Formulation Excipients Research Articles

Potential of Natural-Based Sun Protection Factor (SPF): A Systematic Review of Curcumin as Sunscreen

Exposure to ultraviolet (UV) radiation from the sun significantly damages the skin, leading to premature aging, hyperpigmentation, and oxidative stress that disrupts skin homeostasis. UV radiation increases the production of reactive oxygen species (ROS), accelerating skin deterioration. Although sunscreens remain the primary method for UV protection, chemical-based formulations are often associated with side effects, such as allergic reactions and acne. To address these concerns, the inclusion of natural ingredients in sunscreen formulations has gained attention. Curcumin, an active compound found in turmeric (Curcuma longa) and Java turmeric (Curcuma xanthorrhiza), is well-known for its antioxidant and anti-inflammatory properties. This review explores the potential of curcumin as a natural ingredient for enhancing the Sun Protection Factor (SPF) of sunscreen products. A systematic literature review was conducted, analyzing 200 articles sourced from Google Scholar and PubMed using keywords such as “Curcumin”, “Curcuma”, “Antioxidant”, “Anti-Inflammatory”, and “Sun Protection Factor”. Studies unrelated to UV protection were excluded. The findings, presented in tabular form, indicate that curcumin and Curcuma exhibit significant potential to enhance SPF values due to their antioxidant, anti-inflammatory, and UV-absorbing properties. Additionally, curcumin may aid in skin repair following UV-induced damage. However, the specific concentration of curcumin in various Curcuma species remains unknown, and further research is necessary to determine its optimal use. Consideration of additional excipients in sunscreen formulations is also required to maximize efficacy. In conclusion, curcumin demonstrates considerable promise as a sustainable and effective natural ingredient for protecting the skin from UV radiation, offering a safer alternative to conventional chemical-based sunscreens.

Harnessing the potential of 2-methyl imidazolium dihydrogen phosphate as a protein stabilizer: Assessing its toxicity and impact on aggregation, structural integrity, and functional efficacy of monoclonal antibodies

The development of safe and effective biotherapeutics faces challenges due to protein aggregation. These aggregates, formed due to various stress factors, can lead to irreversible changes and increase the risk of immunogenicity and off-target binding. Ionic liquids (ILs) have recently gained significant attention due to their potential in stabilizing proteins and enzymes. In this investigation, we have assessed the thermal stability of bevacizumab (BmAb), in presence of 2-methyl imidazolium dihydrogen phosphate (2- MIDHP), both alone and in combination with other formulation excipients. SEC, DLS, FFF-MALS and AUC were used to study the protective effect of 2-MIDHP on BmAb aggregation. CD and fluorescence spectroscopy were used to evaluate the impact of 2-MIDHP on structural changes in BmAb, while SPR was used to assess the binding activity in the presence and absence of 2-MIDHP. Subsequently, a cell viability assay (MTT) was conducted to evaluate potential toxic effects of 2-MIDHP with BmAb. Overall, our findings suggested the potential of 2-MIDHP in enhancing the stability of BmAb without any negative impact on its structural and binding activity, and its compatibility with other formulation components, thus indicating its promising prospects for the development of improved biotherapeutics.

Stabilizing effect of HP-β-CD on infliximab in liquid formulations and a solid formulation produced by electrospinning.

The development of stable biopharmaceutical formulations, such as monoclonal antibodies, poses a great challenge in the pharmaceutical industry. This study investigated the stabilizing effect of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in liquid and solid formulations of infliximab during processing and storage. The solid formulation was produced by a scaled-up high-speed electrospinning method, resulting in a product suitable for reconstitution with excellent dissolution properties. Liquid formulations contained exclusively HP-β-CD as a stabilizing excipient at different concentrations. Both types of formulations were stored under various conditions for up to 6 months, and infliximab stability was compared based on monomer recovery and the analysis of fragments and aggregates. The solid formulation stored at low (-18 °C, 4 °C) temperatures and lower humidity conditions show the most promising results. Moreover, the monomer loss was less than 10 % even at room temperature storage after 2 months, indicating a potentially good temperature tolerance. Increasing HP-β-CD content in liquid formulations significantly improved the long-term stability of infliximab while enhancing protection against mechanical stress. Furthermore, to better understand the stabilizing mechanism of HP-β-CD on infliximab, the molecular interactions were investigated by bio-layer interferometry and isothermal titration calorimetry methods. The experiments proved that the presence of HP-β-CD decreased infliximab self-interaction, correlating with the aggregation-suppressing effect of HP-β-CD observed during the stress- and long-term stability studies. The results demonstrate the potential of HP-β-CD as a stabilizing excipient in liquid and solid formulations of infliximab.

