Effect on cerebral blood flow of orally administered indomethacin-loaded poly(isobutylcyanoacrylate) and poly(DL-lactide) nanocapsules

Nanocapsules, containing indomethacin, were prepared either by interfacial polymerization of isobutylcyanoacrylate monomers or by interfacial deposition of a performed (DL-lactide) polymer. In-vitro release of indomethacin from nanocapsules was dependent on the pH of the sink solution and was enhanced by addition of albumin. A decrease in cerebral blood flow was noted 15 min after oral administration to rats of indomethacin nanocapsules (5 mg kg-1) and lasted over 3 h. Empty nanocapsules had no effect. Since release of indomethacin from nanocapsules is unlikely to occur in the lumen of the stomach, due to unsuitable pH conditions, and nanocapsules have been previously shown to be able to cross the intestinal barrier, to reach the villi vessels intact and to protect against the ulcerating effect of the free drug, it is suggested that the rapid onset of the pharmacological effect was sufficiently induced by free indomethacin released in the plasma following absorption of the intact nanocapsules.     

Alkaline hydrolysis as a tool to determine the association form of indomethacin in nanocapsules prepared with poly(eta-caprolactone)

To determine the association form of indomethacin in nanocapsules prepared with poly(eta-caprolactone) as polymer and a triglyceride as oil, two methods were studied. The indomethacin ethyl ester was prepared as control, which showed a higher affinity for the oil than the indomethacin. Two differently loaded nanocapsule formulations were prepared. For both formulations, a burst effect was detected using ethanol as release medium. Light scattering (PCS) and NMR analyses suggested the ethanol diffuses through the nanocapsule polymeric wall promoting the total release of indomethacin and its ester. The results showed the inability of this approach to determine the association form of indomethacin. On the other hand, the alkaline hydrolysis of indomethacin and its ester, followed by their disappearance (HPLC), were evaluated. The nanocapsule suspensions containing indomethacin or its ester were treated with 50 mM NaOH. The total disappearance of indomethacin associated with nanocapsules was determined after 2 min, whereas the ester associated with colloids was consumed during 24 h. The constant particle sizes (264 and 259 nm) during the hydrolysis reactions showed that neither the nanocapsules were dissolved nor the polymer sorbed water during the contact with NaOH aqueous solution. The ester rate hydrolysis was determined by its diffusion from the nanocapsules to the interface particle/water. Finally, the indomethacin association model considers the burst release of drug after the addition of NaOH by the formation of its carboxylate, followed by its hydrolysis in aqueous solution promoted by the excess of NaOH. The adsorption was the mechanism of indomethacin association with nanocapsules.     

Diffusion and mathematical modeling of release profiles from nanocarriers

The aim of this work was to establish models and to differentiate the kinetic release behavior of drug models from nanocapsules, nanoemulsion and nanospheres by physico-chemical characterization and release experiments. SAXS analysis showed that the polymer is organized in the nanocapsules, while in the nanospheres the sorbitan monostearate is organized and acts as an impurity of the poly(epsilon-caprolactone) suggesting that constituents in these nanocarriers are differently organized. Formulations presented particle sizes ranging from 178 to 297 nm, probe content from 0.981 to 0.997 mg/mL, pH values from 4.90 to 5.10 and zeta potential from -37.9 to -51.9 mV. The kinetic experiments showed that the nanostructures present similar behaviors when the probe is adsorbed on the nanocarriers (indomethacin-loaded formulations). However, when the probe is entrapped within the nanocarriers (indomethacin ethyl ester-loaded formulations), nanocapsules, nanospheres and nanoemulsion presented different kinetic behaviors. Mathematical modeling of the release profiles was conducted, showing that the presence of the polymer increases the half-lives of the burst phases (5.9, 4.4 and 2.7 min) while the presence of the oil increases the half-lives of the sustained phases (288.8, 87.7 and 147.5 min) for nanocapsules, nanospheres and nanoemulsion, respectively.     

Nanocapsules prepared via nanoprecipitation and emulsification-diffusion methods: Comparative study

The encapsulation of hydrophobic drugs has been widely investigated using mainly oil phase in order to enhance the encapsulation efficiency. However, the effect of the starting materials on the colloidal properties of the final nanocapsules irrespective of the elaboration process has been neglected, and the hydrophobic drug location in the disperse media has not been completely elucidated. Therefore, this paper describes the effect of the oil used in the recipe and the preparation method on the behavior of nanocapsules prepared via nanoprecipitation and via emulsification-diffusion. The colloidal stability of the final dispersions, drug location and the drug release are preparation method dependent. In turn, the type of oil governs drug encapsulation efficiency regardless of the method and the size when nanocapsules are prepared by nanoprecipitation.     

