Formulation Approach Research Articles

New Directions for Cultural Formulations in Forensic Psychiatry.

Forensic psychiatrists have called for greater attention to cultural and racial topics in assessing examinees. While suggestions for new methods are welcome, they can ignore the extent of scientific progress if existing assessments are not accurately appraised. This article analyzes the arguments of two recent publications in The Journal that mischaracterize the cultural formulation approach. Contrary to the idea that forensic psychiatrists have received little guidance on assessing an examinee's racial identity, the article shows that forensic psychiatrists have contributed to scholarship on assessing racial identifications through cultural formulations that elicit how minoritized ethnoracial examinees interpret their illness experiences and legal involvements. The article also seeks to dispel misunderstandings about the Cultural Formulation Interview (CFI), which clinicians have used to complete person-centered cultural assessments, including in forensic settings. Conducting research, practice, and educational activities on the cultural formulation can be ways for forensic psychiatrists to combat systemic racism.

Off-Label use of Raloxifene hydrochloride in uterine fibroids: A novel insert-based formulation approach and IN-VIVO preclinical evaluation

Most available uterine fibroids (UF) treatments are invasive and administered through either oral or parenteral routes. Raloxifene hydrochloride (RLH), a selective estrogen receptor modulator, is chosen as a drug of choice. Currently, it is used in the prevention and treatment of osteoporosis. However, RLH in recent clinical trials on UF shows a significant reduction in the size of UF; therefore, the present work is proposed to use RLH for its off-label use for the treatment of UF. This research aimed to formulate an RLH-loaded drug eluting insert (DEI) and study its uterine-targeting efficiency after intrauterine administration. Capsular-shaped biodegradable insert was prepared by melting method. PCL was selected as the rate-controlling polymer, while PEG 4000 and Vitamin ETPGS were selected as solubilizers. The insert was characterized using SEM, FTIR, XRD, and DSC and evaluated for mechanical strength, drug loading, in-vitro drug release, in-vivo evaluation, and histology studies. The results signify no interference between the drug and excipients in designing the RLH insert. The drug release showed up to 45–50% in 15 days with the desired degradation. In a healthy New Zealand white female rabbit, uterus fibroid was induced by Diethylstilbestrol. The uterus fibroid was confirmed by ultrasonography before the insertion of the implant surgically. The therapeutic effects of Raloxifene were evaluated based on detecting fibroid shrinkage at specific intervals and tissue histology at the end of the study. The Raloxifene-treated rabbits showed positive therapeutic results in comparison to placebo and untreated animals. Preclinical in vivo results show the biodegradation of DEI with a significant reduction in the size of UF. Uterine targeting of RLH-insert was successfully designed and evaluated for its off-label use in the treatment of UF through intrauterine targeting via. Vaginal route. Drug targeting to the site of action anticipates the dose reduction desired to elicit the therapeutic outcome and overcome the side effects of existing therapies.

What makes a ‘good’ neuropsychological assessment? An evaluation of service user and professional stakeholder perspectives

BackgroundNeuropsychological assessment enables clinicians to use standardised tools and systemic formulation approaches to assess cognition and provide targeted psycho-education and rehabilitative input. The research literature is currently limited regarding the perspectives of different stakeholders on the neuropsychological assessment experience, and resulting reports.AimsThis paper explores what professional stakeholders consider to be a ‘good’ neuropsychological assessment/what is important to them, and examines service user experiences of neuropsychological assessment within a neuropsychology outpatient service.MethodA small-scale service evaluation project comprised an online survey completed by 17 professionals who receive neuropsychological report from this service. A semi-structured schedule was used to guide telephone interviews with nine service users who had recently experienced a neuropsychological assessment.ResultsBoth professional stakeholder surveys and service user telephone interviews provided feedback regarding what they found helpful and unhelpful in neuropsychological assessments, and suggested areas for improvement including: provision of an information booklet, offering a choice of remote or in-person appointments, and offering follow-up appointments after the assessment.DiscussionReeommendations are made for service improvements, and for future larger-scale research projects within this subject area.

