Simulated Gastrointestinal pH Conditions Research Articles

70 A comparative in vitro analysis of coated and non-coated yeast survivability at simulated equine gastrointestinal pH conditions

Fermentation in the equine hindgut is key to ensure the assimilation of dietary components such as vitamins, amino acids, and minerals. Furthermore, microbial fermentation products (of volatile fatty acids) provide horses with energy. Imbalances in the gut microbiota could impact the rate of fermentation leading to physiological responses such as hindgut inflammation, over production of lactic acid and ulceration. Feed supplementation with direct fed microbials (DFMs) is a common approach to restore microbial balance and ensure animal health. DFMs transit the gastrointestinal tract through highly acidic conditions in the stomach could result in a reduction of the initial DFMs concentrations. The use of coating technologies to encapsulate pH sensitive microorganisms is a way to ensure the delivery of high concentrations of DFMs in the hindgut. The aim of this study was to evaluate the survivability of a coated and non-coated concentrated yeast at pH 2, 6.3, and 6.8, to simulate pH conditions and digesta residence times of an equine stomach (1 h), small intestine (5 h) and cecum (17 h), respectively. A total of 2 replicates of Saccharomyces cerevisiae concentrate and a coated protected lyophilized Saccharomyces cerevisiae were added to MRS (selective media) broth and RPMI broth (non-selective media) at pH2; 2 additional replicates of each product were added to each selective and non-selective media at pH 7 (control). Samples were incubated at 38°C for one hour; after incubation samples were washed and media at pH 6.3 was added. Tubes were incubated for 5 h, after incubation media at pH 6.6 was added for a final 17-h incubation. pH was measured and S. cerevisiae counts were plated for enumeration after each incubation period. One-way ANOVA was used to identify statistically significant differences among groups. Counts of the coated S. cerevisiae were between 9.8 and 10.1 log10 cfu/g in selective and 9.6–9.8 log10 cfu/g in non-selective media. These counts were not significantly (P > 0.05) reduced compared with controls in selective (10.3–10.4 log10 cfu/g) and non-selective (9.7–10.3 log10 cfu/g) media. No differences were observed between coated – and non-coated concentrated S. cerevisiae. These results showed that S. cerevisiae used in this study survived the simulated transit times and pH conditions of the equine gastrointestinal tract. Concentrations of S. cerevisiae above 9 log10 cfu/g reached cecum simulated pH conditions, the high concentrations found suggest its potential use as a DFM that could enhance dietary components assimilation in the equine hindgut.

Development of nanoparticle-based orodispersible palatable pediatric formulations

Despite a collaborative effort towards developing suitable oral drug products for pediatrics over the past decade, appropriate pediatric dosage forms have remained lacking due to special considerations in dose flexibility, swallowability, palatability, and safety of excipients for pediatrics. The present research aims to develop a nanoparticle-based orodispersible pediatric drug delivery platform to improve oral bioavailability and taste of poorly water-soluble and unpalatable therapeutics. Two Biopharmaceutics Classification System II/IV compounds lopinavir (LPV) and ritonavir (RTV) with unpleasant taste were chosen as the model compounds. LPV and RTV Eudragit® E PO nanoparticles (NP) were prepared using a nanoprecipitation method and their key quality attributes and taste-masking effect were evaluated. Moreover, in vitro dissolution testing was conducted at simulated gastrointestinal pH conditions. The in vivo bioavailability of the developed NP formulations was assessed using a rat model. Following the formulation optimization, over 98% encapsulation efficiency was obtained for both LPV and RTV NP and both drugs remained amorphous in its respective NP. LPV/RTV NP combination (4/1, w/w) showed comparable in vitro dissolution to that of the commercial LPV/RTV tablet (Kaletra®). In addition, the taste-masking effect of the developed NP formulations was confirmed by an E-tongue study. The lyophilized LPV and RTV NP were completely dispersible in water within 7 sec and remained stable at 4 ± 2 °C over three months. Lastly, the pharmacokinetic study demonstrated that the LPV/RTV NP combination (4/1, w/w) had improved oral bioavailability compared to Kaletra® and their corresponding raw drug powders. The results demonstrated a novel nanoparticle-based orodispersible platform that is capable of improving oral bioavailability and taste of poorly water-soluble and unpalatable therapeutics for pediatric use.

