Exploring the Impact of Surfactant Type and Digestion: Highly Digestible Surfactants Improve Oral Bioavailability of Nilotinib.

The scientific rationale for selection of the surfactant type during oral formulation development requires an in-depth understanding of the interplay between surfactant characteristics and biopharmaceutical factors. Currently, however, there is a lack of comprehensive knowledge of how surfactant properties, such as hydrophilic-lipophilic balance (HLB), digestibility, and fatty acid (FA) chain length, translate into in vivo performance. In the present study, the relationship between surfactant properties, in vitro characteristics, and in vivo bioavailability was systematically evaluated. An in vitro lipolysis model was used to study the digestibility of a variety of nonionic surfactants. Eight surfactants and one surfactant mixture were selected for further analysis using the model poorly water-soluble drug nilotinib. In vitro lipolysis of all nilotinib formulations was performed, followed by an in vivo pharmacokinetic evaluation in rats. The in vitro lipolysis studies showed that medium-chain FA-based surfactants were more readily digested compared to long-chain surfactants. The in vivo study demonstrated that a Tween 20 formulation significantly enhanced the absolute bioavailability of nilotinib up to 5.2-fold relative to an aqueous suspension. In general, surfactants that were highly digestible in vitro tended to display higher bioavailability of nilotinib in vivo. The bioavailability may additionally be related to the FA chain length of digestible surfactants with an improved exposure in the case of medium-chain FA-based surfactants. There was no apparent relationship between the HLB value of surfactants and the in vivo bioavailability of nilotinib. The impact of this study's findings suggests that when designing surfactant-based formulations to enhance oral bioavailability of the poorly water-soluble drug nilotinib, highly digestible, medium chain-based surfactants are preferred. Additionally, for low-permeability drugs such as nilotinib, which is subject to efflux by intestinal P-glycoprotein, the biopharmaceutical effects of surfactants merit further consideration.

Rutin nanosuspension for potential management of osteoporosis: effect of particle size reduction on oral bioavailability, in vitro and in vivo activity.

Clinical significance of Rutin (RUT) is limited by poor dissolution rate and low oral bioavailability. The study was designed to improve the physicochemical and therapeutic potential of the drug by formulating nanosuspension (NS) for osteoporosis. Rutin nanosuspension (RUT-NS) was prepared after screening a range of stabilizers and their combinations at a different concentration by antisolvent precipitation technique. Effect of precipitation on crystallinity (differential scanning calorimetry DSC, X-ray diffraction studies XRD), morphology (scanning electron microscopy, SEM) and chemical interaction (attenuated total reflectance fourier-transform infrared spectroscopy ATR-FTIR) were studied through biophysical techniques. An optimized nanosuspension exhibited a minimum particle size of 122.85 ± 5.02 nm with higher dissolution of RUT-NS (87. 63 ± 2.29%) as compared to pure drug (39.77 ± 2.8 6%). The enhanced intestine absorption and apparent permeability were achieved due to the improved particle size, surface area and dissolution. RUT-NS displayed greater (3 folds) AUC0-24 h than pure drug. In vitro assays with RUT-NS depicted an increased cell proliferation, antioxidant (ROS) activity and osteocalcin production in MG-63 osteoblast cells. The augmented biochemical in vivo biomarkers and bone quality proved the protective effect of RUT-NS. The results supported RUT-NS as a potential therapy for maintaining bone health.

Fungal Cell Wall and Methyl-ß-Cyclodextrin Synergistically Enhance Paclitaxel Biosynthesis and Secretion in Corylus avellana Cell Suspension Culture.

