Development of a Clinically Relevant Dissolution Method for Metaxalone Immediate Release Formulations Based on an IVIVC Model

Purpose

The aim of the present work was to classify metaxalone according to the Biopharmaceutics Classification System (BCS), to develop a clinically relevant dissolution method that can be used to predict the oral absorption of metaxalone and to establish an in vitro-in vivo correlation (IVIVC).

Methods

Solubility of the drug was studied in different pH media and permeability studies were performed using a Caco-2 cell model. The in vitro dissolution and in vivo disposition of metaxalone from 3 different immediate release (IR) tablet formulations were investigated using USP 2 apparatus and a single dose, four-way, crossover bioequivalence study in healthy humans along with an oral solution of the drug, respectively. An IVIVC was established by using a direct, differential based method.

Results

Metaxalone has been confirmed as a Class II drug according to BCS. Bioavailability studies performed in humans demonstrated that dissolution was the rate limiting step for bioavailability of the drug and one of the test products had significantly improved bioavailability compared to the marketed product Skelaxin®. An IVIVC model was developed that demonstrated an acceptable internal predictability.

Conclusion

The IVIVC demonstrated that formulation factors play a significant role in dissolution and absorption of metaxalone. A pH 4.5 dissolution medium containing 0.5% NaCl with 0.2% SLS (USP apparatus 2 at 50 rpm) is clinically relevant to predict bioavailability of the drug and is superior to the USP method in terms of the Quality by Design (QbD) concept.

     

A Review on Solubility Enhancement of Carvedilol—a BCS Class II Drug

Purpose

Carvedilol is a third generation non-cardioselective β-blocker used in the treatment of hypertension and demonstrated a potential in the treatment of cardiovascular diseases such as myocardial infarction and arrhythmias. For any drug to be therapeutically effective, it must enter the systemic circulation and to do so, it should have an optimum aqueous solubility at the site of absorption which is a major hurdle to overcome by a formulation scientist. Carvedilol belongs to BCS (biopharmaceutical classification system) class II drugs, thus having low solubility and poor bioavailability (around 25%). Hence, the purpose of this review is to elaborate on several approaches to increase the solubility, dissolution, and bioavailability of carvedilol.

Methods

Micronization, solid dispersions, cyclodextrin inclusion complex, hydrotropy, nanoformulation which include nanocrystals, nanosuspension, nanoemulsions, dendrimers, and polymeric nanoparticles. It also includes methods that have not been used on carvedilol such as cocrystallization and coamorphous technology.

Results

Several approaches have successfully increased solubility and bioavailability of carvedilol and several other unexplored methods which have the potential to improve the aqueous solubility of carvedilol but have not been applied till date have also been discussed in the review.

Conclusion

There are various approaches explored to increase the solubility of carvedilol with every technique having certain advantages and drawbacks. Micronization and nanoformulations (dendrimers, nanoemulsion, nanosuspension, nanocrystals, polymeric nanoparticles) are the most widely used technique for solubility enhancement of carvedilol on laboratory scale due to higher solubility and dissolution rate but they have poor industrial applicability due to difficulty in scale-up and low yield. Efforts are being made to carry out different solubility enhancement techniques with good industrial applicability for carvedilol, e.g., cocrystals. Cocrystals and coamorphous approach for poorly soluble drugs having similar properties to carvedilol have shown good solubility, dissolution, and bioavailability compared to few techniques discussed in this review, and are being widely explored to overcome the drawbacks associated with its method of preparation by carrying out certain advancements (e.g., hot melt extrusion and sonocrystallization) to produce carvedilol cocrystals and coamorphous compound with unique properties in future development.

     

Temperature-Induced Surface Effects on Drug Nanosuspensions

Purpose

The trial-and-error approach is still predominantly used in pharmaceutical development of nanosuspensions. Physicochemical dispersion stability is a primary focus and therefore, various analytical bulk methods are commonly employed. Clearly less attention is directed to surface changes of nanoparticles even though such interface effects can be of pharmaceutical relevance. Such potential effects in drug nanosuspensions were to be studied for temperatures of 25 and 37°C by using complementary surface analytical methods.

