ABSTRACT
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.
Subject(s)
Biological Availability , Excipients , Solubility , Sucrose , Sucrose/analogs & derivatives , Sucrose/chemistry , Administration, Oral , Animals , Excipients/chemistry , Male , Hypromellose Derivatives/chemistry , Chemistry, Pharmaceutical/methods , Drug Stability , X-Ray Diffraction/methodsABSTRACT
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.
Subject(s)
Excipients , United States Food and Drug Administration , Excipients/analysis , Excipients/chemistry , United States , New Zealand , Humans , Ireland , Drug Approval , Infusions, Parenteral , Chemistry, Pharmaceutical/methodsABSTRACT
INTRODUCTION: The pharmaceutical industry is gradually changing batch-wise manufacturing processes to continuous manufacturing processes, due to the advantages it has to offer. The final product quality and process efficiency of continuous manufacturing processes is among others impacted by the properties of the raw materials. Existing knowledge on the role of raw material properties in batch processing is however not directly transferable to continuous processes, due to the inherent differences between batch and continuous processes. AREAS COVERED: A review is performed to evaluate the role of excipient properties for different unit operations used in continuous manufacturing processes. Unit operations that will be discussed include feeding, blending, granulation, final blending, and compression. EXPERT OPINION: Although the potency of continuous manufacturing is widely recognized, full utilization still requires a number of challenges to be addressed effectively. An expert opinion will be provided that discusses those challenges and potential solutions to overcome those challenges. The provided overview can serve as a framework for the pharmaceutical industry to push ahead process optimization and formulation development for continuous manufacturing processes.
Subject(s)
Chemistry, Pharmaceutical , Drug Compounding , Drug Industry , Excipients , Powders , Tablets , Excipients/chemistry , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Humans , Technology, Pharmaceutical/methods , Pharmaceutical Preparations/chemistryABSTRACT
This study investigates particle size segregation within the powder chamber of a vacuum drum-based capsule filling machine using various stirrer types and proposing novel designs to mitigate segregation. The stirrer is essential to the process, ensuring uniform density during volume-based filling. Three lactose grades, comprising 10% fine, 80% medium, and 10% coarse particles, were used, with tracer particles replacing fine or coarse particles, respectively. Dosages were collected over time for a line-array of five bores, and tracer concentrations were analysed using UV-Vis spectrophotometry. By visual assessments and stagnant zone observations particle segregation was evaluated and quantified by normalised tracer concentrations. Both standard and modified stirrers were examined under the same conditions. Stirrer type significantly influenced particle segregation, with the "spike" standard stirrer yielding the highest segregation, while the modified "3-wirem" and "coreless 3-wirem" stirrers exhibited superior performance, minimizing differences between fine and coarse particle concentrations and eliminating stagnant zones. These findings highlight promising prospects for further analysing the "3-wirem" and "coreless 3-wirem" stirrers. In that respect additional variables such as stirrer speed, rotation direction, and level of vacuum, need to be considered. Stirrer design significantly impacts vacuum drum-based capsule filling machine performance, ensuring reliable pharmaceutical capsule filling. This study offers insights into optimizing the industrial process.
Subject(s)
Capsules , Lactose , Particle Size , Powders , Vacuum , Lactose/chemistry , Powders/chemistry , Equipment Design , Drug Compounding/methods , Drug Compounding/instrumentation , Technology, Pharmaceutical/methods , Technology, Pharmaceutical/instrumentation , Excipients/chemistryABSTRACT
A new theory for the dispersibility enhancing effect of excipient fines for adhesive mixtures for inhalation is presented in this paper, while at the same time the shortcomings of current hypotheses are discussed. The proposed mechanism, denoted the 'viscoelastic damping effect', states that the presence of fines particles acts to dampen the collisions between carrier particles during mixing. As a consequence, fewer fine particles are 'irreversibly' pressed into the carriers, which in turn entails a higher fine particle fraction. The mechanism was demonstrated experimentally at different levels of added lactose fines by studying the influence of processing on fine particle fraction. This approach furthermore enabled quantification of the effect. All fine particles present in the blend (APIs and excipient fines) act together to exert the damping effect. The proposed mechanism is able to explain the main body of published data, including the effect of added excipient fines, the effect of an increased drug load, and the effect of removal of carrier fines. The viscoelastic damping mechanism is general in nature and conveys a broader and more general understanding of the behavior of adhesive mixtures for inhalation.
