Quality Target Product Profile Research Articles

QbD Assisted Development of a Compartment and Sequential Drug Delivery System for Periodontotherapy.

Periodontitis, the burgeoning disease, is at an alarming stage. Although this has triggered dedicated research in this area, as the disease itself demands a multi-component therapy, there is an unmet need for a compartment and sequential drug delivery system to ameliorate disease symptoms completely. The hypothesized work consists of multitherapeutic agents such as an antibiotic, a COX-II inhibitor, an MMP inhibitor, and a bone regenerating agent in an insitu gel. However, for the development of the system, as mentioned above, a thorough investigation at each stage is necessary; therefore, the quality-by-design approach was adopted. Furthermore, the current work is a pursuit of studying the quality by design aspects for the fabrication of a compartment system, i.e., in-situ gel for periodontal delivery. The proposed system in-situ gel consists of antibiotic and nano-encapsulating microcapsules. Furthermore, the microcapsules contain a COX-II inhibitor and nanoparticles of MMP inhibitor and bone regenerating agent for complete amelioration of periodontitis. To develop the system as per the QbD approach, the first initial trials and runs were conducted, which helped to decide the quality target product profile (QTPP). However, based on QTPP, critical quality attributes (CQA), critical process parameters (CPP), and critical material attributes (CMAs) were decided for each stage product, i.e., in-situ gel, microcapsules, and nanoparticles. To assess the influence of CPPs and CMAs on CQAs, Pareto charts were constructed, and various risks, along with possible failure modes were studied. In conclusion, the above work will serve as a well-designed scientific mouthpiece for developing a compartment system for periodontotherapy.

Central composite design augmented quality-by-design-based systematic formulation of erlotinib hydrochloride-loaded chitosan-poly (lactic-co-glycolic acid) nanoparticles.

Aim: This study aimed to formulate erlotinib hydrochloride (ERT-HCL)-loaded chitosan (CS) and poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) using Quality-by-Design (QbD) to optimize critical quality attributes (CQAs). Materials & methods: Quality target product profile (QTPP) and CQAs were initially established. Based on L8-Taguchi screening and risk assessments, central composite design (CCD) design was used to optimize NPs. Results: ERT-HCL-loaded CS-PLGA NPs had a mean particle diameter, zeta potential and entrapment efficiency of 226.50±1.62d.nm, 27.66±0.64mV and 78.93±1.94 %w/w, respectively. The NPs exhibited homogenous spherical morphology and sustained release for 72h. Conclusion: Using systematic QbD approach, ERT-HCL was encapsulated in CS-PLGA NPs, optimizing CQAs. These findings propel future research for improved NSCLC treatment.

Quality by design approach for fabrication of extended-release buccal films for xerostomia employing hot-melt extrusion technology

The study endeavors the fabrication of extended-release adipic acid (APA) buccal films employing a quality by design (QbD) approach. The films intended for the treatment of xerostomia were developed utilizing hot-melt extrusion technology. The patient-centered quality target product profile was created, and the critical quality attributes were identified accordingly. Three early-stage formulation development trials, complemented by risk assessment aligned the formulation and process parameters with the product quality standards. Employing a D-optimal mixture design, the formulations were systematically optimized by evaluating three formulation variables: amount of the release-controlling polymer Eudragit® (E RSPO), bioadhesive agent Carbopol® (CBP 971P), and pore forming agent polyethylene glycol (PEG 1500) as independent variables, and % APA release in 1, 4 and 8 h as responses. Using design of experiment software (Design-Expert®), a total of 16 experimental runs were computed and extruded using a Thermofisher ScientificTM twin screw extruder. All films exhibited acceptable content uniformity and extended-release profiles with the potential for releasing APA for at least 8 h. Films containing 30% E RSPO, 10% CBP 971P, and 20% PEG 1500 released 88.6% APA in 8 h. Increasing the CBP concentration enhanced adhesiveness and swelling capacities while decreasing E RSPO concentration yielded films with higher mechanical strength. The release kinetics fitted well into Higuchi and Krosmeyer-Peppas models indicating a Fickian diffusion release mechanism.

QbD Approach-Based Preparation and Optimization of Hydrophobic Ion-Pairing Complex of Lysozyme with Sodium Dodecyl Sulphate to Enhance Stability in Lipid-Based Carriers.

