Liquid Vehicle Research Articles

Applying liquisolid technique to enhance curcumin solubility: a central composite design study

Turmeric, specifically its curcuminoids such as curcumin (C21H20O6), possesses extensive therapeutic benefits including anti-inflammatory, anticancer, and anti-aging properties. However, curcumin’s clinical effectiveness is significantly limited by its hydrophobic nature, leading to poor bioavailability. This study aims to enhance the solubility and bioavailability of curcumin through the development of liquisolid compact dispersion formulations. To address curcumin’s limited water solubility (3.12 mg/l at 25 °C) and high oil–water partition coefficient (logKow=3.29\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ ext{log}Kow=3.29$$\\end{document}), we employed a central composite design (CCD) to optimize liquisolid compact dispersion formulations. The optimization focused on the tablet’s physical properties, such as hardness, disintegration time, and dissolution rate at 30 min. Critical formulation components included Tween 80 as the liquid vehicle and Aerosil 200 as the coating material, serving as independent variables in the optimization process. The optimized formulation, containing 30 mg of Tween 80 and 75 mg of Aerosil 200, significantly improved curcumin’s dissolution rate. Experimental results confirmed the formulation’s effectiveness, with a marked reduction in the time to dissolve 63.2% of the drug to 165 min, compared to 300 min for conventional formulations. Differential scanning calorimetry and Fourier-transform infrared spectra indicated a transformation of curcumin into a non-crystalline state and the formation of hydrogen bonds with Tween 80, contributing to enhanced solubility. This study successfully demonstrates a viable strategy to enhance the bioavailability of curcumin through liquisolid compact dispersion formulations. By addressing the solubility challenges of curcumin, this technique presents a significant advancement in improving the clinical applicability of BCS class II and IV drugs, potentially benefiting a wide range of therapeutic applications.Graphical abstractGraphical representation of optimizing curcumin liquisolid formulationusing central composite design (CCD) methodology

Improved Dissolution Time and Oral Bioavailability of Pioglitazone Using Liquisolid Tablets: Formulation, In Vitro Characterization, and In Vivo Pharmacokinetics in Rabbits.

In the current study, it was intended to prepare liquisolid tablets of pioglitazone HCl to improve the bioavailability and dissolution time of the drug, as it has low solubility in water. Mathematical formulas were adopted, and the quantities of the carrier (MCC), coating material (colloidal silicon dioxides), and nonvolatile liquid vehicle (Tween 80) were taken. Various ratios of the drug to liquid and carrier to coating had been used in the formulation of liquisolid compacts. The evaluation of the formulated liquisolid compacts was done by performing FTIR, DSC, XRD, and SEM studies. Postcompression parameters, dissolution, stability, and bioavailability were accessed for the optimized formulation. FTIR and DSC studies showed the compatibility of the drugs and excipients. XRD revealed the transition to the amorphous state. It was found that the properties of the newly manufactured liquisolid tablets were within the parameters of what is considered acceptable. The optimized formulation of LST10 showed 99.87 ± 0.19% (p < 0.05) pioglitazone released within 60 min of dissolution. Dissolution data treatments (Q 15, IDR, RDR, %DE, MDT, f 1, and f 2) resulted in better drug release than other drugs studied and marketed tablet formulations. The optimized formulation produced had been proven stable when it was subjected to accelerated stability testing. This suggested that the bioavailability of pioglitazone was enhanced, as indicated by the substantial increase in AUC0-t (3.06-fold) and C max (4.18-fold). According to the findings, the selected combination and method significantly increased the dissolution time and bioavailability of pioglitazone. Moreover, this developed method can be used for other drugs with low water solubility.