Subject(s)
Adhesives , Excipients , Lactose , Particle Size , Lactose/chemistry , Excipients/chemistry , Administration, Inhalation , Adhesives/chemistry , Chemistry, Pharmaceutical/methods , Drug Carriers/chemistryABSTRACT
PURPOSE: Improving the deep lung delivery of aerosol surfactant therapy (AST) with a dry powder formulation may enable significant reductions in dose while providing improved efficacy. The objective of Part I of this two-part study was to present the development of a new dry powder aerosol synthetic lung surfactant (SLS) product and to characterize performance based on aerosol formation and realistic in vitro airway testing leading to aerosol delivery recommendations for subsequent in vivo animal model experiments. METHODS: A new micrometer-sized SLS excipient enhanced growth (EEG) dry powder formulation was produced via spray drying and aerosolized using a positive-pressure air-jet dry powder inhaler (DPI) intended for aerosol delivery directly to intubated infants with respiratory distress syndrome (RDS) or infant-size test animals. RESULTS: The best-case design (D2) of the air-jet DPI was capable of high emitted dose (> 80% of loaded) and formed a < 2 µm mass median aerodynamic diameter (MMAD) aerosol, but was limited to ≤ 20 mg mass loadings. Testing with a realistic in vitro rabbit model indicated that over half of the loaded dose could penetrate into the lower lung regions. Using the characterization data, a dose delivery protocol was designed in which a 60 mg total loaded dose would be administered and deliver an approximate lung dose of 14.7-17.7 mg phospholipids/kg with a total aerosol delivery period < 5 min. CONCLUSIONS: A high-efficiency aerosol SLS product was designed and tested that may enable an order of magnitude reduction in administered phospholipid dose, and provide rapid aerosol administration to infants with RDS.
Subject(s)
Aerosols , Dry Powder Inhalers , Lung , Particle Size , Powders , Pulmonary Surfactants , Respiratory Distress Syndrome, Newborn , Animals , Pulmonary Surfactants/administration & dosage , Respiratory Distress Syndrome, Newborn/drug therapy , Administration, Inhalation , Rabbits , Lung/metabolism , Lung/drug effects , Humans , Infant, Newborn , Excipients/chemistryABSTRACT
This work presents an indicator-based assessment of potential supply risks for pharmaceutical excipients. The assessment was conducted systematically through the steps of survey, data collection, and indicator value calculation. Japan was specified as the target, and all marketed products were analyzed. As the basis of the indicator, the Herfindahl-Hirschman index (HHI), a well-established method for measuring market concentration in economics, was adopted. Modifications were made to enable comparison of the risk levels of compounds, dosage forms, and diseases. Case studies were performed on each of these levels, and recommendations were obtained for risk mitigation. On the compound level, magnesium stearate, a commonly used lubricant, showed the highest risk, and a switch to alternative compounds was recommended. The dosage-form level evaluation showed that tablets and capsules could have higher risk levels than granules, indicating the importance of diversification. Finally, the disease-level evaluation showed that the supply of adult disease drugs might be risky because of the frequent use of tablets; less reliance on tablet forms was advised for adult diseases.
Subject(s)
Excipients , Excipients/chemistry , Japan , Risk Assessment , Pharmaceutical Preparations/chemistry , Tablets , Humans , Dosage FormsABSTRACT
Vitamin D3 is a crucial fat-soluble pro-hormone essential for bolstering bone health and fortifying immune responses within the human body. Orodispersible films (ODFs) serve as a noteworthy formulation strategically designed to enhance the rapid dissolution of vitamin D, thereby facilitating efficient absorption in patients. This innovative approach not only streamlines the assimilation process but also plays a pivotal role in optimizing patient compliance and therapeutic outcomes. The judicious utilization of such advancements underscores a paradigm shift in clinical strategies aimed at harnessing the full potential of vitamin D for improved patient well-being. This study aims to examine the vitamin D3 ODF structure using spectroscopic techniques to analyze interactions with excipients like mannitol. Fourier-transform infrared spectroscopy (FTIR) and ultraviolet-visible (UV-Vis) spectroscopy were utilized to assess molecular composition, intermolecular bonding, and vitamin D3 stability. Understanding these interactions is essential for optimizing ODF formulation, ensuring stability, enhancing bioavailability, and facilitating efficient production. Furthermore, this study involves a translational approach to interpreting chemical properties to develop an administration protocol for ODFs, aiming to maximize absorption and minimize waste. In conclusion, understanding the characterized chemical properties is pivotal for translating them into effective self-administration modalities for Vitamin D films.
