Complex Formulation Research Articles

Complex polymeric nanomicelles co-delivering doxorubicin and dimethoxycurcumin for cancer chemotherapy

Combinational therapy is a new trend in medical sciences to achieve a maximum therapeutic response of the drugs with a comparatively low incidence of severe adverse effects. To overcome the challenges of conventional formulations for cancer chemotherapy, a polymer-based complex nanomicellar system, namely CPM-DD, was developed co-delivering the anti-cancer agent doxorubicin (DOX) and potent antioxidant dimethoxycurcumin (DiMC). The optimal mass ratio of DOX/DiMC in CPM-DD was determined as 1:6 due to the synergistic antiproliferative effect from in vitro cytotoxicity assay, while the biocompatible diblock copolymer of mPEG2000-PLA5000 was selected for drug entrapment at an optimal feeding ratio of 9:1 to both drugs together. The uniform particles of CPM-DD with suitable particle size (∼30 nm) and stable drug loading content (>9%) could be reliably obtained by self-assembly with the encapsulation yield up to 95%. Molecular dynamics simulation revealed the interaction mechanism responsible for forming these complex nanomicelles. The acid-base interaction between two drugs would significantly improve their binding with the copolymer, thus leading to good colloidal stability and controlled drug release characteristics of CPM-DD. Systematic evaluation based on the MCF-7 breast tumor-bearing nude mice model further demonstrated the characteristics of tissue biodistribution of both drugs delivered by CPM-DD, which were closely related to the drug loading pattern and greatly responsible for the improved anti-cancer potency and attenuated toxicity of this complex formulation. Therefore, all the findings indicated that CPM-DD would be a good alternative to the conventional formulations of DOX and worthy of clinical application for cancer chemotherapy.

A Biodegradable Iridium(III) Coordination Polymer for Enhanced Two‐Photon Photodynamic Therapy Using an Apoptosis–Ferroptosis Hybrid Pathway

AbstractThe clinical application of photodynamic therapy is hindered by the high glutathione concentration, poor cancer‐targeting properties, poor drug loading into delivery systems, and an inefficient activation of the cell death machinery in cancer cells. To overcome these limitations, herein, the formulation of a promising IrIII complex into a biodegradable coordination polymer (IrS NPs) is presented. The nanoparticles were found to remain stable under physiological conditions but deplete glutathione and disintegrate into the monomeric metal complexes in the tumor microenvironment, causing an enhanced therapeutic effect. The nanoparticles were found to selectively accumulate in the mitochondria where these trigger cell death by hybrid apoptosis and ferroptosis pathways through the photoinduced production of singlet oxygen and superoxide anion radicals. This study presents the first example of a coordination polymer that can efficiently cause cancer cell death by apoptosis and ferroptosis upon irradiation, providing an innovative approach for cancer therapy.

A Biodegradable Iridium(III) Coordination Polymer for Enhanced Two-Photon Photodynamic Therapy Using an Apoptosis-Ferroptosis Hybrid Pathway.

The clinical application of photodynamic therapy is hindered by the high glutathione concentration, poor cancer-targeting properties, poor drug loading into delivery systems, and an inefficient activation of the cell death machinery in cancer cells. To overcome these limitations, herein, the formulation of a promising IrIII complex into a biodegradable coordination polymer (IrS NPs) is presented. The nanoparticles were found to remain stable under physiological conditions but deplete glutathione and disintegrate into the monomeric metal complexes in the tumor microenvironment, causing an enhanced therapeutic effect. The nanoparticles were found to selectively accumulate in the mitochondria where these trigger cell death by hybrid apoptosis and ferroptosis pathways through the photoinduced production of singlet oxygen and superoxide anion radicals. This study presents the first example of a coordination polymer that can efficiently cause cancer cell death by apoptosis and ferroptosis upon irradiation, providing an innovative approach for cancer therapy.

Evaluation of Host Protein Biomarkers by ELISA From Whole Lysed Peripheral Blood for Development of Diagnostic Tests for Active Tuberculosis.

Tuberculosis (TB) remains a significant global health crisis and the number one cause of death for an infectious disease. The health consequences in high-burden countries are significant. Barriers to TB control and eradication are in part caused by difficulties in diagnosis. Improvements in diagnosis are required for organisations like the World Health Organisation (WHO) to meet their ambitious target of reducing the incidence of TB by 50% by the year 2025, which has become hard to reach due to the COVID-19 pandemic. Development of new tests for TB are key priorities of the WHO, as defined in their 2014 report for target product profiles (TPPs). Rapid triage and biomarker-based confirmatory tests would greatly enhance the diagnostic capability for identifying and diagnosing TB-infected individuals. Protein-based test methods e.g. lateral flow devices (LFDs) have a significant advantage over other technologies with regard to assay turnaround time (minutes as opposed to hours) field-ability, ease of use by relatively untrained staff and without the need for supporting laboratory infrastructure. Here we evaluate the diagnostic performance of nine biomarkers from our previously published biomarker qPCR validation study; CALCOCO2, CD274, CD52, GBP1, IFIT3, IFITM3, SAMD9L, SNX10 and TMEM49, as protein targets assayed by ELISA. This preliminary evaluation study was conducted to quantify the level of biomarker protein expression across latent, extra-pulmonary or pulmonary TB groups and negative controls, collected across the UK and India, in whole lysed blood samples (WLB). We also investigated associative correlations between the biomarkers and assessed their suitability for ongoing diagnostic test development, using receiver operating characteristic/area under the curve (ROC) analyses, singly and in panel combinations. The top performing single biomarkers for pulmonary TB versus controls were CALCOCO2, SAMD9L, GBP1, IFITM3, IFIT3 and SNX10. TMEM49 was also significantly differentially expressed but downregulated in TB groups. CD52 expression was not highly differentially expressed across most of the groups but may provide additional patient stratification information and some limited use for incipient latent TB infection. These show therefore great potential for diagnostic test development either in minimal configuration panels for rapid triage or more complex formulations to capture the diversity of disease presentations.