Tailoring reversible insulin aggregates loaded in electrosprayed arabinoxylan microspheres intended for colon‐targeted delivery

ABSTRACTArabinoxylans (AX) covalent gels are little affected by pH changes and fermentable by colonic microbiota, which make them suitable for insulin oral administration and colon‐targeted delivery. In this work, the tailoring of insulin aggregates size using glutamic acid and their loading in AX microspheres (2%w/v) prepared by triaxial electrospray is presented. Dynamic light scattering showed that insulin‐glutamic acid aggregates are reversible under intestinal conditions. AX microspheres presented a spherical shape, a mean diameter of 233 μm, a heterogeneous microstructure as shown by scanning electron microscopy, and a homogeneous distribution of insulin aggregates as observed by confocal laser scanning microscopy. In this AX‐insulin system, 20% of insulin is released under simulated gastrointestinal pH conditions, indicating that most of the insulin stays into the microspheres, available for colonic release. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47960.

Encapsulation of (─)-epigallocatechin-3-gallate (EGCG) in solid lipid nanoparticles for food applications

A nanoparticlulate delivery system was prepared for developing a food grade carrier for the major bioactive constituent in green tea; (─)-epigallocatechingallate (EGCG), in order to protect it against degradation during storage and digestion under simulated gastrointestinal pH conditions. EGCG-loaded solid lipid nanoparticles (EGCG-SLNs) were produced by the hot homogenization method. The lipid matrix used in the production consisted of pure cocoa butter. A combination of sodium stearoyl-2-lactylate (SSL) and mono- and diglycerides (MDG) was applied as a surfactant blend. The nanoparticles loaded with different concentrations of EGCG had an average particle size in the range of 108–122 nm. A maximal encapsulation efficiency of 68.5% was obtained. The produced food grade SLNs successfully protected the encapsulated EGCG along the storage period as well as under the adverse conditions at neutral pH values. The developed system offers good potential for enriching food products with EGCG.

Stability of Anthocyanins and Their Degradation Products from Cabernet Sauvignon Red Wine under Gastrointestinal pH and Temperature Conditions.

This study investigated the stability of wine anthocyanins under simulated gastrointestinal pH and temperature conditions, and further studied the evolution of anthocyanin degradation products through simulated digestive conditions. The aim of this study was to investigate the relation between anthocyanins’ structure and their digestive stability. Results showed that a total of 22 anthocyanins were identified in wine and most of these anthocyanins remained stable under simulated gastric digestion process. However, a dramatic concentration decrease happened to these anthocyanins during simulated intestinal digestion. The stability of anthocyanins in digestive process appeared to be related to their structure. The methoxy group in the B-ring enhanced the stability of anthocyanins, whereas hydroxyl group resulted in a reduction of their stability. Acylation decreased the stability of malvidin 3-O-glucoside. Pyruvic acid conjugation enhanced the structural stability of pyranoanthocyanins, whereas acetaldehyde attachment weakened their stability. A commercial malvidin 3-O-glucoside standard was used to investigate anthocyanin degradation products under simulated digestion process, and syringic acid, protocatechuic acid and vanillic acid were confirmed to be the degradation products via anthocyanin chalcone conversion path. Gallic acid, protocatechuic acid, vanillic acid, syringic acid, and p-coumaric acid in wine experienced a significant concentration decrease during digestion process. However, wine model solution revealed that phenolic acids remained stable under gastrointestinal conditions, except gallic acid.

SAXS characterization of the interactions among digested food compounds and the anti-oxidant and anti-inflammatory activities of the formed nanocomplexes.