Injectability of high concentrated suspensions using model microparticles

Administration of high-concentrated suspension formulations (i.e., solid particles dispersed in a liquid vehicle) can be limited due to their greater propensity for needle occlusion. The physical interaction between the solid phase (i.e., particles), the vehicle (i.e., flow field), and injection devices could result in the formation of particle bridging or filtering, posing a major risk in dose delivery accuracy and injectability. Here, given the limited understanding on how clogging initiates in syringe and needle delivery systems, we report an experimental approach to fully characterize the transient injection behavior of suspensions. In particular, we first established a custom fluorescence tagging and imaging technique with integrated force sensor to enable visual observation of local particle concentrations and plunger force monitoring throughout injection. Then, we investigated the effects of key formulation properties and device parameters including particle concentration and morphology, carrier viscosity, injection rate, needle and syringe sizes, and tissue backpressure on the incidence of suspension particle jamming and needle clogging. We performed systematic benchmark studies demonstrating that increasing needle inner diameter (ID) and particle density considerably reduced clogging risk, while increasing vehicle viscosity, particle size, and tissue backpressure significantly increased clogging. The experimental framework presented is amenable to quantifying clogging risk in drug-loaded particle suspensions and provides a guideline to make informed decisions on the tradeoffs between creating particles for pharmaceutical impact and feasibility of injection delivery.

Treasury Richness

ABSTRACTWe provide estimates of Treasury convenience premia across the entire term structure of Treasury bills, notes, and bonds over more than a quarter of a century and document a variety of key stylized facts about their time‐series and cross‐sectional patterns. These results raise concerns about the evolving nature of Treasury markets and suggest that investors may now place less weight on the traditional role of Treasury securities as liquid trading vehicles. These stylized facts provide empirical benchmarks that could help guide future theoretical and empirical work about the economics of safe assets in financial markets.

Multi-objective optimization of the wave-proof plate layout of the liquid tank vehicle based on NSGA-II and RSM

Multi-objective optimization of the wave-proof plate layout of the liquid tank vehicle based on NSGA-II and RSM

Exploring the relationship between bulk Young’s Modulus of materials and milling efficiency during wet bead milling of pharmaceutical compounds

Wet bead milling (WBM) is one of the main approaches for manufacturing long acting injectable (LAI) suspensions, wherein the particle size of an Active Pharmaceutical Ingredient (API) is reduced in a liquid vehicle via grinding. A common challenge observed during WBM is long milling time to achieve target particle size, resulting in poor milling efficiency. The objective of this work was to identify potential API attributes predictive of milling efficiency during WBM. In this study, physical and mechanical properties of nine APIs were characterized. Formulations with these APIs were manufactured using WBM. Bulk Young’s Modulus was identified to have a significant influence on the rate of particle attrition. The rank order of Young’s Moduli of the APIs was consistent with that of milling efficiency, estimated by an empirical function defined in this study called Milling Resistance (ϕ), representing the holistic impact of milling time, tip speed, bead loading, and batch to chamber volume ratio. The identification of such intrinsic material properties, which provide an early evaluation of potential manufacturing risks, is beneficial to product development, as these assessments can be performed with limited quantities of materials and help identify and design out scale-up challenges.

EVALUATION OF THE SCATTER OF LIQUID LAUNCH VEHICLE POGO OSCILLATION AMPLITUDES DUE TO THE INFLUENCE OF THE SCATTER OF INTERNAL FACTORS

Almost all liquid launch vehicle developers faced the problem of ensuring stability in relation to POGO oscillations. The level of POGO amplitudes oscillations of the launch vehicle can be significantly affected by the scatter of internal factors. The study aims to create a mathematical model that can determine the range of POGO amplitudes in liquid launch vehicles. This will be demonstrated through the example of the Dnipro launch vehicle, which is affected by a variety of internal factors that cause its POGO amplitudes to vary. We developed the non-linear non-stationary mathematical model of POGO oscillations of the prototype of the Dnipro space launch vehicle. The model is built by taking into account the two lower vibration modes of the LV structure, two lower oscillation modes of the oxidizer feedline, and the first oscillation mode of the fuel feedline of the propulsion system. Modeling of dynamic processes was conducted in a combination of four liquid rocket engines based on the schematic of the staged rocket engine. The simulation takes into account cavitation phenomena in the engine pumps and delay times in the gas generators’ chambers. We have developed a method for determining the scatter of the POGO oscillations caused by the action of internal factors, which is based on the use of the LP uniformly distributed sequences. As internal factors, the frequencies, decrements, and shapes of LV structural oscillation modes, the values of pressurization of the propellant tanks, and the engines’ specific thrust impulses were considered. Based on the results of the calculations, the dependence of the POGO amplitudes in two regions of LV instability was determined, and the lower and upper enveloping curves for the POGO amplitudes were constructed. It is shown that the maximum POGO amplitudes oscillations in the first region of instability lie in the range from 0.23 g to 0.72 g and in the second region of instability — from 0 g to 0.60 g. Variants of combinations of internal factors, which provided the largest and smallest values of POGO amplitudes, were analyzed. This made it possible to determine the internal factors, the scatter of which has the greatest effect on the POGO amplitudes scatter: frequency, decrement, shape coefficients of oscillations of the oxidizer feedlines and the LV 1st mode structural longitudinal oscillations in the payload cross-section.

