Development of an amorphous based sustained release system for apremilast a selective phosphodiesterase 4 (PDE4) inhibitor.

Apremilast is a selective PDE4 inhibitor and has been approved for several inflammatory disorders. It is classified as a BCS-IV drug and has 7 polymorphic forms. In this research we report the development of an ASD based sustained-release (SR) drug delivery system. A simplified material sparing ASD formulation approach was employed to identify ideal carrier polymers for optimum drug loadings. HPMCAS-M at 20% and Copovidone at 40% drug loadings were selected as the lead formulations. A stable single-phase amorphous system of apremilast via spray drying was created and fully characterized by mDSC, XRPD, DMA, micro-dissolution, dissolution, and accelerated stability analysis. Micro-dissolution study of ASD confirmed attainment and maintenance of supersaturated state over 3 h. ASD showed 8-fold higher solubility relative to its crystalline counterpart. Novel monolithic and bilayer SR HPMC tablet matrices containing 30 mg or 60 mg of ASD system were manufactured. Tablets during dissolution exhibited gradual swelling, erosion, and disentanglement over 15-20-hours with over 90% drug released. The designed SR amorphous based matrix system showed ability to increase apremilast solubility, dissolution rate, and inhibit recrystallization or polymorphic interconversion by stabilizing its amorphous form. This new development may allow for once-daily drug administration and improve both bioavailability and patient compliance.

Hot-melt extrusion based sustained release ibrutinib delivery system: An inhibitor of Bruton's Tyrosine Kinase (BTK).

Ibrutinib (IB) is the first Bruton s tyrosine kinase (BTK) inhibitor classified as BCS class-II, with multiple polymorphic forms. Development of its amorphous solid dispersion (ASD) is an effective approach to overcome drug's poor solubility and concerns regarding metastable polymorphic forms. In this work, Hot Melt Extrusion (HME) was used to develop robust ASD of ibrutinib and copovidone at different ratios. The ASDs were blended with a swellable crosslinked super-disintegrant and compressed into a sustained-release (SR) matrix. ASDs representing drug loadings of 20%, 40%, and 60% showed broad, amorphous "halos" and absence of an endotherm as revealed by X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC). Using dynamic oscillatory rheology, storage modulus, and viscosities versus temperature confirmed formation of a homogeneous dispersion with a manifestation of plasticizing effect of API. Micro-dissolution testing of ASDs in fasted state simulated intestinal fluid (FaSSIF) demonstrated >70% drug release compared to the saturation solubility of crystalline IB. Results of USP dissolution testing of SR tablets exhibited a desirable sustained delivery up to six hours with >88% drug release versus 34% release from tablets containing crystalline ibrutinib. Co-existence of ASD within the hydrating matrix provided unhindered drug release and release duration.

Oleic acid-reinforced PEGylated polymethacrylate transdermal film with enhanced antidyslipidemic activity and bioavailability of atorvastatin: A mechanistic ex-vivo/in-vivo analysis.

To enhance the poor bioavailability and extensive liver metabolism of atorvastatin calcium (ATC), we have developed an oleic acid-reinforced PEGylated polymethacrylate (OLA-PEG-E-RLPO) transdermal film as a convenient and alternative delivery system. The effect of varying levels of Eudragit RLPO, PEG 400, and oleic acid on the target product profile was optimized through Quality by Design (QbD) approach. The ATC-loaded OLA-PEG-E-RLPO transdermal films were evaluated in ex-vivo experiments using full thickness skin, utilizing Franz cell studies, and undergone in-vivo pharmacokinetics/pharmacodynamics (PK/PD) assessment, using poloxamer-induced dyslipidemic Sprague-Dawley rats. At 2 and 12 h, the optimized ATC films with a thickness of 0.79 mm showed permeation of 37.34% and 97.23% into the receptor compartment, respectively. Steady-state flux was 0.172 mg/cm2h, with 7.01 × 10-4 cm/h permeability coefficient, and 0.713 × 10-3 cm2/h diffusion coefficient. In-vivo PK results indicated that the absorption profiles (AUC0-∞) of the optimized film in pre-treated group of animals were 8.6-fold and 2.8-fold greater than controls pre-treated with non-PEGylated non-oleic acid film and orally administered ATC, respectively. PD assessment of the lipid panel indicated that the lipid profile of the optimized film pre-treated group reached normal levels after 12 h, along with the significant enhancement over the non-PEGylated non-oleic acid film and the oral marketed tablet groups. The histopathological findings revealed near-normal hepatocyte structure for the optimized film pre-treated animal group. Our results further indicate that transdermal delivery films based on an optimized ATC-loaded OLA-PEG-E-RLPO were successfully developed and their assessment in both ex-vivo and in-vivo suggests enhanced permeability and improvement in bioavailability and antidyslipidemic activity of ATC. This approach can provide several advantages, especially during chronic administration of ATC, including improvement in patient compliance, therapeutic benefits, bioavailability, and feasibility for commercialization and as a platform for other drug classes.