In the present study, small angle X-ray scattering (SAXS) is applied to investigate the interaction between caseinophosphopeptides (CPP), the major digested product of milk protein, and chitosan (CS) under simulated gastrointestinal (GI) pH conditions. The change in pH value from the gastric to small intestinal environment induces complexation between CPP and CS, which is mainly driven by electrostatic interactions. The fractal dimension (Df) value of the domains inside the CPP-CS complexes is greater than 3, indicating the formation of dense particles/aggregates at the nanoscale. The Df value generally increases with an increase in the CS/CPP mass ratio. As a representative of polyphenols, (-)-epigallocatechin gallate (EGCG) associates with CS and CPP, forming nanocomplexes with a spherical shape and average particle size of around 208 nm. The formed CS-EGCG-CPP nanocomplexes do not affect the antioxidant activity of EGCG in the in vitro assays. Moreover, in the cellular assay, the nanocomplexes protect the RAW264.7 cells against H2O2-induced oxidative injury. In addition, the nanocomplexes significantly inhibit the lipopolysaccharide (LPS)-induced production of nitric oxide (NO), TNF-α, IL-1β and IL-6. Furthermore, they inhibit the expression of iNOS, phosphorylation and degradation of IκB, as well as the translocation of NF-κB p65; this indicates that the mechanism for their anti-inflammatory activity is via the mediation of the NF-κB signaling pathway.

Structural Characterization of Febuxostat/l-Pyroglutamic Acid Cocrystal Using Solid-State 13C-NMR and Investigational Study of Its Water Solubility

Febuxostat (FB) is a poorly water-soluble drug that belongs to BCS class II. The drug is employed for the treatment of inflammatory disease arthritis urica (gout), and the free base, FB form-A, is most preferred for drug formulation. In order to achieve a goal of improving the water solubility of FB form-A, this study was carried out using the cocrystallization technique called the liquid-assisted grinding method to produce FB cocrystals. Here, five amino acids containing amine (NH), oxygen (O), and hydroxyl (OH) functional groups, and possessing difference of pKa less than 3 with FB, were selected as coformers. Then, solvents including methanol, ethanol, isopropyl alcohol, n-hexane, dichloromethane, and acetone were used for the cocrystal screening. As a result, a cocrystal was obtained when acetone and l-pyroglutamic acid (PG) of 0.5 eq. were employed as solvent and coformer, respectively. The ratio of 2:1, which is the ratio of FB to PG within FB-PG cocrystal, was predicted by means of solid-state CP/MAS 13C-NMR, solution-state NMR (1H, 13C, and 2D) and FT-IR. Moreover, Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), and Thermogravimetric Analysis (TGA) were used to investigate the characteristics of FB-PG cocrystal. In addition, comparative solubility tests between FB-PG cocrystal and FB form-A were conducted in deionized water and under simulated gastrointestinal pH (1.2, 4, and 6.8) conditions. The result revealed that FB-PG cocrystal has a solubility of four-fold higher than FB form-A in deionized water and two-fold and five-fold greater than FB form-A at simulated gastrointestinal pH 1.2 and pH 4, respectively. Besides, solubilities of FB-PG cocrystal and FB form-A at pH 6.8 were similar to the results measured in deionized water. Therefore, it is postulated that FB-PG cocrystal has a potential overcoming the limitations related to the low aqueous solubility of FB form-A. Accordingly, FB-PG cocrystal is suggested as an alternative active pharmaceutical ingredient of the currently used FB form-A.

Avaliação in vitro da adsorção de aflatoxina B1 por produtos comerciais utilizados na alimentação animal