Paclitaxel is the top-selling chemotherapeutic drug used for the treatment of lung, ovarian and breast cancer as well as Kaposi's sarcoma. Cell suspension culture (CSC) of Corylus avellana has been addressed as a promising alternative for producing paclitaxel. In this study, endophytic fungus strain YEF33 was isolated from Taxus baccata and identified as Coniothyrium palmarum. The effects of the elicitors derived from this fungus including cell extract, culture filtrate and cell wall (CW) and also chitin, alone or in combination with Methyl-ß-Cyclodextrin (MBCD), on paclitaxel biosynthesis in C. avellana CSC were assayed for the first time. CW of C. palmarum was the most efficient fungal elicitor for paclitaxel biosynthesis in C. avellana CSC. The results revealed that MBCD affected paclitaxel biosynthesis differently depending on fungal elicitor type and vice versa. MBCD, either alone or in combination with fungal elicitors, induced a high secretion of paclitaxel, suggesting the decrement of toxicity and retro-inhibition processes of paclitaxel for cells. The joint effects of C. palmarum CW (2.5% (v/v) on 17th day) and 50 mM MBCD synergistically enhanced paclitaxel biosynthesis (402.4 µg l-1; 5.8-fold), 78.6% of which (316.5 µg l-1) were secreted into culture medium, a level 146% higher than that in control.

Washed microbiota transplantation vs. manual fecal microbiota transplantation: clinical findings, animal studies and in vitro screening.

Fecal microbiota transplantation (FMT) by manual preparation has been applied to treat diseases for thousands of years. However, this method still endures safety risks and challenges the psychological endurance and acceptance of doctors, patients and donors. Population evidence showed the washed microbiota preparation with microfiltration based on an automatic purification system followed by repeated centrifugation plus suspension for three times significantly reduced FMT-related adverse events. This washing preparation makes delivering a precise dose of the enriched microbiota feasible, instead of using the weight of stool. Intraperitoneal injection in mice with the fecal microbiota supernatant obtained after repeated centrifugation plus suspension for three times induced less toxic reaction than that by the first centrifugation following the microfiltration. The toxic reactions that include death, the change in the level of peripheral white blood cells, and the proliferation of germinal center in secondary lymphoid follicles in spleen were noted. The metagenomic next-generation sequencing (NGS) indicated the increasing types and amount of viruses could be washed out during the washing process. Metabolomics analysis indicated metabolites with pro-inflammatory effects in the fecal microbiota supernatant such as leukotriene B4, corticosterone, and prostaglandin G2 could be removed by repeated washing. Near-infrared absorption spectroscopy could be served as a rapid detection method to control the quality of the washing-process. In conclusion, this study for the first time provides evidence linking clinical findings and animal experiments to support that washed microbiota transplantation (WMT) is safer, more precise and more quality-controllable than the crude FMT by manual.

The mechanism of solifenacin release from a pH-responsive ion-complex oral suspension in the fasted upper gastrointestinal lumen.

The main objective of this study was to investigate the mechanism of solifenacin release from a pH-responsive ion-complex oral resinate suspension under conditions simulating the environment in the upper gastrointestinal lumen. A secondary objective was to propose an appropriate in vitro methodology for evaluating the quality of orally administered solifenacin suspensions. The mechanism of solifenacin release from polacrilin potassium resin (Amberlite® IRP88) was investigated using biorelevant media and compendial setups (USP Apparatus 2 and USP Apparatus 4) and using newer, recently validated in vitro methodologies [biorelevant gastrointestinal transfer (BioGIT) system]. We evaluated the impact of particle size and concentration of the resin; thickener concentration (carbomer homopolymer, type B); and the impact of pH, cationic strength, agitation intensity and level of simulation of contents in the upper gastrointestinal lumen. Data suggested that solifenacin release from the resinate was determined by the resin particle size, the medium pH, cationic strength (when the conditions in the upper small intestine are simulated) and the level of simulation of contents in the upper small intestine. The interaction of solifenacin with taurocholic acid/lecithin aggregates was significant, but unlikely to affect the degree of solifenacin absorption, as a BCS Class I compound. Under acidic conditions, solifenacin was dissociated and released from the pH-responsive resin rapidly. Under conditions simulating the contents of the upper small intestine, solifenacin was replaced by cations from the testing media and diffused through the resin matrix. All three in vitro systems with or without a pH gradient are useful in distinguishing solifenacin release characteristics from resinate suspensions with different particle sizes. Because of this drug release mechanism, USP Apparatus 2 with fixed pH media demonstrated equivalent or slightly higher discriminative sensitivity than the other setups and appears to be appropriate for product quality control.