Representative training data sets are critical for accurate machine-learning classification of microscopy images of particles formed by lipase-catalyzed polysorbate hydrolysis.

Polysorbate 20 (PS20) is commonly used as an excipient in therapeutic protein formulations. However, over the course of a therapeutic protein product's shelf life, minute amounts of co-purified host-cell lipases may cause slow hydrolysis of PS20, releasing fatty acids (FAs). These FAs may precipitate to form subvisible particles that can be detected and imaged by various techniques, e.g., flow imaging microscopy (FIM). Images of particles can then be classified using supervised convolutional neural networks (CNNs). However, CNNs should be trained on representative images of particles which, as we demonstrate in this work, may be challenging to obtain. Here, we tested several rapid techniques to create FA particles and examined whether CNNs trained on microscopy images of these rapidly formed particles could accurately classify images of particles that had been produced by kinetically slower lipase-catalyzed hydrolysis of PS20. CNNs trained on images of rapidly produced particles were less accurate in classifying images of FA particles that had been produced by enzymatic hydrolysis of PS20 than CNNs trained with images of particles generated by the same slow hydrolysis, highlighting the importance of using representative image data sets for training CNN classifiers.

Mechanism of low molecular weight impurity formation in an IgG1 monoclonal antibody formulation.

Formulation robustness study was performed for a biosimilar monoclonal antibody (IgG1) manufactured at Dr. Reddy's Laboratory, where the pH and concentration level of excipients in the drug product formulation were systematically varied from the target formulation. It was observed that the IgG1 formulation having relatively low pH and high citrate (buffer salt) concentration were predisposed to the formation of low molecular weight impurities. Mass spectrometry analysis of the mAb1 fragments detected the pyroglutamate species from LC-LC dimer and fragmentation in the -DKTH- amino acid sequence of the heavy chain. Blind docking indicated binding of citrate with Lysine 222 residue in the proximity of Cys224 could have potentially fragmented IgG1.

Evaluation of the effect of excipient content on the physical properties of Parkia speciosa Hassk. tablets through regression analysis

Parkia speciosa Hassk. boasts numerous health benefits, yet its raw consumption may be inconvenient or unpalatable for many. To date, limited research has explored the development of Parkia speciosa Hassk. chewable tablets. This study uses regression analysis to analyse the impact of compaction pressure and excipient compositions on the physical characteristics of these tablets. Various compositions of microcrystalline cellulose (MCC, MicroceLac® 100, Lot No.: L103155221) excipient and dried Parkia speciosa Hassk. powder underwent direct compaction at four compaction pressures (22.61, 37.68, 52.75, and 67.82 MPa), with friability and tensile strength measured to assess breakage resistance. The regression analyses were performed using the built-in regression analysis tools available in Microsoft Excel (Version 16.73 (23051401)). Both compaction variables significantly influenced tablet mechanical strength (p-values ≤ 0.05). Higher pressure and increased MCC excipient reduced friability, enhancing breakage resistance. The 44.11% MCC excipient formulation, compacted at 67.82 MPa, demonstrated the lowest friability and high tensile strength. The friability and tensile strength models demonstrate a strong to good fit to the data, with an R- squared value of 86.48% and 63.77%, respectively. The coefficients' findings confirm the hypothesis, indicating that increased excipient composition and compaction pressure decrease friability and enhance tensile strength. This study's findings and predictive model are useful for expedited development and optimization of Parkia speciosa Hassk tablet formulation.