RESUMO: Objetivou-se avaliar a capacidade de adsorção in vitro de aflatoxina B1 (AFB1) por produtos comerciais utilizados na alimentação animal. Muitas pesquisas estão sendo realizadas para a descontaminação de AFB1 em alimentos. Os produtos comerciais utilizados frequentemente na alimentação de peixes, disponíveis na forma de probióticos, são formados por cepas de bactérias e leveduras utilizadas na maioria dos ensaios de adsorção de micotoxinas. Foram utilizados três produtos comerciais: A, composto por Bacillus subtilis, Bifidobacterium bifidum, Enterococcus faecium e Lactobacillus acidophilus; B, por leveduras secas de Saccharomyces cerevisiae provenientes de cervejaria; e C, por Bacillus subtilis, Bacillus licheniformis e Bacillus pumilus. Cinco suspensões da dose máxima recomendada pelo fabricante de cada produto (0; 25; 50; 75 e 100%) foram testadas contra AFB1 (1000 ng.mL-1) em microtubos para determinação da capacidade de adsorção. Para simular o pH do estômago e do intestino de tilápias do Nilo (Oreochromis niloticus) foram formuladas soluções tampão fosfato salino (PBS), com pH 1,5 e 7,5; respectivamente. Os microtubos foram introduzidos em uma centrífuga com agitação mecânica, a 37ºC por 1 h e depois centrifugados por 10 min a 14.000 rpm; os sobrenadantes foram quantificados por cromatografia líquida de alta eficiência. Os produtos comerciais, nas concentrações máximas, foram capazes de adsorver AFB1 em quantidades de 45,01 a 129,59; 123,90 a 215,59 e 209,98 a 370,73 ng.mL-1, respectivamente. Concluiu-se que todos os produtos comerciais analisados adsorvem AFB1 em condições simuladas de pH gastrointestinal e são candidatos potenciais para adsorção de AFB1 para futuros ensaios in vivo.

Ciprofloxacin loaded genipin cross-linked chitosan/heparin nanoparticles for drug delivery application

The aim of the present study is to demonstrate a sustained drug delivery in simulated gastro-intestinal system to target enteropathogenic bacteria. Herein, we report a straightforward method to synthesize model drug ciprofloxacin loaded genipin cross-linked chitosan/heparin nanoparticles (CIPRO-GP-CS/Hep NPs) by ionic gelation. The physiochemical characteristics were analyzed using FTIR, DLS, and FESEM. The synthesized particles had a spherical shape with z-average of 250nm and zeta potential +32mV. The antibacterial activity of the CIPRO-GP-CS/Hep NPs was evaluated against Escherichia coli MTCC 443, which showed that it can be used as an antibacterial agent. In vitro drug release study at simulated gastro-intestinal pH conditions demonstrated that the CIPRO-GP-CS/Hep NPs exhibited a sustained release property.

A poly-l-glutamic acid functionalized nanocomplex for improved oral drug absorption.

Poor permeability of the intestinal epithelium limits the oral absorption of many drugs. Here, a poly-l-glutamic acid (PGA)-based functional ternary nanocomplex (TC) is reported for enhancing the intestinal absorption of poorly permeable drug doxorubicin hydrochloride (Dox·HCl). The particle size and zeta potential of TC were 189.3 ± 13.7 nm and -29.1 ± 7.4 mV, respectively. The TC was shown to be more stable under simulated gastrointestinal changing pH or electrolyte content conditions than the binary nanocomplex Dox·HCl/PGA. Cellular uptake and the apparent permeability coefficient value (Papp) of the TC were determined to be 5.2- and 4.6-fold higher than that of Dox·HCl solutions, respectively. Mechanistic studies showed that active endocytosis caused by specific interactions between γ-glutamyl terminal groups of PGA and membrane-bound γ-glutamyl transferase contributed much to the TC-dependent Dox·HCl absorption. Studies on the rat model also demonstrated the highest efficiency for Dox·HCl absorption by the TC throughout the intestinal tract, with 2.6- and 4.2-fold higher Cmax and AUC0-24h values compared to Dox·HCl solutions. In conclusion, the TC is a promising carrier for improving Dox·HCl intestinal absorption, and the rational design of carriers with functional polymer PGA could implement the efficient active absorption of poorly permeable drugs.

