A 3D in-vitro biomimicking Caco-2 intestinal permeability model-based assessment of physically modified telmisartan towards an alkalizer-free formulation development.

Efficient telmisartan delivery for hypertension management requires the incorporation of meglumine and/or sodium hydroxide as an alkalizer in the formulation. Long-term use of powerful alkalis with formulation as part of chronic therapy can cause metabolic alkalosis, ulcers, diarrhea, and body pain. Here, we aimed to design a telmisartan formulation without alkalizers. Telmisartan properties were tailor-made by microfluidizer-based physical modification. After microfluidization, telmisartan nanosuspension was lyophilized to obtain telmisartan premix powder. The optimized telmisartan nanosuspension had an average particle size of 579.85 ± 32.14 nm. The lyophilized premix was characterized by FT-IR, DSC, and PXRD analysis to ensure its physicochemical characteristics. The solubility analysis of premix showed 2.2 times, 2.3 times, and 6 times solubility improvement in 0.1 N HCl, phosphate buffer pH 7.5, and pH 6.8 compared to pure telmisartan. A 3D in-vitro Caco-2 model was developed to compare apparent permeability of API and powder premix. It showed that the powder premix was more permeable than pure API. The tablet formulation prepared from the telmisartan premix showed a dissolution profile comparable to that of the marketed formulation. The technique present herein can be used as a platform technology for solubility and permeability improvement of similar classes of molecules.

A unifying approach to drug-in-polymer solubility prediction: Streamlining experimental workflow and analysis.

This method paper describes currently used experimental methods to predict the drug-in-polymer solubility of amorphous solid dispersions and offers a combined approach for applying the Melting-point-depression method, the Recrystallization method, and the Melting-and-mixing method. It aims to describe and expand on the theoretical basis as well as the analytical methodology of the recently published Melting-and-mixing method. This solubility method relies on determining the relationship between drug loads and the enthalpy of melting and mixing of a crystalline drug in the presence of an amorphous polymer. This relationship is used to determine the soluble drug load of an amorphous solid dispersion from the recorded enthalpy of melting and mixing of the crystalline drug portion in a drug-polymer sample at equilibrium solubility. Due to the complex analytical methodology of the Melting-and-mixing method, a software solution called the Glass Solution Companion app was developed. Using this new tool, it is possible to calculate the predicted drug-in-polymer solubility and Flory-Huggins interaction parameter from experimental samples, as well as to generate the resulting solubility-temperature curve. This software can be used for calculations for all three experimental methods, which would be useful for comparing the applicability of the methods on a given drug-polymer system. Since it is difficult to predict the suitability of these drug-in-polymer solubility methods for a specific drug-polymer system in silico, some experimental investigation is necessary. By optimizing the experimental protocol, it is possible to collect data for the three experimental methods simultaneously for a specific drug-polymer system. These results can then be readily analyzed using the Glass Solution Companion app to find the most appropriate method for the drug-polymer system, and therefore, the most reliable drug-in-polymer solubility prediction.

Skin Penetration and Permeation Properties of Transcutol® in Complex Formulations.

Percutaneous delivery is explored as alternative pathway for addressing the drawbacks associated with the oral administration of otherwise efficacious drugs. Short of breaching the skin by physical means, the preference goes to formulation strategies that augment passive diffusion across the skin. One such strategy lies in the use of skin penetration and permeation enhancers notably of hydroxylated solvents like propylene glycol (PG), ethanol (EtOH), and diethylene glycol monoethyl ether (Transcutol®, TRC). In a previous publication, we focused on the role of Transcutol® as enhancer in neat or diluted systems. Herein, we explore its' role in complex formulation systems, including patches, emulsions, vesicles, solid lipid nanoparticles, and micro or nanoemulsions. This review discusses enhancement mechanisms associated with hydroalcoholic solvents in general and TRC in particular, as manifested in multi-component formulation settings alongside other solvents and enhancers. The principles that govern skin penetration and permeation, notably the importance of drug diffusion due to solubilization and thermodynamic activity in the vehicle (formulation), drug solubilization and partitioning in the stratum corneum (SC), and/or solvent drag across the skin into deeper tissue for systemic absorption are discussed. Emphasized also are the interplay between the drug properties, the skin barrier function and the formulation parameters that are key to successful (trans)dermal delivery.