<em>Ipomoea batatas</em> and <em>Artocarpus altilis</em> Particles into Tablets

Introduction: Tablets are solid pharmaceutical dosage forms administered orally, composed of granules subjected to compression. They can be formed from particles (excipients and active ingredients) that deform under pressure. There are several naturally derived particles from agricultural products that are malleable and could potentially be used as excipients in tablet formulation. However, there is a research gap regarding the use of these agricultural products in tablets. This study explored the potential of using chemically unmodified Ipomoea batatas and Artocarpus altilis granules as excipients in tablet formulation. Method: The research evaluated physical properties and solubility under varying conditions, including cutting methods, binder addition, and compression forces. The experimental process involved drying, milling, binder mixing (Polyvinylpyrrolidone), and tablet compaction. Particle characterization included size distribution, density, morphology, and porosity, while compacted material analysis focused on hardness, friability, disintegration time, and solubility times. Results: I. batatas particles were spherical with a D50 of 420 µm and 50%-60% porosity. A. altilis particles were irregularly shaped with a D50 of 120–200 µm and 75%-80% porosity. Compacted I. batatas had hardness >4 kgf, friability <1%, disintegration 8-15 min, and solubility 14-18 min. A. altilis had hardness >4 kgf, friability <2%, disintegration 2.5-5 min, and solubility 5-9 min. Conclusions: Binder addition and compression forces reduced weight loss and increased hardness, disintegration, and solubility times. The carbohydrate (mainly starches) composition significantly affected solubility time, while cutting technique influenced drying time, but not the final product behavior. This study demonstrates the feasibility of using granular materials obtained from natural agricultural products to form compressed products.

Optimization of Cream Formulation with Borneo Tallow Nut, Almond Oil, and Olive Oil Using the Simplex Lattice Design Method

Dry skin, a common dermatological issue affecting individuals across all age groups, often disrupts the skin's protective barrier, leading to discomfort and increased sensitivity. Addressing this condition involves the use of moisturizers, which play a vital role in restoring skin hydration. In this study, a cream preparation was successfully developed using vegetable oils, including Borneo Tallow Nut, Almond Oil, and Olive Oil. The cream formula was optimized using the Design-Expert software with the Simplex Lattice Design (SLD) method to evaluate the impact of different concentrations of these oils on the cream's pH, viscosity, spreadability, and adhesion. The results demonstrated that the cream exhibited excellent thermo-physical stability, with optimum values of Borneo Tallow Nut at 1.349% w/w, Almond Oil at 3.598% w/w, and Olive Oil at 4.051% w/w. The cream achieved a pH value of 5.702, viscosity of 16.851 Cp, spreadability of 8.147 cm, and adhesion of 63.682 s, with a desirability score of 0.718. This research confirms that Borneo Tallow Nut, Olive Oil, and Almond Oil have significant potential as excipients in cream formulations.

Hybrid Nanoparticle for Co-delivering Paclitaxel and Dihydroartemisinin to Exhibit Synergic Anticancer Therapeutics.