The corn influence on the adsorption levels of aflatoxin B1 and zearalenone by yeast cell wall

To in vitro evaluate the influence of the corn on the adsorption levels of aflatoxin B1 (AFB1) and zearalenone (ZEA) by yeast cell walls (YCWs). Two commercial YCWs were studied. The YCWs contain different percentages of polysaccharides. YCW1 and 2 contain 5.9 and 21% of mannans and 17.4 and 23% of β-glucans, respectively. Each YCW was resuspended in pH 2 and pH 6 buffer solutions. Corn was used to study the matrix influence. An aliquot of 500 μl YCW suspension was added to each microtube containing 500 μl of 0.1, 0.25, 0.5, 1, 2.5 and 5 μg ml(-1) AFB(1) or 0.5, 5, 10, 20 and 50 μg ml(-1) ZEA. Microtubes were kept with mechanical agitation at 37 °C for 30 min and then centrifuged for 10 min at 16,873 g and; the supernatants were quantified by high-pressure liquid chromatography. The amount of bound toxin was plotted as a function of the amount of added toxin according to mathematical expressions proposed by three theoretical models. Both YCWs were capable of adsorbing AFB(1) and ZEA in amounts from 0.061 to 0.40 and from 0.10 and 0.26 g g(-1), respectively. In the presence of the matrix, both adsorbents were not able to adsorb AFB(1) . However, they could adsorb ZEA at levels from 0.03 to 0.23 g g(-1). Both YCWs adsorbed ZEA in the presence of corn and also under simulated gastrointestinal pH conditions. These results suggest that the studied YCWs are potential candidates for ZEA adsorption. Several in vitro assays have informed the ability of different substrates including yeast walls to adsorb AFB(1) and ZEA; none of them have evaluated their ability to adsorb AFB(1) and ZEA in the presence of the corn. The corn matrix can influence the adsorption phenomena of these mycotoxins.

Antioxidant Property Enhancement of Sweet Potato Flour under Simulated Gastrointestinal pH

Sweet potato is known to be rich in healthful antioxidants, but the stability of its antioxidant properties under gastrointestinal pH is very much unknown. Hence, this study aimed to evaluate the changes in antioxidant properties (total contents of phenolics and flavonoids as well as antioxidant activity) of sweet potato flour (SPF) under simulated gastrointestinal pH conditions. It was found that the yield of SPF crude phenolic extract increased from 0.29 to 3.22 g/100 g SPF upon subjection to gastrointestinal pH conditions (p < 0.05). Also elevated significantly were the total phenolic content (TPC), total flavonoid content (TFC) and antioxidant activity of SPF (p < 0.05). In summary, the antioxidant properties of SPF were enhanced under gastrointestinal pH conditions, suggesting that SPF might possess a considerable amount of bound phenolic and other antioxidative compounds. The antioxidant properties of SPF are largely influenced by pH and thus might be enhanced during the in vivo digestive process.

Contribution of Carboxylesterase in Hamster to the Intestinal First-Pass Loss and Low Bioavailability of Ethyl Piperate, an Effective Lipid-Lowering Drug Candidate

Ethyl piperate is an effective lipid-lowering drug candidate synthesized from piperine. However, its pharmacokinetic characteristics and oral absorption process remain unclear. A liquid chromatography-tandem mass spectrometry method was applied to determine the oral bioavailability of ethyl piperate. Simulated gastrointestinal pH conditions and intestinal washings were prepared to investigate their contributions to the loss of ethyl piperate. Hydrolysis by carboxylesterase (CES) was evaluated in vitro using microsomes and S9 fractions. In situ intestinal single-pass perfusion experiments were performed to estimate the role of CES in ethyl piperate absorption. The bioavailability of ethyl piperate was extremely low (0.47%) in hamster independent of gastrointestinal environmental effects. Ethyl piperate was a typical substrate of CES with kinetic parameters K(m) and V(max) of 7.56 ± 1.491 μM and 0.16 ± 0.008 nmol · min(-1) · mg protein(-1), respectively. CES was responsible for 85.8% of the intestinal hydrolysis of ethyl piperate. Specific inhibition of CES with bis-p-nitrophenyl phosphate (BNPP), decreased degradation clearance to 36% of control with no significant change in absorption clearance. This contrasted with the results of Caco-2 monolayer experiments, which showed a dramatic increase in the apparent permeability coefficient after BNPP treatment. mRNA levels for the CES isozyme, CES2A3, were similar among the three regions of hamster intestine and 60% less than those in liver; CES1B1 mRNA levels were even lower in the intestine and showed a proximal-to-distal decrease. In conclusion, CES markedly contributes to intestinal first-pass hydrolysis of ethyl piperate that is sufficient, but not necessary, to cause the observed extremely low bioavailability.