Hydrophobic ion pairing (HIP) complexation was found to be an efficient approach in modulating the release and enhancing the stability and encapsulation of hydrophilic macromolecules such as proteins in hydrophobic nano/microcarriers. The present work strives to develop and optimize the preparation of the HIP complex of the antimicrobial enzyme lysozyme (LYZ) with the ion-pairing agent (IPA) sodium dodecyl sulphate (SDS) relying on the quality-by-design (QbD) approach. The quality target product profile (QTPP) includes the achievement of maximal lipophilicity in a reversible manner to enable the maintenance of biological activity. The related critical quality attributes (CQAs) were defined as complexation efficacy, complex stability, enzyme recovery and activity. Three risk assessment (RA) tools were used to identify and rank the critical process parameters (CPPs) and critical material attributes (CMAs). From this assessment, the pH of the medium, LYZ:SDS molar ratio and drying conditions were determined as high-risk factors that need to be investigated. To the best of our knowledge, for the first time, electrostatic titration was used as a smart approach to determine the optimum molar ratio at different pH values. Based on the predefined CQAs, pH 8 with an LYZ/SDS molar ratio of 1:8 was found to be the optimal condition for complexation efficiency and recovery (%) of a biologically active enzyme. A cost-effective drying process based on a ventilated oven was developed, which resulted in complex qualities comparable to those obtained by the commonly used freeze-drying method. In a nutshell, the optimum conditions for the preparation of the LYZ/SDS HIP complex were efficiently facilitated by the rational application of QbD principles and the utilization of efficient electrostatic titration and ventilated oven-drying methods.

Development and evaluation of therapeutically useful oral solid tablets containing natural extracts: a quality by design approach

The quality target product profile was created for therapeutically useful oral solid tablets containing natural extracts. Important quality criteria were recognised. The risk priority no. was used to evaluate critical materials for initial risk assessment. Using Central Composite Design, the effects of critical parameters (croscarmellose sodium & PVP K-30) were investigated. The impact of the formulation variables X1: Croscarmellose sodium and X2: PVP K-30 on responses Y1: DT (Disintegration time in minutes) and Y2: Friability (%) were assessed. Factor X2: PVP K-30 was found to have a substantial impact on both the responses. The optimized formulation having Croscarmellose sodium-20mg/tab and PVP K-30 8 mg/tab meets the QTPP (quality target product profile) and essential requirements for oral solid tablets standards. Present research shows that QbD (quality by design) is an excellent method which comprehending the critical parameters for optimising therapeutically useful oral solid tablets containing natural extracts.

Quality by design (QbD) approach-based development of optimized nanocarrier to achieve quality target product profile (QTPP)-targeted lymphatic delivery

Background. Insulin, commonly used for diabetes treatment, needs better ways to improve its effectiveness and safety due to its challenges with poor permeability and stability. Various system has been developed for oral peptide delivery. The non-targeted system can prevent gastric and enzymatic degradation of peptides but cannot increase the bulk transport of peptides across the membrane. However, the non-selectivity is the limitation of the existing system. Numerous carbohydrate-binding receptors overexpressed on intestinal macrophage cells (M-cells) of gut-associated lymphoid tissue. It is the most desirable site for receptor-mediated endocytosis and lymphatic drug delivery of peptides. Objective. The prime objective of the study was to fabricate mannose ligand conjugated nanoparticles (MNPs) employing a quality-by-design approach to address permeability challenges after oral administration. Herein, the study’s secondary objective of this study is to identify the influencing factor for producing quality products. Considering this objective, the Lymphatic uptake of NPs was selected as a quality target product profile (QTPP), and a systematic study was conducted to identify the critical formulation attributes (CFAs) and critical process parameters (CPP) influencing critical quality attributes (CQAs). Mannosylated Chitosan concentrations (MCs) and TPP concentrations were identified as CFAs, and stirring speed was identified as CPP. Methods. MNPs were prepared by the inotropic gelation method and filled into the enteric-coated capsule to protect from acidic environments. The effect of CFAs and CPP on responses like particle size (X) and entrapment (Y) was observed by Box-Behnken design (BBD). ANOVA statistically evaluated the result to confirm a significant level (p < 0.05). The optimal conditions of NPs were obtained by constructing an overlay plot and determining the desirability value. HPLC and zeta-seizer analysis characterized the lyophilized NPs. Cell-line studies were performed to confirm the safety and M-cell targeting of NPs to enhance Insulin oral bioavailability. Results. The morphology of NPs was revealed by SEM. The developed NPs showed a nearly oval shape with the average size, surface potential, and % drug entrapment were 245.52 ± 3.37 nm, 22.12 ± 2.13 mV, and 76.15 ± 1.3%, respectively. MTT assay result exhibited that MNPs safe and Confocal imaging inference that NPs selectively uptake by the M-cell. Conclusion. BBD experimental design enables the effective formulation of optimized NPs. The statistical analysis estimated a clear assessment of the significance of the process and formulation variable. Cell line study confirms that NPs are safe and effectively uptake by the cell.