Anticancer treatment is required to provide effective and safe patient medicines. This research aided in developing and applying nanoparticles (NPs) for cancer treatment. The poor solubility of paclitaxel (PTX) restricts its therapeutic efficacy because of allergic side effects caused by formulation excipients. To overcome this, PTX was coupled with artemisinin derivatives and loaded into an NP drug delivery system to enhance its effects while addressing its low solubility. This study prepared and characterized a hybrid PLGA-lecithin NP containing dihydroartemisinin (DHA) and PTX for synergic anticancer therapy. A lyophilization study improved the stability of the NP drug formulations. Dual PTX- and DHA-loaded PLGA- and lecithin-based NPs were prepared using a single-step solvent evaporation method. The NP suspensions were lyophilized, and the types and ratios of cryoprotectants were investigated. The physicochemical properties of NPs and lyophilized cakes (Lyo-NPs) were characterized. The stability of the Lyo-NPs was investigated at 2-8°C and room conditions. The anticancer effects of the drug combination, NP suspension, and lyophilized powder were analyzed using an in vitro cytotoxicity assay and an in vivo model. The optimal PTX-DHA loaded PLGA-lecithin-NP was formulated (200 nm, PDI: 0.248 ± 0.003, Zeta potential: -33.60 ± 3.39 mV). Mannitol was selected for lyophilization. Lyo-NPs improved the stability of the NPs (1 year), wherein the physicochemical properties of the NPs were maintained (RDI was close to 1.0). An in-vitro cytotoxicity assay of PTX combined with DHA showed a synergistic anticancer effect (CI <1.0). The suppressive effects of Lyo-NPs on tumor growth in vivo were dose-dependent. While the cocktail of free drugs showed high toxicity (7.5 mg PTX-15 mg DHA/kg) in-vivo, Lyo-NPs showed no statistical differences in hematological and biochemical parameters compared to the control. Dual-drug-loaded hybrid PLGA-lecithin NP is a potential system to minimize severe side effects while enhancing antitumor efficacy, in which lyophilization is a key process to increase stability.

Formulation and Evaluation of Paracetamol Tablet Using Konjac Glucomannan as Natural Halal Binder

Introduction: Discovery and development of novel halal excipients in tablet formulation have led to continuous interest in drug delivery research. In this study, Konjac Glucomannan, a polysaccharide derived from the tuber of Amorphophallus konjac, was used as a halal binder in the formulation of paracetamol tablets. Objective: This study aims to formulate and evaluate paracetamol tablets using konjac glucomannan as a halal binder. Methodology: Paracetamol tablets were formulated with different concentrations (5%, 10%, 15%, 20%) of KGM using the wet granulation method. The formulated paracetamol granules and tablets were subjected to different quality control tests. Results: All four formulation granules passed the pre-compression test, indicating good to passable powder flowability. The weight variation, hardness, thickness, and disintegration test results for all four formulations were within the USP limit except for the friability test. Only tablets with 20% KGM passed the test. Conclusion: 20% KGM shows good tablet binding properties compared to 5%, 10%, and 15% KGM. Hence, paracetamol tablets formulated with higher KGM as a binder produce paracetamol tablets with good physical and mechanical properties.

Evaluation of the Potential of Novel Co-Processed Excipients to Enable Direct Compression and Modified Release of Ibuprofen.

Background/Objectives: Improving the production rates of modern tablet presses places ever greater demands on the performance of excipients. Although co-processing has emerged as a promising solution, there is still a lack of directly compressible excipients for modified-release formulations. The aim of the present study was to address this issue by investigating the potential of novel co-processed excipients for the manufacture of modified-release tablets containing ibuprofen. Methods: The excipients were prepared by melt granulation of lactose monohydrate with glyceryl palmitostearate as a binder. The influence of glyceryl palmitostearate particle size, ibuprofen content, compression pressure, and compression speed on the compaction behavior of the tablet blends was analyzed. Results: Novel co-processed excipients ensured good flowability and acceptable mechanical properties of the tablets containing up to 70% ibuprofen. Furthermore, lipid-based co-processed excipients proved to be very promising for directly compressible formulations with high-dose, highly adhesive active pharmaceutical ingredients such as ibuprofen, as they do not require additional lubricants. The influence of compression speed on the tensile strength of the tablets prepared was not pronounced, indicating the robustness of these directly compressible excipients. The investigated lipid-based excipients enabled a prolonged release of ibuprofen over 10 h. Conclusions: The novel lipid-based co-processed excipients have shown great potential for directly compressible formulations with modified release of high-dose, challenging active pharmaceutical ingredients.