Biodegradable polymer nanocapsules containing a sunscreen agent: preparation and photoprotection.

Biodegradable polymer nanocapsules containing the lipophilic sunscreen, Parsol MCX (OMC), as the oil core were prepared by solvent displacement. We investigated the influence of polysorbate 85 (P-85) and poloxamer 188 (P-188) as stabilizing agents, the OMC loading capacity and the photoprotective potential of the formulations. The formation of nanocapsules is probably due to an interfacial instability arising from rapid diffusion of the solvent across the interface. The effectiveness of the stabilizing agents was attributed to their ability to inhibit coalescence during solvent diffusion. P-85 was a better stabilizer of poly(epsilon-Caprolactone)-nanocapsules than P-188. The OMC loading capacity was high (99+/-1% of OMC initial concentration). The in vitro release of OMC-nanocapsules is governed by hydrophobicity and crystallinity of the polymer and by the high lipophilicity of the drug. The OMC-nanocapsules provided partial protection against UV-induced erythema, in a manner significantly better than a conventional gel.     

Improved Ocular Bioavailability of Indomethacin by Novel Ocular Drug Carriers

The ability of different drug carriers to improve the ocular bioavailability of drugs was investigated in the rabbit eye. The assayed drug carriers were suspensions of nanoparticles, nanocapsules and microparticles made of poly-ε-caprolactone (PECL) and a submicron emulsion. Results indicated that the three submicron systems, nanoparticles, nanocapsules and emulsion, increased more than 3-fold the indomethacin concentration in the cornea, aqueous humour and iris-ciliary body at 0.5 and 1 h post-instillation. Furthermore, an increased indomethacin ocular bioavailability of 300% was observed after instillation of the submicron systems in comparison with the value obtained for a commercial solution. In contrast, the microparticles hardly increased the ocular bioavailability of indomethacin. The mechanism of interaction of the colloidal carriers with the corneal epithelium was investigated by confocal laser scanning microscopy. Confocal images indicated that submicron particles penetrate into the corneal epithelium cells by an endocytic mechanism. The similar behaviour of the three colloidal carriers suggests that any of their specific ingredients (PECL, lecithin and oil) acts as a penetration enhancer or an endocytotic stimulator. On the other hand, the favourable ocular penetration of indomethacin when encapsulated in the colloidal carriers, but not in the microparticles, led us to assume that the colloidal nature of these carriers is the main factor responsible for the increased ocular bioavailability of indomethacin. PECL nanoparticles and nanocapsules as well as submicron emulsions are shown to be novel corneal drug carriers, thus representing a useful approach for increasing the ocular bioavailability of drugs.     

Primidone-loaded poly-epsilon-caprolactone nanocapsules: incorporation efficiency and in vitro release profiles

This paper describes the preparation of primidone-loaded poly-epsilon-caprolactone nanocapsules according to the interfacial deposition technique. The colloidal suspension obtained showed a monomodal size distribution with a mean diameter ranging from 308 to 352 nm. By adjusting the process parameters, the encapsulation efficiency was about 74% with good reproducibility. Primidone release from the nanocapsules was found to be slower as compared to the oily control solution despite an important burst-effect. The release profile was not influenced by the pH of the release medium.     

胰岛素壳聚糖胶态纳米粒的制备及体外释药性能

采用离子趋向凝胶化法制备了胰岛素壳聚糖胶态微粒,并考察了外观、粒径和体外释药性能.所得产品呈球形,表面光滑圆整,平均粒径为276nm,多分散系数为0.08.体外释药呈pH依赖性,释药速度受载药量及泊洛沙姆188含量的影响.     

A Novel Nanocapsule Delivery System to Overcome Intestinal Degradation and Drug Transport Limited Absorption of P-glycoprotein Substrate Drugs