Methods

Atomic force microscopy, inverse gas chromatography and UV surface dissolution imaging were used together for the first time to assess pharmaceutical nanosuspensions that were obtained by wet milling. Fenofibrate and bezafibrate were selected as model drugs in presence of sodium dodecyl sulfate and hydroxypropyl cellulose as anionic and steric stabilizer, respectively.

Results

It was demonstrated that in case of bezafibrate nanosuspension, a surface modification occurred at 37°C compared to 25°C, which notably affected dissolution rate. By contrast, no similar effect was observed in case of fenofibrate nanoparticles.

Conclusions

The combined usage of analytical surface methods provides the basis for a better understanding of phenomena that take place on drug surfaces. Such understanding is of importance for pharmaceutical development to achieve desirable quality attributes of nanosuspensions.

     

Preparation,Physicochemical Characterization and Anti-fungal Evaluation of Nystatin-Loaded PLGA-Glucosamine Nanoparticles

Purpose

Nystatin loaded PLGA and PLGA-Glucosamine nanoparticles were formulated. PLGA were functionalized with Glucosamine (PLGA-GlcN) to enhance the adhesion of nanoparticles to Candida Albicans (C.albicans) cell walls.

Method

Quasi-emulsion solvent diffusion method was employed using PLGA and PLGA-GlcN with various drug–polymer ratios for the preparation of nanoparticles. The nanoparticles were evaluated for size, zeta potential, polydispersity index, drug crystallinity, loading efficiency and release properties. DSC, SEM, XRPD, ¹H-NMR, and FT-IR were performed to analyze the physicochemical properties of the nanoparticles. Antifungal activity of the nanoparticles was evaluated by determination of MICs against C.albicans.

Results

The spectra of ¹H-NMR and FT-IR analysis ensured GlcN functionalization on PLGA nanoparticles. SEM characterization confirmed that particles were in the nanosize range and the particle size for PLGA and PLGA-GlcN nanoparticles were in the range of 108.63?±?4.5 to 168.8?±?5.65 nm and 208.76?±?16.85 nm, respectively. DSC and XRPD analysis ensured reduction of the drug crystallinity in the nanoparticles. PLGA-GlcN nanoparticles exhibit higher antifungal activity than PLGA nanoparticles.

Conclusion

PLGA-GlcN nanoparticles showed more antifungal activity with appropriate physicochemical properties than pure Nystatin and PLGA nanoparticles.

     

3D Printed “Starmix” Drug Loaded Dosage Forms for Paediatric Applications

Purpose

Three- dimensional (3D) printing has received significant attention as a manufacturing process for pharmaceutical dosage forms. In this study, we used Fusion Deposition Modelling (FDM) in order to print “candy – like” formulations by imitating Starmix® sweets to prepare paediatric medicines with enhanced palatability.

Methods

Hot melt extrusion processing (HME) was coupled with FDM to prepare extruded filaments of indomethacin (IND), hypromellose acetate succinate (HPMCAS) and polyethylene glycol (PEG) formulations and subsequently feed them in the 3D printer. The shapes of the Starmix® objects were printed in the form of a heart, ring, bottle, ring, bear and lion. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier Transform Infra-red Spectroscopy (FT-IR) and confocal Raman analysis were used to assess the drug – excipient interactions and the content uniformity.

Results

Physicochemical analysis showed the presence of molecularly dispersed IND in the printed tablets. In vivo taste masking evaluation demonstrated excellent masking of the drug bitterness. The printed forms were evaluated for drug dissolution and showed immediate IND release independently of the printed shape, within 60 min.

Conclusions

3D printing was used successfully to process drug loaded filaments for the development of paediatric printed tablets in the form of Starmix® designs.

