables, the percentage of carrier and concentration of Poloxamer® 188. The effect of the studied parameters on the spray dried yield, loading efficiency and in vitro release were thoroughly investigated. Furthermore, physicochemical characterization of the optimized formulation was performed. In vivo bioavailability, ulcerogenic capability and histopathological features were assessed. The results obtained pointed out that poloxamer 188 concentration in the formulation was the predominant factor affecting the dissolution release, whereas the drug loading was driven by the carrier concentration added. Moreover, the yield demonstrated a drawback by increasing both independent variables studied. The optimized formulation presented a complete release within two minutes thus suggesting an immediate release pattern as well, the formulation revealed to be uniform spherical particles with an average size of 7.5μm entrapping the drug in its molecular state as demonstrated by the DSC and FTIR studies. The in vivo evaluation, demonstrated a 10-fold enhancement in bioavailability of the optimized formulation, with absence of ulcerogenic side effect compared to the marketed product. The results provided an evidence for the significance of spray dried emulsion as a leading strategy for improving the solubility and enhancing the bioavailability of class II drugs., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are administered for pain relief from oral mucositis. However, the systemic administration of NSAIDs is limited due to systemic side effects. To avoid these side effects and treat local lesions effectively, a matrix type mucoadhesive tablet was developed. A mixture of hard fat, ethylcellulose (EC) and polyethylene glycol (PEG) was used as a matrix base, and indomethacin (IMC) was used as the principal agent. In tablets consisting of hard fat, EC and IMC, the drug release was sustained. In tablets consisting of hard fat, EC, considerable amounts of PEG and IMC, the drug release was relatively increased and IMC existed as the molecular phase or in an amorphous state. The in vitro adhesive force of the tablets consisting of hard fat, EC, considerable amounts of PEG and IMC was significantly increased as compared with the tablets consisting of hard fat and IMC. A significantly high tissue concentration and significantly low plasma concentration were observed after buccal administration of this matrix type mucoadhesive tablet as compared with that after oral administration of IMC. Thus, the matrix type mucoadhesive tablet has good potential as a preparation for the treatment of pain due to oral aphtha., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Highly efficient nanomedicines were successfully fabricated by the indomethacin (IND) directed self-assembly of β-cyclodextrin (β-CD)-conjugated polyethyleneimine (PEI-CD), taking advantage of the multiple interactions between drug and polymer. These nanoscaled assemblies exhibited spherical shape and positively charged surface. Compared with the commercial tablet, the relative oral bioavailability of IND-nanomedicines was significantly enhanced. Evaluation based on either carrageenan-induced paw edema or complete Freund's adjuvant (CFA)-induced arthritis suggested the newly developed nanomedicines were more effective than raw IND or IND tablet in terms of prophylactic effect and therapeutic activity. Even the low dose of nanomedicines offered the comparable results to those of control groups at the high dosage in most cases. Moreover, the nanoformulation exhibited ameliorated gastrointestinal stimulation. All these positive results indicated that this type of nanomedicines might serve as a highly efficient and effective delivery nanoplatform for the oral delivery of water-insoluble therapeutics., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Biocompatible double-hydrophilic PNIPAM-g-PEO copolymers containing 0.3-3.2 mol% PEO grafts were synthesized and utilized to prepare indomethacin (IMC)-loaded core-shell nanoparticles by dialysis and nanoprecipitation methods. IMC loading was conducted at room temperature using the organic solvents ethanol and DMF, which induced phase separation in the copolymers aqueous solutions due to the cononsolvency of PNIPAM. In ethanol-water solutions, the cononsolvency-induced phase separation of the copolymers promoted effective drug incorporation into the formed micellar structures. In DMF-water system, the formation of the nanoparticles did not correspond to the cononsolvent region of PNIPAM-g-PEO. In this case, hydrophobic interactions between PNIPAM and IMC allowed the copolymer self-association and drug loading. Irrespective of the solvents or preparation methods applied, the drug loading content (DLC) depended on the drug-to-copolymer feed weight ratio. DLC was relatively low at the 0.5:1 ratio but it significantly increased at the ratios of 0.75:1 and 1:1 (DLC approximately 90%). The particle size was strongly affected by the different mechanisms of nanoparticles formation. The nanoprecipitation from ethanol produced significantly smaller particles (<150 nm) with narrow size distribution than the dialysis from DMF. The velocity of indomethacin release from the nanoparticles was influenced by the amount of encapsulated drug, the process being faster at lower DLC.