Release rate determination from in situ gel forming PLGA implant: a novel 'shape-controlled basket in tube' method.

OBJECTIVES: This study aimed to examine the impact of syringe-needle assembly differences in making implants of different shapes as well as its influence on the release kinetics and investigate the release kinetics of the in situ forming implant under various release arrangements. METHODS: PLGA in situ forming implant was prepared in different shape and then subjected to in vitro release testing. Mathematical modelling was used to investigate drug release mechanisms. KEY FINDINGS: The in situ forming implant was investigated for the first time how implant shapes can affect release results. It was demonstrated that implant shape differences could lead to significant variation in the release data. Here, we addressed this issue by developing a shape-controlled method to provide a consistent surface to volume ratio and, therefore, a reliable release result. Injectability in the in vitro release was discussed for the first time. Comparisons between various release methods were also evaluated. The release arrangement was found to be of great importance in release kinetics. CONCLUSIONS: The developed 'shape-controlled basket in tube' method can provide the most reproducible release profiles by minimizing implant adhesion to the release vessels or movement without sacrificing full contact between the release medium and the implant surface.

Delivery Considerations of Highly Viscous Polymeric Fluids Mimicking Concentrated Biopharmaceuticals: Assessment of Injectability via Measurement of Total Work Done "WT".

An account is given of the recent development of the highly viscous complex biopharmaceuticals in relation to syringeability and injectability. The specific objective of this study is to establish a convenient method to examine problem of the injectability for the needle-syringe-formulation system when complex formulations with diverse viscosities are used. This work presents the inter-relationship between needle size, syringe volume, viscosity, and injectability of polymeric solutions having typical viscosities encountered in concentrated biologics, by applying a constant probe crosshead speed on the plunger-syringe needle assembly and continuously recording the force-distance profiles. A computerized texture analyzer was used to accurately capture, display, and store force, displacement, and time data. The force-distance curve and area under the curve are determined, and total work done for complete extrusion of the syringe content was calculated automatically by applying an established Matlab program. Various concentrations (i.e., 0.5-4% w/v of polymeric fluids/dispersions) of polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) with viscosity ranges of 5-100 cP mimicking concentrated monoclonal antibody solutions and complex biopharmaceutical formulations are investigated. Results indicate that calculated values of total work done to completely extrude the syringe content are the most appropriate parameter that describes viscosity-injection force of dispersed formulations. Additionally, the rheological properties of HPMC and PEO fluids in the context of syringeability and injectability are discussed.

Amorphous-based controlled-release gliclazide matrix system.

The aim of this study was to develop a hydrophilic oral controlled release system (CRS) using the amorphous form of gliclazide, a BCS class II compound, listed on the WHO list of essential medicines. For this purpose, spray-dried dispersions (SDDs) of gliclazide were produced using various grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or copovidone as carrier under fully automated conditions. The solid-state properties of prepared SDDs were characterized using X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), modulated differential scanning calorimetry (MDSC), and Fourier transform infrared spectroscopy (FTIR). Supersaturated micro-dissolution testing of SDDs in fasted state-simulated intestinal fluid showed prolonged supersaturation state, with solubility increases of 1.5- to 4.0-fold. Solubility and stability characteristics of the most desirable SDDs in terms of relative dissolution area under the curves (AUCs) (AUC(SDD)/AUC(crystalline)) and stable supersaturated state concentration ratio up to 180 min (C180/Cmax) were determined. The optimized gliclazide-SDD amorphous forms were included into matrix tablets with HPMC blends using compaction simulator. Developed matrix systems were subjected to standard USP dissolution testing. Dissolution profiles obtained were linear with different slopes indicating varying rates of dissolution. Six-month storage stability testing was performed, and dissolution profiles remained stable with "similarity factor" (f 2 = 85). Results show that the use of various HPMCAS as a drug carrier in the spray-drying process produces homogeneous single-phase SDDs which are stable and promising for inclusion into HPMC-based hydrophilic matrix systems.