The effect of light, phenylalanine and methyl jasmonate, alone or in combination, on growth and secondary metabolism in cell suspension cultures of Vitis vinifera.

The cultivated grapevine V. vinifera is a rich source of stilbene compounds such as resveratrol, which are widely believed to provide dietary protection against the development of cardiovascular disease and some forms of cancer. Elicitation is a well-known strategy to increase commercial production of natural products in plant cell suspension culture systems. Callus tissues obtained from berry slices of V. vinifera cv. Shahani grown on an optimized medium were used to develop cell suspension cultures used to study the effects of elicitation on stilbene synthesis. The effect of two light regimes (135.1 µmol. s-1 m-2 radiation, and dark), the concentration of phenylalanine (Phe; 0, 0.1, 0.5 and 1 mM) and of methyl jasmonate elicitor (MeJA; 0 and 25 µM), alone or in combination, were tested. The results showed that cultures grown in darkness resulted in significantly higher levels of the accumulation of total stilbenes (resveratrol + piceid) compared with the high light condition. The combined treatments of dark +1 mM Phe and dark +25 µM MeJA induced the synthesis of high levels of total phenolics, total flavonoids and total stilbenes. Finally, the combined elicitation of dark +1 mM Phe + 25 µM MeJA gave the highest synergistic coefficient (1.24) and proved to be the most effective treatment for the production of total phenolics, total flavonoids, and total stilbenes with mean contents of 384.80 mg GA/g DW, 527.62 mg catechin/g DW and 188.34 µg/g DW, respectively. The results of our study suggest that the combinations of dark together with MeJA and/or Phe can be used as an efficient method for the future scale-up of V. vinifera cell cultures for the production of high value stilbene compounds in a bioreactor system.

Self microemulsifying drug delivery system of lurasidone hydrochloride for enhanced oral bioavailability by lymphatic targeting: In vitro, Caco-2 cell line and in vivo evaluation.

The global aim of this research was to develop and evaluate self-microemulsifying drug delivery system (SMEDDS) to improve oral bioavailability of Lurasidone Hydrochloride (LH). A chylomicron flow blocking approach was used to evaluate lymphatic drug transport. The developed LH-SMEDDS was composed of Capmul MCM C8 (oil), Cremophor EL (surfactant) and Transcutol HP (co-surfactant). Highest microemulsifying area was obtained at 3:1 ratio (surfactant:cosurfactant) and mean globule size was found to be 49.22 ±â€¯1.60 nm. More than 98% drug release was obtained with LH-SMEDDS in phosphate buffer pH 6.8. Confocal microscopy and flow cytometry studies revealed higher fluorescence indicating deeper penetration across Caco-2 cells with Coumarin-6 SMEDDS as compared to Coumarin-6 solution. Mean Fluorescence Intensity (MFI) with Coumarin-6 loaded SMEDDS was increased 25.57 times with respect to Coumarin-6 solution. The permeability across Caco-2 cells was enhanced 3 times with LH-SMEDDS as compared to LH-suspension. Furthermore, Area Under Curve with LH-SMEDDS was found to be 2.92 times higher than that of LH suspension indicating improved bioavailability after formulating SMEDDS. Lymphatic transport in oral absorption of LH-SMEDDS was proved via lymphatic uptake study. All the findings suggest the effectiveness of lipid-based formulation i.e. SMEDDS of LH to augment the oral bioavailability via intestinal lymphatic pathway.

Effects of Formulation Variables on Lung Dosimetry of Albuterol Sulfate Suspension and Beclomethasone Dipropionate Solution Metered Dose Inhalers.