A quality-by-design strategic approach for the development of bedaquiline-pretomanid nanoparticles as inhalable dry powders for TB treatment

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (M.tb) and is the second leading cause of death from an infectious disease globally. The disease mainly affects the lungs and forms granulomatous lesions that encapsulate the bacteria, making treating TB challenging. The current treatment includes oral administration of bedaquiline (BDQ) and pretomanid (PTD); however, patients suffer from severe systemic toxicities, low lung drug concentration, and non-adherence. In this study, we developed BDQ-PTD loaded nanoparticles as inhalable dry powders for pulmonary TB treatment using a Quality-by-Design (QbD) approach. The BDQ-PTD combination showed an additive/synergistic effect for M.tb inhibition in vitro, and the optimized drug ratio (1:4) was successfully loaded into polymeric nanoparticles (PLGA NPs). The QbD approach was implemented by identifying the quality target product profile (QTPPs), critical quality attributes (CQAs), and critical process parameters (CPPs) to develop efficient design space for dry powder preparation using spray drying. The three-factorial and three-level Box-Behnken Design was used to assess the effect of process parameters (CPPs) on product quality (CQAs). The Design of Experiments (DoE) analysis showed different regression models for product quality responses and helped optimize process parameters to meet QTPPs. The optimized dry powder showed excellent yield (72 ± 2 % w/w), high drug (BDQ-PTD) loading, low moisture content (<1% w/w), and spherical morphology. Further, aerosolization performance revealed the suitability of powder for deposition in the respiratory airways of the lungs (MMAD 2.4 µm and FPF > 75 %). In conclusion, the QbD approach helped optimize process parameters and develop dry powder with a suitable quality profile for inhalation delivery in TB patients.

QbD-Based Stability-Indicating RP-HPLC Method Development and Validation for the Estimation of Favipiravir-An Eco-Friendly Approach.

Analytical quality by design (AQbD) affords a systematic scaffolding to triumph a continuously validated, robust assay as well as life cycle management. The resuscitative repurposed drug favipiravir, an oral drug approved for reemerging pandemic influenza in Japan in 2014, is used for the treatment of life-threatening pathogens such as Ebola, Lassa virus, and currently COVID-19. Favipiravir is gaining a great deal of medical importance due to its pharmaceutical applications. To develop and validate a risk-based stability-indicating RP-HPLC method employing an AQbD approach using Central Composite Design (Design Expert Software 13.0) for the estimation of favipiravir. The Quality Target Product Profile optimized were flow rate and mobile phase composition, thus assessing the critical analytical attributes (retention time, tailing factor, and number of theoretical plates) as the constraints of method robustness. The proposed technique was optimized with a C18 (150 × 4.6 mm, 5 µm) column and 0.1% orthophosphoric acid buffer-acetonitrile (50:50, v/v) as the mobile phase at a flow rate of 1 mL/min using diode-array detector (230 nm) eluted favipiravir at 2.3 min. The optimized method validated as per ICH guideline Q2 (R1) was found to be eco-friendly, simple, precise (RSD 0.0051-1.2%), accurate (99.86-100.22%), linear (25-150 µg/mL), rugged (RSD 0.70%), and robust (RSD 0.6-1.6%) with a limit of detection and limit of quantitation of 1.140 µg/mL and 4.424 µg/mL, respectively. Forced degradation studies (acidic, alkaline, thermal, photolytic, and oxidative conditions) revealed the suitability of the AQbD method for the analysis of favipiravir in tablet formulation.The developed and validated AQbD method is less time consuming and can be used in the industry for routine quality control/analysis of bulk drug and marketed Favipiravir products. A robust Design of Experiment enhanced stability-indicating analytical method was developed and validated for the estimation of favipiravir. Furthermore, the contemporary method would aid in extending the analysis of favipiravir in other formulations.