Assessing disintegration effectiveness: A thorough evaluation using the SeDeM-ODT expert system for doxylamine succinate orodispersible formulation.

BACKGROUND: The SeDeM-ODT expert system is designed to assess the suitability of the pharmaceutical ingredients for their conversion into an orodispersible formulation by direct compression. The tool can be utilized to select the most appropriate excipients that improve the compressibility and buccodispersibility of the formulation. OBJECTIVE: This study aimed to utilize the SeDeM-ODT expert system to evaluate the performance of superdisintegrants and select an appropriate superdisntegrant for Doxylamine Succinate orodispersible formulation. METHOD: The SeDeM-ODT expert system scrutinized the excipients to develop an orodispersible Doxylamine Succinate formulation. Among the 15 parameters of the tool, some of them were determined through experimental work, while the remaining were calculated through the experimental values of other parameters. The central composite design approach was used for formulation development. The prepared powder blends were compressed using the direct compression method and evaluated for different parameters (hardness, thickness, diameter, friability, weight variation, water absorption ratio, wetting time, and disintegration time). RESULTS: The results of the SeDeM-ODT expert system were correlated with the values obtained by the post-compression tests. The Crospovidone formulation (F7) was found to be an optimized formulation as it disintegrated quickly compared with the other formulations containing other superdisintegtrants. The results perfectly endorsed the SeDeM-ODT expert system evaluation, as Crospovidone showed the highest IGCB value of 6.396. CONCLUSION: The study observed the effectiveness of the expert system in accurately examining the performance of disintegrating agents. The study observed the effectiveness of the expert system in accurately examining the performance of disintegrating agents. The assessment proved Crospovidone to produce quicker disintegration in Doxylamine Succinate orodispersible formulation.

Enhanced bioavailability and efficacy in antimalarial treatment through QbD approach enteric encased inclusion delivery.

Aim: In this study, we aimed to prepare enteric encapsulated spheroids containing inclusion complex using quality by design approach.Methods: A Box-Behnken design was employed to determine effects of variables on selected responses. Risk assessment was conducted using Ishikawa fishbone diagram. A model with a p-value was less than 0.5 for being a significant error of model was determined based on significance 'lack of fit' value. Spheroids were formulated using the extrusion spheronization technique and were characterized using analytical techniques.Results: In vitro release was performed in both acidic (pH 1.2) and simulated intestinal (pH 6.8) conditions. Permeability studies demonstrated tenfold enhancement compared with arteether. In vivo studies further validated increase of 51.8% oral bioavailability. Ex vivo studies revealed 3.4-fold enhancement in antimalarial activity compared with arteether.Conclusion: These findings highlight effectiveness of inclusion complexation technique as a viable approach to enhance solubility and bioavailability for drugs with low aqueous solubility.

[Box: see text].

Exploring Co-Amorphous Formulations Of Nevirapine: Insights From Computational, Thermal, And Solubility Analyses.

This study aimed to assess the formation of nevirapine (NVP) co-amorphs systems (CAM) with different co-formers (lamivudine-3TC, citric acid-CAc, and urea) through combined screening techniques as computational and thermal studies, solubility studies; in addition to develop and characterize suitable NVP-CAM. NVP-CAM were obtained using the quench-cooling method, and characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), Fourier Transform Infrared Spectroscopy (FTIR), and polarized light microscopy (PLM), in addition to in vitro dissolution in pH 6.8. The screening results indicated intermolecular interactions occurring between NVP and 3TC; NVP and CAc, where shifts in the melting temperature of NVP were verified. The presence of CAc impacted the NVP equilibrium solubility, due to hydrogen bonds. DSC thermograms evidenced the reduction and shifting of the endothermic peaks of NVP in the presence of its co-formers, suggesting partial miscibility of the compounds. Amorphization was proven by XRD and PLM assays. In vitro dissolution study exhibited a significant increase in solubility and dissolution efficiency of NVP-CAM compared to free NVP. Combined use of screening studies was useful for the development of stable and amorphous NVP-CAM, with increased NVP solubility, making CAM promising systems for combined antiretroviral therapy.