Research on matching supply of power and cold energy of liquid hydrogen cold chain logistics vehicles

Liquid hydrogen cold-chain logistics vehicle (LHCCLV) is a special vehicle using liquid hydrogen (LH2) as the source of both power and cold energy. A significant weakness of LH2 is its high energy consumption during the hydrogen liquefaction process, thus the utilization of cold energy in LHCCLV can improve the economic performance and competitiveness of LH2. Because of the high energy storage density of LH2 and the relatively high efficiency of fuel cells, we find that cold energy can not meet the demand of LHCCLV. Therefore, we consider enlarging the cold energy by efforts including the para-ortho hydrogen conversion (POC), whose reverse reaction consumes an energy level exceeding 20% during the hydrogen liquefaction process. In this paper, numerical models of discharging hydrogen from the LH2 and subcooling hydrogen tank are established, and the influence of POC and other efforts on the supply of cold energy is analyzed. The changes in instantaneous and total cold energy supply under different working conditions are analyzed, and the important influence of POC and other efforts is confirmed. The beneficial effect of POC is quantified in the paper, especially for the cold energy supply. This paper provides an essential reference for the research and development of LHCCLV. Also, it guides the comprehensive utilization of cold energy in other situations to promote the improvement of the economy of hydrogen energy utilization routes in the form of LH2.

Evaluation of amorphous and lipid-based formulation strategies to increase the in vivo cannabidiol bioavailability in piglets

Cannabidiol (CBD) suffers from poor oral bioavailability due to poor aqueous solubility and high metabolism, and is generally administered in liquid lipid vehicles. Solid-state formulations of CBD have been developed, but their ability to increase the oral bioavailability has not yet been proven in vivo. Various approaches are investigated to increase this bioavailability. This study aimed to demonstrate the enhancement of the oral bioavailability of oral solid dosage forms of amorphous CBD and lipid-based CBD formulation compared to crystalline CBD. Six piglets received the three formulations, in a cross-over design. CBD and 7 − COOH − CBD, a secondary metabolite used as an indicator of hepatic degradation, were analyzed in plasma. A 10.9-fold and 6.8-fold increase in oral bioavailability was observed for the amorphous and lipid formulations, respectively. However, the lipid-based formulation allowed reducing the inter-variability when administered to fasted animals. An entero-hepatic cycle was confirmed for amorphous formulations. Finally, this study showed that the expected protective effect of lipids against hepatic degradation of the lipid-based formulation did not occur, since the ratio CBD/metabolite was higher than that of the amorphous one.

Mucoadhesive Budesonide Solution for the Treatment of Pediatric Eosinophilic Esophagitis.

Eosinophilic Esophagitis is an antigen-mediated inflammatory disease characterized by thickening of the esophageal wall, leading to dysphagia, vomiting, reflux, and abdominal pain. This disease can be treated with a therapeutic approach ranging from diet to pharmacological therapy. Jorveza® (budesonide) and Dupixent® (dupilumab) are treatments for Eosinophilic Esophagitis approved by the European Medicines Agency in adults but not in children. Budesonide-based extemporaneous oral liquid suspensions could be prepared for pediatric use. The main limit of this formulation is that budesonide needs a longer residence time on the esophageal mucosa to solubilize and diffuse in it to exert its local anti-inflammatory effect. Herein, we propose the development of an extemporaneous mucoadhesive oral budesonide solution for the pediatric population. A liquid vehicle containing hydroxypropyl-beta-cyclodextrin as a complexing agent and carboxymethylcellulose sodium as a mucoadhesive excipient was used to prepare budesonide-based formulations. A stable solution at a concentration of 0.7 mg/mL was successfully prepared and characterized. The formulation showed rheological and mucoadhesive properties suitable for an Eosinophilic Esophagitis local prolonged treatment. In this way, pharmacists can prepare stable budesonide-based mucoadhesive solutions, providing both patients and physicians with a new therapeutic option for Eosinophilic Esophagitis pediatric treatment.