PURPOSE: To design a double-coated nanoparticulate delivery system of tacrolimus capable of overcoming the P-glycoprotein pump and CYP3A barriers without affecting their physiological activities. MATERIALS AND METHODS: Tacrolimus loaded oil cores were first nanoencapsulated with two polymethacrylate polymers followed by the microencapsulation of these nanocapsules within hydroxypropylmethylcellulose using a spray drying technique. The Trojan effect of these double-coated nanocapsules was evaluated in Caco-2 monolayer by monitoring the tacrolimus uptake and measuring the transport of tacrolimus across the rat jejunum membrane. RESULTS: The formulation was shown to release nanocapsules rather than dissolved drug under sink conditions. The nanocapsules protected tacrolimus from degradation in the diluted intestinal fluids following 2 h incubation. The Caco-2 and intestinal segment uptake of tacrolimus from the novel delivery system with and without verapamil was significantly higher than the uptake of tacrolimus from the aqueous solution and emulsion. The blank drug delivery system did not inhibit the P-gp pump activity. The nanocapsules internalized rapidly in the enterocytes as confirmed by the histological results. CONCLUSION: The overall results suggest that the novel nanodelivery system which does not alter the activity of the P-gp is a potential platform for intestinal transport of sensitive lipophilic molecules that are P-gp substrates.     

Jejunal Absorption,Pharmacological Activity,and Pharmacokinetic Evaluation of Indomethacin-Loaded Poly(d,l-Lactide) and Poly(Isobutyl-Cyanoacrylate) Nanocapsules in Rats

The jejunal absorption of indomethacin nanocapsules was studied using an in vivo infusion technique. Jejunal absorption of indomethacin from the nanocapsules was slightly delayed as compared to a commercial indomethacin solution. The plasma and jejunal mucosa indomethacin concentrations were similar in both cases. However, the nanocapsules protected the rat jejunum from the ulcerating effect of indomethacin, probably by avoiding direct contact of the free drug with the surface of the mucosa. The pharmacokinetic profile of indomethacin nanocapsule formulations was compared to a solution of free drug following oral administration of 5 mg/kg in rats; no difference in the mean concentration–time profiles of the drug was observed. Blood levels of thromboxane showed a sustained biological activity, over a period of 24 hr, of indomethacin-loaded nanocapsules, relative to the drug in solution, following oral administration.     

Influence of Poly(DL-Lactide) Nanocapsules on the Biliary Clearance and Enterohepatic Circulation of Indomethacin in the Rabbit

Following intravenous administration, the uptake of colloidal drug carriers by cells of the mononuclear phagocyte system, mainly the Kuppfer cells, may concentrate an encapsulated drug close to the liver parenchymal cells and facilitate its biliary excretion and enterohepatic circulation. To test this hypothesis indomethacin was administered (10 mg/kg) in four groups of 10 rabbits each by intravenous infusion at a constant rate over 2 hr, either in its free form (aqueous solution) or as nanocapsules prepared from preformed poly(DL-lactide). Unchanged drug was assayed in plasma of the two control (sham-operated) groups and in both plasma and bile of the two bile-cannulated groups. Pharmacokinetic analysis led to the conclusion that the uptake of nanocapsules by liver macrophages reduces the concentration of the drug by enhancing its total clearance. This enhancement was due to an increase in biliary clearance, as a result of parallel increases in bile concentration and biliary excretion of the drug. It was also demonstrated that nanocapsules enhance the enterohepatic circulation of indomethacin.     

Spray-dried indomethacin-loaded polyester nanocapsules and nanospheres: development, stability evaluation and nanostructure models

The industrial development of polymeric nanoparticle suspensions, as drug delivery systems, is limited due to the problems in maintaining stability of suspensions. In this work, a spray-drying technique was applied to dry nanocapsule and nanosphere suspensions prepared by nanoprecipitation of polyesters using SiO₂ as adjuvant. Powders obtained from nanocapsules presented stable drug recoveries and morphological characteristics after 5 months. For nanocapsules, nanostructures around 200 nm were observed by scanning electron microscopy (SEM) on the surface of microparticles of SiO₂, whereas for the nanosphere formulation, nanostructures with a reduced diameter (60–90 nm) were observed, despite the particle sizes of each original suspension being similar, when measured by photon correlation spectroscopy (PCS). In order to investigate the morphological aspects of nanocapsule and nanosphere powders, several nanosphere formulations were spray-dried using different concentrations of SiO₂ and a comparative study of the different colloidal systems (nanocapsules, nanospheres, nanoemulsion or nanodispersion) was carried out by PCS. SEM analyses showed that nanostructures with reduced diameter are formed independently of the adjuvant concentration. The dynamic properties of these systems allowed to suggest that the structure of the nanosphere particle (polymer, sorbitan monostearate and polysorbate 80) was a polymeric matrix dispersing the sorbitan monostearate which, when submitted to the spray-drying process in the presence of SiO₂, gave nanostructures presenting diameters around 80 nm covering the microparticles due to the release of lipophilic surfactant from the polymeric matrix.     