Role of rheology in formulation and process design of hot melt extruded amorphous solid dispersions.

Hot melt extrusion (HME) has been widely used as a continuous and highly flexible pharmaceutical manufacturing process for the production of a variety of dosage forms. In particular, HME enables preparation of amorphous solid dispersions (ASDs) which can improve bioavailability of poorly water-soluble drugs. The rheological properties of drug-polymer mixtures can significantly influence the processability of drug formulations via HME and eventually the end-use product properties such as physical stability and drug release. The objective of this review is to provide an overview of various rheological techniques and properties that can be used to evaluate the flow behavior and processability of the drug-polymer mixtures as well as formulation characteristics such as drug-polymer interactions, miscibility/solubility, and plasticization to improve the HME processability. An overview of the thermodynamics and kinetics of ASD processing by HME is also provided, as well as aspects of scale-up and process modeling, highlighting rheological properties on formulation design and process development. Overall, this review provides valuable insights into critical rheological properties which can be used as a predictive tool to optimize the HME processing conditions.

Development, Pharmacokinetics and Antimalarial Evaluation of Dose Flexible 3D Printlets of Dapsone for Pediatric Patients.

The focus of current studies was to fabricate dose flexible printlets of dapsone (DDS) for pediatric patients by selective laser sintering (SLS) 3D printing method, and evaluate its physicochemical, patient in-use stability, and pharmacokinetic attributes. Eight formulations were fabricated using Kollicoat® IR, Eudragit® L-100-55 and StarCap®as excipients and evaluated for hardness, disintegration, dissolution, amorphous phase by differential scanning calorimetry and X-ray powder diffraction, in-use stability at 30 oC/75% RH for a month, and pharmacokinetic study in Sprague Dawley rats. The hardness, and disintegration of the printlets varied from 2.6±1.0 (F4) to 7.7±0.9 (F3) N and 2.0±0.4 (F2) to 7.6±0.6 (F3) sec, respectively. The drug was partially present as an amorphous form in the printlets. The drug was completely (>85%) dissolved in 20 min. No change in drug form or dissolution extent was observed after storage at in use condition. Pharmacokinetic profiles of both formulations (tablets and printlets) were almost superimposable with no statistical difference in pharmacokinetic parameters (Tmax, Cmax, and AUC0-¥)between formulations (p>0.05). Values of EC50 (half maximal effective concentration) and EC90 (maximal concentration inducing 90% maximal response) were 0.50±0.15 and 1.32±0.26 mM, 0.41±0.06 and 1.11±0.21, and 0.42±0.13 and 1.36±0.19 mM for DDS, printlet and tablet formulations, respectively, and differences were statistically insignificant (p>0.05). In conclusion, tablet and printlet formulations are expected to be clinical similar, thus clinically interchangeable.

Preparation and In Vitro Evaluation of Montelukast Sodium-Loaded 3D Printed Orodispersible Films for the Treatment of Asthma.

This research aims to produce orodispersible films (ODFs) and determine their potential use in the oral delivery of montelukast sodium for asthma treatment and allergic rhinitis. ODFs were successfully developed by Three-dimensional (3D) printing using propylene glycol (PG), and hydroxypropyl methylcellulose (HPMC), polyethylene glycol 400 (PEG). Finally, the amount of montelukast sodium in the ODFs was 5% (w/w). Drug-excipients compatibility with Fourier Transformed Infrared (FTIR) spectroscopy, mass uniformity, thickness, disintegration time, folding endurance, moisture absorption, pH, in vitro drug release (dissolution), drug content, moisture loss, moisture content, mechanical properties, and cytotoxicity studies were performed on the prepared films. All formulations disintegrated in approximately 40 s. Over 98% of drug release from all films within 2 min was confirmed. It was reported that Fm1-4 (8% HPMC and 1% PEG) and Fm2-4 (10% HPMC and 3% PEG) are more suitable for drug content, but Fm2-4 may be the ideal formulation considering its durability and transportability properties. Based on the characterization results and in vitro release values, the montelukast sodium ODF can be an option for other dosage forms. It was concluded that the formulations did not show toxic potential by in vitro cytotoxicity study with 3T3 cells. This new formulation can efficiently treat allergic rhinitis and asthma diseases.