Thermodynamics and energy properties of the lowest eutectic mixture of TNBA/MTNP

In light of the challenges posed by the low density, diminished energy levels, and shrinkage holes in the loading arise of the current cast-cured explosive liquid vehicle, TNT, the investigation of low-melting eutectic materials as potential substitutes for TNT has emerged as a focal point of research. By employing the solvent-nonsolvent method, the lowest eutectic mixture of TNBA(2,4,6-trinitro-3-bromoanisole)/MTNP(1-methyl-3,4,5-trinitropyrazole) was synthesized, distinguished by a moderate melting point and markedly elevated energy levels as compared to TNT. Comprehensive SEM, EDS, IR, XRD, and XPS analyses were conducted on the lowest eutectic mixture, substantiating the absence of any chemical interaction between TNBA and MTNP and affirming their exceptional compatibility. Moreover, an exploration into the thermal decomposition behavior and mechanism of the lowest eutectic mixture was undertaken, its mechanical sensitivity was tested, and its detonation performance was evaluated by EXPLO-5 software. The thermal decomposition parameters of the lowest eutectic mixture closely paralleled those of the precursor materials, with the thermal decomposition kinetics model function being identified as the Jander function. The impact sensitivity of the lowest eutectic was 48.1 cm and the friction sensitivity was 12%. Furthermore, the density of the lowest eutectic mixture surpassed 1.8 g/cm3, and its detonation velocity approached 8000 m/s, markedly surpassing the explosive performance of TNT.

An interval construction belief rule base with interpretability for complex systems

Complex system modeling using only subjective judgment is insufficient to address the needs of more extensive and complex actual systems. The expert knowledge base in the belief rule base (BRB) take part in complex system modeling well, but there are still the following problems. On the one hand, BRB cannot deal with the overabundance of combination rules caused by the excessive number of complex system attributes. On the other hand, parameters may lose their interpretability after BRB modeling, reasoning, and optimization. Given the above two problems, an interval construction belief rule base with interpretability for complex systems (IBRB-i) model is proposed. The IBRB-i model uses interval addition to create belief tables and adds rule reliability to prevent combination rule explosion in traditional BRB. In addition, interpretable constraints are added to the IBRB-i model to ensure its interpretability. In the case study, the validity and precision of the IBRB-i are analyzed and verified by two examples of power fault detection and liquid launch vehicle’s structure safety assessment.

Cyclodextrin-based supramolecular deep eutectic solvent (CycloDES): A vehicle for the delivery of poorly soluble drugs

The aim of this work was to develop a new class of deep eutectic solvent (DES) composed of a complexation agent, namely hydroxy-propyl-β-cyclodextrin (HPβCD), to exploit a synergic solubilization-enhancing approach. For this purpose, cyclodextrin-based supramolecular DES (CycloDES) were physical–chemical characterized and loaded with three different BCS class II model drugs, specifically Cannabidiol, Indomethacin, and Dexamethasone, evaluating the influence of different factors on the observed solubility and permeation compared with the only HPβCD/drug complexation.Hence, CycloDESs were presented as a possible vehicle for drugs and represent a novel potential approach for solving BCS class II and IV solubility issues, demonstrating at least a 100-fold improvement in the investigated drug solubilities. Furthermore, CycloDESs demonstrated a significantly improved resistance to dilution preserving a high percentage of drug in solution (i.e. 93% for Indomethacin) when water is added to the DES if compared with a glucose-choline chloride DES, used as a standard. This evidence guarantees the solubility-enhancing effect useful for the delivery of BCS class II and IV drugs converting solid raw material to advantageous liquid vehicles bypassing the rate-determining dissolution step.

Crushed Tablet Administration for Patients with Dysphagia and Enteral Feeding: Challenges and Considerations.