The Potential of Quality Target Product Profile in the Optimization of Nanoemulsions

Abstract: The application of Quality Target Product Profile (QTPP) in optimizing nanoemulsion (NEM) shows immense potential in advancing pharmaceutical formulation design for effective drug delivery. By aligning QTPP with nanoemulsion attributes, this approach offers a pathway to tailored formulations that meet specific therapeutic objectives and responses. Incorporating QTPP facilitates informed choices in formulating design, covering pivotal factors like stability, drug re-lease kinetics, bioavailability, and precise targeting. Moreover, this review extensively explores the real-world application of QTPP-guided tactics in refining nanoemulsion optimization. It high-lights their pivotal role in anticipating and regulating in vivo responses, encompassing vital as-pects like pharmacokinetics and pharmacodynamics. By conducting thorough examinations of case studies and research outcomes, this article clarifies the effectiveness of aligning QTPP crite-ria with NEM characteristics. This approach fosters the creation of customized formulations pre-cisely suited to achieve distinct therapeutic objectives. This review amalgamates contemporary insights into harnessing QTPP for nanoemulsion optimization, illuminating its capacity to stream-line formulation design, amplify treatment effectiveness by desiring drug release, and catalyze transformative shifts in pharmaceutical research.

Metabolic switching, growth kinetics and cell yields in the scalable manufacture of stem cell-derived insulin-producing cells

BackgroundDiabetes is a disease affecting over 500 million people globally due to insulin insufficiency or insensitivity. For individuals with type 1 diabetes, pancreatic islet transplantation can help regulate their blood glucose levels. However, the scarcity of cadaveric donor islets limits the number of people that could receive this therapy. To address this issue, human pluripotent stem cells offer a potentially unlimited source for generating insulin-producing cells through directed differentiation. Several protocols have been developed to make stem cell-derived insulin-producing cells. However, there is a lack of knowledge regarding the bioprocess parameters associated with these differentiation protocols and how they can be utilized to increase the cell yield.MethodsWe investigated various bioprocess parameters and quality target product profiles that may influence the differentiation pipeline using a seven-stage protocol in a scalable manner with CellSTACKs and vertical wheel bioreactors (PBS-Minis).ResultsCells maintained > 80% viability through all stages of differentiation and appropriately expressed stage-specific markers. During the initial four stages leading up to the development of pancreatic progenitors, there was an increase in cell numbers. Following pancreatic progenitor stage, there was a gradual decrease in the percentage of proliferative cells, as determined by Ki67 positivity, and a significant loss of cells during the period of endocrine differentiation. By minimizing the occurrence of aggregate fusion, we were able to enhance cell yield during the later stages of differentiation. We suggest that glucose utilization and lactate production are cell quality attributes that should be considered during the characterization of insulin-producing cells derived from stem cells. Our findings also revealed a gradual metabolic shift from glycolysis, during the initial four stages of pancreatic progenitor formation, to oxidative phosphorylation later on during endocrine differentiation. Furthermore, the resulting insulin-producing cells exhibited a response to several secretagogues, including high glucose.ConclusionThis study demonstrates process parameters such as glucose consumption and lactate production rates that may be used to facilitate the scalable manufacture of stem cell-derived insulin-producing cells.

Quality by design approach for development and optimization of rifampicin loaded nanoparticles and characterization

Background: Rifampicin is an effective in the treatment of sensitive, non-resistant strains of mycobacterium tuberculosis. Thus there is need to develop a rifampicin loaded nanoparticles. Aim: This study is focused on development of RFM loaded nanoparticles, characterization to achieve lung targeting using quality by design approach. Objectives: The main objective of this study is optimizing particle size and entrapment efficiency of rifampicin-loaded nanoparticles and making them suitable for nebulizer application using QbD approach. Methods: Quality target product profile was defined along with critical quality attributes for the formulation. Preparation of nanoparticle dry powder inhaler formulation were numerous methods such as microemulsion solvent evaporation, ionic gelation and modified ionic gelation followed by probe sonication were employed for the preparation of nanoparticles and the final method of preparation was selected based on particle size, zeta potential, entrapment efficiency and drug loading. Results: The optimized RFM-loaded nanoparticles were characterized by UV spectroscopy, FTIR, DSC techniques. The observed nanoparticles were spherical in shape. The TPP concentration, stirring speed and concentration of acetic acid were playing a crucial role in the successful formation of nanoparticles and were selected for optimization. In vitro release study showed 100% release of pure RFM within 12 hrs and the optimized chitosan nanoparticle formulation loaded with RFM showed nearly 90% release of RFM within 24 hr. Conclusion: Rifampicin loaded nanoparticle DPI formulations achieve lung targeting and the delivery of drug into the lungs will also prevent the first pass metabolism, thus, leading to reduction in the dose of the drug as well as related side effects. These drug targeting approaches may serve as a boon in the effective treatment of tuberculosis.

