Multiscale structure analysis of a pH-responsive gelatin/hydroxypropyl methylcellulose phthalate blend using small-angle scattering.

HYPOTHESIS: Hydroxypropyl methylcellulose phthalate (HPMCP) is an enteric polymer that has been employed in drug delivery systems to delay the release of the encapsulated active pharmaceutical ingredients through its pH-responsive solubility change. This has been recently demonstrated as an effective means for delaying the drug release from gelatin/HPMCP hydrogels at gastric pH values. However, structural characteristics of HPMCP agglomeration in gelatin/HPMCP hydrogels is not well understood thus limiting further tailoring of their material properties. EXPERIMENTS: We investigated the multiscale structure of a gelatin/HPMCP hydrogel (1:1 by weight) between pH 2 and 6 at 37 °C, i.e. above the upper critical solution transition temperature of gelatin, using small-angle X-ray scattering and contrast-variation small-angle neutron scattering to understand the pH-responsive structure of HPMCP and the cross-correlation between gelatin and HPMCP. FINDINGS: Agglomeration of HPMCP between pH 2 and 4 was evidenced by the formation of mass fractal structures, with a fractal dimension ranging from 1.5 to 2.7, comprising primary particles with a radius of gyration ranging from 70 to 140 Å. Blending with gelatin influenced the fractal structure of HPMCP and the primary particle size. Gelatin and HPMCP exhibited negative cross-correlation in all probed length scales and pH values, which was attributed to volume-exclusion interaction in a double-network-like solution architecture.

Enteric coating of tablets containing an amorphous solid dispersion of an enteric polymer and a weakly basic drug: A strategy to enhance in vitro release.

Recent work has highlighted that amorphous solid dispersions (ASDs) containing delamanid (DLM) and an enteric polymer, hypromellose phthalate (HPMCP), appear to be susceptible to crystallization during immersion in simulated gastric fluids. The goal of this study was to minimize contact of the ASD particles with the acidic media via application of an enteric coating to tablets containing the ASD intermediate, and improve the subsequent drug release at higher pH conditions. DLM ASDs were prepared with HPMCP and formulated into a tablet that was then coated with a methacrylic acid copolymer. Drug release was studied in vitro using a two-stage dissolution test where the pH of the gastric compartment was altered to reflect physiological variations. The medium was subsequently switched to simulated intestinal fluid. The gastric resistance time of the enteric coating was probed over the pH range of 1.6-5.0. The enteric coating was found to be effective at protecting the drug against crystallization in pH conditions where HPMCP was insoluble. Consequently, the variability in drug release following gastric immersion under pH conditions reflecting different prandial states was notably reduced when compared to the reference product. These findings support closer examination of the potential for drug crystallization from ASDs in the gastric environment where acid-insoluble polymers may be less effective as crystallization inhibitors. Further, addition of a protective enteric coating appears to provide a promising remediation strategy to prevent crystallization at low pH environments, and may mitigate variability associated with prandial state that arises due to pH changes.

Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer.

Weakly acid polymers with pH-responsive solubility are being used with increasing frequency in amorphous solid dispersion (ASD) formulations of drugs with low aqueous solubility. However, drug release and crystallization in a pH environment where the polymer is insoluble are not well understood. The aim of the current study was to develop ASD formulations optimized for release and supersaturation longevity of a rapidly crystallizing drug, pretomanid (PTM), and to evaluate a subset of these formulations in vivo. Following screening of several polymers for their ability to inhibit crystallization, hypromellose acetate succinate HF grade (HPMCAS-HF; HF) was selected to prepare PTM ASDs. In vitro release studies were conducted in simulated fasted- and fed-state media. Drug crystallization in ASDs following exposure to dissolution media was evaluated by powder X-ray diffraction, scanning electron microscopy, and polarized light microscopy. In vivo oral pharmacokinetic evaluation was conducted in male cynomolgus monkeys (n = 4) given 30 mg PTM under both fasted and fed conditions in a crossover design. Three HPMCAS-based ASDs of PTM were selected for fasted-state animal studies based on their in vitro release performance. Enhanced bioavailability was observed for each of these formulations relative to the reference product that contained crystalline drug. The 20% drug loading PTM-HF ASD gave the best performance in the fasted state, with subsequent dosing in the fed state. Interestingly, while food improved drug absorption of the crystalline reference product, the exposure of the ASD formulation was negatively impacted. The failure of the HPMCAS-HF ASD to enhance absorption in the fed state was hypothesized to result from poor release in the reduced pH intestinal environment resulting from the fed state. In vitro experiments confirmed a reduced release rate under lower pH conditions, which was attributed to reduced polymer solubility and an enhanced crystallization tendency of the drug. These findings emphasize the limitations of in vitro assessment of ASD performance using standardized media conditions. Future studies are needed for improved understanding of food effects on ASD release and how this variability can be captured by in vitro testing methodologies for better prediction of in vivo outcomes, in particular for ASDs formulated with enteric polymers.