     

An Investigation into Formulation and Processing Strategies to Drive Gastroretention of Gabapentin Tablets

Purpose

The aim of the present work was to develop gastroretentive drug delivery system of gabapentin from different matrices prepared by hot melt or conventional wet granulation, which may enhance drug bioavailability. The influence of core type, granulation process, and coating level on the drug release rates was investigated.

Methods

Tablet cores were prepared from hydrophilic system of hypermellose, carboxy melthyl celloulse, and Avicel or hydrophobic system of ethyl cellulose, alginic acid, and stearic acid. The tablets were coated by Eudragit RL with triethyl citrate and compressed directly. These tablets were evaluated according to their in vitro dissolution profiles and release mechanisms.

Results

Hydrophobic matrices allowed the control of drug release. Hot melt granulation was an effective tool over wet granulation or coating for slowing release rates from hydrophobic tablets. Both hydrophobic polymer ratio and coating level influenced the drug release mechanism. The drug release of samples with minor proportion of ethyl cellulose and stearic acid or low Eudragit RL level was driven by anomalous transport and the increase of their proportions contributed to the erosion of the matrix.

Conclusions

Hydrophobic core tablet prepared from hot melt granulation and coated by Eudragit RL has shown to be a promising formulation intended to gastroretentive gabapentin delivery system.

     

General Pharmacokinetic Model for Topically Administered Ocular Drug Dosage Forms

Purpose

In ocular drug development, an early estimate of drug behavior before any in vivo experiments is important. The pharmacokinetics (PK) and bioavailability depend not only on active compound and excipients but also on physicochemical properties of the ocular drug formulation. We propose to utilize PK modelling to predict how drug and formulational properties affect drug bioavailability and pharmacokinetics.

Methods

A physiologically relevant PK model based on the rabbit eye was built to simulate the effect of formulation and physicochemical properties on PK of pilocarpine solutions and fluorometholone suspensions. The model consists of four compartments: solid and dissolved drug in tear fluid, drug in corneal epithelium and aqueous humor. Parameter values and in vivo PK data in rabbits were taken from published literature.

Results

The model predicted the pilocarpine and fluorometholone concentrations in the corneal epithelium and aqueous humor with a reasonable accuracy for many different formulations. The model includes a graphical user interface that enables the user to modify parameters easily and thus simulate various formulations.

Conclusions

The model is suitable for the development of ophthalmic formulations and the planning of bioequivalence studies.

     

Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Effects of Nasal Spray Suspension Particle Size and Properties

Purpose

The objective of this study was to use a recently developed nasal dissolution, absorption, and clearance (DAC) model to evaluate the extent to which suspended drug particle size influences nasal epithelial drug absorption for a spray product.

Methods

Computational fluid dynamics (CFD) simulations of mucociliary clearance and drug dissolution were used to calculate total and microscale epithelial absorption of drug delivered with a nasal spray pump. Ranges of suspended particle sizes, drug solubilities, and partition coefficients were evaluated.

Results

Considering mometasone furoate as an example, suspended drug particle sizes in the range of 1-5 μm did not affect the total nasal epithelial uptake. However, the microscale absorption of suspended drug particles with low solubilities was affected by particle size and this controlled the extent to which the drug penetrated into the distal nasal regions.

Conclusions

The nasal-DAC model was demonstrated to be a useful tool in determining the nasal exposure of spray formulations with different drug particle sizes and solubilities. Furthermore, the model illustrated a new strategy for topical nasal drug delivery in which drug particle size is selected to increase the region of epithelial surface exposure using mucociliary clearance while minimizing the drug dose exiting the nasopharynx.

     

A Lower Temperature FDM 3D Printing for the Manufacture of Patient-Specific Immediate Release Tablets

Purpose

The fabrication of ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing.

Methods

Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of the drugs and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus.

Results

Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication of immediate release tablets at temperatures as low as 110°C. The integrity of two model drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in-batch variability and an immediate in vitro release pattern.

Conclusions

Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms.