Mechanistic Approach to Understanding the Influence of USP Apparatus I and II on Dissolution Kinetics of Tablets with Different Operating Release Mechanisms.

This article provides an analysis of dissolution kinetics associated with formulations subjected to different dissolution methods with the purpose of revealing credible direction on selection of apparatus type and hydrodynamics on in vitro drug release profiles using three different formulations. The dissolution kinetics of immediate release (IR) and controlled release (CR) ibuprofen tablets under different hydrodynamic conditions were determined, and potential existence of any correlation between USP apparatus I and II were analyzed using adequate kinetic models. Two types of CR tablets based on PEO (polyethylene oxide-N80) and HPMC (hydroxypropyl methylcellulose- K100M) polymers were prepared. Marketed ibuprofen 200-mg IR tablets were also used. Dissolution studies were carried out using USP 34 apparatuses I and II methods at stirring speed of 100 and 50 rpm in 900 mL phosphate buffer, pH 7.2 at 37°C. The drug release profiles for each formulation was determined and statistically analyzed using model-dependent, model-independent (f 2 ), and ANOVA methods. No significant dissolution differences existed between IR tablets, whereas CR tablets were significantly impacted by apparatus types and hydrodynamics. PEO matrices displayed higher sensitivity to hydrodynamics relative to HPMC matrices, and differences in dissolution profiles were confirmed by ANOVA and boxplot analysis. It is concluded that in the case of CR systems, selection of apparatus type and adherence to the monograph specifications and hydrodynamic conditions is critical, while for IR tablets, both apparatus types and agitation rates had no significant impact on drug release rate, suggesting the possibility of apparatus interchangeability if desired.

Supersaturated controlled release matrix using amorphous dispersions of glipizide.

Spray dried dispersions (SDDs) of glipizide, a BCS Class II model drug, were prepared using various grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone S-630 as carriers. The SDDs appeared as a single amorphous phase with up to 60% drug loading level as revealed by X-ray powder diffraction (XRPD), modulated differential scanning calorimetry (mDSC) and scanning electron microscopy (SEM). Supersaturated micro-dissolution testing of various SDDs in fasted state simulated intestinal fluid showed prolonged supersaturation state (up to 180min) with solubility increases of 5.2-13.9 fold relative to crystalline drug under similar conditions. Solubility and stability characteristics of the most desirable SDDs in terms of relative dissolution AUCs (AUC(SDD)/AUC(crystalline)) and supersaturated concentration ratios (C180/Cmax) were determined. Results show that HPMCAS-based SDDs achieve a higher degree of supersaturation compared to Copovidone S-630 and that SDDs comprising HPMCAS-M and HPMCAS-H maintained stable supersaturated concentration. Dissolution data showed that SDD-loaded CR tablets provide stable supersaturated concentration within the hydrated matrix with increased rate and extent of drug dissolution over 24h. Co-existence of HPMCAS and HPMC within the hydrating matrix showed strong suppression of drug crystallization and allowed achievement of zero-order and slow-first order release kinetics.

Solid-state interactions at the core-coat interface: physicochemical characterization of enteric-coated omeprazole pellets without a protective sub-coat.