Enteric Polymer-Based Amorphous Solid Dispersions Enhance Oral Absorption of the Weakly Basic Drug Nintedanib via Stabilization of Supersaturation.

The pH−induced crystallization of weakly basic drugs in the small intestine limits oral bioavailability. In this study, we investigated the solubilization and inhibitory effects on nintedanib in the presence of enteric polymers (HPMCAS LG, HPMCAS MG, Eudragit L100 55, and Eudragit L100). These polymers provided maintenance of supersaturation by increasing the solubility of nintedanib in PBS 6.8 in a concentration-dependent manner, and the improved ranking was as follows: Eudragit L100 > Eudragit L100 55 > HPMCAS MG > HPMCAS LG. After being formulated into amorphous solid dispersions (ASDs) by a solvent evaporation method, the drug exhibited an amorphous state. The pH shift dissolution results of polymer-ASDs demonstrated that four polymers could effectively maintain the drug supersaturation even at the lowest ratio of nintedanib and polymer (1:1, w/w). Eudragit L100−ASD could provide both acid resistance and the favorable mitigation of crystallization in GIF. In comparison to the coarse drug, the relative bioavailability of Eudragit L100−ASD was 245% after oral administration in rats, and Tmax was markedly delayed from 2.8 ± 0.4 h to 5.3 ± 2.7 h. Our findings indicate that enteric ASDs are an effective strategy to increase the intestinal absorption of nintedanib by improving physiologically generated supersaturation and subsequent crystallization.

Improved dissolution of an enteric polymer and its amorphous solid dispersions by polymer salt formation.

Weakly acidic polymers, historically used as enteric coatings, are increasingly being employed in solubility-enhancing amorphous solid dispersion (ASD) formulations. However, there is a lack of fundamental understanding around how these carboxylic acid-containing polymers dissolve, in particular when molecularly mixed with a lipophilic drug, as in an ASD. Identification of critical factors dominating their dissolution is vital for rational design of new polymers with enhanced release properties to address contemporary ASD delivery challenges, notably achieving good release at higher drug loadings. Herein, after identification of polymer solubilization via ionization as the rate limiting step for dissolution, hydroxypropylmethyl cellulose phthalate (HP-50) was converted to a salt by neutralization of the phthalic acid groups with different bases. Surface normalized dissolution was performed to assess the dissolution rate improvement achieved by polymer pre-ionization via salt formation. Polymer salts showed âˆ¼ 3-fold faster release than HP-50 at pH 6.8 (50 mM sodium phosphate buffer). Importantly, a polymer salt was able to maintain a rapid dissolution rate, irrespective of the buffer capacity of the medium, whereas the protonated polymer showed greatly diminished dissolution as medium buffer capacity decreased toward physiological gastrointestinal tract values. HP-50 and two polymer salts were formulated into ASDs with miconazole, a lipophilic and weakly basic antifungal drug, at a 20% drug loading. Rapid drug release rates were achieved with polymer salt ASDs, whereby drug release was 14 times faster than from the protonated HP-50 ASD. This study highlights the critical role of polymer ionization and buffer capacity in the dissolution of HP-50-based systems and how pre-ionization via polymer salt formation is a successful strategy for the design of new polymers for improved ASD performance.

pH-Dependent supersaturation from amorphous solid dispersions of weakly basic drugs.