Elucidation of Mg2+ induced size and charge heterogeneity in monoclonal antibody therapeutics

Changes in charge variant profile are known to affect mAb stability and vice versa. This report elucidates the effects of magnesium metal (0.5 mM Mg2+) on trastuzumab (IgG1 antibody). Mg2+ is often used as an excipient (50–100 mM) and lubricant (5–10 % w/w) in biopharmaceutical formulations. Analytical size-exclusion chromatography (SEC) and cation-exchange chromatography (CEX) coupled with mass spectrometry (MS) were used to evaluate the size and charge heterogeneity in the thermal and metal stressed samples and compared to the control sample (room temperature). The present study unveils that presence of Mg2+ significantly increases the rate of aggregation with 9 % aggregation observed in Mg2+ stressed samples as compared to that from thermal stress (~2 %) or control sample (<1 %). Similarly, a 2-fold elevation in acidic variants was observed both in presence of Mg2+ and thermal stress, when contrasted with the control sample. Application of stress also led to the formation of 17 additional chemical modifications (7 due to thermal stress and 10 due to Mg2+ stress) which were not identified in control, predominantly involving deamidation, isomerization of aspartic acid, oxidation, and succinimide modifications. The results indicate the need for a detailed analysis of the impact of presence of metals in biotherapeutic formulations.

Azelaic acid-based lyotropic liquid crystals gel for acne vulgaris: Formulation optimization, antimicrobial activity and dermatopharmacokinetic study

The proposed study aimed to develop a topical gel containing azelaic acid (AZA)-based lyotropic liquid crystals (LLCs) for the treatment of acne vulgaris. AZA-based LLCs were optimized by varying Poloxamer-407 and polyvinyl alcohol concentration using a central composite design, which showed that both independent variables had a significant effect on the formulation. The highest desirable trial of AZA-based LLCs (Batch-7) containing 300 mg poloxamer-407 and 100 mg polyvinyl alcohol depicted the particle size, zeta potential, and entrapment efficiency of 184.2 nm, −16.1 mV, and 79.96 %, respectively. TEM images confirmed the globular vesicles of LLCs, and ATR-FTIR and DSC results confirmed the compatibility of formulation excipients. In vitro, the release of AZA, AZA-based LLCs, AZA-based LLC gel, and marketed gel showed a release of 23.29, 95.24, 91.07 and 59.88 %, respectively, after 24 h in phosphate buffer pH 6.8. Ex vivo release of AZA-based LLC gel displayed an 86.56 % release after 24 h. The antimicrobial activity of AZA-based LLC gel exhibited a comparable efficacy with marketed gel against Cutibacterium acnes, Staphylococcus epidermis and Staphylococcus aureus. The acute dermal irritation study indicated excellent safety and skin compatibility of AZA-based LLC gel without any erythema and edema. The dermatopharmacokinetic study displayed an enhanced drug retention for AZA-based LLC gel (146.121 ± 21.13 µg/cm2) than marketed gel (58.58 ± 15.95 µg/cm2) in the dermal layer, which would improve its therapeutic effect. These outcomes proved that AZA-based LLC gel has the potential to enhance skin penetration and retention for effective management of acne vulgaris.

Multidomain Protein-Urea Interactions: Differences in Binding Behavior Lead to Different Destabilization Tendencies for Monoclonal Antibodies.

We study the influence of urea on the stability of monoclonal antibodies (mAbs) using molecular dynamics (MD) simulations in combination with differential scanning fluorimetry (DSF). We show that a denaturing cosolute such as urea binds strongly to the protein, which can lead to denaturation and enhanced aggregation behavior at high temperatures. The interaction between protein and urea crucially depends on the surface properties of the individual mAb domains and therefore affects the general binding to the protein differently. The study of these mechanisms for proteins with multiple domains, such as mAbs, encounters significant limitations in experimental analysis methods due to their complexity. Using computational and experimental methods, we are able to separate the protein-urea interaction by domain and show that Lennard-Jones interactions are mainly responsible for significant binding effects. Our results emphasize the potential of MD simulations in combination with Kirkwood-Buff theory to study the interactions between proteins with multiple domains and cosolutes as formulation excipients for drug discovery and development.

