Development and characterization of extended release Kollidon SR mini-matrices prepared by hot-melt extrusion

Kollidon^® SR as a drug carrier and two model drugs with two different melting points, ibuprofen and theophylline, were studied by hot-melt extrusion. Powder mixtures containing Kollidon^® SR were extruded using a twin-screw extruder at temperatures 70 and 80 °C for ibuprofen and 80 and 90 °C for theophylline. The glass transition temperature (T_g) and maximum torque were inversely related to ibuprofen concentrations, indicating its plasticizing effect. The results of differential scanning calorimetry (DSC) and X-ray diffraction analysis showed that ibuprofen remained in an amorphous or dissolved state in the extrudates containing drug up to 35%, whereas theophylline was dispersed in the polymer matrix. The increase in amounts of ibuprofen or theophylline in the hot-melt extrudates resulted in the increase in the drug release rates. Theophylline release rate in hot-melt extruded matrices decreased as the extrusion temperature increased. In contrast, a higher processing temperature caused the higher ibuprofen release. This was a clear indication of the plasticizing effect of ibuprofen on Kollidon^® SR and a result from water uptake. Theophylline release rate from hot-melt extrudates decreased with increasing triethyl citrate (TEC) level because of the formation of a denser matrix. By adding of Klucel^® LF as a water-soluble additive to the hot-melt extruded matrices, an increase in ibuprofen and theophylline release rates was obtained.     

Internal mouthpiece designs as a future perspective for enhanced aerosol deposition. Comparative results for aerosol chemotherapy and aerosol antibiotics

Background

In an effort to identify factors producing a finest mist from Jet-Nebulizers we designed 2 mouthpieces with 4 different internal designs and 1–3 compartments.

Materials and methods

Ten different drugs previous used with their “ideal” combination of jet-nebulizer, residual-cup and loading were used. For each drug the mass median aerodynamic diameter size had been established along with their “ideal” combination.

Results

For both mouthpiece, drug was the most important factor due the high F-values (F_large = 251.7, p < 0.001 and F_small = 60.1, p < 0.001) produced. The design affected the droplet size but only for large mouthpiece (F_large = 5.99, p = 0.001, F_small = 1.72, p = 0.178). Cross designs create the smallest droplets (2.271) so differing from the other designs whose mean droplets were greater and equal ranging between 2.39 and 2.447. The number of compartments in the two devices regarding the 10 drugs was found not statistically significant (p-values 0.768 and 0.532 respectively). Interaction effects between drugs and design were statistically significant for both devices (F_large = 8.87, p < 0.001, F_small = 5.33, p < 0.001).

Conclusion

Based on our experiment we conclude that further improvement of the drugs intended for aerosol production is needed. In addition, the mouthpiece design and size play an important role in further enhancing the fine mist production and therefore further experimentation is needed.     

An approach to a cold chain free oral cholera vaccine: in vitro and in vivo characterization of Vibrio cholerae gastro-resistant microparticles

The present work describes the formulation of Eudragit^® L30 D-55 microparticles (MP) alone or with mucoadhesive agents, alginate or Carbopol^®, as an approach for the development of an oral cholera vaccine. In the first part, a spray drying technique was optimized for microparticle elaboration, obtaining a microparticle size ranging from 7 to 9 μm with high encapsulation efficiencies. Moreover, gastro resistant properties and Vibrio cholerae (VC) antigenicity were maintained, but for Eudragit^®-Carbopol^® microparticles which showed low antigenicity values, ≈25%. Next, a stability study was performed following ICH Q1 A (R2) guidelines, i.e. 25 °C-60% relative humidity (RH) for 12 months, and 30 °C-65% RH and 40 °C-75% RH for 6 months. Upon storage, microparticle size changed slightly, 1 μm for Eudragit^®-alginate MPs and 0.36 μm for Eudragit^®MP. However, gastro resistance and antigenicity values were kept in an acceptance range. In the third stage of this work, in vivo experiments were performed. The immune response evoked was measured by means of vibriocidal titer quantification, observing that Eudragit^®-alginate MPs were able to induce stronger immune responses, comparable to the free VC. Therefore, microencapsulation of VC by spray drying could be proposed as an approach to a cold chain free and effective oral cholera vaccine.     