Multivariate Analysis and Computational Predictability of Modified Release Formulation of Chirally Pure Metoprolol Succinate

This study employs computational techniques to predict the performance of a modified-release matrix formulation of chirally pure S (-) Metoprolol Succinate, using a Quality by Design (QbD) approach. The research defines the Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQAs) of the S (-) Metoprolol Succinate matrix formulation. To assess risks, an Ishikawa diagram and Failure Mode Effect Analysis (FMEA) following ICH Q8 guidelines were conducted. The formulation screening process utilized Plackett–Burman design, followed by optimization through Box–Behnken design. The modified-release formulation was developed using high shear granulation, incorporating a combination of high and low viscosity Hydroxypropyl Methylcellulose (HPMC) polymers along with other excipients. The impact of polymer composition and stearic acid on the release profile of S (-) Metoprolol Succinate was investigated, revealing their significant influence on the drug delivery system's desired effect. Specifically, the variables X1: HPMC K4M and X2: HPMC K100M were identified as key factors affecting drug release (Y1). Statistical analysis (ANOVA) confirmed the significance of the selected model, with predicted outcomes aligning well with observed results, comparable to the reference product Seleken® XL range. Both drug content and release performance were found to be similar to the innovator formulation. In summary, this investigation underscores the potential of employing a QbD approach with a combination of low and high viscosity HPMC polymers to achieve precise single-dose delivery of S (-) Metoprolol Succinate.

Phyto-nanoemulsion Containing Tea Leaves Extract Incorporated into A Hydrogel-based Peel-off Mask Formulation: Development, Antioxidant Assay, and Ex-vivo Transport Study

Background: Tea leaves contain remarkable antioxidant compounds suitable for cosmetics formulation development targeting anti-aging purposes. However, due to its hydrophilicity, it faced the main hurdle, namely the permeation of the potential antioxidant compounds. Nanoemulsion formulation offers the permeation improvement of water-soluble compounds Therefore, this work purposed to formulate and develop the nanoemulsion formulation containing tea leaf extract incorporated into a peel-off mask formulation and an ex-vivo transport study. Methods: The nanoemulsion formulation was developed according to self-nano emulsification. The optimization process was performed using a design of experiment to define optimized formulation based on quality target product profiles. Dried green tea leaf extract (DGTE) was obtained by lyophilizing the boiled water-based extract. Antioxidant and phenolic content assays were also evaluated. The optimized formulation was incorporated into a hydrogel-based peel-off mask formulation. Permeated polyphenol through a rat skin membrane was carried out along with deposited polyphenols in the skin membrane. Results: The results indicated that DGTE had powerful antioxidants with IC50 less than 15 mg/mL. The optimized nanoemulsion comprised 21.62% virgin coconut oil, 48.38% Tween 80, and 30% PEG 400, producing a droplet size of less than 50 nm. The peel-off formulation was successfully formulated along with PVA 10-11% and HPMC 0.25-1% with a drying time of around 30 min. The nanoemulgel peel-off mask formulation played significant roles in enhancing the permeation and deposition in the percutaneous transport using rat skin membrane for roughly 200% and 50%, respectively. Conclusion: The nanoemulsion incorporated into a hydrogel-based peel-off mask enhanced the permeation of DGTE polyphenol compounds.