Effect of Liquid Load Level and Binder Type on the Tabletability of Mesoporous Silica Based Liquisolids

Mesoporous silica offers an easy way to transform liquids into solids, due to their high loading capacity for liquid or dissolved active ingredients and the resulting enhanced dissolution properties. However, the compression of both unloaded and loaded mesoporous silica bulk material into tablets is challenging, due to poor/non-existing binding capacity. This becomes critical when high drug loads are to be achieved and the fraction of additional excipients in the final tablet formulation needs to be kept at a minimum. Our study aimed to investigate the mechanism of compression and tabletability dependent on the Liquid Load Level of the silica and type of filler/binder in binary tabletting mixtures. To this end, Vivapur® 101, FlowLac® 90, Pearlitol® 200 SD and tricalcium citrate tetrahydrate were selected and mixed with Syloid® XDP 3050 at various Liquid Load Levels. Compaction characteristics were analysed using the StylOne® Classic 105 ML compaction simulator. Additionally, the Overall Liquid Load (OLL) was defined as a new critical quality attribute for liquisolid tablets. The Overall Liquid Load allows straightforward, formulation-relevant comparisons between various fillers/binders, liquid components, and silica types. Results indicate strong binding capacity and high plasticity of the fillers/binders as key components for successful high liquid load silica tablet formulation. A volumetric combination of 30% Vivapur® 101 and 70% 0.75 mL/g loaded Syloid® XDP 3050 proved to be the most effective mixture, achieving an Overall Liquid Load of 36–41% [v/v] and maintaining a tensile strength of 1.5 N/mm2 with various liquid vehicles.Graphical

Molecular Dynamics Simulations Reveal How Competing Protein-Surface Interactions for Glycine, Citrate, and Water Modulate Stability in Antibody Fragment Formulations.

The design of stable formulations remains a major challenge for protein therapeutics, particularly the need to minimize aggregation. Experimental formulation screens are typically based on thermal transition midpoints (Tm), and forced degradation studies at elevated temperatures. Both approaches give limited predictions of long-term storage stability, particularly at low temperatures. Better understanding of the mechanisms of action for formulation of excipients and buffers could lead to improved strategies for formulation design. Here, we identified a complex impact of glycine concentration on the experimentally determined stability of an antibody Fab fragment and then used molecular dynamics simulations to reveal mechanisms that underpin these complex behaviors. Tm values increased monotonically with glycine concentration, but associated ΔSvh measurements revealed more complex changes in the native ensemble dynamics, which reached a maximum at 30 mg/mL. The aggregation kinetics at 65 °C were similar at 0 and 20 mg/mL glycine, but then significantly slower at 50 mg/mL. These complex behaviors indicated changes in the dominant stabilizing mechanisms as the glycine concentration was increased. MD revealed a complex balance of glycine self-interaction, and differentially preferred interactions of glycine with the Fab as it displaced hydration-shell water, and surface-bound water and citrate buffer molecules. As a result, glycine binding to the Fab surface had different effects at different concentrations, and led from preferential interactions at low concentrations to preferential exclusion at higher concentrations. During preferential interaction, glycine displaced water from the Fab hydration shell, and a small number of water and citrate molecules from the Fab surface, which reduced the protein dynamics as measured by root-mean-square fluctuation (RMSF) on the short time scales of MD. By contrast, the native ensemble dynamics increased according to ΔSvh, suggesting increased conformational changes on longer time scales. The aggregation kinetics did not change at low glycine concentrations, and so the opposing dynamics effects either canceled out or were not directly relevant to aggregation. During preferential exclusion at higher glycine concentrations, glycine could only bind to the Fab surface through the displacement of citrate buffer molecules already favorably bound on the Fab surface. Displacement of citrate increased the flexibility (RMSF) of the Fab, as glycine formed fewer bridging hydrogen bonds to the Fab surface. Overall, the slowing of aggregation kinetics coincided with reduced flexibility in the Fab ensemble at the very highest glycine concentrations, as determined by both RMSF and ΔSvh, and occurred at a point where glycine binding displaced neither water nor citrate. These final interactions with the Fab surface were driven by mass action and were the least favorable, leading to a macromolecular crowding effect under the regime of preferential exclusion that stabilized the dynamics of Fab.