Alternative buffer systems in biopharmaceutical formulations and their effect on protein stability.

The formulation of biopharmaceutical drugs is designed to eliminate chemical instabilities, increase conformational and colloidal stability of proteins, and optimize interfacial stability. Among the various excipients involved, buffer composition plays a pivotal role. However, conventional buffers like histidine and phosphate buffers may not always be the optimal choice for all monoclonal antibodies (mAbs). In this study, we investigated the effects of several alternative buffer systems on seven different mAbs, exploring various combinations of ionic strengths, concentrations of the main buffer component, mAb concentrations, and stress conditions. Protein stability was assessed by analyzing soluble aggregate formation through size exclusion chromatography. At low protein concentrations, protein instability after temperature stress was exclusively observed in the bis-TRIS/ glucuronate buffer. Conversely, freeze-thaw stress led to a significant increase in aggregate formation in tested formulations, highlighting the efficacy of several alternative buffers, particularly arginine/ citrate, in preserving protein stability. Under temperature stress, the introduction of arginine to histidine buffer systems provided additional stabilization, while the addition of lysine resulted in protein destabilization. Similarly, the incorporation of arginine into histi-dine/HCl buffer further enhanced protein stability during freeze--thaw cycles. At high protein concentrations, the histidine/citrate buffer emerged as one of the most optimal choices for addressing temperature and light-induced stress. The efficacy of histidine buffers in combating light stress might be attributed to the light-absorbing properties of histidine molecules. Our findings demonstrate that the development of biopharmaceutical formulations should not be confined to conventional buffer systems, as numerous alternative options exhibit comparable or even superior performance.

Novel analytical solutions for convolution in compartmental pharmacokinetic models and application to non-bioequivalent formulations.

Deconvolution and convolution are powerful tools that allow decomposition and reconstruction, respectively, of plasma versus time profiles from input and impulse functions. While deconvolution have commonly used compartmental approaches (e.g., Wagner-Nelson or Loo-Riegelman), convolution most typically used the convolution integral which can be solved with numerical methods. In 2005, an analytical solution for one-compartment pharmacokinetic was proposed and has been widely used ever since. However, to the best of our knowledge, analytical solutions for drugs distributed in more than one compartment have not been reported yet. In this paper, analytical solutions for compartmental convolution from both original and exact Loo-Riegelman approaches were developed and evaluated for different scenarios. While convolution from original approach was slightly more precise than that from the exact Loo-Riegelman, both methods were extremely accurate for reconstruction of plasma profiles after respective deconvolutions. Nonetheless, convolution from exact Loo-Riegelman was easier to interpret and to be manipulated mathematically. In fact, convolution solutions for three and more compartments can be easily written with this approach. Finally, our convolution analytical solution was applied to predict the failure in bioequivalence for levonorgestrel, demonstrating that equations in this paper may be useful tools for pharmaceutical scientists.

A Comparative Mathematical Analysis of Drug Release from Lipid-Based Nanoparticles.

Mathematical modeling of drug release from drug delivery systems is crucial for understanding and optimizing formulations. This research provides a comparative mathematical analysis of drug release from lipid-based nanoparticles. Drug release profiles from various types of lipid nanoparticles, including liposomes, nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), and nano/micro-emulsions (NEMs/MEMs), were extracted from the literature and used to assess the suitability of eight conventional mathematical release models. For each dataset, several metrics were calculated, including the coefficient of determination (R2), adjusted R2, the number of errors below certain thresholds (5%, 10%, 12%, and 20%), Akaike information criterion (AIC), regression sum square (RSS), regression mean square (RMS), residual sum of square (rSS), and residual mean square (rMS). The Korsmeyer-Peppas model ranked highest among the evaluated models, with the highest adjusted R2 values of 0.95 for NLCs and 0.93 for other liposomal drug delivery systems. The Weibull model ranked second, with adjusted R2 values of 0.92 for liposomal systems, 0.94 for SLNs, and 0.82 for NEMs/MEMs. Thus, these two models appear to be more effective in forecasting and characterizing the release of lipid nanoparticle drugs, potentially making them more suitable for upcoming research endeavors.