Development of enteric submicron particle formulation of papain for oral delivery

BackgroundParticulate systems have received increasing attention for oral delivery of biomolecules. The objective of the present study was to prepare submicron particulate formulations of papain for pH-dependent site-specific release using pH-sensitive polymers.MethodsEnteric submicron particle formulations of papain were prepared by w/o/w emulsion solvent evaporation using hydroxypropyl methylcellulose phthalate (HPMCP), Eudragit L100, and Eudragit S100, to avoid gastric inactivation of papain.ResultsSmaller internal and external aqueous phase volumes provided maximum encapsulation efficiency (75.58%–82.35%), the smallest particle size (665.6–692.4 nm), and 25%–30% loss of enzyme activity. Release studies in 0.1 N HCl confirmed the gastroresistance of the formulations. The anionic submicron particles aggregated in 0.1 N HCl (ie, gastric pH 1.2) due to protonation of carboxylic groups in the enteric polymer. Aggregates < 500 μm size would not impede gastric emptying. However, at pH > 5.0 (duodenal pH), the submicron particles showed deaggregation due to restoration of surface charge. HPMCP submicron particles facilitated almost complete release of papain within 30 minutes at pH 6.0, while Eudragit L100 and Eudragit S100 particles released 88.82% and 53.00% of papain at pH 6.8 and pH 7.4, respectively, according to the Korsmeyer–Peppas equation. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorescence spectroscopy confirmed that the structural integrity of the enzyme was maintained during encapsulation. Fourier transform infrared spectroscopy revealed entrapment of the enzyme, with powder x-ray diffraction and differential scanning calorimetry indicating an amorphous character, and scanning electron microscopy showing that the submicron particles had a spherical shape.ConclusionIn simulated gastrointestinal pH conditions, the HPMCP, Eudragit L100, and Eudragit S100 submicron particles showed good digestion of paneer and milk protein, and could serve as potential carriers for oral enzyme delivery. Stability studies indicated that formulations with approximately 6% overage would ensure a two-year shelf-life at room temperature.

Characterization of calcium alginate and chitosan-treated calcium alginate gel beads entrapping allyl isothiocyanate

Calcium alginate (CA), chitosan-coated calcium alginate (CCA-I), and chitosan–calcium alginate complex (CCA-II) gel beads, in which an oil-in-water emulsion containing allyl isothiocyanate (AITC) was entrapped, were prepared and characterized for efficient oral delivery of AITC. The AITC entrapment efficiency was 81% for CA gel beads, whereas about 30% lower values were determined for the chitosan-treated gel beads. Swelling studies showed that all the gel beads suddenly shrunk in simulated gastric fluid (pH 1.2). In simulated intestinal fluid (pH 7.4), CA and CCA-I gel beads rapidly disintegrated, whereas CCA-II gel beads highly swelled without degradation probably due to the strong chitosan–alginate complexation. Release studies revealed that most entrapped AITC was released during the shrinkage, degradation, or swelling of the gel beads, and the chitosan treatments, especially the chitosan–alginate complexation, were effective in suppressing the release. CCA-II gel beads showed the highest bead stability and AITC retention under simulated gastrointestinal pH conditions.

Insulin encapsulation in reinforced alginate microspheres prepared by internal gelation