Goals were to evaluate indomethacin ethyl ester-nanoencapsules (IndOEt-NC) pharmacokinetics in rats and the in vivo ester conversion to indomethacin (IndOH). After i.v. and oral administration exclusively IndOH was detected in plasma. The AUC(IndOEt-NC)/AUC(IndOH) ratio after i.v. dosing was 0.68, accounting for dose and molecular weight differences, probably due to increased IndOH clearance after IndOEt-NC administration (alpha=0.05). The results confirm that antiedematogenic activity reported for IndOEt-NC is due to IndOH. Encapsulation did not protect the ester which in vivo is rapidly released and converted to IndOH, acting as a pro-drug.

Indomethacin (IDM) was encapsulated in gelatin-cellulose acetate phthalate (CAP) microcapsules (A) by complex coacervation method and in CAP microcapsules (B) by simple coacervation method. Microcapsules A and B, having mean diameters of 38.24 and 35.74 microm, respectively, were used to prepare sustained-release tablets A and B. The activation energy of thermal degradation for tablets A and B was calculated based on differential scanning calorimetry (DSC) to be 258.9 and 284.8 kcal/mol, respectively. In vitro release profiles showed no burst effect and release t(1/2) of the two sustained-release tablets were found to be 41.30+/-1.86 and 33.25+/-2.84 min, respectively, while that of IDM plain tablets C was 6.30+/-0.39 min (P<0.01). In vitro release of IDM from tablets A and B could be described by Higuchi equation and zero-order kinetics, respectively. After per os (po) administration with physiological saline, their irritation to rat stomach was obviously reduced in comparison with tablets C. Pharmacokinetic study in rabbits showed that t(max) was delayed and C(max) lowered compared with tablets C and the values of AUC(0-24 h) of the three tablets were very close.

Sigmoidal release pattern is therapeutically beneficial for timed release and colonic drug delivery, and is always observed in coated systems. In this study, sigmoidal release from pectin matrix tablets with indomethacin as a model drug was investigated. The underlying mechanisms are calcium cation-induced in situ crosslinking that retard the initial drug release to a limited percentage. Power law equation n values were estimated for sigmoidal release profiles. Results indicated that calcium chloride incorporated in pectin matrix functioned as retarding mechanisms on drug release. Larger amount of calcium chloride led to slower drug release and matrix erosion. Even at extremely high levels, retarding on drug release and matrix erosion rate was obvious, which highlighted the effect of calcium-induced in situ crosslinking as calcium chloride was a freely water-soluble salt. The sigmoidal release profiles were characterized by power law equation with high correlation coefficients of about 0.99 or over. Power law n values increased up to as high as 1.20 when calcium chloride content kept increasing. Erosion correlated well with release in almost all pectin matrix tablets indicating erosion-controlled mechanisms. It is concluded that large amount of calcium induces in situ crosslinking of pectin matrix and leads to sigmoidal release of indomethacin, and power law n values, sometimes larger than 1.0, are suitable to be used to describe sigmoidal release profiles.

The purpose of this study is to investigate the release mechanism of poorly water-soluble drug from the extended release solid dispersion systems with water-insoluble ethylcellulose (EC) and water-soluble hydroxypropylmethylcellulose (HPMC) (1:1). Indomethacin (IND) was used as a model of poorly water-soluble drug. Two kinds of solid dispersions were prepared by the solvent evaporation methods, which consist of the same formulation but exhibit different physical performance. It appeared that the dissolution behavior of IND depended on the structures of EC-HPMC matrices, which were governed by the preparation method. In addition, the dissolution behavior showed pH dependency that the dissolution rate of IND was slower in acidic medium than that in neutral medium. The experimental results revealed that the hydrophobic interaction between IND and EC occurred under lower pH and strongly delayed the dissolution rate of IND. The relationship between this hydrophobic interaction and the dissolution rate of IND was also proposed.