PURPOSE: In amorphous solid dispersions (ASDs), the chemical potential of a drug can be reduced due to mixing with the polymer in the solid matrix, and this can lead to reduced drug release when the polymer is insoluble in the dissolution media. If both the drug and the polymer composing an ASD are ionizable, drug release from the ASD becomes pH-dependent. The goal of this study was to gain insights into the pH-dependent solubility suppression from ASD formulations. METHODS: The maximum release of clotrimazole, a weakly basic drug, from ASDs formulated with insoluble and pH-responsive polymers, was determined as a function of solution pH. Drug-polymer interactions in ASDs were probed using melting point depression, moisture sorption, and solid-state Nuclear Magnetic Resonance spectroscopy (SSNMR) measurements. RESULTS: The extent of solubility suppression was dependent on polymer type and drug loading. The strength of drug-polymer interactions was found to correlate well with the degree of solubility suppression. For the same ASD, the degree of solubility suppression was nearly constant across the solution pH range studied, suggesting that polymer-drug interactions in residual ASD solids was independent of solution pH. The total drug release agrees with the Henderson-Hasselbalch relationship if the suppressed amorphous solubility of the free drug is independent of solution pH. CONCLUSIONS: The mechanism of solubility suppression at different solution pHs appeared to be drug-polymer interactions in the solid-state, where the concentration of the free drug remains the same at variable pHs and the total drug concentration follows the Henderson-Hasselbalch relationship.

Enteric and hydrophilic polymers enhance dissolution and absorption of poorly soluble acidic drugs based on micro-environmental pH-modifying solid dispersion.

The oral bioavailability of poorly water-soluble active pharmaceutical ingredient (API) is often inadequate for the desired therapeutic effect. Micro-environmental pH-modifying solid dispersion (micro pHm SD) is an effective method for enhancing the dissolution of pH-dependent soluble APIs. However, erratic bioavailability of these drugs was often found when the micro pHm SD of the drugs was orally administrated and passed through the gastrointestinal tract. Because the added alkalizer in micro pHm SD could be neutralized by the acid in the stomach, as a result not enough alkalizer is left to form alkaline micro-environment around the drug in the intestine, leading to poor dissolution and bioavailability of API. Enteric polymers are applicable materials for site-specific drug delivery that are insoluble in gastric tract but soluble in the intestine targeted for drug release. In this study, a poorly water-soluble model drug, toltrazuril (TOL), was prepared as enteric micro pHm SD with enteric, hydrophilic polymers and alkalizer. The surface of enteric micro pHm SD tablets staining and alkalizer protection test in the acid dissolution medium qualitatively and quantitatively confirmed the protective effects of the enteric polymer on the alkalizer. Dissolution studies revealed that the drug release from the enteric micro pHm SDs was improved significantly compared with micro pHm SD with no enteric polymer. The pH-dependent solubility of enteric polymer had effects on the dissolution of APIs from the SDs in neutral medium. Enteric micro pHm SDs with higher proportion of enteric polymer showed higher Cmax and dissolution rate of TOL. The physicochemical characterization and the molecular interaction between drug and matrix were analyzed by electron microscopy (SEM), differential scanning calorimetry (DSC), and fourier transform infrared spectroscopy (FTIR), finding that the formation of hydrogen bonds between TOL and matrix was helpful to promote dissolution of TOL. Ca(OH)2-TOL-PVPk30-HPMCAS 8: 8: 18: 6 was determined as the most optimal enteric micro pHm SD, which significantly improved the bioavailability of TOL and its active metabolism (TOLSO, TOLSO2) in pharmacokinetic study and could effectively reduce the irritation of the gastrointestinal mucosa caused by the alkalizer Ca(OH)2 when the SD was orally administrated to rabbits. The present study demonstrates that formulating APIs with poor water solubility as enteric micro pHm SD is an effective method for protecting the alkalizer in SD and improving the dissolution of APIs and the bioavailability following oral administration.

Effect of dietary coated granules containing garlic oil diallyl disulphide and diallyl trisulphide on performance, in vitro digestibility and gastrointestinal functionality in laying hens.