Subject(s)
Cholecalciferol , Cholecalciferol/chemistry , Spectroscopy, Fourier Transform Infrared , Humans , Administration, Oral , Spectrophotometry, Ultraviolet , Excipients/chemistry , Solubility , Biological AvailabilityABSTRACT
Aqueous suspensions containing crystalline drug in the sub-micron range is a favorable platform for long-acting injectables where particle size can be used to obtain a desired plasma-concentration profile. Stabilizers are added to the suspensions and screened extensively to define the optimal formulation composition. In the initial formulation screening the amount of drug compound can be limited, necessitating milling methods for small-volume screening predictable for scale-up. Hence, adaptive focused ultrasound was investigated as a potential milling method for rapid small-volume suspensions by identifying the critical process parameters during preparation. Suspensions containing drug compounds with different mechanical properties and thereby grindability, i.e., cinnarizine, haloperidol, and indomethacin with brittle, elastic, and plastic properties, respectively, were investigated to gain an understanding of the manufacturing with adaptive focused acoustics as well as comparison to already established milling techniques. Using a DoE-design, peak incident power was identified as the most crucial process parameter impacting the milling process for all three compounds. It was possible to decrease the sizes of drug particles to micron range after one minute of focused ultrasound exposure which was superior compared to other milling techniques (e.g., non-focused ultrasound exposure). The addition of milling beads decreased the drug particle sizes even further, thus to a lower degree than other already established milling techniques such as milling by dual centrifugation. This study thereby demonstrated that adaptive focused ultrasonication was a promising method for rapid homogenization and particle size reduction to micron range for different compounds varying in grindability without altering the crystalline structure.
Subject(s)
Chemistry, Pharmaceutical , Particle Size , Suspensions , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Indomethacin/chemistry , Water/chemistry , Sonication/methods , Cinnarizine/chemistry , Ultrasonics/methods , Technology, Pharmaceutical/methods , Haloperidol/chemistry , Excipients/chemistryABSTRACT
Oil-in-water emulsions (EM) have been extensively used for the encapsulation of lipophilic bioactive compounds and posterior incorporation into food matrices to obtain functional foods. Conversely, novel excipient oil-in-water emulsions (EXC) present identical composition and structure as EM, albeit are not bioactive by themselves since no bioactive compound is encapsulated. Instead, EXC aims at improving the bioavailability of foods' natural bioactive compounds upon co-ingestion with nutrient-rich foods. In this work, EM and EXC were produced and their stability and functionality as delivery systems for α-tocopherol compared. Emulsions were formulated with corn oil and lecithin, and their composition was optimized using experimental designs. Formulations produced with 3 % lecithin and 5 % oil attained smallest particles sizes with the lowest polydispersity index of all tested formulations and remained stable up to 60 days. Encapsulation of α-tocopherol did not have a significative impact on the structural properties of the particles produced with the same composition. α-tocopherol stability during in vitro digestion was superior in EM regardless the processing methodology (EM stability < 50 %, EXC stability < 29 %), indicating that EM offered greater protection against the digestive environment. α-tocopherol's bioaccessibility was significantly increased when encapsulated or when digested with added excipient emulsions (82-92 % and 87-90 % for EM and EXC, respectively). In conclusion, EM were more efficient vehicles for the selected bioactive compound, however, the good results obtained with EXC imply that excipient emulsions have a great potential for applications on foods to improve their natural bioactive compounds' bioavailability without the need of further processing.