Dysphagia is increasingly common in older adults; it is especially prevalent in long-term care settings. Patients with dysphagia likely require pharmacologic treatment for multiple comorbidities but may find it difficult or impossible to swallow oral medications. Administering crushed medications mixed with a soft food or liquid vehicle, or via a feeding tube, is a common strategy to circumvent swallowing difficulties in patients with dysphagia. However, inappropriate medication use and improper crushing technique can reduce the medication dose a patient receives, alter medication pharmacokinetics and pharmacodynamics, and compromise treatment efficacy and patient safety. Clinical judgment is needed to identify medications that can and cannot be crushed, select a crushing methodology and vehicle for administering crushed medications, and create a strategy for administering multiple medications. A coordinated effort from the entire care team-including physicians, pharmacists, nurses, advanced practice providers, speech therapists, patients, and caregivers-is necessary to develop and implement an individualized plan for administering medications to patients with dysphagia. This review details the current literature regarding the administration of medications that have been altered, such as by crushing tablets or opening capsules, for patients with dysphagia or who are receiving enteral feeding and provides recommendations on best practices.

Stage separation of recoverable liquid launch vehicle by using moving pulsating ball analogue for propellant sloshing

In the process of stage separation of recoverable liquid launch vehicles, because of the large amount of residual fuel in the storage tanks, the influence of liquid sloshing on separation safety must be considered. Considering calculation simplicity and operation practicability, the Moving Pulsating Ball Model (MPBM) of large amplitude liquid sloshing is introduced into the calculation of launch vehicle stage separation. Combining the dynamic equation of the model with the energy relationship during “breathing movement”, the formula calculating the force of liquid on the rigid body is derived. Compared with the calculations of commercial CFD calculation software, the accuracy of MPBM model is verified. Then, all the external forces and moments are applied to the rigid body of the stages, so that the translational and rotational dynamic equations of the stages are obtained respectively. According to the relative position of the two stages, the geometric shape of the interstage section and the engine of the second stage, the minimum clearance in the separation process can be decided to guarantee that the separation process is safe.

A critical review of carbon-based thermal interface materials

This review of carbon-based thermal interface materials (TIMs) covers carbon pastes, carbon nanotube (CNT)-based TIMs, graphene-based TIMs, 3D-structured TIMs and other hybrid TIMs. The TIM material design is related to the TIM performance, which is described by the thermal contact conductance of the sandwich consisting of two surfaces sandwiching the TIM. The thermal conductivity alone is a misleading and inadequate description of TIM performance, although it is considered as the sole criterion that governs TIM performance in much of the TIM literature. TIMs comprising vertically aligned carbons (CNTs, graphene sheets and carbon fibers) have received much recent attention. However, due to the cost and performance, the practical hurdles to implementation are significant. The combined use of an array and a metal cap (involving a low-melting metal) alleviates the inadequacy of the interface between the top of the array and the surface that the TIM should touch. The carbon black paste (inexpensive and effective) excels due to the solid-state conformability of the carbon black. The liquid vehicle of the pastes is commonly an oil. The solid content needs to be optimized, as the conformability decreases with increasing solid content, whereas the thermal conductivity increases with increasing solid content. The pastes are effective at small TIM thicknesses, whereas the vertically aligned carbons and 3D-structured carbons tend to be effective at large TIM thicknesses.

Evaluating Neutral PFAS for Potential Dermal Absorption from the Gas Phase.

Exposures to per- and polyfluoroalkyl substances (PFAS) are of increasing concern. Assessments typically focus only on ingestion and inhalation exposure due to a lack of generally accepted approaches for estimating dermal absorption. Prior work indicates limited dermal absorption of ionic PFAS, but absorption of neutral PFAS has not been examined from the liquid vehicle or from vapor. Partitioning of semivolatile organic compounds from the gas phase to the skin surface (i.e., stratum corneum) is well known, but the potential for partitioning of neutral PFAS from the gas phase to the stratum corneum has yet to be estimated. The SPARC-estimated physicochemical properties were used to calculate transdermal permeability coefficients (kp_g) and dermal-to-inhalation (D/I) exposure ratios for two groups of neutral PFAS, including those on a U.S. Environmental Protection Agency PFAS list. 11 neutral PFAS gave calculated D/I ratios >5, indicating that direct transdermal absorption may be an important exposure pathway compared to inhalation. Data on consumer products or indoor air is needed for the 11 neutral PFAS, followed by possible biomonitoring to experimentally verify dermal absorption from air. Additional PFAS should be estimated by the protocol used here as they are identified in commercial products.