The performance of pressurized metered dose inhalers (MDIs) is affected by formulation and device variables that impact delivered dose, aerodynamic particle size distribution, and consequently lung deposition and therapeutic effect. Specific formulation variables of relevance to two commercially available products-Proventil® HFA [albuterol sulfate (AS) suspension] and Qvar® [beclomethasone dipropionate (BDP) solution]-were evaluated to determine their influence on key performance attributes measured experimentally with in vitro cascade impaction studies. These commercial MDIs, utilized as model systems, provided mid-points for a design of experiments (DoE) plan to manufacture multiple suspension and solution MDI formulations. The experimental results were utilized as input variables in a computational dosimetry model to predict the effects of MDI formulation variables on lung deposition. For the BDP solution DoE MDIs, increased concentrations of surfactant oleic acid (0-2% w/w) increased lung deposition from 24 to 46%, whereas changes in concentration of the cosolvent ethanol (7-9% w/w) had no effect on lung deposition. For the AS suspension DoE MDIs, changes in oleic acid concentration (0.005-0.25% w/w) did not have significant effects on lung deposition, whereas lung deposition decreased from 48 to 26% as ethanol concentration increased from 2 to 20% w/w, and changes in micronized drug volumetric median particle size distribution (X50, 1.4-2.5 µm) increased deposition in the tracheobronchial airways from 5 to 11%. A direct correlation was observed between fine particle fraction and predicted lung deposition. These results demonstrate the value of using dosimetry models to further explore relationships between performance variables and lung deposition.

Strategies to Suspension Serum-Free Adaptation of Mammalian Cell Lines for Recombinant Glycoprotein Production.

Serum-free suspension cultures are preferably required for recombinant protein production due to its readiness in upstream/downstream processing and scale-up, therefore increasing process productivity and competitiveness. This type of culture replaces traditional cell culturing as the presence of animal-derived components may introduce lot-a-lot variability and adventitious pathogens to the process. However, adapting cells to serum-free conditions is challenging, time-consuming, and cell line and medium dependent. In this chapter, we present different approaches that can be used to adapt mammalian cell lines from an anchorage-dependent serum supplemented culture to a suspension serum-free culture.

Large-Scale Transient Transfection of Suspension Mammalian Cells for VLP Production.

Large-scale transient transfection of mammalian cell suspension cultures enables the production of biological products in sufficient quantity and under stringent quality attributes to perform accelerated in vitro evaluations and has the potential to support preclinical or even clinical studies. Here we describe the methodology to produce VLPs in a 3L bioreactor, using suspension HEK 293 cells and PEIPro as a transfection reagent. Cells are grown in the bioreactor to 1 × 106 cells/mL and transfected with a plasmid DNA-PEI complex at a ratio of 1:2. Dissolved oxygen and pH are controlled and are online monitored during the production phase and cell growth and viability can be measured off line taking samples from the bioreactor. If the product is labeled with a fluorescent marker, transfection efficiency can be also assessed using flow cytometry analysis. Typically, the production phase lasts between 48 and 96 h until the product is harvested.

Novel strategy for improving the bioavailability of curcumin based on a new membrane transport mechanism that directly involves solid particles.