Subject(s)
Biological Availability , Digestion , Emulsions , Excipients , Particle Size , alpha-Tocopherol , Emulsions/chemistry , alpha-Tocopherol/chemistry , Excipients/chemistry , Lecithins/chemistry , Corn Oil/chemistry , Drug Delivery SystemsABSTRACT
Near UV and visible light photodegradation can target therapeutic proteins during manufacturing and storage. While the underlying photodegradation pathways are frequently not well-understood, one important aspect of consideration is the formulation, specifically the formulation buffer. Citrate is a common buffer for biopharmaceutical formulations, which can complex with transition metals, such as Fe(III). In an aqueous solution, the exposure of such complexes to light leads to the formation of the carbon dioxide radical anion (â¢CO2-), a powerful reductant. However, few studies have characterized such processes in solid formulations. Here, we show that solid citrate formulations containing Fe(III) lead to the photochemical formation of â¢CO2-, identified through DMPO spin trapping and HPLC-MS/MS analysis. Factors such as buffers, the availability of oxygen, excipients, and manufacturing processes of solid formulations were evaluated for their effect on the formation of â¢CO2- and other radicals such as â¢OH.
Subject(s)
Anions , Carbon Dioxide , Ferric Compounds , Light , Photolysis , Ultraviolet Rays , Carbon Dioxide/chemistry , Anions/chemistry , Ferric Compounds/chemistry , Buffers , Chromatography, High Pressure Liquid/methods , Citric Acid/chemistry , Chemistry, Pharmaceutical/methods , Tandem Mass Spectrometry/methods , Excipients/chemistry , Free Radicals/chemistryABSTRACT
The increasing focus on patient centricity in the pharmaceutical industry over the past decade and the changing healthcare landscape, driven by factors such as increased access to information, social media, and evolving patient demands, has necessitated a shift toward greater connectivity and understanding of patients' unique treatment needs. One pharmaceutical technology that has supported these efforts is long acting injectables (LAIs), which lower the administration frequency for the patient's provided convenience, better compliance, and hence better therapeutical treatment for the patients. Furthermore, patients with conditions like the human immunodeficiency virus and schizophrenia have positively expressed the desire for less frequent dosing, such as that obtained through LAI formulations. In this work, a comprehensive analysis of marketed LAIs across therapeutic classes and technologies is conducted. The analysis demonstrated an increasing number of new LAIs being brought to the market, recently most as aqueous suspensions and one as a solution, but many other technology platforms were applied as well, in particular, polymeric microspheres and in situ forming gels. The analysis across the technologies provided an insight into to the physicochemical properties the compounds had per technology class as well as knowledge of the excipients typically used within the individual formulation technology. The principle behind the formulation technologies was discussed with respect to the release mechanism, manufacturing approaches, and the possibility of defining predictive in vitro release methods to obtain in vitro in vivo correlations with an industrial angle. The gaps in the field are still numerous, including better systematic formulation and manufacturing investigations to get a better understanding of potential innovations, but also development of new polymers could facilitate the development of additional compounds. The biggest and most important gaps, however, seem to be the development of predictive in vitro dissolution methods utilizing pharmacopoeia described equipment to enable their use for product development and later in the product cycle for quality-based purposes.
Subject(s)
Delayed-Action Preparations , Humans , Delayed-Action Preparations/administration & dosage , Injections/methods , Drug Industry/methods , Technology, Pharmaceutical/methods , Drug Compounding/methods , Excipients/chemistry , Drug Liberation , Chemistry, Pharmaceutical/methods , Drug ImplantsABSTRACT
Para estabelecer medidas equivalentes para o ensaio de produtos de tabaco em escala mundial é necessário que haja métodos consensuais de medição do conteúdo e das emissões específicas dos cigarros. Nenhum regime de tragada obtido por máquinas é capaz de representar plenamente o comportamento humano de fumar: os ensaios realizados em máquinas de fumar são úteis para caracterizar as emissões de cigarro para fins de design e regulação, mas a divulgação aos fumantes das medições em máquinas pode resultar em interpretações equivocadas a respeito das diferenças de exposição e risco existentes entre as marcas. Os dados de emissão de fumaça obtidos por medições em máquinas podem ser usados como elementos para a avaliação do perigo do produto, mas não são e nem se destinam a ser medidas válidas de exposição ou risco para os seres humanos. A apresentação de diferenças nas medições em máquina como diferenças de exposição ou risco constitui uso indevido dos resultados do ensaio com métodos recomendados da TobLabNet da OMS. Este documento foi preparado por membros da Rede de Laboratórios de Tabaco (TobLabNet) da Organização Mundial da Saúde (OMS) como um procedimento operacional padrão (POP) de método analítico para determinação de umectantes no tabaco do cigarro.