Compounding of Liquid and Solid Dose Adjustable Formulations with Pantoprazole: Comparison of Stability, Applicability and Suitability.

Pantoprazole is a model substance that requires dosage form adjustments to meet the needs of all patients. Pediatric pantoprazole formulations in Serbia are mostly compounded as capsules (divided powders), while in Western Europe liquid formulations are more common. The aim of this work was to examine and compare the characteristics of compounded liquid and solid dosage forms of pantoprazole. Three syrup bases were used: a sugar-free vehicle for oral solution (according to USP43-NF38), a vehicle with glucose and hydroxypropyl cellulose (according to the DAC/NRF2018) and a commercially available SyrSpend Alka base. Lactose monohydrate, microcrystalline cellulose and a commercially available capsule filler (excipient II, composition: pregelatinized corn starch, magnesium stearate, micronized silicon dioxide, micronized talc) were used as diluents in the capsule formulations. Pantoprazole concentration was determined by the usage of the HPLC method. Pharmaceutical technological procedures and microbiological stability measurements were performed according to the recommendations of the EP10. Although dose appropriate compounding with pantoprazole is suitable using both liquid vehicles as well as solid formulations, chemical stability is enhanced in solid formulation. Nevertheless, according to our results, if liquid formulation is a pH adjusted syrup, it could be safely kept in a refrigerator for up to 4 weeks. Additionally, liquid formulations could be readily applied, while solid formulation should be mixed with appropriate vehicles with higher pH values.

Safety Assessment of Liquid Launch Vehicle Structures Based on Interpretable Belief Rule Base

A liquid launch vehicle is an important carrier in aviation, and its regular operation is essential to maintain space security. In the safety assessment of fluid launch vehicle body structure, it is necessary to ensure that the assessment model can learn self-response rules from various uncertain data and not differently to provide a traceable and interpretable assessment process. Therefore, a belief rule base with interpretability (BRB-i) assessment method of liquid launch vehicle structure safety status combines data and knowledge. Moreover, an innovative whale optimization algorithm with interpretable constraints is proposed. The experiments are carried out based on the liquid launch vehicle safety experiment platform, and the information on the safety status of the liquid launch vehicle is obtained by monitoring the detection indicators under the simulation platform. The MSEs of the proposed model are 3.8000e-03, 1.3000e-03, 2.1000e-03, and 1.8936e-04 for 25%, 45%, 65%, and 84% of the training samples, respectively. It can be seen that the proposed model also shows a better ability to handle small sample data. Meanwhile, the belief distribution of the BRB-i model output has a high fitting trend with the belief distribution of the expert knowledge settings, which indicates the interpretability of the BRB-i model. Experimental results show that, compared with other methods, the BRB-i model guarantees the model’s interpretability and the high precision of experimental results.

Preparation of extemporaneous solutions with chemotherapeutic agents for pediatric patients: Ensuring safe and effective treatment

The treatment of pediatric oncology patients involves the use of specialized drugs adapted to their specific needs, thus, in view of the need for pharmacotherapeutic follow-up with oral dosage forms (ODF), in the unavailability of liquid formulations, a strategy is the preparation of extemporaneous solutions from the manipulation of tablets and capsules added to liquid vehicles (eg: water, simple syrup) adjusting palatability and facilitating access. This review article will serve as a guide, providing information on the preparation, stability and storage of extemporaneous oral chemotherapy formulations (tablets, capsules, injection powder or injection solution) for use in clinical practice, with the aim of promoting adherence to treatment linked to safety and effectiveness, based on good handling practices and occupational risk. The results of this review are summarized in a table and based on a composition of the cited documents, tests carried out and the authors' judgment on all the data collected. Twenty drugs were identified as potentially important for clinical practice. Strategies for preparing extemporaneous solutions of chemotherapeutic agents for pediatric patients require more scientific data or even publications of adaptations used. Even with the scarcity of data for some drugs, this review covers the most trivial drugs in clinical practice, including information on preparation, warning about stability and storage, and also included relevant guidelines on the mode of administration in view of the adherence and effectiveness of the drug. The professional who handles these cytotoxic drugs needs to understand from pharmacotechnical aspects and guard against exposure in the preparation, so that he can continue to guarantee access and adherence to treatment and follow rigorous literature and protocols, implementing the best practices and providing adequate, effective, and personalized treatment.