     

Glucose-Based Mesoporous Carbon Nanospheres as Functional Carriers for Oral Delivery of Amphiphobic Raloxifene: Insights into the Bioavailability Enhancement and Lymphatic Transport

Purpose

Oral therapy with raloxifene (RXF), an amphiphobic drug for remedy of the postmenopausal osteoporosis and estrogen-dependent breast cancer, is less effective due to its poor bioavailability (2% or so). This work aimed to devise mesoporous carbon nanospheres (MCNs) for oral delivery of RXF and evaluate their performance in bioavailability enhancement and lymphatic transport.

Methods

Glucose-based MCNs were fabricated by hydrothermal reaction followed by high-temperature activation. RXF-loaded MCNs (RXF-MCNs) were prepared by solvent-diffusion/high-pressure homogenization and stabilized by phospholipid. RXF-MCNs were fully characterized by particle size, morphology, in vitro drug release and metabolism, in vivo pharmacokinetics and lymphatic transport, and ex vivo fluorescent imaging.

Results

The prepared RXF-MCNs were 230 nm around in particle size, showing high entrapment efficiency (95.35%) and satisfactory physical stability. The oral bioavailability of RXF was enhanced by 2.07 folds through MCNs compared with RXF suspensions in rats. It was shown that reduced intestinal metabolism due to entrapment into MCNs, active transcellular uptake and increased lymphatic transport were responsible for enhanced bioavailability as a result of transport improvement.

Conclusions

The results suggest that MCNs are suitable nanocarriers for oral delivery of poorly bioavailable RXF.

     

Formulating Inhalable Dry Powders Using Two-Fluid and Three-Fluid Nozzle Spray Drying

Purpose

The spray drying process is widely applied for pharmaceutical particle engineering. The purpose of this study was to investigate advantages and disadvantages of two-fluid nozzle and three-fluid nozzle spray drying processes to formulate inhalable dry powders.

Methods

Budesonide nanocomposite microparticles (BNMs) were prepared by co-spray drying of budesonide nanocrystals suspended in an aqueous mannitol solution by using a two-fluid nozzle spray drying process. Budesonide-mannitol microparticles (BMMs) were prepared by concomitant spray drying of a budesonide solution and an aqueous mannitol solution using a spray drier equipped with a three-fluid nozzle. The resulting dry powders were characterized by using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA) and Raman microscopy. A Next Generation Impactor was used to evaluate the aerodynamic performance of the dry powders.

Results

XRPD and DMA results showed that budesonide remained crystalline in the BNMs, whereas budesonide was amorphous in the BMMs. Spray drying of mannitol into microparticles resulted in a crystalline transformation of mannitol, evident from XRPD, DSC and Raman spectroscopy analyses. Both BMMs and BNMs displayed a faster dissolution rate than bulk budesonide. The yield of BNMs was higher than that of BMMs. The mass ratio between budesonide and mannitol was preserved in the BNMs, whereas the mass ratio in the BMMs was higher than the theoretical ratio.

Conclusions

Spray drying is an enabling technique for preparation of budesonide amorphous solid dispersions and nanocrystal-embedded microparticles. Two-fluid nozzle spray drying is superior to three-fluid nozzle spray drying in terms of yield.

     

Predicting Pulmonary Pharmacokinetics from <Emphasis Type="Italic">In Vitro</Emphasis> Properties of Dry Powder Inhalers

Purpose

The ability of two semi-mechanistic simulation approaches to predict the systemic pharmacokinetics (PK) of inhaled corticosteroids (ICSs) delivered via dry powder inhalers (DPIs) was assessed for mometasone furoate, budesonide and fluticasone propionate.

Methods

Both approaches derived the total lung doses and the central to peripheral lung deposition ratios from clinically relevant cascade impactor studies, but differed in the way the pulmonary absorption rate was derived. In approach 1, the rate of in vivo drug dissolution/absorption was predicted for the included ICSs from in vitro aerodynamic particle size distribution and in vitro drug solubility estimates measured in an in vivo predictive dissolution medium. Approach 2 derived a first order absorption rate from the mean dissolution time (MDT), determined for the test formulations in an in vitro Transwell^® based dissolution system.