Amorphization has been widely recognized as a useful solubilization technique for poorly water-soluble drugs, such as curcumin. We have recently reported the novel finding that the membrane transport of curcumin was markedly enhanced when amorphous solid particles of curcumin came into direct contact with the lipid membrane surface, but this was not true for crystalline solid particles. The increase in the permeation of curcumin was found to be independent of the improvements in aqueous solubility brought about by amorphization. Thus, we have identified a novel membrane transport mechanism that directly involves solid particles. In addition, it might represent a novel strategy for improving the bioavailability of curcumin that does not focus on the aqueous solubility of the drug. In this study, the direct effects of the administration of amorphous nanoparticles of curcumin (ANC) on the in vivo intestinal absorption of curcumin were investigated. After the intraduodenal administration of a curcumin suspension, the area under the curve of the plasma concentration of curcumin increased in a manner that was dependent on the curcumin concentration of the suspension, while no significant absorption was observed from a saturated solution. This finding is consistent with the results from our in vitro transepithelial transport study. In the latter experiment, the bioavailability of curcumin was found to be 1-2%. The intrapulmonary insufflation of ANC powder resulted in a significant increase in the bioavailability of curcumin (it was two orders of magnitude higher than that seen after the application of a crystalline suspension). This was due to the ANC particles coming into contact with epithelial cells in a more efficient manner after the pulmonary application of the ANC powder than after the intestinal application of the ANC suspension. Therefore, the pulmonary insufflation of amorphous powder is a novel approach to improving the bioavailability of curcumin and might be a useful way of increasing the bioavailability of poorly water-soluble drugs, such as curcumin.

The artificial membrane insert system as predictive tool for formulation performance evaluation.

In view of the increasing interest of pharmaceutical companies for cell- and tissue-free models to implement permeation into formulation testing, this study explored the capability of an artificial membrane insert system (AMI-system) as predictive tool to evaluate the performance of absorption-enabling formulations. Firstly, to explore the usefulness of the AMI-system in supersaturation assessment, permeation was monitored after induction of different degrees of loviride supersaturation. Secondly, to explore the usefulness of the AMI-system in formulation evaluation, a two-stage dissolution test was performed prior to permeation assessment. Different case examples were selected based on the availability of in vivo (intraluminal and systemic) data: (i) a suspension of posaconazole (Noxafil®), (ii) a cyclodextrin-based formulation of itraconazole (Sporanox®), and (iii) a micronized (Lipanthyl®) and nanosized (Lipanthylnano®) formulation of fenofibrate. The obtained results demonstrate that the AMI-system is able to capture the impact of loviride supersaturation on permeation. Furthermore, the AMI-system correctly predicted the effects of (i) formulation pH on posaconazole absorption, (ii) dilution on cyclodextrin-based itraconazole absorption, and (iii) food intake on fenofibrate absorption. Based on the applied in vivo/in vitro approach, the AMI-system combined with simple dissolution testing appears to be a time- and cost-effective tool for the early-stage evaluation of absorption-enabling formulations.

Optimizing Human Induced Pluripotent Stem Cell Expansion in Stirred-Suspension Culture.

Human induced pluripotent stem cells (hiPSCs) hold great hopes for application in regenerative medicine due to their inherent capacity to self-renew and differentiate into cells from the three embryonic germ layers. For clinical applications, a large quantity of hiPSCs produced in standardized and scalable culture processes is required. Several groups, including ours, have developed methodologies for scaled-up hiPSC production in stirred bioreactors in chemically defined medium. In this study, we optimized the critical steps and factors that affect hiPSC expansion and yield in stirred-suspension cultures, including inoculation conditions, seeding density, aggregate size, agitation rate, and cell passaging method. After multiple passages in stirred-suspension bioreactors, hiPSCs remained pluripotent, karyotypically normal, and capable of differentiating into all three germ layers.

Mitochondrial Ca2+ dynamics in cells and suspensions.

Mitochondria play a significant role in shaping cytosolic Ca2+ signals. Thus, transfer of Ca2+ across the mitochondrial membrane is much studied, not only in intact cells but also in artificial systems such as mitochondrial suspensions or permeabilised cells. Observed rates of Ca2+ changes vary by at least one order of magnitude. In this work, we investigate the relationship between the Ca2+ dynamics observed in various experimental conditions using a computational model calibrated on experimental data. Results confirm that mitochondrial Ca2+ exchange fluxes through the mitochondrial Ca2+ uniporter (MCU) and the Na+ /Ca2+ exchanger obey the same basic kinetics in cells and in suspensions, and emphasise the important role played by the high Ca2+ levels reached in mitochondria-associated endoplasmic reticulum membranes in intact cells. Tissue specificity can be ascribed to the different modes of regulation of the MCU by Ca2+ , probably related to the specific levels of expression of the Ca2+ sensing regulator subunit of this channel. The model emphasises the importance of mitochondrial density and buffering in controlling the rate of Ca2+ exchanges with mitochondria, as verified experimentally. Finally, we show that heterogeneity between individual mitochondria can explain the large range of amplitudes and rates of rise in mitochondrial Ca2+ concentration that have been observed experimentally.