A significant problem with solid dispersion (SD) systems is the difficulty in preparing dosage forms. This difficulty can be overcome using crospovidone (CrosPVP) as a carrier. A powder SD of indomethacin (IM) with CrosPVP was prepared using mechanical mixing followed by heating to temperatures below the melting point. IM and CrosPVP interacted to produce IM in an amorphous state when its concentration was <40%. The solubility of IM was improved about fourfold compared to IM crystal. The SD had good fluidity, and tablets were prepared by direct compression. Tablets with small weight variation and acceptable hardness were obtained using only 1% of magnesium stearate as excipient. The dissolution of IM from tablets was similar to that of SD powder because CrosPVP, a disintegration agent, caused the tablets to break up rapidly.

The solid dispersion particles of indomethacin (IMC) were prepared with different types of silica, non-porous (Aerosil 200) or porous silica (Sylysia 350) by using spray-drying method. Powder X-ray diffraction analysis showed that IMC in solid dispersion particles is in amorphous state irrespective of the type of silica formulated. In DSC analysis, the melting peak of IMC in solid dispersion particles with Sylysia 350 shifted to lower temperature than that in solid dispersion particles with Aerosil 200 although the peak of each solid dispersion particles was much smaller than that of original IMC crystals. Dissolution property of IMC was remarkably improved by formulating the silica particles to the solid dispersion particles. In comparing the effect of the type of the silica particles, the dissolution rate of solid dispersion particles with Sylysia 350 was faster than that with Aerosil 200. The formulation amount of IMC did not affect on the amorphous state of IMC in the resultant solid dispersion particles in powder X-ray diffraction patterns. However, the area of the melting peak of IMC in the solid dispersion particles increased and an exothermic peak owing to recrystallization was observed with increasing the IMC content in the DSC patterns. The dissolution rate of IMC from the solid dispersion particles with Sylysia 350 was faster than that of Aerosil 200 irrespective of IMC content. In stability test, amorphous IMC in the solid dispersion particles with each silica particles did not crystallize under storing at severe storage conditions (40 degrees C, 75% RH) for 2 months, while amorphous IMC without silica easily crystallized under same conditions.

Conventional lipid microspheres (LM) were prepared using soybean oil and lipid at a 5.5:1 weight ratio with lipid phase consisting of PC (phosphatidyl choline):CH (cholesterol) (1:0.5) by molar ratio. The average diameter of the particles was 150 nm. Long-circulating microspheres (S-LM) were also prepared similarly but the lipid phase consisted of PC:CH:DSPE-PEG (phosphatidyl choline:cholesterol:distearoyl phosphatidyl ethanolamine-polyethylene glycol) 1:0.5:0.16 by molar ratio. A comparative biodistribution study was conducted between free indomethacin and lipo-indomethacin (LM and S-LM) in the arthritic rats by administering the formulations at a dose equivalent to 12 mg of indomethacin/kg. It was observed that the free drug as well as the encapsulated drug followed biphasic clearance from the blood. Pharmacokinetic parameters, such as AUC(0-t), terminal half-life, MRT increased significantly when the drug was used in encapsulated form (p < 0.05). Clearance of the drug was reduced 1.4 times with the conventional lipid microspheres and was reduced three-fold when encapsulated in polyethylene glycol-coated lipid microspheres. The overall drug targeting efficiency (T(e)) with the PEG-coated lipid microspheres was 7.5-fold higher than the conventional lipid microspheres. The high accumulation of the drug in arthritic paw with S-LM system may be accounted for by the reduced uptake by RES cells, and thereby, availability for extravascularization in the inflammatory tissues.