Results

Approach 1 suggested PK profiles which agreed well with the published pharmacokinetic profiles. Similarly, within approach 2, input parameters for the pulmonary absorption rate constant derived from dissolution rate experiments were able to reasonably predict the pharmacokinetic profiles published in literature.

Conclusion

Approach 1 utilizes more complex strategies for predicting the dissolution/absorption process without providing a significant advantage over approach 2 with regard to accuracy of in vivo predictions.

     

Physicochemical Properties of Solid Phospholipid Particles as a Drug Delivery Platform for Improving Oral Absorption of Poorly Soluble Drugs

Purpose

A novel drug delivery platform, mesoporous phospholipid particle (MPP), is introduced. Its physicochemical properties and ability as a carrier for enhancing oral absorption of poorly soluble drugs are discussed.

Methods

MPP was prepared through freeze-drying a cyclohexane/t-butyl alcohol solution of phosphatidylcholine. Its basic properties were revealed using scanning electron microscopy, x-ray diffraction, thermal analysis, hygroscopicity measurement, and so on. Fenofibrate was loaded to MPP as a poorly soluble model drug, and effect of MPP on the oral absorption behavior was observed.

Results

MPP is spherical in shape with a diameter typically in the range of 10–15 μm and a wide surface area that exceeds 10 m²/g. It has a bilayer structure that may accommodate hydrophobic drugs in the acyl chain region. When fenofibrate was loaded in MPP as a model drug, it existed partially in a crystalline state and improvement in the dissolution behavior was achieved in the presence of a surfactant, because of the formation of mixed micelles composed of phospholipids and surfactants in the dissolution media. MPP greatly improved the oral absorption of fenofibrate compared to that of the crystalline drug and its efficacy was almost equivalent to that of an amorphous drug dispersion.

Conclusion

MPP is a promising option for improving the oral absorption of poorly soluble drugs based on the novel mechanism of dissolution improvement.

     

The Impact of Solid Dispersion on Formulation,Using Confocal Micro Raman Spectroscopy as Tool to Probe Distribution of Components

Purpose

Solid dispersions (SDs) of a poorly water-soluble drug were prepared, and their physicochemical properties were compared to those of control physical mixtures (PMs). Among the multiple techniques used to characterize the solid state of preparations, confocal micro Raman spectroscopy (CMRS) was used as a non-destructive tool to qualitatively probe content uniformity and distribution of drug and carrier.

Methods

SDs and PMs of drug (fenbendazole, FBZ) were prepared containing two different carriers (poloxamer P188 or P407) with different drug polymer ratios. The preparations were characterized by powder X-ray diffractometry, Fourier transform infrared spectroscopy, thermal analysis, scanning electron microscopy, and in vitro dissolution assay. In addition, CMRS technique and principal component analysis (PCA) were used in order to statistically define the content uniformity and distribution of the drug within the polymeric matrix.

Results

In vitro dissolution results exhibited a marked improvement when the drug was formulated as SD compared to control PM and to pure drug. The solid state of these preparations characterized by X-ray powder diffraction and Fourier transform infrared spectroscopy showed no changes in the crystalline state of the drug and no chemical interactions between the components. Raman studies showed a better content uniformity of the drug within the polymeric matrix when subjected to SD process, correlating with the improved dissolution profile.

Conclusion

This study provides evidence of the potential of the confocal Raman imaging technique, providing a fast and powerful method to characterize solid dispersions which could be incorporated towards the use of quality by design (QbD) approaches in pharmaceutical development.

     

Methotrexate-Loaded Nanomixed Micelles: Formulation,Characterization, Bioavailability,Safety, and In Vitro Anticancer Study

Purpose

Methotrexate (MTX), a potent anticancer drug, shows low oral bioavailability due to its low aqueous solubility and permeability. Moreover, its multidrug resistance (MDR) in cancer and toxic effects restricts its clinical applications. The aim of the study was to prepare novel MTX-loaded Poloxamer 407 and Gelucire^®44/14 (GL44) mixed micelles (MTX-PGMM) to improve its oral bioavailability and cytotoxicity and to reduce its systemic toxicity.