Denaturants and Solutol® HS15 in ophthalmic formulations: Insights into their combined effects

In the field of ophthalmology, significant attention is dedicated to developing micellar carriers to enhance ocular drug delivery. Urea is a well-known denaturant and has been used as an excipient in several ocular formulations due to its efficacy as an ocular hypotensive agent. The presence of urea as an excipient may influence the characteristics of the micellar nanocarrier in the formulation and needs to be investigated. Solutol® HS15, a well-known nonionic surfactant and a commonly used nanocarrier in drug formulations, enhances the solubilization and stability of ocular drugs. However, a detailed study of its interaction with various pharmaceutical excipients is still lacking. With this intention, the present study focuses on comprehending the interaction between Solutol® HS15 micelles with urea and its derivatives. Here, we present a detailed analysis on the influence of urea and its derivatives (methylurea, dimethylurea) on Solutol® HS15 using small-angle neutron scattering (SANS), dynamic light scattering (DLS), and cloud point (CP) measurements. The presence of urea and its derivatives strongly affects the CP, leading to a significant increase in its values when urea derivatives are present. Additionally, the SANS and DLS results also indicate a significant decrease in micellar size, suggesting demicellization. The observed effects of urea derivatives on Solutol® HS15 micelles underscore the importance of considering solvent-surfactant interactions in understanding the behavior of surfactant-based systems. This research will provide greater insight into the interactions between urea and its derivatives and Solutol® HS15, which will assist in understanding the morphology and size distribution of surfactant micelles for drug delivery applications.

Evaluation of different techniques for wet granulation and pelletization processes using milk as innovative pharmaceutical excipient for pediatric use

The present study focused on the use of milk as a novel excipient for the manufacture of pharmaceutical dosage forms specifically designed for the pediatric population. Dairy milks with different fat contents were studied to deliver paracetamol orally. The World Health Organization included milk in the list of GRAS (generally recognized as safe) substances, which together with its taste-masking ability and solubility solving properties, makes it a good candidate as an excipient in formulations containing paracetamol for pediatrics. The influence of the fat content in the milk, the fraction of paracetamol, the type of diluent and drying temperature (considered independent variables) were systematically investigated using a Design of Experiments (DoE) approach for the preparation of granules for oral administration, by wet agglomeration using different processing techniques, enabled the construction of mathematical models reflecting the correlation between the variables. Four different techniques were evaluated: wet granulation by low shear mixer, wet granulation by high shear mixer, wet granulation by fluidized bed, and extrusion and spheronization. The granules and pellets obtained were characterized for size, and size distribution of agglomerates, and complete release of the drug (dependent variables), according to the European Pharmacopoeia. The fraction of fat content in the milk promoted an increase on the dissolution rate of paracetamol. The key finding of the first two process techniques was a migration of paracetamol from powdered agglomerates towards the larger particles, probably due to friction and attrition events, which created a fraction of smaller size granules due to the fragmentation and loss of powder from the larger granules. The study has confirmed the potential of milk to be a novel and efficient excipient that can be used as a liquid binder in various agglomeration techniques to deliver drugs orally.

Harnessing spectrophotometry resolution power for determining ternary mixture for respiratory disorders treatment in their pharmaceutical formulation.