In an effort to improve the bioavailability of the insoluble drug indomethacin, three complexes were prepared with indomethacin and the soluble complexing agents beta-, hydroxyethyl-beta-, and hydroxypropyl-beta-cyclodextrin. The indomethacin content was similar among the complexes (P

3-l-Menthoxypropane-1,2-diol (MPD) is a derivative of l-menthol, which has an enhancement effect on drug permeation through skin. In this study, the effect of MPD on drug permeation through skin was compared with that of l-menthol. MPD or l-menthol at final concentrations of 3% in 40% ethanol was added to the drugs indomethacin or antipyrine and each mix then applied to Yucatan micropig skin in vitro. Drug concentrations in the skin were higher in the presence of either MPD or l-menthol, however, only l-menthol shortened the lag time of permeation. MPD enhanced the skin permeation of the drugs only by increasing the skin concentration of the drugs. In contrast, l-menthol enhanced the skin permeation of the drugs by increasing both the skin concentration and the diffusion rate in skin. The infrared (IR) spectra and X-ray diffraction patterns of stratum corneum after treatment with MPD did not differ from those of intact stratum corneum. A change in the IR spectra of stratum corneum after treatment with l-menthol was observed at the CH band, and the peaks representative of the lipid structure in the X-ray diffraction patterns decreased in intensity. These results suggest that l-menthol, but not MPD, disrupts the intercellular lipid structure of stratum corneum. Thus, MPD is expected to be a moderate skin permeation enhancer.

The effects of hydrogenated and unhydrogenated phosphatidylcholine (HPC, PC) on the permeation of indomethacin (IM) through hairless rat skin were investigated using liquid paraffin (LP) and a gel prepared with LP and hydrogenated soybean phospholipid (HSL). IM solubility at 95 degrees C increased in proportion to the concentration of HPC or PC, whereas solubility at 37 degrees C did not increase with HPC. IM showed no permeation until 10 h from LP without HPC/PC, but permeated at rates of approximately 5 and 10 microg/cm2 within 10 h from LP with HPC and PC, respectively. The permeation from the gel with various formulations (HSL, 15%; PC/HPC, 0-5%; IM, 0.5-2%) was determined. Permeation rates were 1.7-4.8 microg/cm2 per h and were proportional to the skin concentration. Skin concentration was correlated to the release rate from the gel. We concluded that IM was solubilized by phospholipids, high activity in the vehicle led to high partition of IM in skin, and permeation increased due to a high skin concentration.

Twelve medium to long chain fatty acid Esters (Esters), the total number of carbon atoms of which ranged from 17 to 34, were used to study the effect of the vehicle on the permeation of ketoprofen, and the effect was compared with the case of indomethacin. The solubility of ketoprofen was higher in Esters with a smaller number of carbon atoms. The permeation rate of ketoprofen from the Ester suspension through excised hairless rat skin was proportional to its solubility in the suspension, which was the same in the case of indomethacin. The diffusion constant and partition coefficient were calculated using the computer program MULTI(FILT). The diffusion constant decreased with increasing number of carbon atoms, and the partition coefficient was increased with increasing number of carbon atoms, in both cases of ketoprofen and indomethacin. Esters also penetrated the skin with the concentration of about 10 mg/g, independent of the number of carbon atoms. The Esters in the skin increase the diffusion rate of the drugs, especially in the case of Esters with a small number of carbon atoms. Also the drug solubility in the skin was improved, although the effect was similar for the range of Esters investigated in the present study. Then the permeation rate of ketoprofen and indomethacin increased.

Cholic acid (CA) was coupled with amine-terminated poly (N-isopropylacrylamide) (ATPNIPAAm) using N,N'-dicyclohexyl carbodiimide as a coupling agent. Self-assembled CA/PNIPAAm conjugate (abbreviated as CN) micelles were prepared by diafiltration method in water. The CN micelles exhibited the lower critical solution temperature (LCST) at 31.5 degrees C. The CN micelles were observed as spherical shapes and their dried sizes were ranged between 30 and 50 nm by the transmission electron microscope (TEM) images. Hydrated micelle sizes measured by photon correlation spectroscopy (PCS) were ranged 337.5+/-67.8 nm. And reversible size changes of CN micelles were observed with two point temperature 10 and 40 degrees C, respectively. From the fluorescence spectra, fluorescence intensity of pyrene in the CN micelles was increased and red-shifted as the concentration of CN increased, indicating the formation of self-assembled polymeric micelles in water. The critical micelle concentration (CMC) was evaluated as 8.9 x 10(-2) g/l. Much more indomethacin (IN) was released from th CN micelles at 10 than at 40 degrees C due to the thermo-sensitivity of the PNIPAAm in the CN polymer.