Acid-induced assembly of a reconstituted silk protein system.

Silk cocoons are reconstituted into an aqueous suspension, and protein stability is investigated by comparing the protein's response to hydrochloric acid and sodium chloride. Aggregation occurs for systems mixed with hydrochloric acid, while sodium chloride over the same range of concentrations does not cause aggregation. We measure the structures present on the protein and aggregate length scales in these solutions using both optical and small-angle neutron scattering, while mass spectrometry techniques shed light on a possible mechanism for aggregate formation. We find that the introduction of acid modulates the aggregate size and pervaded volume of the protein, an effect that is not observed with salt.

Exploration of alginates as potential stabilizers of nanosuspension.

The objective of this study was to explore the feasibility of using alginate as a potential stabilizer of nanosuspension and elaborate the corresponding stabilization mechanism. Using lovastatin as a Biopharmaceutics Classification System (BCS) II drug model, alginate-stabilized nanosuspension was fabricated by the high-pressure homogenization method. The particle size, zeta potential, short-term stability, and dissolution behavior of the nanosuspension were characterized. Thereafter, the surface morphology, crystallinity, redispersability, and stability of the spray-dried nanosuspension were investigated. The spray-dried powder was further compressed into tablets via direct compression, and stressing test was carried out to investigate the stability of nanocrystal loaded tablets. It was demonstrated that alginate could stabilize nanocrystals by providing both electrostatic and steric stabilization, and the effective concentration was much lower than that of the commonly used stabilizers. Good redispersability was achieved after spray drying of the nanosuspension, and the existing state of lovastatin was not changed as indicated by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) studies. The stress test indicated that nanocrystal-loaded tablets possessed a favorable stability. In conclusion, alginate could be used as a potential stabilizer of nanosuspension with preferable stabilizing ability at a very low concentration either in liquid or in solid state.

Distribution of phospholipid based formulations in the skin investigated by combined ATR-FTIR and tape stripping experiments.

The spatial distribution of exogenous substances in the stratum corneum (SC) could have an influence on their skin irritation potential. In this study it was possible to monitor the distribution of phospholipids with their phosphatidylcholine scaffold on porcine ear skin by combining tape stripping and in vitro ATR-FTIR spectroscopy. Significant vibrational modes in the spectra could be successfully assigned to the functional groups of the molecules. Thus it was possible to track the phospholipids without the need of their deuterated form by calculating difference spectra from the treated - untreated skin samples. The correlation between four characteristic bands (R2≥0.9909) revealed the excellent suitability of this semi-quantitative method for deep profiling analysis. The penetration capabilities of aqueous suspensions of the different phospholipid compositions as well as two monoacyl-phosphatidylcholine based liposome formulations were investigated using this method. Nevertheless, differences in the distribution of the investigated phospholipid species, having different amounts of monoacyl-phosphatidylcholine, could not be found. It could be clearly shown that the deepest skin penetration was seen in the irritating anionic SDS (sodium dodecyl sulfate) out of the aqueous solution. The aqueous suspensions based on different phospholipid surfactants showed the same range of penetration depth (10-15% of SC), whereas the smallest skin penetration depth was observed after the application of liposomal formulations.

Influence of sodium chloride on the colloidal and rennet coagulation properties of concentrated casein micelle suspensions.