A ternary mixture incorporating Hydroxyzine hydrochloride (HYX), Ephedrine hydrochloride (EPH) and Theophylline (THP) frequently prescribed for the treatment of respiratory diseases. Herein, two spectrophotometric methods are designated and applied to resolve these three components in their mixture. Method A is ratio-subtraction combined with derivative spectrophotometry, where THP can be determined directly at its λmax 271 nm (neither HYX or EPH interfere), then for determination of HYX and EPH, the ternary mixture was divided by 22 μg/mL of THP and after subtraction of the plateau region, HYX can be determined directly at its λmax 234.2 nm (absence of EPH intervention). Finally, the third derivative (3D) spectrophotometric approach was utilized to estimate EPH by detecting the peak amplitude at 222 nm with Δλ = 4 and a scaling factor 100. Principal Component Regression (PCR) and Partial Least Squares (PLS), two multivariate calibration approaches, were applied effectively in Method B. This method effectively quantified the mixture under investigation by using the absorption spectra obtained from suitable solutions of the three components in the 210-230 nm region. The calibration models were evaluated using cross-validation with PCR and PLS, producing statistical characteristics that demonstrate the effectiveness of the calibration models. Synthetic and pharmaceutical preparations were also used to conduct external validation. In pharmaceutical formulation, these methods were successfully applied to analyze HYX, EPH, and THP without overlap from formulation's excipients. Moreover, the study's findings were statistically contrasted with those of earlier reported HPLC method. Appraisal approaches were used to determine whether the new spectrophotometric methods had an adverse environmental impact involving the Green Analytical Procedure Index (GAPI) and the AGREE (Analytical Greenness). These evaluations delivered information about the methods' eco-friendliness and sustainability, proving that they are in line with ecologically attributed practices. Furthermore, the Blue Applicability Grade Index (BAGI) was utilized to identify and verify the feasibility and practicality of the suggested approaches.

Nanoscale lipid-methylprednisolone conjugates: Effective anti-inflammatory, antioxidant, and analgesic agents

In this study, we have investigated new lipid-drug conjugates (LDCs) of methylprednisolone. Methylprednisolone is a corticosteroid, used for the potential treatment of inflammatory diseases. The LDCs 1–2; methylprednisolone palmitate (1) and methylprednisolone palmityl carbonate (2), were designed by conjugating a C16 aliphatic chain via an ester or carbonate bond, respectively. Their structures were comprehensively characterized using mass spectrometry, nuclear magnetic resonance spectroscopy, and infrared spectroscopy. These LDCs 1–2 were subsequently formulated into nanoscale particles (NPs) using ethanol injection method. Hydrogenated soybean phosphatidylcholine (HSPC) and tween-80 served as excipients in the NPs formulation. Characterization via dynamic light scattering, scanning electron microscopy, and atomic force microscopy confirmed the formation of spherical NPs with a diameter ranging from 100 to 120 nm. The LDCs NPs 1–2 exhibited excellent stability for about a month, with good polydispersity (around 0.2) and a negative zeta potential between −20 mV and −34 mV. Encapsulation efficiency of the LDCs within the LDCs NPs 1–2 surpassed 90 %, as determined by HPLC analysis. In vitro cytotoxicity studies utilizing LPS-activated THP-1 cells demonstrated no adverse effects associated with LDCs NPs 1–2 at concentrations up to 100 μg/mL. Furthermore, the LDCs NPs 1–2 effectively retained the anti-inflammatory activity, as evidenced by the suppression of IL-1β, TNF-α, and MCP-1 secretion in LPS-stimulated THP-1 cells. The therapeutic potential of these LDCs NPs 1–2 was further evaluated in rat intervertebral disc-derived nucleus pulposus cells (NPCs). Curative and preventive treatment regimens with the free drug and LDCs NPs 1–2 were employed. Quantitative PCR analysis revealed a significant downregulation of pain and inflammation markers (Substance P and COX-2) along with a concomitant upregulation of antioxidant markers (GPX1, PRDX1, and SOD1) in NPCs treated with both the drug and LDCs NPs 1–2 compared to oxidative stress-induced and control NPCs. Our novel LDCs NPs 1–2 exhibited promising therapeutic potential for treating inflammatory and pain related complications, (including intervertebral disc degeneration). This promise stems from their multifaceted properties, encompassing anti-inflammatory, antioxidant, and analgesic effects. Further research is warranted to fully explore LDCs NPs 1–2 as potential drug candidates in future pre-clinical and clinical trials.