Precellys® Evolution Homogenizer - a versatile instrument for milling, mixing, and amorphization of drugs in preformulation

The aim of this work was the evaluation and introduction of the Bertin Precellys® Evolution homogenizer with Cryolys® as a valuable and versatile tool for the improvement of workflows in the preformulation phase of drug development. The presented pilot experiments indicate that the instrument can be applied for (1) screening of appropriate vehicles for the generation of micro- and nano suspensions, (2) small-scale manufacturing of suspension formulations for preclinical animal studies, (3) drug amorphization and identification of appropriate excipients for amorphous systems, and (4) preparation of homogenous powder blends. The instrument allows the rapid, parallel, and compound-sparing screening of formulation approaches and small-scale formulation manufacturing, in particular for low solubility compounds. For the characterization of generated formulations, miniaturized methods are introduced such as a screening tool for suspension sedimentation and redispersion and a non-sink dissolution model in biorelevant media in microtiter plates. This work summarizes exploratory, proof-of-concept studies and opens up new opportunities for more extended studies with this instrument in various application areas.

Geometric Two-Scale Integrators for Highly Oscillatory System: Uniform Accuracy and Near Conservations

In this paper, we consider a class of highly oscillatory Hamiltonian systems which involve a scaling parameter . The problem arises from many physical models in some limit parameter regime or from some time-compressed perturbation problems. The solution of the model exhibits rapid temporal oscillations with -amplitude and -frequency, which makes classical numerical methods inefficient. We apply the two-scale formulation approach to the problem and propose two new time-symmetric numerical integrators. The methods are proved to have the uniform second order accuracy for all at finite times and some near-conservation laws in long times. Numerical experiments on a Hénon–Heiles model, two nonlinear Schrödinger equations, and a charged-particle system illustrate the performance of the proposed methods over the existing ones.

Unique Symbolic Factorization for Fast Contingency Analysis Using Full Newton–Raphson Method

Contingency analysis plays an important role in assessing the static security of a network. Its purpose is to check whether a system can operate safely when some elements are out of service. In a real-time application, the computational time required to perform the calculation is paramount for operators to take immediate actions to prevent cascading outages. Therefore, the numerical performance of the contingency analysis is the main focus of this current research. In power flow calculation, when solving the network equations with a sparse matrix solver, most of the time is spent factorizing the Jacobian matrix. In terms of computation time, the symbolic factorization is the costliest operation in the LU (Lower-upper) factorization process. This paper proposes a novel method to perform the calculation with only one symbolic factorization using a full Newton–Raphson-based generic formulation and modular approach (GFMA). The symbolic factorization retained can be used during the iterations of any power flow contingency scenario. A computer study demonstrates that reusing the same symbolic factorization greatly reduces computation time and improves numerical performance. Power system security assessment under N-1 and N-2 contingency conditions is performed for the IEEE standard 54-bus and 108-bus to evaluate the numerical performance of the proposed method. A comparison with the conventional power flow method shows that the time required for the analysis is shortened considerably, with a minimum gain of 228%. The comparative analysis demonstrates that the proposed solution has better numerical performance for large-scale networks.

Development of low-cost, weight-adjustable clofazimine mini-tablets for treatment of tuberculosis in pediatrics

Clofazimine (CFZ) is an important component of the World Health Organization's (WHO) recommended all-oral drug regimen for treatment of multi-drug resistant tuberculosis (MDR-TB). However, the lack of a dividable oral dosage form has limited the use of the drug in pediatric populations, who may require lowering of the dose to reduce the likelihood of adverse drug events. In this study, pediatric-friendly CFZ mini-tablets were prepared from micronized powder via direct compression. Rapid disintegration and maximized dissolution in GI fluids was achieved using an iterative formulation design process. Pharmacokinetic (PK) parameters of the optimized mini-tablets were obtained in Sprague-Dawley rats and compared against an oral suspension of micronized CFZ particles to examine the effect of processing and formulation on the oral absorption of the drug. Differences in maximum concentration and area under the curve between the two formulations were non-significant at the highest dosing level tested. Variability between rats prevented bioequivalence from being determined according to guidelines outlined by the Food and Drug Administration (FDA). These studies provide an important proof-of-concept for an alternative, low-cost formulation and processing approach for the oral delivery of CFZ in manner that is suitable for children as young as 6 months of age.