Oral Bioavailability Enhancement of Poorly Soluble Drug by Amorphous Solid Dispersion Using Sucrose Acetate Isobutyrate.

The focus of the present work was to develop amorphous solid dispersion (ASD) formulation of aprepitant (APT) using sucrose acetate isobutyrate (SAIB) excipient, evaluate for physicochemical attributes, stability, and bioavailability, and compared with hydroxypropyl methylcellulose (HPMC) based formulation. Various formulations of APT were prepared by solvent evaporation method and characterized for physiochemical and in-vivo performance attributes such as dissolution, drug phase, stability, and bioavailability. X-ray powder diffraction indicated crystalline drug conversion into amorphous phase. Dissolution varied as a function of drug:SAIB:excipient proportion. The dissolution was more than 80% in the optimized formulation (F10) and comparable to HPMC based formulation (F13). Stability of F10 and F13 formulations stored at 25 C/60% and 40°C/75% RH for three months were comparable. Both ASD formulations (F10 and F13) were bioequivalent as indicated by the pharmacokinetic parameters Cmax and AUC0-∞. Cmax and AUC0-∞ of F10 and F13 formulations were 2.52 ± 0.39, and 2.74 ± 0.32 µg/ml, and 26.59 ± 0.39, and 24.79 ± 6.02 µg/ml.h, respectively. Furthermore, the bioavailability of ASD formulation was more than twofold of the formulation containing crystalline phase of the drug. In conclusion, stability and oral bioavailability of SAIB based ASD formulation is comparable to HPMC-based formulation of poorly soluble drugs.

Development and Evaluation of Solidified Supersaturated SNEDDS Loaded with Triple Combination Therapy for Metabolic Syndrome.

The present study aimed to develop and optimize solidified supersaturated self-nanoemulsifying drug delivery systems (SNEDDS) for the combined administration of antihypertensive, antihyperglycemic, and antihyperlipidemic drugs to enhance their solubility and dissolution during the treatment of metabolic syndrome. Various SNEDDS formulations were prepared and subjected to pharmaceutical assessment. The solubility of candesartan (CC), glibenclamide (GB), and rosuvastatin (RC) in SNEDDS and supersaturated SNEDDS formulations was evaluated. The optimized formulation was solidified using Syloid adsorbent at different ratios. Pharmaceutical characterization of the formulations included particle size, zeta potential, in-vitro dissolution, PXRD, FTIR, and SEM analysis. The prepared optimized formulation (F6) was able to form homogeneous nanoemulsion droplets without phase separation, which is composed of Tween 20: PEG-400: Capmul MCM (4: 3: 3). It was mixed with 5% PVP-K30 to prepare a supersaturated liquid SNEDDS formulation (F9). In addition, it was found that the addition of PVP-K30 significantly increased solubility CC and GB from 20.46 ± 0.48 and 6.73 ± 0.05 to 27.67 ± 1.72 and 9.45 ± 0.32 mg/g, respectively. In-vitro dissolution study revealed that liquid and solid SNEDD formulations remarkably improved the dissolution rates of CC, GB, and RC compared to pure drugs. XRPD and FTIR analysis revealed that all drugs present in an amorphous state within prepared solidified supersaturated SNEDDS formulation. SEM images showed that liquid SNEDDS formulation was successfully adsorbed on the surface of Syloid. Overall, optimized F9 and solidified supersaturated SNEDDS formulations showed superior performance in enhancing drug solubility and dissolution rate. The present study revealed that the proposed triple combination therapy of metabolic syndrome holds a promising strategy during the treatment of metabolic syndrome. Further in-vivo studies are required to evaluate the therapeutic efficacy of prepared solidified supersaturated SNEDDS formulation.

Design and Evaluation of Microemulsion-Based Drug Delivery Systems for Biofilm-Based Infection in Burns.