Formulation and characterization of eprosartan mesylate and β-cyclodextrin inclusion complex prepared by microwave technology

The goal of this work was to improve the aqueous solubility and dissolution rate of eprosartan mesylate by preparing inclusion complex of drug with β-cyclodextrin (β-CD) by microwave technique. In order to determine the solubility of eprosartan, phase solubility was determined and dissolution study was also conducted. Further, analytical techniques for instance, particle size distribution, differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, Fourier-transform infrared spectroscopy, and nuclear magnetic resonance spectroscopy were used for the characterization of inclusion complex. In addition, the binding pattern of eprosartan with the β-CD was investigated by molecular modeling study. Phase solubility study revealed that approximately 4.48 folds improvement in the solubility of drug was noted with β-CD (10 mM). The estimated stability constant (K c) values for eprosartan:β-CD binary mixture was found to be 280.78 M–1. The prepared inclusion complex of drug with β-CD presented better drug release profile (62.96 ± 2.01% in 1 h) as compared to their physical mixture (41.41 ± 1.77% in 1 h) or drug per se (29.97 ± 3.13%). The inclusion complex demonstrated different features and properties from pure drug, and we inferred that this could be due to the inclusion of drug into cyclodextrin cavity that confirmed by different analytical method. Molecular modeling study demonstrated a good affinity of eprosartan to entangle to β-CD. The outcomes have shown that guest molecule has many significant interactions with the host molecule. These observations are very interesting and may be a valuable approach to improve the solubility and in turn the bioavailability of eprosartan.

Probing Selective Adsorption in Cationic-Polymer Induced Aggregation of Binary Anionic Particulate Dispersions Using Solvent Relaxation NMR.

NMR solvent relaxation has been used to characterize the surfaces present in binary anionic particle dispersions, before and after exposure to a cationic polymer. In the polymer-free case, it is shown that the measured specific relaxation rate of the solvent is a population-weighted average of all surfaces present, enabling preferential adsorption to be explored. The addition of the oppositely charged polymer led to phase separation, which was accelerated by gentle centrifugation. The measured relaxation rates and the equilibrium particle concentrations indicate that the cationic hydroxyethylcellulose polymer (HEC LR) exhibited no significant preference for either latex or laponite in binary blends with silica, but a strong preference for TiO2. This study illustrates the versatility of solvent relaxation to probe surface area, surface type and dispersion composition in complex formulations.

RDIVpSGP motif of ASPP2 binds to 14-3-3 and enhances ASPP2/k18/14-3-3 ternary complex formulation to promote BRAF/MEK/ERK signal inhibited cell proliferation in hepatocellular carcinoma.

The Apoptosis Stimulating Protein of p53 2 (ASPP2) is a heterozygous insufficient tumor suppressor; however, its molecular mechanism(s) in tumor suppression is not completely understood. ASPP2 plays an essential role in cell growth, as shown by liver hepatocellular carcinoma (LIHC) RNA-seq assay using the Cancer Genome Atlas (TCGA) and High-Throughput-PCR assay using ASPP2 knockdown cells. These observations were further confirmed by in vivo and in vitro experiments. Mechanistically, N-terminus ASPP2 interacted with Keratin 18 (k18) in vivo and in vitro. Interestingly, the RDIVpSGP motif of ASPP2 associates with 14-3-3 and promotes ASPP2/k18/14-3-3 ternary-complex formation which promotes MEK/ERK signal activation by impairing 14-3-3 and BRAF association. Additionally, ASPP2-rAd injection promotes paclitaxel-suppressed tumor growth by suppressing cell proliferation in the BALB/c nude mice model. ASPP2 and k18 were preferentially downregulated in Hepatocellular Carcinoma (HCC), which predicted poor prognosis in HCC patients. Overall, these findings suggested that ASPP2 promoted BRAF/MEK/ERK signal activation by promoting the formation of an ASPP2/k18/14-3-3 ternary complex via the RDIVpSGP motif at the N terminus. Moreover, this study provides novel insights into the molecular mechanism of tumor suppression in HCC patients.

The replacement of helper lipids with charged alternatives in lipid nanoparticles facilitates targeted mRNA delivery to the spleen and lungs.