Development and evaluation of niacinamide transdermal formulation by artificial membrane permeability

Despite many efforts to improve the transdermal permeability of drugs, most of them are blocked by the skin barrier. Niacinamide (NAC) is a Biopharmaceutics Classification System class I drug with high aqueous solubility and intestinal permeability. Due to the high solubility and intestinal permeability of NAC, the development of new formulations is insufficient as transdermal, injection etc. Thus, this study aimed to develop the novel NAC formulation with improved skin permeability and secured stability. The NAC formulation approach is to first select a solvent that improves skin permeability, and then select a second penetration enhancer to determine the final formulation. All formulations were evaluated for skin permeability using an artificial membrane (Strat-M®). The optimal formulation (non-ionic formulations (NF1) consisted of NAC/Tween®80 = 1:1 wt ratio in dipropylene glycol [DPG]) showed the highest permeability in all formulations in PBS buffer (pH 7.4). The thermal properties of NF1 were altered. Moreover, NF1 maintained a stable drug content, appearance, and pH value for 12 months. In conclusion, DPG had an excellent effect in increasing the NAC permeation, and Tween®80 played a boosting role. Through this study, an innovative NAC formulation was developed, and good results are expected for human transdermal research.

Polymer-embedded deep eutectic solvents (PEDES) as a novel bio-enabling formulation approach

There is a growing interest in using deep eutectic solvents (DES) as a pharmaceutical delivery system for poorly water-soluble compounds. To reduce the risk of drug precipitation following oral administration, this study addresses the hypothesis that directly including a polymeric precipitation inhibitor (PI) in a DES mixture could obtain a polymer-embedded deep eutectic system (PEDES) as a novel bio-enabling formulation principle. Following broad formulation screening, a PEDES embedding 15% w/w of polyvinyl pyrrolidone K30 (PVP) in L-carnitine:ethylene glycol (1:4, molar ratio) DES was successfully formulated as a supersaturating formulation using indomethacin as model compound. The drug solubility of 175.6 mg/mL obtained in DES was remarkably high, and upon release (phosphate buffer, pH 6.5) a maximum supersaturation factor of 9.8 was recorded, whereby the release kinetics displayed a suitable “parachute effect”. The formulation was further characterized to include a molecular dynamics simulation. It can be concluded that PEDES appears to be a viable novel formulation approach, setting solid grounds for further research to assess the full potential of this novel type of supersaturating drug delivery system.

A strategy for the treatment of non-small-cell lung cancer by Ag nanoparticles

This work describes an eco-friendly approach for the green formulation of Ag nanoparticles by Allium ampeloprasum extract, without using any toxic reducing and capping agents. The morphology, structure, and physicochemical properties were characterized by several analytical techniques such as fourier transformed infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and Ultraviolet–visible spectroscopy (UV–Vis). The nanoparticles were explored biologically in the anticancer assays. Exposure of the nanoparticles samples to non-small-cell lung cancer cells resulted in cell death, which was mostly due to necrosis but slightly due to late apoptosis. The viability of malignant cell lines reduced dose-dependently in the presence of nanoparticles. The IC50 of nanoparticles were 301, 266, 255, and 250 µg/mL against EKVX, HOP-62, A549 and NCI-H460 cancer cell lines, respectively. The green-synthesized nanoparticles induced cell death, suggesting anticancer prospects that may offer new insight into the development of an anticancer nanomedicine.