Normal skin is the first line of defense in the human body. A burn injury makes the skin susceptible to bacterial infection, thereby delaying wound healing and ultimately leading to sepsis. The chances of biofilm formation are high in burn wounds due to the presence of avascular necrotic tissue. The most common pathogen to cause burn infection and biofilm is Pseudomonas aeruginosa. The purpose of this study was to create a microemulsion (ME) formulation for topical application to treat bacterial burn infection. In the present study, tea tree oil was used as the oil phase, Tween 80 and transcutol were used as surfactants, and water served as the aqueous phase. Pseudo ternary phase diagrams were used to determine the design space. The ranges of components as suggested by the design were chosen, optimization of the microemulsion was performed, and in vitro drug release was assessed. Based on the characterization studies performed, it was found that the microemulsion were formulated properly, and the particle size obtained was within the desired microemulsion range of 10 to 300 nm. The I release study showed that the microemulsion followed an immediate release profile. The formulation was further tested based on its ability to inhibit biofilm formation and bacterial growth. The prepared microemulsion was capable of inhibiting biofilm formation.

Tailored Sticky Solutions: 3D-Printed Miconazole Buccal Films for Pediatric Oral Candidiasis.

In this research, 3D-printed antifungal buccal films (BFs) were manufactured as a potential alternative to commercially available antifungal oral gels addressing key considerations such as ease of manufacturing, convenience of administration, enhanced drug efficacy and suitability of paediatric patients. The fabrication process involved the use of a semi-solid extrusion method to create BFs from zein-Poly-Vinyl-Pyrrolidone (zein-PVP) polymer blend, which served as a carrier for drug (miconazole) and taste enhancers. After manufacturing, it was determined that the disintegration time for all films was less than 10 min. However, these films are designed to adhere to buccal tissue, ensuring sustained drug release. Approximately 80% of the miconazole was released gradually over 2 h from the zein/PVP matrix of the 3D printed films. Moreover, a detailed physicochemical characterization including spectroscopic and thermal methods was conducted to assess solid state and thermal stability of film constituents. Mucoadhesive properties and mechanical evaluation were also studied, while permeability studies revealed the extent to which film-loaded miconazole permeates through buccal tissue compared to commercially available oral gel formulation. Histological evaluation of the treated tissues was followed. Furthermore, in vitro antifungal activity was assessed for the developed films and the commercial oral gel. Finally, films underwent a two-month drug stability test to ascertain the suitability of the BFs for clinical application. The results demonstrate that 3D-printed films are a promising alternative for local administration of miconazole in the oral cavity.

Thermally-Induced Supersaturation Approach for Optimizing Drug Loading and Biopharmaceutical Properties of Supersaturated Lipid-Based Formulations: Case Studies with Ibrutinib and Enzalutamide.

Lipid-based formulations (LbFs) have demonstrated success in pharmaceutical applications; however, challenges persist in dissolving entire doses of the drug into defined liquid volumes. In this study, the temperature-induced supersaturation method was employed in LbF to address drug loading and pill burden issues. Supersaturated LbFs (super-LbF) were prepared using the temperature-induced supersaturation method, where the drug load is above its equilibrium solubility. Further, the influence of the drug's physicochemical and thermal characteristics on drug loading and their relevance with an apparent degree of supersaturation (aDS) was studied using two model drugs, ibrutinib and enzalutamide. All the prepared LbFs were evaluated in terms of physical stability, dispersion, and solubilization capacity, as well as pharmacokinetic assessments. Drug re-crystallization was observed in the lipid solution on long-term storage at higher aDS values of 2-2.5. Furthermore, high-throughput lipolysis studies demonstrated a significant decrease in drug concentration across all LbFs (regardless of drug loading) due to a decline in the formulation solvation capacity and subsequent generation of in-situ supersaturation. Further, the in vivo results demonstrated comparable pharmacokinetic parameters between conventional LbF and super-LbF. The short duration of the thermodynamic metastable state limits the potential absorption benefits. However, super-LbFs of Ibr and Enz showed superior profiles, with 1.7-fold and 5.2-fold increased drug exposure compared to their respective crystalline suspensions. In summary, this study emphasizes the potential of temperature-induced supersaturation in LbF for enhancing drug loading and highlights the intricate interplay between drug properties, formulation characteristics, and in vivo performance.

Design and Evaluation of Ophthalmic Thermosensitive In Situ Gel of Compound Salvia.