A self-emulsifying system (SES), a mixture of an oil and a surfactant which forms an oil-in-water emulsion, is expected to improve the in vitro drug dissolution and enhance the in vivo drug absorption. In this study, a poorly water-soluble drug, indomethacin (IDM) was incorporated into the SES to increase bioavailability. The SES with 30% of Tween 85 and 70% of ethyl oleate, EO (w/w) was selected as an optimized formulation (high drug loading, low surfactant concentration, and small particle size). After an oral administration of the SES containing IDM and IDM suspension, (IDM was suspended in methyl cellulose), 22.5 mg/kg as IDM, to rats, the area under the plasma concentration-time curve from time zero to the last measured time in plasma, 12 h (AUC(0-12 h)) was significantly greater (57% increase) in the SES, suggesting that oral absorption of IDM increased significantly by the SES. After a rectal administration of gelatin hollow type suppositories, filled with the SES containing IDM and IDM powder physically mixed with the SES, 22. 5 mg/kg, to rats, the AUC(0-12 h) also increased significantly (41% increase) by the SES, suggesting that rectal absorption of IDM also increased significantly by the SES.

The potential, as sustained release vehicles, of gels formed in situ following the oral administration of dilute aqueous solutions of a xyloglucan polysaccharide derived from tamarind seed has been assessed by in vitro and in vivo studies. Aqueous solutions of xyloglucan that had been partially degraded by beta-galactosidase to eliminate 44% of galactose residues formed rigid gels at concentrations of 1.0 and 1.5% w/w at 37 degrees C. The in vitro release of indomethacin and diltiazem from the enzyme-degraded xyloglucan gels followed root-time kinetics over a period of 5 h at 37 degrees C at pH 6.8. Plasma concentrations of indomethacin and diltiazem, after oral administration to rats of chilled 1% w/w aqueous solutions of the enzyme-degraded xyloglucan containing dissolved drug, and a suspension of indomethacin of the same concentration were compared. Constant indomethacin plasma concentrations were noted from both formulations after 2 h and were maintained over a period of at least 7 h. Bioavailability of indomethacin from xyloglucan gels formed in situ was increased approximately threefold compared with that from the suspension. The results of this study suggest the potential of the enzyme-degraded xyloglucan gels as vehicles for oral delivery of drugs., (Copyright.)

A series of acyloxymethyl drug derivatives of the NH-acidic drugs, phenytoin and theophylline and of the carboxylic acid drugs, thioctic acid and indomethacin, were prepared in order to determine the effect of varying the nature of the drug on the in vitro rate of hydrolysis catalyzed by porcine liver esterase and human plasma. The acyl portion was comprised of either valeric acid (val) or gamma-linolenic acid (GLA). With the exception of some GLA prodrugs, the derivatives displayed first-order kinetics in both enzyme systems. The NH-acidic drug derivatives were hydrolyzed faster than the carboxylic drug derivatives by porcine liver esterase and human plasma. It was found that the short chain valeric acid derivatives were hydrolyzed faster than the GLA derivatives. The rates of hydrolysis for the relatively smaller prodrugs of theophylline and thioctic acid were greater than the rates of hydrolysis for the bulkier phenytoin and indomethacin prodrugs indicating steric hindrance was important. The lipophilicity index, log K, of the valeric acid drug derivatives was plotted against the logarithm of the hydrolysis rate constant, k, and it was observed that log k decreased with an increase in log K. A comparison of these results with those of previous studies where the alkyl and acyl moieties were varied of acyloxyalkyl theophylline derivatives has provided a rationale, based on lipophilicity, for the structure of a prodrug to be designed based on an in vitro desired rate of hydrolysis., (Copyright.)