This experiment was conducted to investigate the effects of dietary supplementation with coated granules (CG) on performance, in vitro digestibility and the gastrointestinal functionality in laying hens. A total of 40 Hisex Brown laying hens (36 weeks of age) were randomly divided into five equal groups; one served as a control and the other four were actual experimental groups supplemented with 0.75, 1.5, 3 or 6 g CG per day. All the hens were fed restrictively with target feed intake of 100 g basal diet/hen per day. There were no differences in egg production or egg weight among the groups, but feed conversion ratio was significantly improved (linearly, p < 0.05) with the dose level of CG in diet. Dietary CG increased the jejunal weight (linear and quadratic terms, p < 0.05) but decreased the ileal weight (linearly, p < 0.05). There was mostly statistical interaction between dietary CG and specific activity of intestinal digestive enzymes with similar patterns for dietary CG treatments (p < 0.05). A positive linear correlation was observed with in vitro protein digestibility by using the crude enzyme extract from dietary CG supplementation. Dietary CG decreased the caecal Escherichia coli population while the Lactobacillus spp.: E. coli ratio increased (quadratic fit, p < 0.05). CG supplementation, on the other hand, significantly altered intestinal morphology by increasing the height of duodenal and ileal villi (linearly, p < 0.05). Also, duodenal antioxidant capacity observed via remaining reducing power improved linearly (p < 0.05). This suggests that CG, unlike garlic oils without encapsulation, may be a good candidate for feed supplementation in commercial egg production. It could be included up to 6 g CG per day without any adverse effects on performance, which may relate to improving nutrient digestibility and better utilization of limited feed intake when using a low amount of diet or other observations in this study.

Balancing Solid-State Stability and Dissolution Performance of Lumefantrine Amorphous Solid Dispersions: The Role of Polymer Choice and Drug-Polymer Interactions.

Amorphous solid dispersions (ASDs) are of great interest due to their ability to enhance the delivery of poorly soluble drugs. Recent studies have shown that, in addition to acting as a crystallization inhibitor, the polymer in an ASD plays a role in controlling the rate of drug release, notably in congruently releasing formulations, where both the drug and polymer have similar normalized release rates. The aim of this study was to compare the solid-state stability and release performance of ASDs when formulated with neutral and enteric polymers. One neutral (polyvinylpyrrolidone-vinyl acetate copolymer, PVPVA) and four enteric polymers (hypromellose acetate succinate; hypromellose phthalate; cellulose acetate phthalate, CAP; methacrylic acid-methyl methacrylate copolymer, Eudragit L 100) were used to formulate binary ASDs with lumefantrine, a hydrophobic and weakly basic antimalarial drug. The normalized drug and polymer release rates of lumefantrine-PVPVA ASDs up to 35% drug loading (DL) were similar and rapid. No drug release from PVPVA systems was detected when the DL was increased to 40%. In contrast, ASDs formulated with enteric polymers showed a DL-dependent decrease in the release rates of both the drug and polymer, whereby release was slower than for PVPVA ASDs for DLs < 40% DL. Drug release from CAP and Eudragit L 100 systems was the slowest and drug amorphous solubility was not achieved even at 5% DL. Although lumefantrine-PVPVA ASDs showed fast release, they also showed rapid drug crystallization under accelerated stability conditions, while the ASDs with enteric polymers showed much greater resistance to crystallization. This study highlights the importance of polymer selection in the formulation of ASDs, where a balance between physical stability and dissolution release must be achieved.

Design of a pH-responsive oral gel formulation based on the matrix systems of gelatin/hydroxypropyl methylcellulose phthalate for controlled drug release.

Extensive efforts have been directed toward developing novel easily digested formulations with desirable controlled-release properties. The present study sought to develop pH-responsive oral gel formulations using combinations of gelatin and enteric polymers for controlled drug release under stimulated gastric conditions using acetaminophen and fluorescein isothiocyanate (FITC)-labeled dextran as model compounds. Hydroxypropyl methylcellulose phthalate (HPMCP) was identified as the optimal excipient for the pH-responsive drug release system because the release rates of acetaminophen in gelatin/HPMCP gels at pH 1.2 were exceedingly lower than those in other polymer-containing gels. Texture profile analysis of gelatin/HPMCP gels revealed the optimal content of excipients concerning ingestibility. FITC-labeled dextran of varying molecular weights was used to investigate the mechanism of compound release from the gelatin/HPMCP system under acidic conditions. The release properties practically depended on the molecular weight of FITC-dextran, and the compound release rate was proportional to the square root of time. The matrix structures of gelatin/HPMCP gels at low pH offer advantageous pH-responsive drug release profiles.