Genistein-loaded poloxamer 403/407 mixed micelles: preparation and pharmacokinetic study in rats

In the present study, we aimed to prepare poloxamer 403/407 mixed micelles in order to improve the solubility and oral bioavailability of genistein.Genistein was incorporated in the mixed poloxamer micelles by thin-film hydration method, and its physicochemical properties, including particle size, zeta potential, entrapment efficiency and drug loading, were investigated.In vitro release of genistein from the mixed micelles was monitored by dialysis method, and pharmacokinetic study of genistein loaded mixed micelles was carried out in rats. We found that the particle size and zeta potential of mixed micelles were (20.31±0.43) nm and (–8.94±0.35) mV, with encapsulation efficiency 90.59%±0.67% and drug loading 7.74%±0.05%. Solubility of genistein in mixed micelles reached 3.80 mg/mL, which was about 130 times higher than that in water.Genistein-loaded mixed micelles showed sustained release characteristics in vitro with no burst release phenomenon, but it was faster than suspension.The AUC_0–t andAUC_0–∞ of mixed micelles were 196.74% and 204.62% greater than that of genisein suspension, respectively.Consequently,poloxamer 403/407 mixed micelles significantly improved the solubility and oral bioavailability of genistein, which could be used as an effective drug delivery system for oral administration of poorly soluble drugs.     

硝酸毛果芸香碱温敏凝胶的研制及溶蚀性能研究

目的制备硝酸毛果芸香碱温敏凝胶,考察其载药凝胶溶蚀行为。方法以泊洛沙姆为温敏凝胶基质制备硝酸毛果芸香碱眼用凝胶,通过凝胶相变温度筛选最佳处方,采用无膜溶蚀实验研究凝胶释药特性。结果18%、19%、20%的泊洛沙姆407溶液在体温范围内发生相变形成凝胶,其pH≈7,凝胶中硝酸毛果芸香碱释放速度分别为0.462、0.393、0.294 mg.min-1。结论18%-20%泊洛沙姆407溶液适合作为眼部给药的温敏凝胶基质,凝胶中药物释放基本符合零级释放行为。     

Association of cyclosporin to isohexylcyanoacrylate nanospheres and subsequent release in human plasma in vitro.

Polyisohexylcyanoacrylate nanocapsules containing cyclosporin were prepared by mixing in a 1:2 ratio an oil/ethanol solution of monomer and drug with an aqueous phase. Drug nanoencapsulation rate was controlled by its partition coefficient between the inner (organic) and outer (aqueous) phases. Thus highest encapsulation yields (88 per cent) were achieved by reducing cyclosporin solubility in the aqueous phase, i.e. by reducing ethanol concentration under reduced pressure, achieving a 3-fold volume reduction. Due to the relative insolubility of cyclosporin in water, no drug was released from the nanocapsules during storage in this injectable vehicle. Upon a 1/5 dilution in human plasma at 37 degrees C in vitro around 40 per cent of the initially encapsulated cyclosporin diffused quickly out of the capsules and an equilibrium was reached, the drug being most likely dissolved in the fatty compartment of the plasma such as lipoproteins, etc. This release mechanism is different from plain polymeric nanoparticles. Indeed, in this case the drug was released in two phases: an initial burst (around 60 per cent) of adsorbed drug as a result of the dilution, followed by a slow release (around 20 per cent over 3 h) which is likely to result from the progressive enzymatic erosion of the polymer. The initial burst was markedly more pronounced (around 80 per cent) when nanoparticle suspensions were evaporated to 1/3 of their initial volume under reduced pressure. Finally, experiments performed at 0 degree C allowed a reduction of the fraction released immediately from both types of nanospheres, probably because of a reduced solubility in plasma. In the case of nanoparticles the second phase of slow release is also inhibited at 0 degree C, in agreement with an enzymatically controlled release mechanism.     

In vitro drug release mechanism from lipid nanocapsules (LNC)

Lipid nanocapsules are recently developed lipid nanocarriers for delivery of lipophilic drugs. Due to their small size and biocompatible nature, lipid nanocapsules (LNC) may be promising carriers for drug delivery with different routes of administration. The aim of this work was to study the effect of formulation variables on the in vitro drug release from LNC. Ibuprofen as a model drug was entrapped in the oily core while Cremophor A25 and Cremophor A6 were used as hydrophilic surfactants in different ratios ranging from 1:1 to 1:0. All the prepared LNC were of comparable particle sizes around 50 nm. Varying Cremophor compositions as well as the presence of lecithin, cetyl or stearyl alcohol had no significant effect on the in vitro drug release profiles. However, drug release rates increased significantly with increasing the temperature from 4 to 50 °C, i.e. the flux increased from 1.5 to 7 μg/(cm² min). This was explained by the increased ibuprofen–lipid interactions at reduced temperature where the increased viscosity of the lipid significantly slows down the drug diffusion to the external aqueous phase. In summary, the physicochemical properties of the drug as well as the oil phase have a high impact on the drug release rate while the surfactant type, composition or density exerted only a minor effect.     