Methods

MTX-PGMM was prepared by dialysis method, compared with blank or MTX-free blank mixed micelles (BMM) and aqueous dispersion of MTX (MTX-AD) with respect to morphology, size, zeta potential, entrapment efficiency, in vitro release, and in vitro cytotoxicity, bioavailability, and toxicity study in rats.

Results

The developed MTX-PGMM exhibited small particle size, good encapsulation efficiency, and good stability in media simulating the physiological conditions of the gastrointestinal tract. The MTX-PGMM micelles demonstrated sustained release, enhanced (6.5-fold) oral bioavailability, slow plasma elimination, and long circulation of MTX. Biocompatibility was also established as there were no signs of tissue toxicity. Moreover, MTX-PGMM produced higher in vitro cytotoxicity (GI₅₀ of 1.44?±?0.33 μg/mL) than free MTX (GI₅₀ 13.71?±?0.99 μg/mL) in human breast cancer MCF-7 cells.

Conclusion

Poloxamer 407 and Gelucire^®44/14 (GL44) mixed micelles are promising carriers for oral delivery of MTX and can be utilized for other Biopharmaceutical Classification System class IV anticancer drugs having poor oral bioavailability and multidrug resistance in cancer.

     

Population <Emphasis Type="BoldItalic">In Vitro-In Vivo</Emphasis> Correlation Model Linking Gastrointestinal Transit Time,pH, and Pharmacokinetics: Itraconazole as a Model Drug

Purpose

To establish an in vitro-in vivo correlation (IVIVC) model for Sporanox and SUBA-itraconazole formulations and to understand the impact of gastrointestinal (GI) pH and transit times on itraconazole dissolution and absorption.

Methods

IVIVC was developed based on fed/fasted pharmacokinetic data from randomized cross-over trials, in vitro dissolution studies, and prior information about typical and between subject variability of GI pH and transit times. Data were analysed using the population modelling approach as implemented in NONMEM.

Results

Dissolution kinetics were described using first order models. The in vivo pharmacokinetics of itraconazole was described with a 2-compartment model with 4-transit absorption compartments. Pharmacokinetic profiles for fasted itraconazole periods were described based on the in vitro dissolution model, in vivo disposition model, and the prior information on GI pH and transit times. The IVIVC model indicated that drug dissolution in the fed state required an additional pH-independent dissolution pathway. The IVIVC models were presented in a ‘Shiny’ application.

Conclusion

An IVIVC model was established and internally evaluated for the two itraconazole formulations. The IVIVC model provides more insight into the observed variability of itraconazole pharmacokinetics and indicated that GI pH and transit times influence in vivo dissolution and exposure.

     

Real-Time UV Imaging of Nicotine Release from Transdermal Patch

Purpose

This study was conducted to characterize UV imaging as a platform for performing in vitro release studies using Nicorette® nicotine patches as a model drug delivery system.

Methods

The rate of nicotine release from 2 mm diameter patch samples (Nicorette®) into 0.067 M phosphate buffer, pH 7.40, was studied by UV imaging (Actipix SDI300 dissolution imaging system) at 254 nm. The release rates were compared to those obtained using the paddle-over-disk method.

Results

Calibration curves were successfully established which allowed temporally and spatially resolved quantification of nicotine. Release profiles obtained from UV imaging were in qualitative agreement with results from the paddle-over-disk release method.

Conclusion

Visualization as well as quantification of nicotine concentration gradients was achieved by UV imaging in real time. UV imaging has the potential to become an important technology platform for conducting in vitro drug release studies.

     

Drug Regulation and Oversight,from Local to Global

Purpose

The purpose of this perspective piece is to address the potential for drug and medical product innovation through sound regulation and strengthened international harmonization.