The research investigated the influence of NaCl on the colloidal and rennet coagulation properties of concentrated milk. Milk was concentrated to 1×, 3×, and 5× using ultrafiltration. Rennet gelation was followed by rheology and diffusing wave spectroscopy. Soluble protein, total and diffusible calcium and phosphate, size, and zeta potential were also measured as a function of concentration history. In the presence of 300mM NaCl, colloidal calcium phosphate solubilized and pH and the negative charge on the surface of casein micelles decreased. Increasing the volume fraction caused the formation of stiffer gels for both samples with or without NaCl. The addition of NaCl caused a significant increase in the bulk viscosity of the milk concentrated 5× and a decrease in turbidity. The concentration had no effect on the gelation time of control samples, nor on the kinetics of caseinomacropeptide release. On the other hand, rennet gelation was retarded by the addition of NaCl, and the gels showed lower elastic moduli compared with those obtained with control milk.

In Vitro and In Vivo Characterization of Drug Nanoparticles Prepared Using PureNano™ Continuous Crystallizer to Improve the Bioavailability of Poorly Water Soluble Drugs.

PURPOSE: The aim of this study was to enhance the dissolution and oral absorption of poorly water-soluble active pharmaceutical ingredients (APIs) using nanoparticle suspensions prepared with a PureNano™ continuous crystallizer (PCC). METHOD: Nanoparticle suspensions were prepared with a PCC, which is based on microfluidics reaction technology and solvent-antisolvent crystallization. Phenytoin, bezafibrate, flurbiprofen, and miconazole were used as model APIs. These APIs were dissolved in ethanol and precipitated by the addition of water and polyvinyl alcohol. Batch crystallization (BC) using a beaker was also performed to prepare the suspensions. Both PCC and BC formulations were freeze-dried before being characterized in vitro and in vivo. RESULTS: The particle sizes of the nanoparticle suspensions prepared with the PCC were smaller than those prepared by BC. The dissolution rate of each API in vitro significantly increased after crystallization. Reducing the particle size of either the BC or PCC formulation led to increased API flux across Caco-2 cell monolayers. PCC preparations showed higher plasma concentrations after oral administration, demonstrating the advantages of a fast dissolution rate and increased interaction with the gastrointestinal tract owing to the smaller particle size. CONCLUSIONS: PCC can continuously produce nanoparticle APIs and is an efficient approach for improving their oral bioavailability.

Development of a taste-masked oral suspension of clindamycin HCl using ion exchange resin Amberlite IRP 69 for use in pediatrics.

PURPOSE: The purpose of this study is to develop an oral suspension of clindamycin resin complex for the potential use in pediatrics. METHODS: Several types of Ion exchange resins were screened for their binding efficiency with clindamycin. In order to develop a suspension formulation, several thickening agents, surfactants, sweeting, and flavoring agents were evaluated for their influence on the release of clindamycin from resinate. Rheological studies were also conducted to select the optimum amounts of the suspending agents. The release profiles of clindamycin in SGF and SIF were also evaluated from freshly prepared suspension and from suspension formulation after storage for 1 month at 25 °C and 40 °C. Clindamycin bitterness threshold was determined based on volunteers' evaluation, and taste evaluation was conducted in 12 adult volunteers who evaluated the taste of the optimized suspension against clindamycin solution. RESULTS: Among all resins tested, Amberlite IRP 69 showed the highest binding efficiency to clindamycin. Several excipients were selected into the suspension formulation based on no or minimum influence on the release of clindamycin from the resinate complex. Moreover, xanthan gum was selected as the optimal suspending agent for the suspension. Clindamycin release profiles in SGF or SIF showed 90% release within 30 min from freshly prepared sample. Clindamycin exhibited good stability profiles at 25 °C and 40 °C over 1 month storage. The mean bitterness threshold of clindamycin was 12.5 µg/ml, and taste evaluation study in adults showed sustainable taste improvement for suspension over clindamycin solution. CONCLUSION: Clindamycin/resin complexation has shown to be an efficient method to mask the taste of clindamycin and was developed into a suspension formulation that can be used in pediatrics.