Insulin-loaded alginate microspheres prepared by emulsification/internal gelation were reinforced by blending with polyanionic additive polymers and/or chitosan-coating in order to increase the protection of insulin at simulated gastric pH and obtain a sustained release at simulated intestinal pH. Polyanionic additive polymers blended with alginate were cellulose acetate phtalate (CAP), Eudragit ® L100 (EL100), sodium carboxymethylcellulose (CMC), polyphosphate (PP), dextran sulfate (DS) and cellulose sulfate (CS). Chitosan-coating was applied by using a one-stage procedure. The influence of additive polymers and chitosan-coating on the size distribution of microspheres, encapsulation efficiency and release profile of insulin in simulated gastrointestinal pH conditions was studied. The mean diameter of blended microspheres ranged from 65 to 106 μm and encapsulation efficiency of insulin varied from 14 to 100%, reaching a maximum value when CS and DS were incorporated in the alginate matrix. Insulin release, at pH 1.2, was almost prevented by the incorporation of PP, DS and CS. When uncoated microspheres were transferred to pH 6.8, a fast dissolution occurred, independently of the additive polymer blended with alginate, and insulin was completely released. Increasing the additive polymer concentration in the alginate matrix and/or chitosan-coating the blended alginate microspheres did not promote a sustained release of insulin from microspheres at pH 6.8.

A novel pH-dependent gradient-release delivery system for nitrendipine: II. Investigations of the factors affecting the release behaviors of the system

Nitrendipine, a dihydropyridine calcium antagonist, was used as a poorly water-soluble model drug. To improve its dissolution rate and extend the therapeutic period in vivo as well, a novel pH-dependent gradient-release drug delivery system for nitrendipine having a solid dispersed matrix structure was developed. Four factors, i.e. the amount of excipients, the pH of the dissolution medium, the rotating speed of the paddle of the dissolution apparatus and the particle size of the microspheres, all of which affect the drug-release behavior of the pH-dependent microspheres of the system were investigated in detail. The release profiles of the pH-dependent drug delivery system under simulated gastrointestinal tract pH conditions were also investigated. The results showed that the release rate of drug from the microspheres increased on increasing the amount of respective pH-dependent polymers formulated. Due to the fact that the active drug was incorporated in pH-dependent polymers and was present in a solid dispersion state in the microspheres, the release rate of the drug from the microspheres depended on the dissolution rate of the polymers, which was mainly influenced by the pH of dissolution medium, whereas the rotating speed of the paddle and the particle size of the microspheres had only a relatively minor effect. The release behavior of the system under simulated gastrointestinal tract conditions exhibited obvious gradient-release characteristics, showing that the release rate of the active drug could be controlled efficiently before the microspheres reached the appropriate region of the gut for absorption. These findings suggest that the pH-dependent drug delivery system could be fabricated by using present microspheres.

A novel pH-dependent gradient-release delivery system for nitrendipineI. Manufacturing, evaluation in vitro and bioavailability in healthy dogs

A novel pH-dependent gradient-release delivery system was developed by mixing three kinds of pH-dependent microspheres. Nitrendipine, a dihydropyridine calcium antagonist, was selected as the poorly water-soluble model drug. To obtain gradient-release of the active drug in the stomach, duodenum and lower segment of the small intestine, respectively, three kinds of pH-dependent polymers, i.e. Acrylic resins Eudragit E-100, Hydroxypropylmethylcellulose phthalate and Hydroxypropylmethylcellulose acetate succinate, were formulated to produce the microspheres, which dissolve at an acid condition, the pH of ≥5.5 and ≥6.5, respectively. The quasi-emulsion solvent diffusion method was employed in the manufacturing process for the microspheres. All three kinds of microspheres had a highly spherical shape and high incorporation efficiency (>91.0%). The particle sizes were mainly affected by the agitation speed and temperature of the manufacturing process. The results of X-ray diffraction suggested that nitrendipine in the microspheres was molecularly dispersed in an amorphous state. The drug dissolution behavior of the system under the simulated gastrointestinal pH conditions revealed obvious gradient-release characteristics. The dissolution profiles and content of the systems stored at a temperature of 40 °C and a relative humidity of 75% were unchanged during a 3-month period of accelerating storage conditions. The results of the bioavailability testing in six healthy dogs suggested that the pH-dependent gradient-release delivery system could improve efficiently the uptake of the poorly water-soluble drug and prolong the Tmax value in vivo.