Conventionally, scanning electron or transmission microscopy, Raman and near infrared (NIR) spectroscopy, terahertz, florescence, and nuclear magnetic resonance imaging have been used to characterize functional coating structure. This study highlights the use of fluorescence microscopy to investigate the physicochemical stability and coating integrity of the commercially available enteric-coated omeprazole pellets containing a basic excipient and prepared by extrusion and spheronization or drug layering on the nonpareil seed, immediately followed by enteric coating (i.e., absence of protective sub-coat). The nature of coating interface and the likely development of an in situ interfacial layer after the application of enteric coating solution was examined using HPLC, NMR, differential scanning calorimetry (DSC), and fluorescent imaging methods. Likewise for the characterization of the solid pellet structure via fluorescence microscopy, a new approach based on fracturing technique (to avoid surface contamination) rather than microtome sectioning was used and validated. Analytical data showed that the pellets containing omeprazole remained chemically stable (>99.5% recovered). Control of the microenvironmental pH by the addition of alkalinizing excipient within a core formulation or as part of drug layering on top of nonpareil seed appears to efficiently neutralize the acidic effect of enteric coating dispersion. Fluorescence images further illustrate the absence of any discernable in situ layer formation at the coat-core interface.

A novel approach in distinguishing between role of hydrodynamics and mechanical stresses similar to contraction forces of GI tract on drug release from modified release dosage forms.

The objective of this study was to determine the influence of mechanical stresses simulating gastrointestinal contraction forces of 2.0 N (stomach) and 1.2 N (intestine) on the gel properties and drug release characteristics from sustained release swelling and eroding hydrophilic matrices during dissolution studies. Two batches of tetracycline-sustained release tablets containing hydroxypropyl methyl cellulose (HPMC) were manufactured and subjected to USP apparatus II (pH 2.2 buffer) dissolution studies. Hydrated tablets were periodically removed, placed in a petri dish, and multiple times (six cycle) compressed with a flat-ended probe (diameter 1.3 cm) on a texture analyzer at preprogrammed force of either 2.0 or 1.2 N to determine force-distance profiles and changes in drug release rate. The calculated similarity factor values showed dissimilar dissolution profiles using standard dissolution profile as a reference. The similarity factor (f2) values were especially lower than 50 at 2.0 N and, when profiles between the two batches compressed at 1.2 and 2.0 N, were compared with each other. The changes in dissolution pattern and release rate were significantly different after 4 h of dissolution. At 8 h, tablets were fully hydrated and no force could be detected by the probe, indicating a very soft gel matrix. It appears that the contraction forces in the stomach and intestine are capable of altering drug release from modified release hydrophilic matrices during transit in the human GI tract. Accounting for these forces during dissolution can enhance predictions of in vivo drug release, achieve better in vitro and in vivo correlation, introduce improvement in dissolution methods, and better understand the critical quality attributes (CQAs) and factors in quality by design (QbD) during the product development process.

Influence of colloidal silicon dioxide on gel strength, robustness, and adhesive properties of diclofenac gel formulation for topical application.

The objective of this study is to identify the extent of stiffness, adhesiveness, and thixotropic character of a three-dimensional gel network of a 1% diclofenac sodium topical gel formulation in the presence and absence of colloidal silicon dioxide (CSD) and assess its ease of application and adhesiveness using both objective and subjective analysis. The 1% diclofenac gel was mixed with different amounts of CSD (e.g., 0.5, 1, 2, 3, and 5% w/w) and allowed to equilibrate prior to testing. The texture analyzer in combination with a cone-cap assembly was used to objectively investigate the changes in spreadability and adhesiveness of the gel system before and after addition of CSD. Results indicate that an increase in pliability and adhesiveness at levels ≥2 to ≤5% w/w of CSD dispersed in the gel ensues. For subjective analysis, gels with (2% w/w) CSD and in the absence of CSD were uniformly applied to a 20-cm(2) (5 cm × 4 cm) surface area on the forearms of healthy volunteers and vehicle preferences by the volunteers regarding ease of application, durability on the skin, compliance, and feelings concerning its textural properties were assessed. It appears that changes in the gel formulation with the addition of CSD enhance gel viscosity and bonding to the skin. Results further show that changes in physical and rheological characteristics of gel containing 2% w/w CSD did not significantly change subject preferences for the gel preparations. These findings may help formulators to have additional options to develop more robust and cost-effective formulations.

Psychometrics of the scale of attitudes toward physician-pharmacist collaboration: a study with medical students.