Polymeric coatings for a multiple-unit pulsatile delivery system: Preliminary study on free and applied films

In order to adapt a previously described swellable/erodible pulsatile delivery system to a multiple-unit configuration, insoluble films with adequate permeability and flexibility were proposed for application to its functional hydroxypropyl methylcellulose (HPMC) layer. By slowing down the penetration of water into the system, such films would be expected to improve the relevant effectiveness in delaying the onset of release without possibly impacting on the mechanism involved. Free films of Eudragit^®NE containing differing amounts (10–20%) of a superdisintegrant, i.e. Explotab^®V17, Ac-Di-Sol^®, Kollidon^®CL or Kollidon^®CL-M, were prepared by spraying technique and evaluated for hydration, permeability and tensile properties. The hydration and permeability characteristics were enhanced by the addition of the superdisintegrants, generally as a function of their concentration. Explotab^®V17 was shown particularly useful to increase the film permeability. Moreover, it exerted a minor impact on the advantageous tensile properties of the acrylic polymer, especially in the wet state. Based on these results and on a preliminary release study performed with two-layer devices, the Eudragit^®NE film with Explotab^®V17 at the highest investigated percentage was identified as a potential formulation candidate for being applied to HPMC-coated cores thus allowing the onset of release to effectively be delayed by coatings of reduced thickness.     

Formulation of thermoresponsive and bioadhesive gel for treatment of oesophageal pain and inflammation

The aim of this study was the formulation and examination of a novel thermoresponsive and bioadhesive, in situ gelling drug delivery system, which can be used in the treatment of oesophageal pain and inflammation. A bioadhesive cellulose derivative (Metolose^® 60SH) was used as a thermoresponsive material, because Metolose^® has thermal gelation properties at certain temperature. The thermal gelation temperature (T₂) of Metolose^® 60SH 2 w/w% solution is above body temperature (65-66 °C), but by using different methods (Metolose^® 60SH concentration, auxiliary materials), it can be shifted near to body temperature. The pH alteration between pH = 2-10 and the application of different alcohols did not influence the gelation temperature, but using water-soluble salts and changing the concentration of Metolose^® 60SH solution between 2 and 3 w/w% the thermal gelation point could be decreased. Different NSAIDs were used as model drugs and which had not influence on thermal gelation temperature, but difference in in vitro liberation and penetration can be observed. In vitro adhesion test pointed out that the condition of investigated membrane can change the adhesion. Morphological test of oesophageal tissue showed that investigated materials had no irritative or tissue-damaging effect on the oesophageal mucosa even after 12 h.     

Influence of borneol and muscone on geniposide transport through MDCK and MDCK-MDR1 cells as blood–brain barrier in vitro model

The objective of this study was (1) to characterize geniposide transport through MDCK and MDCK-MDR1 cell lines to confirm its transport mechanism and (2) to evaluate the effect of borneol and muscone as enhancers of geniposide transport in the BBB models so as to explore the enhancement mechanism. Transport studies of geniposide were performed in both directions, from apical to basolateral and from basolateral to apical sides. Drug concentrations were analyzed by HPLC. Geniposide showed relatively poor absorption in MDCK and MDCK-MDR1 cells, apparent permeability coefficients ranging from 0.323 × 10⁻⁶ to 0.422 × 10⁻⁶ cm/s. The in vitro experiments showed that geniposide transport in both directions was not concentration dependent and saturable, indicating purely passive diffusion. The efflux ratio of geniposide was less than 2 in the two cell models, which suggested that geniposide was not P-gp substrates. Geniposide transport in both directions significantly increased when co-administrated with increasing concentrations of borneol and muscone. Actin staining results indicated that borneol and muscone increased geniposide transport in the BBB models may attribute to disassembly effect on tight junction integrity.     