Subject(s)
Tobacco Products , Smoking , Excipients , Glycerol , Propylene Glycol , Toxicity TestsABSTRACT
We have used pulsed field gradient (PFG)-NMR diffusion experiments, also known as DOSY, in combination with small angle X-ray scattering measurements to investigate structure and molecular exchange dynamics between pharmaceutical lipid nanoparticles and the bulk phase. Using liposomes and lipoplexes formed after complexation of the liposomes with messenger mRNA as test systems, information on dynamics of encapsulated water molecules, lipids and excipients was obtained. The encapsulated fraction, having a diffusivity similar to that of the liposomes, could be clearly identified and quantified by the NMR diffusion measurements. The unilamellar liposome membranes allowed a fast exchange of water molecules, while sucrose, used as an osmolyte and model solute, showed very slow exchange. Upon interactions with mRNA a topological transition from a vesicular to a lamellar organization took place, where the mRNA was inserted in repeating lipid bilayer stacks. In the lipoplexes, a small fraction of tightly bound water molecules was present, with a diffusivity that was influenced by the additional presence of sucrose. This extended information on dynamic coherencies inside pharmaceutical nanoparticle products, provided by the combined application of SAXS and PFG-NMR diffusion measurements, can be valuable for evaluation of quality and comparability of nanoscaled pharmaceuticals.
Subject(s)
Liposomes , Magnetic Resonance Spectroscopy , Nanoparticles , RNA, Messenger , Scattering, Small Angle , X-Ray Diffraction , Nanoparticles/chemistry , Magnetic Resonance Spectroscopy/methods , Diffusion , Kinetics , X-Ray Diffraction/methods , Sucrose/chemistry , Lipids/chemistry , Water/chemistry , Excipients/chemistry , Lipid Bilayers/chemistryABSTRACT
Due to their potential adverse health effects, some N-nitrosamines in drug products are strictly regulated with very low maximum daily intake limits. Nitrosamines can be formed from the reaction of nitrite and secondary or tertiary amines when both species co-exist in the drug synthesis or formulation process. One key strategy to mitigate nitrosamine risk in drugs is to select low-nitrite containing pharma excipients for formulation. It is necessary to develop a sensitive method for trace nitrite determination in pharma excipients as it enables drug producers to study nitrosamine formation kinetics and select excipient suppliers. This study details the development and validation of a two-dimensional ion chromatography mass spectrometry (2D-IC/MS) method for trace nitrite determination in hydroxypropyl methylcellulose (HPMC), one of the most important pharmaceutical excipients used in many drug formulations. The 2D-IC system was operated in heart-cutting mode with a concentrator column coupling the two dimensions. A standard bore anion-exchange column was used in the first dimension (1D) to enable a large volume injection for increased sensitivity and provide improved resolution between nitrite and the interfering chloride peak. A high efficiency microbore anion-exchange column with different selectivity was used in the second dimension (2D) to resolve nitrite from other interfering species. The use of 2D-IC resulted in significantly improved resolution, solving the sensitivity loss issue due to ion suppression from an otherwise 1D separation. MS detection with selective ion monitoring and isotope labeled nitrite internal standard further improve the method specificity, accuracy, and ruggedness, as compared with conductivity detection. For trace determination, it is also extremely important to have a clean blank. For this purpose, a novel cleaning procedure using a strong anion wash was developed to remove nitrite contamination from labware. The optimized method was validated with linearity of nitrite in the concentration range of 18.5-5005.8â¯ng/g having a regression coefficient of >0.9999, precision with RSD at 3.5-10.1â¯% and recovery of 90.5-102.4â¯%. The limit of detection and limit of quantitation were 8.9 and 29.6â¯ng/g relative to the HPMC sample, or equivalent to 89 and 296â¯pg/g in the sample solution, respectively.