BACKGROUND: Despite the emphasis placed on interdisciplinary education and interprofessional collaboration between physicians and pharmacologists, no psychometrically sound instrument is available to measure attitudes toward collaborative relationships. AIM: This study was designed to examine psychometrics of an instrument for measuring attitudes toward physician-pharmacist collaborative relationships for administration to students in medical and pharmacy schools and to physicians and pharmacists. METHODS: The Scale of Attitudes Toward Physician-Pharmacist Collaboration was completed by 210 students at Jefferson Medical College. Factor analysis and correlational methods were used to examine psychometrics of the instrument. RESULTS: Consistent with the conceptual framework of interprofessional collaboration, three underlying constructs, namely "responsibility and accountability;" "shared authority;" and "interdisciplinary education" emerged from the factor analysis of the instrument providing support for its construct validity. The reliability coefficient alpha for the instrument was 0.90. The instrument's criterion-related validity coefficient with scores of a validated instrument (Jefferson Scale of Attitudes Toward Physician-Nurse Collaboration) was 0.70. CONCLUSIONS: Findings provide support for the validity and reliability of the instrument for medical students. The instrument has the potential to be used for the evaluation of interdisciplinary education in medical and pharmacy schools, and for the evaluation of patient outcomes resulting from collaborative physician-pharmacist relationships.

Application of a novel symmetrical shape factor to gastroretentive matrices as a measure of swelling synchronization and its impact on drug release kinetics under standard and modified dissolution conditions.

OBJECTIVES: We have assessed the kinetics of drug release in relation to the full or partial hydration and swelling of matrices under standard and modified United States Pharmacopeia (USP) apparatus II using a novel index, defined as the symmetrical shape factor. The symmetrical shape factor describes the regularity of the hydration rate of the matrix perimeter relative to its central regions. METHODS: Monolithic and three-layer matrices based on hypromellose, polyethylene oxide, Kollidon SR, theophylline, diltiazem hydrochloride and alfuzosin hydrochloride were subjected to dissolution testing. KEY FINDINGS: Our results indicated that Kollidon SR matrices and the three-layer composite systems with and without effervescing components were not significantly affected by the dissolution conditions. However, in the case of the floating monolithic systems based on hypromellose and polyethylene oxide, both release profiles and swelling dynamics in accordance with the similarity factor (f(2)) and symmetrical shape factor values were significantly influenced. CONCLUSIONS: The symmetrical shape factor values were positively impacted. Consequently the drug release kinetics were more predictable and reproducible. The modified USP method resulted in a more synchronized axial and radial swelling with symmetrical shape factor values approaching unity. Data further indicated that the modified USP method provided for complete matrix hydration and swelling as the dosage form remained fully submerged, allowing for more reliable release mimicking the in-vivo conditions.

Development and in-vitro evaluation of a colon-specific controlled release drug delivery system.

The major challenges in targeting drug to various parts of the gastrointestinal tract include control of drug release with respect to its environment and transit time. These two variables should be taken into consideration in designing a rational colonic drug delivery system. To this end, a swelling matrix core containing pectin, hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose and 5-aminosalicylic acid was developed. This was subjected to a dual coating operation: an inner pH-sensitive enteric and an outer semi-permeable membrane coat with a pore former. In-vitro dissolution studies were carried out in USP apparatus-I using sequential pH media. The first 2 h of dissolution studies were done in HCl buffer at pH 1.5, the next 2 h in pH 5.5 and, finally, in phosphate buffer at pH 6.8 with and without pectinolytic enzyme present. Less than 2% drug was released in the first 6 h and about 90% released in the following 12 h in a controlled manner. The stability studies of the coated systems were performed for 90 days under various conditions and it was found that drug release was not adversely affected. Results indicate that this delivery system has potential for site-specific delivery of drugs to the colon irrespective of transit time and rapid changes in the proximal pH of the gastrointestinal tract.

Zero-order delivery of a highly soluble, low dose drug alfuzosin hydrochloride via gastro-retentive system.