Quality by Design Approach for Development and Characterization of Granisetron Hydrochloride-Loaded Orodispersible Films

AbstractGranisetron hydrochloride can be used to prevent and treat nausea and vomiting induced by chemotherapy. Its prolonged half-life and reduced dose requirement improve patient acceptance. However, patients undergoing chemotherapy often suffer from dysphagia and drug spitting due to emesis. Hence, the development of a patient-centered formulation of granisetron hydrochloride with simple medication and high compliance is crucial. The current study employed a polymer combination of polyvinylpyrrolidone/polyvinyl alcohol (PVP/PVA) as film-forming materials and Lycoat® RS 780 as a disintegrant to formulate orodispersible films (ODFs) loaded with granisetron hydrochloride. Guided by the concept of quality by design, the quality target product profile and critical quality attributes (CQAs) for the ODF were defined. Through the quality risk assessment, essential factors that have a significant impact on CQAs were identified. The formulation was screened using the Box–Behnken statistical design with three factors and three levels. Our data suggested that all ODF formulations exhibited a disintegration time of less than 60 seconds and complete dissolution within 5 minutes. Furthermore, the formulation displayed appropriate mechanical properties, water residue, and pH values. Thus, the granisetron hydrochloride-loaded ODF is regarded as a patient-friendly formulation that enhances compliance and consequently aids in therapeutic effectiveness.

Soft Gelatine Capsules- Critical Quality Attributes of Chosen Excipients and Capsules Parameters Following the Quality by Design Concept

Soft gel capsules are a common form of medicine and food supplements. Quality, productivity and manufacturing time is crucial for producers during their development and industrial operations. To ensure the best quality of the product, it is necessary to know all critical process steps and parameters. The use of QbD elements is to ensure the quality of the drug product throughout its "life cycle". Quality by design (QbD) and its elements are described by the International Council of Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and in their guideline - chapter ICH Q8 (Pharmaceutical Development). One of the first steps in pharmaceutical product development is to prepare Quality Target Product Profile (QTPP) and analyse Critical Material Attributes (CMAs) and Critical Quality Attributes (CQAs) of excipients, active pharmaceutical ingredient (API) and final product. During this research, we investigated the CQAs of the excipients used in vitamin D3 soft gelatin capsules containing high doses of cholecalciferol, from 10 000 to 200 000 IU per capsule. We considered the viscosity of the gelatin mass, the effect of the addition of dye on the viscosity, and the impact of the colour of the gelatin mass on the active substance content in the final capsules. It was also investigated oily carriers (medium chain triglycerides and safflower oil) and antioxidants (alpha-tocopherol acetate vs butylhydroxytoluene), and their effect on API concentration in the capsule.

DEVELOPMENT OF ACECLOFENAC LOADED MICROSPONGE GELS: A STATISTICAL QUALITY BY DESIGN (QBD) APPROACH TOWARDS OPTIMIZATION AND EVALUATION

Objective: The current research aims to deliver Aceclofenac in a controlled manner through a microsponges-loaded drug delivery system for the treatment of inflammation. Methods: The formulations were prepared by the Quasi-emulsion solvent diffusion method and characterized for particle size and drug entrapment efficiency. For the optimization of the formulation through the Quality by Design (QbD) approach, Quality target product profiles (QTPP) were set up considering various key factors that affect the quality of the formulation. Further optimization of the important factors in relation to the major Critical Quality Attributes (CQAs) was conducted by applying full factorial design using the Design of Expert Software (11.0 software, Stat-Ease, Inc., USA). The optimized formulation was incorporated into the gel, and characterized for morphological analysis by Scanning Electron Microscopy (SEM), drug content, and ex-vivo permeation studies (DD solver, Version 2.0). Results: It was found that process parameters such as drug-to-polymer ratio, the volume of the internal phase, and concentration of the emulsifier and polyvinyl alcohol (PVA), played a crucial role in improving the drug entrapment efficiency and particle size. On the other hand, stirring time did not significantly affect the particle size. Through Design of Expert (DOE) analysis, a PVA concentration of 0.641 mg/ml and an internal phase volume of 12.5 ml were identified to be the ideal concentrations to obtain the optimized microspongal gel formulation (MS4). Characterization studies were carried out on MS4, which displayed a drug encapsulation of 94%, with a Cmax of 81.62 mg/ml, and a Tmax of 12 h. Stability studies carried out as per the International Conference of Harmonization (ICH) guidelines confirmed no noticeable change in physical appearance and drug content. Conclusion: Overall, this study focused on optimizing the formulation of microsponges for efficient dermal drug delivery, considering various critical variables and process parameters. The resulting optimized formulation demonstrated promising drug release and potential for the effective management of inflammation disorders.