The compound Salvia Recipe has been shown to have a relatively significant curative effect in management of cardiovascular and cerebrovascular diseases. This work aimed to prepare a thermosensitive in situ gel (ISG) delivery system that utilizes Poloxamer 407, Poloxamer 188, and hydroxypropyl methylcellulose for ocular administration of the compound Salvia recipe to treat cardiovascular and cerebrovascular diseases. The central composite design-response surface method was utilized to improve the prescription of the gel. The formulated gel was characterized and assessed in terms of stability, retention time, in vitro release, rheology, ocular irritation, pharmacokinetics studies, and tissue distribution. The gel was a liquid solution at room temperature and became semisolid at physiological temperature, prolonging its stay time in the eye. Pharmacokinetics and tissue distribution experiments indicated that thermosensitive ISG had enhanced targeting of heart and brain tissues. Additionally, it could lower drug toxicity and side effects in the lungs and kidneys. The compound Salvia ophthalmic thermosensitive ISG is a promising drug delivery system for the management of cardiovascular and cerebrovascular illnesses.

A Semi-Mechanistic Physiologically Based Biopharmaceutics Model to Describe Complex and Saturable Absorption of Metformin: Justification of Dissolution Specifications for Extended Release Formulation.

Physiologically based pharmacokinetic (PBPK) or physiologically based biopharmaceutics models (PBBM) demonstrated plethora of applications in both new drugs and generic product development. Justification of dissolution specifications and establishment of dissolution safe space is an important application of such modeling approaches. In case of molecules exhibiting saturable absorption behavior, justification of dissolution specifications requires development of a model that incorporates effects of transporters is critical to simulate in vivo scenario. In the present case, we have developed a semi-mechanistic PBBM to describe the non-linearity of BCS class III molecule metformin for justification of dissolution specifications of extended release formulation at strengths 500 mg and 1000 mg. Semi-mechanistic PBBM was built using physicochemical properties, dissolution and non-linearity was accounted through incorporation of multiple transporter kinetics at absorption level. The model was extensively validated using literature reported intravenous, oral (immediate & extended release) formulations and further validated using in-house bioequivalence data in fasting and fed conditions. Virtual dissolution profiles at lower and upper specifications were generated to justify the dissolution specifications. The model predicted literature as well as in-house clinical study data with acceptable prediction errors. Further, virtual bioequivalence trials predicted the bioequivalence outcome that matched with clinical study data. The model predicted bioequivalence when lower and upper specifications were compared against pivotal test formulations thereby justifying dissolution specifications. Overall, complex and saturable absorption pathway of metformin was successfully simulated and this work resulted in regulatory acceptance of dissolution specifications which has ability to reduce multiple dissolution testing.

Comparison of Excipients in Approved Parenteral Products and Their Maximum Daily Exposure Values.

The following article analyses the excipients used in the parenteral formulations registered by the U.S. Food and Drug Administration (FDA) in the years 2011 and 2021. It adds real-word data for parenteral excipients in approved products from the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) and the Irish Health Products Regulatory Authority (HPRA) in 2021. Maximum daily exposures (MDEs) for all parenteral excipients that had their amount listed either in the Medsafe or HPRA database are presented. Altogether, there were 355 excipients found in the parenteral dosage forms across all markets (US, New Zealand, and Ireland). Only 90 excipients (25.3%) were found in all three markets. In contrast, there were 187 (52.7%) excipients found in only one market. The MDE values of parenteral excipients from New Zealand and Ireland are frequently higher than the values found in the FDA inactive ingredients database (IID), adding important new information when the toxicity of these excipients is considered. There is a heterogenicity between the markets in use of parenteral excipients, with the US market leading in the number of total excipients as well as excipients present only in the US market. Nevertheless, there are several excipients not found in the US market that are registered in other markets. The comprehensive listing of parenteral excipients used worldwide presented in this article enables formulation scientists to quickly reference all potential parenteral excipients that are already proven safe and acceptable when designing a new parenteral formulation. Further, a list of new values for the MDE, often higher than those listed in the IID, provides important information for formulation scientists and toxicologists about the potential toxicity of these excipients.