A composite gastro-retentive matrix for zero-order delivery of highly soluble drug alfuzosin hydrochloride (10mg) has been designed and characterized. Two systems containing polyethylene oxide (PEO), hydroxypropylmethylcellulose (HPMC), sodium bicarbonate, citric acid and polyvinyl pyrrolidone were dry blended and compressed into triple layer and bi-layer composite matrices. Dissolution studies using the USP 27 paddle method at 100 and 50rpm in pH 2.0 and 6.8 were performed using UV spectroscopy at 244nm, with automatic sampling over a 24h period using a marketed product as a reference to calculate the "f(2)" factor. Textural characteristics of each layer, the composite matrix as a whole, and floatation potential were determined under conditions similar to dissolution. Percent matrix swelling and erosion along with digital images were also obtained. Both systems proved to be effective in providing prolonged floatation, zero-order release, and complete disentanglement and erosion based on the analysis of data with "f(2)" of 68 and 71 for PEO and HPMC based systems, respectively. The kinetics of drug release, swelling and erosion, and dynamics of textural changes during dissolution for the designed composite systems offer a novel approach for developing gastro-retentive drug delivery system that has potential to enhance bioavailability and site-specific delivery to the proximal small intestine.

Development of a robust once-a-day glipizide matrix system.

The robustness of a new hydroxypropylmethylcellulose (HPMC) based modified release glipizide (10 mg) formulation was studied. The tablet formulations were prepared by dry blending the ingredients and direct compression, incorporating a range of release modifying agents up to +/-20% w/w relative to an optimized formulation. The dissolution was assessed in 900 mL pH 6.8 buffer at 75 rev min(-1) paddle speed. Calculated difference and similarity factors (f(1) and f(2)) and results of analysis of variance suggest that the overall release profiles were similar. Compositional changes up to +/-20% w/w and a reduction of drug dose to half did not change the general release pattern of this low dose/pH-dependent drug in a significant way. It is concluded that the drug release from the developed matrix systems is highly dependent on the kinetics of hydration and erosion, and that the proposed compositional changes within +/-20% w/w did not alter this relationship. The particulate systems used were characterized by determining the Carr index, Hausner ratio and the rheological properties using a texture analyser. Results indicate that the release is reproducible and the system has potential for successful scale-up operation, while complying with recommended Food and Drug Administration guidelines "Scale Up and Post Approval Changes".

Development of a controlled release low dose class II drug-Glipizide.

The purpose of this study was to develop a new monolithic matrix system to completely deliver glipizide, a Biopharmaceutics Classification System (BCS) Class II drug in a zero order manner over an extended time period. Two approaches were examined using drug in formulations that contain swellable hydroxypropylmethylcellulose (HPMC) or erodible polyethylene oxide (PEO). The matrices were prepared by dry blending selected ratios of polymers and ingredients using direct compression technique. Dissolution was assessed using modified USP apparatus II. Glucotrol XL push-pull osmotic pump (PPOP) was used as the reference. The interrelationship between matrix hydration, erosion and textural properties were determined and analyzed under the dissolution test conditions. Linear and reproducible release similar to that of Glucotrol XL was achieved for optimized matrices (f2>50) independent of hydrodynamic conditions. The kinetics of drug delivery was directly related to the synchronization of swelling, erosion and fractional release. HPMC matrices showed a significantly greater degree of hydration and swelling and stronger texture property relative to PEO matrices. Results indicate that in the case of low dose/low soluble drug, total drug release in a zero order manner heavily depends on the synchronization of erosion and swelling fronts during the entire dissolution study.

Application of powder rheometer to determine powder flow properties and lubrication efficiency of pharmaceutical particulate systems.

The objective of this study was to understand the behavior of particulate systems under different conditions of shear dynamics before and after granulation and to investigate the efficiency of powder lubrication. Three drug powders, metronidazole, colloidal bismuth citrate, and tetracycline hydrochloride, were chosen as model drugs representing noncohesive and cohesive powder systems. Each powder was individually granulated with microcrystalline cellulose and 5%PVP as a binder. One portion from each granulation was lubricated with different levels of magnesium stearate for 5 minutes. The powder characterization was performed on the plain powders, nonlubricated and lubricated granules using powder rheometer equipped with a helical blade rotating and moving under experimentally fixed set of parameters. The profiles of interaction during the force-distance measurements indicate that powder compresses, expands, and shears many times in a test cycle. Test profiles also clearly reveal existence of significant differences between cohesive and noncohesive powders. In all cases lubrication normalized the overall interactive nature of the powder by reducing peaks and valleys as observed from the profiles and reduced the frictional effect. The developed methods are easy to perform and will allow formulation scientists to better understand powder behavior and help in predicting potential impact of processing factors on particulate systems.