The kinetics of cohesive powder de-agglomeration from three inhaler devices

Purpose

The purpose of the current investigation is to understand the kinetics of de-agglomeration (k_d) of micronised salbutamol sulphate (SS) and lactohale 300 (LH300) under varying air flow rates (30-180 l min⁻¹) from three dry powder inhaler devices (DPIs), Rotahaler^® (RH), Monodose Inhaler^® (MI) and Handihaler^® (HH).

Results

Cumulative fine particle mass vs. time profiles were obtained from the powder concentration, emitted mass and volume percent <5.4 μm, embedded in the particle size distributions of the aerosol at specific times. The rate of de-agglomeration (k_d), estimated from non-linear least squares modelling, increased with increasing air flow rates. The k_dvs. air flow rate profiles of SS and LH300 were significantly different at high air flow rates. The k_d was highest from RH and lowest from MI. Differences in k_d between the devices were related to device mode of operation while the differences between the materials were due to the powder bed structure.

Conclusion

This approach provided a methodology to measure the rate constant for cohesive powder de-agglomeration following aerosolisation from commercial devices and an initial understanding of the influence of device, air flow rate and material on these rate constants.     

Dry powder inhalers: mechanistic evaluation of lactose formulations containing salbutamol sulphate

The purpose of this study was to evaluate the relationships between physicochemical properties and aerosolisation performance of different grades of lactose. In order to get a wide range of physicochemical properties, various grades of lactose namely Flowlac^®100 (FLO), Lactopress anhydrous^®250 (LAC), Cellactose^®80 (CEL), Tablettose^®80 (TAB), and Granulac^®200 (GRA) were used. The different lactose grades were carefully sieved to separate 63-90 μm particle size fractions and then characterised in terms of size, shape, density, flowability, and solid state. Formulations were prepared by blending each lactose with salbutamol sulphate (SS) at ratio of 67.5:1 (w/w), and then evaluated in terms of SS content uniformity, lactose-SS adhesion properties, and in vitro aerosolisation performance delivered from the Aerolizer^®. Sieved lactose grades showed similar particle size distributions (PSDs) and good flow properties but different particle shape, particle surface texture, and particle solid state. Content uniformity assessments indicated that lactose particles with rougher surface produced improved SS homogeneity within DPI formulation powders. Lactose-SS adhesion assessments indicated that lactose particles with more elongated shape and the rougher surface showed smaller adhesion force between lactose and salbutamol sulphate. Lactose powders with higher bulk density and higher tap density produced smaller emission (EM) and higher drug loss (DL) of SS. In vitro aerosolisation for various lactose grades followed the following rank order in terms of deposition performance: GRA > TAB > LAC ≈ CEL > FLO. Linear relationships were established showing that in order to maximize SS delivery to lower airway regions, lactose particles with more elongated shape, more irregular shape, and rougher surface are preferred. Therefore, considerable improvement in DPI performance can be achieved by careful selection of grade of lactose included within DPI formulations.     

Properties of Free Films Prepared from Aqueous Polymers by a Spraying Technique

A spray method for the preparation of free films from aqueous polymeric dispersions was investigated. Free films were prepared from aqueous dispersions of methacrylic acid-ethyl methacrylate copolymer (Eudragit^® L 30D), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), and ethyl cellulose (EC) by a spray method and a cast method, and their mechanical properties and reproducibility were investigated. Uniform films were obtained from the dispersions of Eudragit^® L 30D, HPMCAS, and EC by the spray method, but films could not be formed by spraying the CAP dispersion. The tensile strength, elongation, and elastic modulus of the sprayed Eudragit^® L 30D films were similar to the properties of the cast films, and good reproducibility was obtained from both methods. Marked within-run variation in the mechanical properties was observed for the cast HPMCAS and CAP films, which could be due to a settling of the solid particles during the drying step. The variation in the mechanical properties of the sprayed HPMCAS films was lower and the tensile strength significantly higher than that of the cast films. There were also significant differences in tensile strength and elongation of EC films between products of the two methods. The results indicated that the spray method used to prepare the free films from aqueous polymeric dispersions provided uniform films with consistent and reproducible properties.     