Hamel’s equations and geometric mechanics of constrained and floating multibody and space systems

Modern geometric approaches to analytical mechanics rest on a bundle structure of the configuration space. The connection on this bundle allows for an intrinsic splitting of the reduced Euler–Lagrange equations. Hamel’s equations, on the other hand, provide a universal approach to non-holonomic mechanics in local coordinates. The link between Hamel’s formulation and geometric approaches in local coordinates has not been discussed sufficiently. The reduced Euler–Lagrange equations as well as the curvature of the connection are derived with Hamel’s original formalism. Intrinsic splitting into Euler–Lagrange and Euler–Poincaré equations and inertial decoupling is achieved by means of the locked velocity. Various aspects of this method are discussed.

Long-Acting Injectable Aqueous Suspensions-Summary From an AAPS Workshop.

Through many years of clinical application of long-acting injectables, there is clear proof that this type of formulation does not just provide the patient with convenience, but more importantly a more effective treatment of the medication provided. The formulation approach therefore contains huge untapped potential to improve the quality of life of many patients with a variety of different diseases. This review provides a summary of some of the central talks provided at the workshop with focus on aqueous suspensions and their use as a long-acting injectable. Elements as formulation, manufacturing, in vitro dissolution methods, in vitro and in vivo correlation, in silico modelling provide an insight into some of the current understandings, learnings, and not least gaps in the field.

Pediatric Drug Development Process: A Review

This review includes New Formulation approaches to improve Pediatric compliance such as Mini tablets, 3D printing, Orodispersible films, Chewable tablets. Various strategies to improve patient adherence such as ‘nipple shield’ delivery system, dry solid formulations to be converted to liquid at the point of administration, pill swallowing cups, Medicated dosing straw. It is important to formulate pediatric medicines that are tailored to a child’s age, size, physiological condition, and treatment requirements. Legislations for pediatric formulation to ensure that products to treat pediatric patients are appropriately authorized for use in the pediatric population, minimize the worst effect of Off-label medication and to improve the information available on the use of these products in the various pediatric populations. Also, the review consists of Information on legislative obligation and requirement, current State, challenges and effect of regulations. Recent progress has been made in the development of pediatric formulations due to new regulations, additional funding opportunities, and collaborative research initiatives.

Ameliorating the antiparasitic activity of the multifaceted drug ivermectin through a polymer nanocapsule formulation

Ivermectin (IVM) is a potent antiparasitic widely used in human and veterinary medicine. However, the low oral bioavailability of IVM restricts its therapeutic potential in many parasitic infections, highlighting the need for novel formulation approaches. In this study, poly(ε-caprolactone) (PCL) nanocapsules containing IVM were successfully developed using the nanoprecipitation method. Pumpkin seed oil (PSO) was used as an oily core in the developed nanocapsules. Previously, PSO was chemically analyzed by headspace solid-phase microextraction coupled to gas chromatography/mass spectrometry (HS-SPME/GC–MS). The solubility of IVM in PSO was found to be 4266.5 ± 38.6 μg/mL. In addition, the partition coefficient of IVM in PSO/water presented a logP of 2.44. A number of nanocapsule batches were produced by factorial design resulting in an optimized formulation. Negatively charged nanocapsules measuring around 400 nm demonstrated unimodal size distribution, and presented regular spherical morphology under transmission electron microscopy. High encapsulation efficiency (98–100%) was determined by HPLC. IVM-loaded capsules were found to be stable in nanosuspensions at 4 °C and 25 °C, with no significant variations in particle size observed over a period of 150 days. Nanoencapsulated IVM (0.3 mM) presented reduced toxicity to J774 macrophages and L929 fibroblasts compared to free IVM. Moreover, IVM-loaded nanocapsules also demonstrated enhanced in vitro anthelmintic activity against Strongyloides venezuelensis in comparison to free IVM. Collectively, the present findings demonstrate the promising potential of PCL-PSO nanocapsules to improve the antiparasitic effects exerted by IVM.