Methods

Current literature, recommendations and guidelines in regulatory agencies assisted in this perspective review.

Results

Multiple guidelines and recommendations provide for strategic planning and process improvement capabilities at local, national and international levels.

Conclusions

Seeking best practice starts with identifying and improving individual nation drug regulatory bodies, including the US Food and Drug Administration (FDA). Inefficiency causes and process improvement solutions have been suggested and outlined in strategic plans at the FDA as well as with multiple stakeholder organizations and public-private partnerships. Cohesively, these groups should be tasked with formal, consistent updates on improvement as well as ongoing supportive research and evaluation of the changes implemented. Simultaneously, the international community has a tremendous opportunity to act on best practice for drug and medical product innovation by aligning sound and consistent approach to regulation.

     

Effect of Microenvironmental pH Modulation on the Dissolution Rate and Oral Absorption of the Salt of a Weak Acid – Case Study of GDC-0810

Purpose

The purpose of this work is to investigate the effect of microenvironmental pH modulation on the in vitro dissolution rate and oral absorption of GDC-0810, an oral anti-cancer drug, in human.

Methods

The pH-solubility profile of GDC-0810 free acid and pH_max of its N-Methyl-D-glucamine (NMG) salt were determined. Precipitation studies were conducted for GDC-0810 NMG salt at different pH values. GDC-0810 200-mg dose NMG salt tablet formulations containing different levels of sodium bicarbonate as the pH modifier were tested for dissolution under the dual pH-dilution scheme. Three tablet formulations were evaluated in human as a part of a relative bioavailability study. A 200-mg dose of GDC-0810 was administered QD with low fat food.

Results

Intrinsic solubility of GDC-0810 free acid was found to be extremely low. The pH_max of the NMG salt suggested a strong tendency for form conversion to the free acid under GI conditions. In vitro dissolution profiles showed that the dissolution rate and extent of GDC-0810 increased with increasing the level of sodium bicarbonate in the formulation. The human PK data showed a similar trend for the geometric mean of C_max and AUC_0-t for formulations containing 5%, 10%, and 15% sodium bicarbonate, but the difference is not statistically significant.

Conclusion

Incorporation of a basic pH modifier, sodium bicarbonate, in GDC-0810 NMG salt tablet formulations enhanced in vitro dissolution rate of GDC-0810 via microenvironmental pH modulation. The human PK data showed no statistically significant difference in drug exposure from tablets containing 5%, 10%, and 15% sodium bicarbonate.

     

Iron-Based Metal-Organic Frameworks as a Theranostic Carrier for Local Tuberculosis Therapy

Purpose

The purpose of the study was initial evaluation of applicability of metal organic framework (MOF) Fe-MIL-101-NH₂ as a theranostic carrier of antituberculous drug in terms of its functionality, i.e. drug loading, drug dissolution, magnetic resonance imaging (MRI) contrast and cytotoxic safety.

Methods

Fe-MIL-101-NH₂ was characterized using X-ray powder diffraction, FTIR spectrometry and scanning electron microscopy. The particle size analysis was determined using laser diffraction. Magnetic resonance relaxometry and MRI were carried out on phantoms of the MOF system suspended in polymer solution. Drug dissolution studies were conducted using Franz cells. For MOF cytotoxicity, commercially available fibroblasts L929 were cultured in Eagle’s Minimum Essential Medium supplemented with 10% fetal bovine serum.

Results

MOF particles were loaded with 12% of isoniazid. The particle size (3.37–6.45 μm) depended on the micronization method used. The proposed drug delivery system can also serve as the MRI contrast agent. The drug dissolution showed extended release of isoniazid. MOF particles accumulated in the L929 fibroblast cytoplasmic area, suggesting MOF release the drug inside the cells. The cytotoxicity confirmed safety of MOF system.

Conclusions

The application of MOF for extended release inhalable system proposes the novel strategy for delivery of standard antimycobacterial agents combined with monitoring of their distribution within the lung tissue.