Study of drug release and tablet characteristics of silicone adhesive matrix tablets

Matrix tablets of a model drug acetaminophen (APAP) were prepared using a highly compressible low glass transition temperature (T_g) polymer silicone pressure sensitive adhesive (PSA) at various binary mixtures of silicone PSA/APAP ratios. Matrix tablets of a rigid high T_g matrix forming polymer ethyl cellulose (EC) were the reference for comparison. Drug release study was carried out using USP Apparatus 1 (basket), and the relationship between the release kinetic parameters of APAP and polymer/APAP ratio was determined to estimate the excipient percolation threshold. The critical points attributed to both silicone PSA and EC tablet percolation thresholds were found to be between 2.5% and 5% w/w. For silicone PSA tablets, satisfactory mechanical properties were obtained above the polymer percolation threshold; no cracking or chipping of the tablet was observed above this threshold. Rigid EC APAP tablets showed low tensile strength and high friability. These results suggest that silicone PSA could eliminate issues related to drug compressibility in the formulation of directly compressed oral controlled release tablets of poorly compressible drug powder such as APAP. No routinely used excipients such as binders, granulating agents, glidants, or lubricants were required for making an acceptable tablet matrix of APAP using silicone PSA.     

Leptin and IL-8: Two novel cytokines screened out in childhood lead exposure

Lead is a toxic heavy metal with many recognized adverse health side effects. The central nervous system is the main target of lead toxicity. Although many studies on lead toxicity were conducted, the mechanism of lead toxicity remains uncertain. One possible attribution is the immature blood–brain barrier that causes lead exposure in children. Few studies have investigated the cytokine changes caused by this exposure. Novel cytokines were detected by RayBio^® Human Cytokine Antibody Array and validated by enzyme-linked immunosorbent assay. Several children were admitted to West China Second University Hospital, after a serious lead pollution event in longchang, Sichuan, China. A total of 4 children with elevated blood lead levels (BLLs) and 4 children with low BLLs were randomly chosen in the discovery set, and 40 children with elevated BLLs and 40 children with low BLLs were included in the validation set. Leptin and interleukin-8 (IL-8) were identified to be significantly different between children with elevated and low BLLs via RayBio^® Human Cytokine Antibody Array. In the validation set, IL-8 was higher in children with elevated BLLs [median(P₂₅–P₇₅), 117.69(52.31–233.63) pg/mL] than in children with low BLLs [median(P₂₅–P₇₅): 17.70(10.75–26.52) pg/mL] (p = 0.000). Leptin was lower in children with elevated BLLs [median(P₂₅–P₇₅): 1658.23(1421.86–2606.55) pg/mL] than in children with low BLLs [median(P₂₅–P₇₅): 4168.68(3246.32–4744.94) pg/mL] (p = 0.000). In children with low BLLs, leptin was higher in children with BLLs < 3 μg/dL (N = 7) [median(P25–P75): 7220.86(4265.72–7555.15) pg/mL] than in children with BLL ≥ 3 μg/dL (N = 33) [median(P₂₅–P₇₅): 4103.86(3163.40–4678.34) pg/mL] (p = 0.026); IL-8 was significantly different in children with BLL < 4 μg/dL (N = 13) [median(P₂₅–P₇₅): 12.49(8.25–14.86) pg/mL] than in children with BLL ≥ 4 μg/dL (N = 27) [median(P₂₅–P₇₅): 21.98(13.64–33.50) pg/mL] (p = 0.013). The results defined specific changes in cytokine expressions to lead exposure, which can be used to explore the mechanism of lead toxicity and monitor lead exposure.     