Incorporating valsartan in sesame oil enriched self-nanoemulsifying system-loaded liquisolid tablets to improve its bioavailability

Valsartan (VST) is a poorly soluble antihypertensive drug characterized by its limited dissolution rate and low bioavailability. This study aims to improve VST solubility and dissolution rate via developing liquisolid tablets (LSTs) containing a self-nanoemulsifying drug delivery system (SNEDDS), which is expected to enhance VST bioavailability. This aim was achieved via two designs of experiment. The first was the simplex-lattice design to optimize VST-loaded-SNEDDS using sesame oil, Tween 80, and polyethylene glycol 400. The second was the 32-3-level factorial design to optimize the liquisolid system using the SNEDDS-loaded VST and Neusilin®US2 as a carrier and fumed silica as a coating material. Different excipient ratios (X1) and varioussuper-disintegrants (X2) were also used in developing the optimized VST-LSTs. Thein vitrodissolution of VST from LSTs was compared with the marketed product (Diovan®). Non-compartmental analysis of plasma data after extravascular input with the linear trapezoidal method was used to calculate thepharmacokinetic parameters of the optimized VST-LSTs compared with the marketed tablet in male Wistar rats. The optimized SNEDDS compromised 24.9% sesame oil, 33.3% surfactant, and 41.8% cosurfactant, giving 173.9 nm size and 63.9 mg/ml loading capacity. Also, the SNEDDS-loaded VST tablet revealed good quality attributes with the release of 75% of its content in 5 min and 100% within 15 min. On the other hand, the marketed product took 1 h for the entire drug to be released.Moreover, the maximum plasma concentration (Cmax) of the optimizedVST-LSTwas6585.33 ng/ml within 1 h (Tmax), compared to 2884.67 ng/ml within 2 h of the marketed tablet.The relative bioavailability of the SNEDDS-loaded VST tablet was 213.7% compared to that of the marketed tablet, indicating that this formulation approach could be applied for increasing solubility, dissolution behavior in GIT, and bioavailability of poorly water-soluble drugs.

Existence of multi-dimensional pulsating fronts for KPP equations: a new formulation approach

Existence of multi-dimensional pulsating fronts for KPP equations: a new formulation approach

Utility of Quality by Design approach in RP-HPLC method development for quantification of lamivudine and effavirenz in combination formulation

Objective: For the measurement of lamivudine(LAM) and effavirenz (EVZ) in combination formulation, a uncomplicated and reliable liquid chromatographic approach has been proposed.
 Material and Method: Multivariate optimization of the RP-HPLC method, experimental conditions were accomplished using the design of experiments (DoE). The crucial method parameters were determined by a risk assessment. The mathematical models were created using three independent variables: percentage of acetonitrile, percentage of methanol, and buffer pH. The impacts of these independent elements were thoroughly investigated using the central composite design (CCD), which was utilized to analyze the response surface methodology. 
 Result and Discussion: The LAM and EVZ retention time and resolution were both concurrently optimized using the desirability function. Acetonitrile, methanol, and phosphate buffer (pH 7.0) in the proportions of 40:20:40 v/v each were used in the optimized and anticipated data from the contour diagram, with detection occurring at a wavelength of 215 nm. Baseline separation of both pharmaceuticals with high resolution and a run time of under 6 minutes was accomplished under these ideal conditions. The validated test parameters followed ICH recommendations. As a consequence, the findings demonstrated that the Quality by Design methodology could be successfully used to optimize the RP-HPLC technique for the concurrent quantification of LAM and EVZ.