A novel pH-dependent gradient-release delivery system for nitrendipine: I. Manufacturing, evaluation in vitro and bioavailability in healthy dogs

A novel pH-dependent gradient-release delivery system was developed by mixing three kinds of pH-dependent microspheres. Nitrendipine, a dihydropyridine calcium antagonist, was selected as the poorly water-soluble model drug. To obtain gradient-release of the active drug in the stomach, duodenum and lower segment of the small intestine, respectively, three kinds of pH-dependent polymers, i.e. Acrylic resins Eudragit E-100, Hydroxypropylmethylcellulose phthalate and Hydroxypropylmethylcellulose acetate succinate, were formulated to produce the microspheres, which dissolve at an acid condition, the pH of ≥5.5 and ≥6.5, respectively. The quasi-emulsion solvent diffusion method was employed in the manufacturing process for the microspheres. All three kinds of microspheres had a highly spherical shape and high incorporation efficiency (>91.0%). The particle sizes were mainly affected by the agitation speed and temperature of the manufacturing process. The results of X-ray diffraction suggested that nitrendipine in the microspheres was molecularly dispersed in an amorphous state. The drug dissolution behavior of the system under the simulated gastrointestinal pH conditions revealed obvious gradient-release characteristics. The dissolution profiles and content of the systems stored at a temperature of 40 °C and a relative humidity of 75% were unchanged during a 3-month period of accelerating storage conditions. The results of the bioavailability testing in six healthy dogs suggested that the pH-dependent gradient-release delivery system could improve efficiently the uptake of the poorly water-soluble drug and prolong the T max value in vivo.

Preparation of the Traditional Chinese Medicine Compound Recipe Heart-Protecting Musk pH-Dependent Gradient-Release Pellets

ABSTRACTIn this study a sustained-release formulation of traditional Chinese medicine compound recipe (TCMCR) was developed by selecting heart-protecting musk pills (HPMP) as the model drug. Heart-protecting musk pellets were prepared with the refined medicinal materials contained in the recipe of HPMP. Two kinds of coated pellets were prepared by using pH-dependent methacrylic acid as film-forming material, which could dissolve under different pH values in accordance with the physiological range of human gastrointestinal tract (GIT). The pellets coated with Eudragit L30D-55, which dissolves at pH value over 5.5, were designed to disintegrate and release drug in the duodenum. The pellets coated with Eudragit L100–Eudragit S100 combinations in the ratio of 1:5, which dissolve at pH value 6.8 or above, were designed to disintegrate and release drug in the jejunum to ileum. The pellets coated with HPMC, which dissolves in water at any pH value, were designed to disintegrate and release drug in the stomach. Finally, the heart-protecting musk sustained-release capsules (HPMSRC) with a pH-dependent gradient-release pattern were prepared by encapsulating the above three kinds of coated pellets at a certain ratio in hard gelatin capsule. The results of dissolution of borneol (one of the active compounds of the TCMCR) in vitro demonstrated that the coating load and the pH value of the dissolution medium had little effect on the release rate of borneol from pellets coated with hydroxypropyl methyl cellulose (HPMC), but had a significant effect on the release rate of borneol from pellets coated with Eudragit L30D-55 or Eudragit L100–Eudragit S100 combinations in the ratio of 1:5. The pellets coated with Eudragit L30D-55 at 30% (w/w) coating load or above had little drug release in 0.1 mol/L HCl for 3 hr and started to release drug at pH value over 5.5. The pellets coated with Eudragit L100–Eudragit S100 combinations in the ratio of 1:5 at 36% (w/w) coating load or higher had little drug release in 0.1 mol/L HCl for 3 hr and in phosphate buffer of pH value 6.6 for 2 hr, and started to release drug at pH value 6.8 or above. The release profiles of lipophilic bornoel and hydrophilic total ginsenoside from HPMSRC, consisting of three kinds of pellets respectively coated at a certain ratio with HPMC, Eudragit L30D-55, and Eudragit L100–Eudragit S100 in the ratio of 1:5, showed a characteristic of pH-dependent gradient release under the simulated gastrointestinal pH conditions and no significant difference between them. The results indicated that various components with extremely different physicochemical properties in the pH-dependent gradient-release delivery system of TCMCR could release synchronously while sustained-releasing. This complies with the organic whole concept of compound compatibility of TCMCR.