An enteric polymer mitigates the effects of gastric pH on oral absorption of poorly soluble weak acid drugs from supersaturable formulations: A case study with dantrolene.

This study demonstrated that an enteric polymer can mitigate the effects of gastric pH on the oral absorption of a poorly water-soluble weak acid drug, dantrolene (DNT). An amorphous solid dispersion (ASD) of DNT with hydroxypropyl methylcellulose (HPMC) acetate succinate (ASD-HPMCAS) was prepared as the enteric released ASD (ER-SF). ASD with HPMC (ASD-HPMC) and DNT sodium salt were also used as immediate-release supersaturable formulations (IR-SFs) with and without water-soluble polymer, respectively. In vivo study with rats and in vitro study with a dissolution/permeation (D/P) system were performed to evaluate oral DNT absorption from each formulation under normal and high gastric pH conditions in rats and humans, respectively. The oral absorption of DNT from both IR-SFs in rats with a high gastric pH was significantly higher than that in rats with a normal gastric pH. In contrast, ASD-HPMCAS attenuated the difference in oral absorption between normal and high gastric pH conditions with significant improvement of DNT absorption. In vivo results implied that an enteric polymer delayed the onset of dissolution until after gastric emptying. ASD-HPMCAS generated supersaturation in the small intestine irrespective of gastric conditions, which was supported bythe in vitrostudy using the D/P system. This study suggested that an enteric polymer is useful to mitigate the inter- and intra-individual differences in oral absorption of poorly water-soluble weak acid drugs.

Effect of Gellan Gum and Xanthan Gum Synergistic Interactions and Plasticizers on Physical Properties of Plant-Based Enteric Polymer Films.

The mechanical and barrier properties of plant-based enteric polymer films were enhanced by synergistic interactions between binary gum mixtures and adding plasticizers. The results indicated that the best ratio of gellan gum (GG) and xanthan gum (XG) was 7:3 by comparing tensile strength, tensile elongation, transmittance, and water vapor permeability of plant-based enteric polymer films and rheological properties of solutions. Polyethylene glycol 400 (PEG-400) was an effective plasticizer in improving plasticity and water vapor barrier property of the plant-based enteric polymer film. Rheology measurement and different characterization methods, including Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy, were used to explain interactions between GG and XG as well as PEG-400 and components of the film. The new mixed system, composed of GG/XG mixture with ratio of 7:3 as a novel gelling agent and PEG-400 as a plasticizer, was applied to prepare plant-based enteric hard capsules, which have potential applications in medicines and functional food preparations.

Printfills: 3D printed systems combining fused deposition modeling and injection volume filling. Application to colon-specific drug delivery.

Three-dimensional printing has become a feasible manufacturing technique for pharmaceutical products providing cheap and accurate freeform systems with a great potential for personalized-dose drugs. Fused Deposition Modeling (FDM) highlights among other 3D technologies due to its low cost and easy to operate but, until now, it has the drawbacks of the low drug loaded and the impossibility to print thermosensitive drugs. So, intermediate processes such as hot melt extrusion are frequently associated with FDM. Here, pharmaceutical dosage forms have been manufactured for the first time with a 3D printer combining two different printing technologies: FDM and injection volume filling (IVF), performing customized extruded scaffolds in which a liquid or semisolid system can be injected at room temperature. A model drug and a pH-sensitive polymer were successfully incorporated during the construction of the extruded backbone of the systems, called printfills (printed systems filled with a liquid or semisolid). SEM microphotographs of printfills show the sealing of the structure in the perimeter and the homogeneity of the colonic film formed in the upper side. Thus, the addition of the pH-sensitive polymer does not need an additional process in a fluidized bed or coating pan. Results from drug release studies performed at different pH confirm the ability of printfills for colon-specific drug delivery. Therefore, IVF technology complements FDM, solving its main limitations providing an easy, automatized and versatile technology to manufacture tailored drug delivery platforms, avoiding other intermediate processes.

Ethanol effect on acid resistance of selected enteric polymers.