Review on Nanosuspension as a Novel Method for Solubility and Bioavailability Enhancement of Poorly Soluble Drugs

The formulation development of a drug is majorly based on the solubility of drugs. Nearly 40% of newly developed drugs show poor water solubility. Several approaches are used for the increasing solubility of such drugs for formulation development. Nanosuspension is one such attractive tactic which can be used for the enhancement of solubility, stability as well as bioavailability of such drugs. Nanosuspension can be defined as a two-phasic dosage form where solid drug particles of size less than 1 μm are dispersed in an aqueous phase with the help of a stabilizer. Particle size reduction in the nanoscale causes an increase in the surface area leading to an increase in dissolution rate and ultimately bioavailability is increased. A variety of excipients are used for the formulation of nanosuspension. Stabilizers, surfactants, co-surfactants, natural as well as organic solvents, buffers, salts, polyols, osmogents, and cryoprotectants are used in the formulation of nanosuspension. Various methods used in the formulation of nanosuspension can be classified into top-down and bottom-up approaches. Wet milling, high-pressure homogenization, anti-solvent techniques, melt emulsification, supercritical fluid extraction and ultrasonic homogenization are some of the methods for the preparation of nanosuspension. These methods are easy and appropriate for all poor water-soluble drugs. Nanosuspensions technology can be applied for the preparation of oral, pulmonary, injectable, ocular as well as targeted drug delivery. This review emphasizes various advantages and disadvantages of nanosuspension, its methods of preparation, formulation approaches, evaluation parameters, pharmaceutical applications, marketed products and patents of nanosuspension.

Complex formulation strategies to overcome the delivery hurdles of lapatinib in metastatic breast cancer

Breast cancer (BC) is the most prevalent cause of death in women due to cancer worldwide. In 2020, globally, almost 3 million new cases of BC were recognized out of which approximately 684,900 BC-associated deaths were reported due to consequences of metastatic BC (MBC). For its efficient treatment lapatinib (LTN), a dual receptor tyrosine kinase inhibitor (TKI) combination with capecitabine was approved by USFDA. It is a Biopharmaceutical Classification System (BCS) class II drug with water solubility of (0.0223 mg/mL) and exhibits a positive food effect (2.67–4.25-fold). The lower aqueous solubility of LTN restricts its dissolution in a gastrointestinal fluid resulting in variable absorption and poor bioavailability. Furthermore, 99% of LTN binds to plasma proteins resulting in minimal accessibility of free LTN at the cancer site. Hence, a large daily dose of LTN is required to be prescribed. The patent expiry on the innovated product in 2021 has fuelled up the need to develop complex delivery system to overcome the biopharmaceutical hurdles of the drug. The present review critically analyses the various intrinsic fundamental properties of drug molecule that should be taken into consideration while designing a complex delivery system for LTN and the such several formulation approaches reported in literature so far to enhance the pharmacokinetic and pharmacodynamic properties of LTN. This review also discusses the various combinational approaches reported with LTN to overcome the hurdles related to the drug. It also covers various recent ongoing clinical trials on LTN and to provide new perspectives for the development of complex formulations.

Nano formulation approaches for curcumin delivery- a review

Curcumin is a polyphenol molecule derived from Curcuma longa Linn's rhizomes. Curcumin appears to have been the target of substantial research, with cancer, viral, fungal infections, bacterial, arthritis, antioxidant, anti-inflammatory, allergies, Alzheimer's disease, and other chronic diseases and disorders all being explored. Curcumin has undesirable features such as inadequate intake and low aqueous solubility. To resolve these challenges, research has taken numerous attempts to improve its absorption, solubility, and bioavailability. Nanotechnology plays a critical role in the creation of nanostructured devices, nanomedicines, targeted therapy, and nanocarriers. Curcumin nano formulation has alleviated some of the major disadvantages of curcumin-based medication delivery. The emphasis of the study is on nano-based techniques to address therapeutic activity, efficacy, bioavailability, and solubility. Curcumin was localized to a certain cellular and molecular level by combining nano-curcumin with a specific molecule to enhance activity at the target site. A detailed description of solubility and bioavailability enhancement technique using protein carriers, solid dispersions, nanofiber, carbon dots, liposomes, and polymer carrier drug delivery systems is provided in this review.