Subject(s)
Hypromellose Derivatives , Nitrites , Nitrites/analysis , Hypromellose Derivatives/chemistry , Chromatography, Ion Exchange/methods , Mass Spectrometry/methods , Reproducibility of Results , Excipients/chemistry , Excipients/analysis , Nitrosamines/analysis , Nitrosamines/chemistry , Limit of DetectionABSTRACT
PURPOSE: Employing polymer additives is an effective strategy to realize the manipulation of polymorphic transformation. However, the manipulation mechanism is still not clear, which limit the precise selection of polymeric excipients and the development of pharmaceutical formulations. METHODS: The solubility of cimetidine (CIM) in acetonitrile/water mixtures were measured. And the polymorphic transformation from CIM form A to form B with the addition of different polymers was monitored by Raman spectroscopy. Furthermore, the manipulation effect of polymers was determined based on the results of experiments and molecular simulations. RESULTS: The solubility of form A is consistently higher than that of form B, which indicate that form B is the thermodynamically stable form within the examined temperature range. The presence of polyvinylpyrrolidone (PVP) of a shorter chain length could have a stronger inhibitory effect on the phase transformation process of metastable form, whereas polyethylene glycol (PEG) had almost no impact. The nucleation kinetics experiments and molecular dynamic simulation results showed that only PVP molecules could significantly decrease the nucleation rate of CIM, due to the ability of reducing solute molecular diffusion and solute-solute molecular interaction. A combination of crystal growth rate measurements and calculations of the interaction energies between PVP and the crystal faces of CIM indicate that smaller molecular weight PVP can suppress crystal growth more effectively. CONCLUSION: PVP K16-18 has more impact on the stabilization of CIM form A and inhibition of the phase transformation process. The manipulation mechanism of polymer additives in the polymorphic transformation of CIM was proposed.
Subject(s)
Cimetidine , Molecular Dynamics Simulation , Povidone , Solubility , Cimetidine/chemistry , Povidone/chemistry , Polyethylene Glycols/chemistry , Polymers/chemistry , Crystallization , Excipients/chemistry , Spectrum Analysis, Raman , Thermodynamics , Kinetics , Water/chemistryABSTRACT
We applied computing-as-a-service to the unattended system-agnostic miscibility prediction of the pharmaceutical surfactants, Vitamin E TPGS and Tween 80, with Copovidone VA64 polymer at temperature relevant for the pharmaceutical hot melt extrusion process. The computations were performed in lieu of running exhaustive hot melt extrusion experiments to identify surfactant-polymer miscibility limits. The computing scheme involved a massively parallelized architecture for molecular dynamics and free energy perturbation from which binodal, spinodal, and mechanical mixture critical points were detected on molar Gibbs free energy profiles at 180 °C. We established tight agreement between the computed stability (miscibility) limits of 9.0 and 10.0 wt% vs. the experimental 7 and 9 wt% for the Vitamin E TPGS and Tween 80 systems, respectively, and identified different destabilizing mechanisms applicable to each system. This paradigm supports that computational stability prediction may serve as a physically meaningful, resource-efficient, and operationally sensible digital twin to experimental screening tests of pharmaceutical systems. This approach is also relevant to amorphous solid dispersion drug delivery systems, as it can identify critical stability points of active pharmaceutical ingredient/excipient mixtures.