The aim of this study was to investigate under in vitro conditions the influence of ethanol on acid resistance of four commercially-available enteric polymers (Acryl-EZE®, AQOAT®, Hypromellose phthalate, and Sureteric®). For this purpose, custom-prepared paracetamol tablets were coated with the enteric polymers and tested for release using the buffer-addition method. Ten different hydro-ethanolic media were used in the acid stage corresponding to five levels of ethanol (0, 5, 10, 20, and 40% v/v) in two acidic solutions representing low and high gastric pH (0.1 N HCl pH 1.2, LGpH, and phosphate buffer pH 4.0, HGpH, respectively). The coats were found to resist both types of acidic solution with ethanol percentages up to 10% leading to release profiles that conformed with the pharmacopeial requirements (<10% release after 2 h in acid stage) except for Acryl-EZE®, which showed a premature release in HGpH media. At the higher ethanol levels (20 and 40%), premature release associated with increased acid uptake by coated tablets was noticed for all polymers and more remarkably in HGpH media. ANOVA tests revealed significant effects of polymer type, acidic solution type, and ethanol level on the onset and extent of premature release.

Investigation of a new pH-responsive nanoparticulate pore former for controlled release enteric coating with improved processability and stability.

Water-soluble polymers are often used as pore formers to tailor permeability of film-forming hydrophobic polymers on coated dosage forms. However, their addition to a coating formulation could significantly increase the viscosity thus making the coating process difficult. Moreover, the dissolution of pore formers after oral administration could compromise film integrity resulting in undesirable, inconsistent release profiles. Therefore, a non-leaching, pH-responsive nanoparticulate pore former is proposed herein to preserve film integrity and maintain pH-dependent permeability. Poly(methacrylic acid)-polysorbate 80-grafted-starch terpolymer nanoparticles (TPNs) were incorporated within an ethylcellulose (EC) film (TPN-EC) by casting or spray coating. TPNs at 10%wt (pore former level) only increased viscosity of EC coating suspension slightly while conventional pore formers increased the viscosity by 490-11,700%. Negligible leaching of TPNs led to superior mechanical properties of TPN-EC films compared to Eudragit® L-EC films. As pH increased from 1.2 to 6.8, TPN-EC films with 10% pore former level exhibited an 8-fold higher diltiazem permeability compared to Eudragit® L-EC films. The pH-dependent drug release kinetics of diltiazem HCl beads coated with TPN-EC films was tunable by adjusting the pore former level. These results suggest that the TPNs are promising pH-sensitive nanoparticulate pore formers in EC-coated dosage forms.

Improved Dissolution of Dipyridamole with the Combination of pH-Modifier and Solid Dispersion Technology.

The aim of this study was to develop a pH-independent release formulation of dipyridamole (DP) by the combined use of pH-modifier technology and solid dispersion (SD) technology employing enteric polymer, Eudragit® S100 (Eud). Tartaric acid (TA) was selected as an appropriate pH-modifier in terms of improving the dissolution behavior of DP under neutral conditions. Upon optimization of the ratio of TA to DP, SD of DP with Eud and TA (SD-Eud/DP/TA) was prepared by a freeze-drying method. Scanning electron microscopic images revealed that DP was dispersed in the polymer in SD-Eud/DP/TA, and DP in SD-Eud/DP/TA was in an amorphous state, supported by powder X-ray diffraction and differential scanning calorimetry analyses. The dissolution behavior of SD-Eud/DP/TA was not dependent on the pH of the medium, although SD-Eud/DP exhibited very limited dissolution behavior under neutral conditions. Spectroscopic analysis suggested that there might be inter-molecular interaction among DP, TA and enteric polymer in SD-Eud/DP/TA, possibly leading to the stable pH-independent dissolution behavior of SD-Eud/DP/TA. TA in SD-Eud/DP/TA promoted the degradation of DP, suggesting that improving the stability of DP in SD-Eud/DP/TA might be key for its practical use. From these results, pH-independent dissolution behavior of SD-Eud/DP/TA could be achieved by an enteric polymer-based solid dispersion with a pH-modifier.