Quality by Design-driven Development of 5-fluorouracil Loaded Mucoadhesive Microparticulate Drug Delivery Systems for Effective Chemotherapy for Colorectal Cancer

Aims: To enhance oral bioavailability and decrease the dosing frequency of 5-Fluorouracil Background: Cancer is one of the most dreadful diseases for which complete cures are not possible, but colorectal cancer is completely curable if diagnosed at an early stage. If diagnosed in late-stage, 5-Fluorouracil (5-FU) is mostly recommended for its effective treatment, but the challenges associated with this drug are short elimination half-life, severe side effects, as well as non-specificity. The challenges can be better addressed by fabricating microbeads using the QbD approach. To enhance the oral bioavailability of 5-FU and to target the colon for the effective treatment of colorectal cancer, the microbeads were fabricated by emulsification crosslinking method using Box-Behnken design. Objective: To target the colon for effective treatment of colorectal cancer with enhanced oral bioavailability. Methods: The microparticulate drug delivery system was fabricated by using the emulsification crosslinking method by implementing a quality design approach with risk assessment followed by characterization such as FTIR, DSC, TGA, XRD, in vitro drug release, in vitro cytotoxicity study and in vivo pharmacokinetic studies. Results: The patient-centric quality target product profile (QTPP) was set. QTPP inspired critical quality attributes (CQAs) were searched out. The critical material attributes (CMAs) and critical process parameters (CPPs) influencing CQAs were distinguished. The seventeen formulations were fabricated employing Box Behnken Design, followed by optimization using numerical and graphical optimization techniques and the optimized microbeads were subjected to in vivo pharmacokinetic and in vitro cytotoxicity studies using HT 29 cell lines. The results revealed that 5-FU-loaded microbeads exhibited significantly more cytotoxic, and bioavailability was found to be nearly doubled as compared to pure drugs. Conclusion: 5-FU-loaded microbeads can be developed and optimized successfully by using quality by design approach and coating with eudragit S100, which can be targeted to the colon for the effective treatment of colorectal cancer.

Development of Bedaquiline-Loaded SNEDDS Using Quality by Design (QbD) Approach to Improve Biopharmaceutical Attributes for the Management of Multidrug-Resistant Tuberculosis (MDR-TB).

Background: The ever-growing emergence of antibiotic resistance associated with tuberculosis (TB) has become a global challenge. In 2012, the USFDA gave expedited approval to bedaquiline (BDQ) as a new treatment for drug-resistant TB in adults when no other viable options are available. BDQ is a diarylquinoline derivative and exhibits targeted action on mycobacterium tuberculosis, but due to poor solubility, the desired therapeutic action is not achieved. Objective: To develop a QbD-based self-nanoemulsifying drug delivery system of bedaquiline using various oils, surfactants, and co-surfactants. Methods: The quality target product profile (QTPP) and critical quality attributes (CQAs) were identified with a patient-centric approach, which facilitated the selection of critical material attributes (CMAs) during pre-formulation studies and initial risk assessment. Caprylic acid as a lipid, propylene glycol as a surfactant, and Transcutol-P as a co-surfactant were selected as CMAs for the formulation of bedaquiline fumarate SNEDDS. Pseudo-ternary phase diagrams were constructed to determine the optimal ratio of oil and Smix. To optimize the formulation, a Box-Benkhen design (BBD) was used. The optimized formulation (BDQ-F-SNEDSS) was further evaluated for parameters such as droplet size, polydispersity index (PDI), percentage transmittance, dilution studies, stability studies, and cell toxicity through the A549 cell. Results: Optimized BDQ-F-SNEDDS showed well-formed droplets of 98.88 ± 2.1 nm with a zeta potential of 21.16 mV. In vitro studies showed enhanced drug release with a high degree of stability at 25 ± 2 °C, 60 ± 5% and 40 ± 2 °C, 75 ± 5%. Furthermore, BDQ-F-SNEDDS showed promising cell viability in A549 cells, indicating BDQ-F-SNEDDS as a safer formulation for oral delivery. Conclusion: Finally, it was concluded that the utilization of a QbD approach in the development of BDQ-F-loaded SNEDDS offers a promising strategy to improve the biopharmaceutical properties of the drug, resulting in potential cost and time savings.