Investigation of polymeric excipients for dutasteride solid dispersion and its physicochemical characterization

To investigate the effects of polymeric excipients for dutasteride solid dispersion, experimental approaches together with physical interactions at molecular level were evaluated. The drug and various polymers (anionic, amphiphilic, and hydrophilic) were mixed physically into different ratios and their thermodynamic and physical properties were analyzed by differential scanning calorimetry and Fourier transform-infrared spectroscopy, respectively. The enhanced equilibrium solubility of dutasteride was also investigated. Dutasteride is non-ionic and showed low solubility in the tested pH ranges (lower than the detection limit of 20 ng/mL). Kollidon^® MAE 100P, an anionic polymer, showed enhanced dutasteride solubility in aqueous solution followed by hydrophilic Kollidon^® SR and the amphiphilic polymer, Soluplus^®. Melting point (T _m ) of dutasteride was 249.7 °C and was decreased to 229.84 °C when mixed evenly with Kollidon^® MAE 100P. However, the melting point was not detected at a ratio of 1:4 since it fully dissolved or dispersed in the polymer. Glass transition temperature (T _g ) of different compositions exhibited strong interaction of polymer and drug. The result was supported by spectra evidence that Kollidon^® MAE 100P forms hydrogen bonds with dutasteride presenting strong physical interaction with the primary amine group of dutasteride. This study supports a convenient method that together with microscopic observation can perform polymer selection and characterize solid dispersions.     

Beneficial effects of citrulline malate on skeletal muscle function in endotoxemic rat

Although citrulline malate (CM; CAS 54940-97-5, Stimol^®) is used against fatigue states, its anti-asthenic effect remains poorly documented. The objective of this double-blind study was to evaluate the effect of oral ingestion of CM on a rat model of asthenia, using in situ ³¹Phosphorus magnetic resonance spectroscopy (³¹P-MRS). Muscle weakness was induced by intraperitoneal injections of Klebsiella pneumoniae endotoxin (lipopolysaccharides at 3 mg/kg) at t₀ and t₀ + 24 h. For each animal, muscle function was investigated strictly non-invasively before (t₀ − 24 h) and during (t₀ + 48 h) endotoxemia, through a standardized rest-stimulation-recovery protocol. The transcutaneous electrical stimulation protocol consisted of 5.7 min of repeated isometric contractions at a frequency of 3.3 Hz, and force production was measured with an ergometer. CM supplementation in endotoxemic animals prevented the basal phosphocreatine/ATP ratio reduction and normalized the intracellular pH (pH_i) time-course during muscular activity as a sign of an effect at the muscle energetics level. In addition, CM treatment avoided the endotoxemia-induced decline in developed force. These results demonstrate the efficiency of CM for limiting skeletal muscle dysfunction in rats treated with bacterial endotoxin.     

Adenosine A3 receptor-mediated cardioprotection against doxorubicin-induced mitochondrial damage

Cardiotoxicity associated with doxorubicin (DOX) treatment limits the therapeutic efficiency of this drug against cancer. 2-Chloro-N(6)-(3-iodobenzyl)adenosine-5′-N-methyluronamide (Cl-IB-MECA), a selective agonist of A₃ adenosine receptor (A₃R), reduces DOX toxicity in newborn rat cultured cardiomyocytes. The study's aim was to determine whether the protection demonstrated by Cl-IB-MECA attenuates cardiac depression in vivo. In addition, we wished to examine whether this protective pathway affects the sarcoplasmic reticulum (SR) calcium uptake and release, as well as intramitochondrial Ca²⁺ accumulation induced by DOX.Rats were injected every alternate day (6 times) with (1) saline, (2) 2.5 mg/kg i.p. DOX, (3) 33 μg/kg i.v. Cl-IB-MECA, (4) DOX + Cl-IB-MECA. Left ventricular functions were assessed by invasive (pressure) and non-invasive (echocardiography) techniques at the end of the injection period and 4 weeks later. Cytosolic and intramitochondrial calcium levels were measured with indo-1 and rhod-2 probes. SR Ca²⁺ content was determined by exposing cultured rat cardiomyocytes to caffeine.Echocardiography data demonstrate left ventricular wall thinning (23%), an increase in the end systolic dimension (170%) and decreased fractional shortening (35 ± 5% vs. 54 ± 5%, p < 0.01) in DOX-treated animals, compared to the control group. DOX increased Ca²⁺ levels in the cytosol and in mitochondria by diminishing the SR Ca²⁺ uptake. Pretreatment with Cl-IB-MECA attenuated left ventricular dysfunction, improved SR calcium storage capacity and prevented mitochondrial Ca²⁺ overload.We conclude that the adenosine A₃ receptor agonist is effective in vivo against DOX cardiotoxicity via the restoration of Ca²⁺ homeostasis and prevention of mitochondrial damage that occurs as a result of Ca²⁺ overload.     