Subject(s)
Excipients , Polysorbates , Excipients/chemistry , Polysorbates/chemistry , Vitamin E/chemistry , Surface-Active Agents/chemistry , Pyrrolidines/chemistry , Molecular Dynamics Simulation , Thermodynamics , Hot Melt Extrusion Technology/methods , Vinyl CompoundsABSTRACT
INTRODUCTION: Dry powder inhaler (DPI) formulations are gaining attention as universal formulations with applications in a diverse range of drug formulations. The practical application of DPIs to pulmonary drugs requires enhancing their delivery efficiency to the target sites for various treatment modalities. Previous reviews have not explored the relation between particle morphology and delivery to different pulmonary regions. This review introduces new approaches to improve targeted DPI delivery using novel particle design such as supraparticles and metal-organic frameworks based on cyclodextrin. AREAS COVERED: This review focuses on the design of DPI formulations using polysaccharides, promising excipients not yet approved by regulatory agencies. These excipients can be used to design various particle morphologies by controlling their physicochemical properties and manufacturing methods. EXPERT OPINION: Challenges associated with DPI formulations include poor access to the lungs and low delivery efficiency to target sites in the lung. The restricted applicability of typical excipients contributes to their limited use. However, new formulations based on polysaccharides are expected to establish a technological foundation for the development of DPIs capable of delivering modalities specific to different lung target sites, thereby enhancing drug delivery.
Subject(s)
Drug Delivery Systems , Dry Powder Inhalers , Excipients , Lung , Polysaccharides , Powders , Humans , Polysaccharides/chemistry , Administration, Inhalation , Lung/metabolism , Excipients/chemistry , Particle Size , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/chemistry , Drug Compounding/methods , Animals , Chemistry, Pharmaceutical , Metal-Organic Frameworks/chemistryABSTRACT
Pulmonary delivery and formulation of biologics are among the more complex and growing scientific topics in drug delivery. We herein developed a dry powder formulation using disordered mesoporous silica particles (MSP) as the sole excipient and lysozyme, the most abundant antimicrobial proteins in the airways, as model protein. The MSP had the optimal size for lung deposition (2.43 ± 0.13 µm). A maximum lysozyme loading capacity (0.35 mg/mg) was achieved in 150 mM PBS, which was seven times greater than that in water. After washing and freeze-drying, we obtained a dry powder consisting of spherical, non-aggregated particles, free from residual buffer, or unabsorbed lysozyme. The presence of lysozyme was confirmed by TGA and FT-IR, while N2 adsorption/desorption and SAXS analysis indicate that the protein is confined within the internal mesoporous structure. The dry powder exhibited excellent aerodynamic performance (fine particle fraction <5 µm of 70.32%). Lysozyme was released in simulated lung fluid in a sustained kinetics and maintaining high enzymatic activity (71-91%), whereas LYS-MSP were shown to degrade into aggregated nanoparticulate microstructures, reaching almost complete dissolution (93%) within 24 h. MSPs were nontoxic to in vitro lung epithelium. The study demonstrates disordered MSP as viable carriers to successfully deliver protein to the lungs, with high deposition and retained activity.
Subject(s)
Lung , Muramidase , Particle Size , Powders , Silicon Dioxide , Silicon Dioxide/chemistry , Muramidase/administration & dosage , Muramidase/chemistry , Lung/metabolism , Lung/drug effects , Porosity , Powders/chemistry , Drug Carriers/chemistry , Administration, Inhalation , Drug Delivery Systems/methods , Nanoparticles/chemistry , Humans , Excipients/chemistry , Animals , Chemistry, Pharmaceutical/methods , Spectroscopy, Fourier Transform Infrared , Freeze DryingABSTRACT
This study aims to optimize and evaluate drug release kinetics of Modified-Release (MR) solid dosage form of Quetiapine Fumarate MR tablets by using the Artificial Neural Networks (ANNs). In training the neural network, the drug contents of Quetiapine Fumarate MR tablet such as Sodium Citrate, Eudragit® L100 55, Eudragit® L30 D55, Lactose Monohydrate, Dicalcium Phosphate (DCP), and Glyceryl Behenate were used as variable input data and Drug Substance Quetiapine Fumarate, Triethyl Citrate, and Magnesium Stearate were used as constant input data for the formulation of the tablet. The in-vitro dissolution profiles of Quetiapine Fumarate MR tablets at ten different time points were used as a target data. Several layers together build the neural network by connecting the input data with the output data via weights, these weights show importance of input nodes. The training process optimises the weights of the drug product excipients to achieve the desired drug release through the simulation process in MATLAB software. The percentage drug release of predicted formulation matched with the manufactured formulation using the similarity factor (f2), which evaluates network efficiency. The ANNs have enormous potential for rapidly optimizing pharmaceutical formulations with desirable performance characteristics.