Formulation Development and Evaluation of Freeze-dried Aviptadil Injection using Mannitol as Cryoprotectant

physiological effects that have been well-documented, including anti-inflammatory, immune-modulatory, anti-hypertensive, enhancement of cardiac contractility, vasodilation, and fostering immune-neuroendocrine connection. Aviptadil (AVP) is the name of the vasoactive intestinal polypeptide’s synthetic version. Aims and Objectives: The main goal of this work was to create a novel, stable, lyophilized version of aviptadil injection. The stability of aviptadil is of utmost importance due to its classification as a polypeptide, recommended storage condition of -20°C, and susceptibility to degradation in aqueous solutions. To achieve this, the aviptadil injection was processed using freeze-drying technology with the addition of mannitol, serving as a bulking and cryoprotectant agent, within an aqueous solvent system. The choice of cryoprotectant and solvent system was based on factors such as the drug substance’s solubility, stability, and feasibility in the manufacturing process. During the development of the formulation, the bulk solution underwent evaluation to assess the effects of process time, temperature, and compatibility with the materials it came into contact with. Results and Discussion: The incorporation of mannitol, a sugar alcohol, led to the stability of the bulk solution for up to 24 hours before lyophilization when stored at temperatures between 2 and 8°C. Moreover, enhanced stability was observed post freeze-drying. The lyophilization process was meticulously optimized, taking into account critical quality attributes such as description, active drug content, pH of the reconstituted solution, reconstitution time, moisture content, and color absorption percentage. The bulk solution demonstrated compatibility with various materials employed in manufacturing the drug product, such as stainless-steel vessels, polyethersulfone (PES) and polyvinylidene difluoride (PVDF) membrane filters. Notably, when the drug product bulk solution was kept refrigerated for up to 24 hours, there were no appreciable changes in the critical quality features found. The optimized freeze-dried product successfully meets the quality target product profile (QTPP)’s preset acceptance criteria. Conclusions: The stabilization of AVP injection was successfully achieved through the implementation of the lyophilization process with mannitol as the cryoprotectant. The envisaged injectable formulation proves to be safe and showcases its economic viability, convenience, and overall safety in the preparation methods. These findings strongly support the viability of the freeze-dried formulation as a technically sound solution for ensuring the stability of aviptadil as a drug substance within the freeze-dried injectable dosage form. This formulation warrants more research due to its potential to treat patients with conditions such acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, and sarcoidosis.

A quality by design framework for developing nanocrystal bioenabling formulations

The present study aims to outline a rational framework for the design and development of a 1.0% (w/v) hydrocortisone nanocrystal-based formulation, resorting to a simple, efficient, and scalable nanonization methodology, based on the high-pressure homogenization (HPH) technique. Accordingly, the innovative product was comprehensively optimized following a Quality by Design (QbD) approach. The thorough selection of formulation composition was driven by a dual purpose: improving skin permeation and stability. In the early stage of development, a Failure Mode, Effects and Criticality Analysis (FMECA) diagram was employed to identify the most impactful variables for the critical quality attributes (CQAs). In this sense, a rotatable, three-factor and five-level circumscribed central composite design (CCCD) was applied to investigate how squalene concentration (x1), soluplus concentration (x2) and HPH-time (x3) influence physicochemical properties, performance and physical stability of the formulation. A robust Design Space (DS) was defined, establishing the optimal settings for the critical variables, whose combination meets the requirements set in the quality target product profile (QTPP). Morphological analysis revealed the cuboidal shape of hydrocortisone nanocrystals. In what concerns colloidal properties, the most promising formulation disclosed a small particle size (Dx(50) = 311.8 ± 1.5 nm), along with narrow size distribution (span value = 1.91 ± 0.17). Zeta potential results (−2.19 ± 0.15 mV–−12.1 ± 0.4 mV) suggested a steric hindrance stabilization. FTIR spectra showed no chemical interactions between drug and formulation components. XRD diffractograms confirmed loss of crystallinity during the downsizing process. In vitro studies revealed an improvement on drug release rate (316 ± 21–516 ± 35 μg/cm2/√t), compared to the coarse suspension and commercial products, and a straight dependence on the stabilizer concentration and HPH time. The permeation flux across the skin (0.16 ± 0.02–1.2 ± 0.5 μg/cm2/h) appeared to be dependent on the drug physicochemical properties, in particular saturation solubility. Further characterization of the experimental formulations pointed out the role of the stabilizing component to prevent against physical instability phenomena. This organic solvent-free, and therefore “green” nanocrystal production technology offers great potential for pharmaceutical R&D and drug delivery by enabling the development of new forms of conventional drugs with optimal physicochemical properties and performance.