Nanostructured fluids from pluronic mixtures

Micellization and gelation of binary mixtures of EO₉₉PO₆₉EO₉₉ (pluronic^® F127) and EO₈₀PO₂₇EO₈₀ (pluronic^® F68) in aqueous solutions were investigated by means of micro-differential scanning calorimetry and rheology and for a total copolymer concentration fixed at 20 wt%. The aim of this investigation is to determine the interplay between micellization and macroscopic gelation of the mixed solutions. Micro-DSC reveals the formation of two distinct populations in F127/F68 mixtures during heating and subsequent cooling of the solutions. The enthalpies of micellization of each copolymer and the respective onset temperatures remained constant after mixing indicating the predominance of two independent processes of micellization in the mixtures. The F127 exhibits a crystallization transition, at a distinct temperature which persists, but increases in the mixtures with concentrations higher than 10 wt%. Rheological measurements were performed during heating ramps or after maturation periods versus frequency. They showed two types of gelation transitions: either a steep increase of the storage and the loss moduli, which corresponds to the crystallization temperature of the F127 micelles or a progressive jamming transition when no crystal can form. Maturation process has a major effect on the rheological properties of the mixed gels, possibly related to local rearrangements of the two micellar phases. This investigation highlights the unique features of the binary pluronic^® mixtures, compared to dilution effects of single component aqueous solutions.     

Note on the formulation of thermosensitive and mucoadhesive vaginal hydrogels containing the miniCD4 M48U1 as anti-HIV-1 microbicide

The miniCD4 M48U1 was formulated into thermosensitive and mucoadhesive pluronic^® hydrogels as anti-HIV-1 microbicide. The release kinetics of M48U1 from F127/HPMC (20/1 wt%) and F127/F68/HPMC (22.5/2.5/1 wt%) studied during 24 h by using Franz diffusion cells showed that HEC hydrogel (1.5 wt%) used as control released 93% of the peptide, while about 25% of M48U1 remained in pluronic^® hydrogels. The formulation of M48U1 in pluronic^® hydrogels ensures a local delivery because no diffusion of the peptide was detected through vaginal Cynomolgus macaque mucosa using Ussing chamber. Finally, toxicological studies showed no significant difference in the HeLa cell viability of the pluronic^® hydrogels in comparison with HEC and phosphate buffer saline.     

Composite microparticles with in vivo reduction of the burst release effect

The aim of this study was to develop microparticles containing nanoparticles (composite microparticles) for prolonged drug delivery with reduced burst effect in vitro and in vivo. Such composite microparticles were prepared with hydrophobic and biodegradable polymers [poly(ε-caprolactone), poly(lactic-co-glycolic) acid]. Ibuprofen was chosen as the model drug, and microparticles were prepared by the extraction technique with ethyl acetate as the solvent. Nanoparticles and microparticles and an ibuprofen solution (Pedea^®) were administered subcutaneously at the dose of 1 mg of ibuprofen per kg to overnight-fasted rats (male Wistar). Composite microparticles showed prolonged ibuprofen release and less burst effect when compared to simple microparticles (without nanoparticles inside) or nanoparticles both in vitro (PBS buffer) and in vivo. Moreover, ibuprofen was still detected in the plasma after 96 h with composite microparticles. Consequently, it has been demonstrated that composite microparticles were able to reduce burst release and prolong the release of ibuprofen for a long period of time.     