Formulation and in vitro evaluation of polymeric enteric nanoparticles as dermal carriers with pH-dependent targeting potential.

pH-sensitive nanoparticles which release in a controlled fashion on the skin or dissolve in the hair follicle could significantly improve treatment effectiveness and make transfollicular drug delivery a success. Dexamethasone-loaded Eudragit® L 100 nanoparticles were prepared by nanoprecipitation from an organic drug-polymer solution. Their toxicity potential was assessed using isolated human fibroblasts. pH-dependent swelling and erosion kinetics of the nanoparticles were investigated by dynamic light scattering and viscosity measurements and its effect on drug release was assessed in vitro with Franz diffusion cells. Stable, 100-550nm-sized dexamethasone-loaded Eudragit® L 100 nanoparticles with drug loading capacity and entrapment efficiency as high as 8.3% and 85%, respectively, were obtained by using polyvinyl alcohol as a stabilizer and ethanol as organic solvent. The nanoparticles showed little or no toxicity on isolated normal human fibroblasts. Dexamethasone existed in the nanoparticles as solid solution or in amorphous form. The nanoparticles underwent extensive swelling and slow drug release in media with a low buffer capacity (as low as 10mM) and a higher pH or at a pH close to the dissolution pH of the polymer (pH6) and a higher buffer capacity. In 40mM buffer and above pH6.8, the nanoparticles eroded fast or dissolved completely and thus released the drug rapidly. pH-sensitive nanoparticles which potentially release in a controlled manner on the stratum corneum but dissolve in the hair follicle could be prepared.

Oral dietary developmental toxicity study with polyvinyl acetate phthalate (PVAP) in the rat.

Polyvinyl acetate phthalate (PVAP) was evaluated in a developmental toxicity study with Crl:CD(SD) rats. Female rats were provided continual access to the formulated diets on days 6 through 20 of presumed gestation (DGs 6 through 20) at concentrations of 0%, 0.75%, 1.5% and 3%. All surviving rats were sacrificed and Caesarean-sectioned on DG 21. The following parameters were evaluated: viability, clinical observations, body weights, feed consumption, necropsy observations, Caesarean-sectioning and litter observations, including gravid uterine weights, fetal body weights and sex, and fetal gross external, soft tissue and skeletal alterations. There were no treatment-related adverse effects reported in the developmental toxicity study. The maternal and developmental no-observable-adverse-effect level (NOAEL) of PVAP was the highest concentration administered, i.e., 3.0% (equivalent to 2324mgPVAP/kg/day).

Design of indomethacin-loaded nanoparticles: effect of polymer matrix and surfactant.

Despite recent advances in nonsteroidal anti-inflammatory drug (NSAID) formulations, the design of targeted delivery systems to improve the efficacy and reduce side effects of NSAIDs continues to be a focus of much research. Enteric nanoparticles have been recognized as a potential system to reduce gastrointestinal irritations caused by NSAIDs. The aim of this study was to evaluate the effect of EUDRAGIT® L100, polyethylene glycol, and polysorbate 80 on encapsulation efficiency of indomethacin within enteric nanoparticles. Formulations were developed based on a multilevel factorial design (three factors, two levels). The amount of polyethylene glycol was shown to be the factor that had the greatest influence on the encapsulation efficiency (evaluated response) at 95% confidence level. Some properties of nanoparticles like process yield, drug-polymer interaction, particle morphology, and in vitro dissolution profile, which could affect biological performance, have also been evaluated.

Design of tablets for the delayed and complete release of poorly water-soluble weak base drugs using SBE7M-ß-CD as a solubilizing agent.

The challenge of designing a delayed-release oral dosage form is significantly increased when the drug substance is poorly water soluble. This manuscript describes the design and characterization of a novel controlled-release film-coated tablet for the pH-triggered delayed and complete release of poorly water-soluble weak base drugs. Delivery of weak bases is specifically highlighted with the use of dipyridamole and prazosin as model compounds. Tailored delayed release is achieved with a combination of an insoluble but semipermeable polymer and an enteric polymer, such as cellulose acetate and hydroxypropyl cellulose phthalate, respectively, as coatings. The extent of the time lag prior to complete release depends on the film-coating composition and thickness. Complete release is achieved by the addition of a cyclodextrin, namely SBE7M-ß-CD with or without a pH modifier added to the tablet core to ensure complete solubilization and release of the drug substance. The film-coating properties allow the complex formation/solubilization to occur in situ. Additionally, the drug release rate can be modulated on the basis of the cyclodextrin to drug molar ratio. This approach offers a platform technology for delayed release of potent but poorly soluble drugs and the release can be modulated by adjusting the film-coating composition and thickness and/or the cyclodextrin and pH modifier, if necessary.