Colloidal carriers for benzathine penicillin G: nanoemulsions and nanocapsules

The main purpose of this work is to formulate benzathine penicillin G nanoemulsion and nanocapsules, to evaluate their physicochemical and stabilising characteristics, and to determine their antimicrobial activity and penicillin in vitro release kinetics. Nanoemulsions were produced by the spontaneous emulsification approach and nanocapsules of poly (D,L-lactic acid-co-glycolic acid) polymer (PLGA) were prepared by the method of interfacial deposition of a pre-formed polymer. A 207+/-8 nm mean diameter nanoemulsion formulation maintained stability for more than 5 months at 4 degrees C. Stable nanocapsules with 224+/-58 nm mean diameter were obtained, which remained stabilised over 120 days at 4 degrees C. The penicillin encapsulation ratio in the nanocapsules was 85%. The in vitro release profiles indicated that penicillin released from the nanoemulsion was similar to the one observed from nanocapsules. However it can be clearly deduced from the in vitro kinetic analysis that the antibiotic cannot be protected in colloidal delivery systems. Nevertheless, stable formulations obtained in this investigation supply a potential dosage form to encapsulate more easily soluble drugs.     

Influence of benzyl benzoate as oil core on the physicochemical properties of spray-dried powders from polymeric nanocapsules containing indomethacin

To prepare spray-dried powders of poly(D,L-lactic acid) (PLA) or poly-epsilon-caprolactone (P epsilonC) from colloidal suspensions containing indomethacin (IND) using benzyl benzoate (BnB), nanocapsules (NC) were prepared by nanoprecipitation. To select the best NC formulations, increasing drug concentrations were tested (1.0, 1.5, or 2.0 mg/mL). The particle size was measured by Nanosizer. Spray-dried powders (SDP) were prepared by addition of Aerosil 200 into suspensions of NC. IND was assayed by HPLC. Free IND was determined using an Ultrafree. NC-SPD were examined under SEM. The particle sizes of all formulations are in the sub-300 nm range and are IND-associated, with drug recovery close to 100%. After 1 month, the formulations with highest drug content (2.0 mg/mL) showed a decline of total quantity of IND. After spray-drying, IND recovery for SDP presented values above 100%, indicating that the drug was concentrated from loss of mass during the process. To verify the relationship of oil phase with this loss of mass, similar NC (IND 1.5 mg/mL) prepared with Miglyol 810 (MI) were spray-dried, and SEM analysis showed nanostructures adsorbed onto SiO2. Similar nano-structures were not visualized for NC samples prepared with BnB. A swelling experiment showed the complete dissolution of both polymer by the BnB, whereas for MI the polymer masses remained unchanged. In conclusion, BnB is a solvent for PLA and P epsilonC and this ester is entrained during spray-drying. Despite the use of BnB in formulations of NC, PLA, or P epsilonC, colloidal suspensions prepared with BnB could be micelles instead of nanocapsules.     

Drug Solubilization Behavior During in Vitro Digestion of Simple Triglyceride Lipid Solution Formulations

PURPOSE: The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during digestion of either long-chain or medium-chain triglyceride (TG) lipid formulations. METHODS: TG solution formulations of five selected drugs (griseofulvin, diazepam, danazol, cinnarizine, and halofantrine) were digested in ritro and drug distribution/solubilization behavior in the resulting digests assessed. RESULTS: For the less lipophilic drugs, the mass of drug dissolved in either medium or long-chain TG was low and the drugs partitioned rapidly into the aqueous digestion phase. For the higher log P drugs, drug transfer to the aqueous phase was limited by accumulation in undigested long-chain TG. In contrast, medium-chain TG was digested completely producing a dispersed aqueous phase that was capable, at least in the case of the high log P drugs, of supporting supersaturated drug concentrations. CONCLUSIONS: The solubilization behavior of lipophilic drugs on digestion of simple TG lipid formulations is a function of the lipophilicity of the drug (which dictates the drug dose and the partitioning behavior), the nature of the colloidal phases produced on digestion of the different formulation lipids, and the kinetics of drug transfer between the digesting formulation and the colloidal phases produced.     

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.