Baclofen ester and carbamate prodrug candidates: a simultaneous chromatographic assay, resolution optimized with DryLab

Baclofen exhibits insufficient CNS-availability when dosed systemically. Hence, prodrug candidates (methyl, ethyl, 1-propyl, 2-propyl and butyl 4-(tert-butoxycarbonyl amino)-3-(4-chlorophenyl) butanoate) were synthesized aiming at CNS-levels appropriate for the treatment of spastic disorders. The characterization of some biopharmaceutically highly relevant physicochemical properties (Log P and aqueous solubility) and the evaluation of biophase levels represent one important component of the project. The overall research aim was to generate an HPLC optimized method using DryLab^®, a simulation software for the optimization of a RP-HPLC method, which was optimized using a simulation software (DryLab^®), for the simultaneous determination of baclofen and ten synthesized prodrug candidates. The chromatographic resolution predicted and obtained via the simulation is Rs >1.5 for all baclofen derivatives, as well as, with parent baclofen. The method was used to assay the prodrugs and determine their purities, solubility and lipophilicity parameters. The designed analytical method also permits the tracking of the new prodrug candidates’ hydrolysis in vitro and in vivo. The determined physicochemical properties indicate for some of the compounds that they might be suitable for CNS-targeting which was exemplified by the detection of significant baclofen levels in rat brain tissues following an i.p. dose of ethyl carbamate (vs. ethyl ester, for which only traces of baclofen were detected).     

Mucoadhesive platforms for targeted delivery to the colon

A novel platform system, comprising a mucoadhesive core and a rapid release carrier, was designed for targeted drug delivery to the colon. Prednisolone pellets containing different carbomers, including Carbopol 971P, Carbopol 974P and Polycarbophil AA-1, with or without organic acids, were produced by extrusion-spheronization. Mucoadhesive pellets were coated with a new enteric double-coating system, which dissolves at pH 7. This system comprises an inner layer of partially neutralized Eudragit^® S and buffer salt and an outer coating of standard Eudragit^® S. A single layer of standard Eudragit S was also applied for comparison purposes. Dissolution of the coated pellets was assessed in USP II apparatus in 0.1 N HCl followed by Krebs bicarbonate buffer pH 7.4. Visualization of the coating dissolution process was performed by confocal laser scanning microscopy using fluorescent markers in both layers. The mucoadhesive properties of uncoated, single-coated and-double coated pellets were evaluated ex vivo on porcine colonic mucosa. Mucoadhesive pellets coated with a single layer of Eudragit^® S release its cargo after a lag time of 120 min in Krebs buffer. In contrast, drug release from the double-coated mucoadhesive pellets was significantly accelerated, starting at 75 min. In addition, the mucoadhesive properties of the core of the double coated pellets were higher than those from single-coated pellets after the core had been exposed to the buffer medium. This novel platform technology has the potential to target the colon and overcome the variability in transit and harmonize drug release and bioavailability.     

Rapid separation of desloratadine and related compounds in solid pharmaceutical formulation using gradient ion-pair chromatography

We reported the development of an ion-pair chromatographic method to separate desloratadine and all known related compounds in Clarinex Tablets, which use desloratadine as active pharmaceutical ingredient (API). For the first time, baseline separation for desloratadine and all known related compounds was achieved by utilizing a YMC-Pack Pro C₁₈ column (150 mm × 4.6 mm I.D., 3 μm particle size, 120 Å pore size) and a gradient elution method. The mobile phase A contains 3 mM sodium dodecylsulfate (SDS), 15 mM sodium citrate buffer at pH 6.2, and 40 mM sodium sulfate, while the mobile phase B is acetonitrile. Chromsword^®, an artificial intelligence method development tool, was used to optimize several key chromatographic parameters simultaneously including buffer pH/solvent strength, and temperature/gradient profile. The resolution of desloratadine and desloratadine 3,4-dehydropiperidine derivative, one of the critical pairs was improved by adding 40 mM sodium sulfate. Ultraviolet detection at 267 nm was used to achieve the detection for desloratadine and all compounds. This method has been successfully validated according to ICH guidelines in terms of linearity, accuracy, quantitation limit/detection limit, precision, specificity and robustness. It could be used as a stability indicating method for desloratadine drug substances or drug products that use desloratadine as active pharmaceutical ingredient.