The broad clinical application of mRNA therapeutics has been hampered by a lack of delivery vehicles that induce protein expression in extrahepatic organs and tissues. Recently, it was shown that mRNA delivery to the spleen or lungs is possible upon the addition of a charged lipid to a standard four-component lipid nanoparticle formulation. This approach, while effective, further complicates an already complex drug formulation and has the potential to slow regulatory approval and adversely impact manufacturing processes. We were thus motivated to maintain a four-component nanoparticle system while achieving shifts in tropism. To that end, we replaced the standard helper lipid in lipidoid nanoparticles, DOPE, with one of eight alternatives. These lipids included the neutral lipids, DOPC, sphingomyelin, and ceramide; the anionic lipids, phosphatidylserine (PS), phosphatidylglycerol, and phosphatidic acid; and the cationic lipids, DOTAP and ethyl phosphatidylcholine. While neutral helper lipids maintained protein expression in the liver, anionic and cationic lipids shifted protein expression to the spleen and lungs, respectively. For example, replacing DOPE with DOTAP increased positive LNP surface charge at pH7 by 5-fold and altered the ratio of liver to lung protein expression from 36:1 to 1:56. Similarly, replacing DOPE with PS reduced positive charge by half and altered the ratio of liver to spleen protein expression from 8:1 to 1:3. Effects were consistent across ionizable lipidoid chemistries. Regarding mechanism, nanoparticles formulated with neutral and anionic helper lipids best transfected epithelial and immune cells, respectively. Further, the lung-tropic effect of DOTAP was linked to reduced immune cell infiltration of the lungs compared to neutral or anionic lipids. Together, these data show that intravenous non-hepatocellular mRNA delivery is readily achievable while maintaining a four-component formulation with modified helper lipid chemistry.

Severe Sporotrichosis Treated with Amphotericin B: A 20-Year Cohort Study in an Endemic Area of Zoonotic Transmission.

Although rare, disseminated sporotrichosis is increasing in several countries. Despite its limiting toxic potential, amphotericin B is the only intravenous antifungal available to treat severe sporotrichosis. We aimed to describe the effectiveness and safety of amphotericin B treatment for severe sporotrichosis. Clinical records of patients with disseminated sporotrichosis at a reference center were reviewed. This study included 73 patients. Most (53.4%) were men and non-white. HIV coinfection was the main comorbidity (52.1%). Most reported contact with cats (76.7%). Sporothrix brasiliensis was the causative species. Affected sites were skin (98.6%), osteoarticular system (64.4%), upper airway (42.5%), central nervous system (20.5%), eyes (12.3%), and lungs (8.2%). Median doses of amphotericin B used were 750 mg and 4500 mg for deoxycholate and lipid complex formulations, respectively. Amphotericin B discontinuation occurred in 20.5% due to adverse events, mainly azotemia. The outcomes included cure (52.1%), death due to sporotrichosis (21.9%), death due to other causes (9.6%), and loss to follow-up (8.2%). Survival analysis showed an association between cure and the absence of bone, upper airway, and central nervous system involvement. Amphotericin B is the first-choice treatment for disseminated sporotrichosis; however, the severity of systemic dissemination might predict its response. Favorable clinical results depend on prompt diagnosis, investigation of fungal dissemination, and early therapy initiation.

Film Forming Nanogels for Needle-Free Transdermal Vaccination.

Transcutaneous immunization (TCI) provides a valuable alternative approach to conventional vaccination because of the high accessibility and the exceptional immunological characteristics of the skin, but its application is limited by the low permeability of the stratum corneum. Although nanogels (NGs) have proven to enhance skin penetration of macromolecules with minimum damage, their use in TCI remains almost unexplored. In this context, this article evaluates the performance of novel film-forming NGs (FF-NGs) as TCI. This TCI platform consists of NGs with multilobular morphology that positively combines the properties of cross-linked poly(N-vinylcaprolactam), like thermoresponsiveness and the ability to load and release a cargo, with the film-forming capacity of low Tg lobes. FF-NGs and formed films are characterized at different levels. Formed films show to be able to uniformly load an antigenic protein and release it with a profile depending on the temperature and on their FF-NGs content. In vivo studies have demonstrated that FF-NGs promote the penetration of not only an antigenic protein, but also an adjuvant until the immunocompetent area of skin, generating an adjuvant-dependent specific immune response. Finally, this study provides a successful proof of concept that FF-NGs can be a powerful tool for the transcutaneous release of complex formulations.

Tea Tree (Melaleuca alternifolia (Maiden & Betche) Cheel) Oil an important medicinal essential oil

Melaleuca alternifolia (Maiden & Betche) Cheel oil (Tea Tree Oil, TTO) is an essential oil appropriate for medicinal and cosmetic usage. Tea tree oil is composed of complex formulation with more than 100 components; however, the most pharmaceutically active one is terpinen-4-ol. TTO can be implemented for decolonization of multi-resistant Staphylococcus aureus, anti-tumor therapy and antifungal activity based on different doses and exposure-duration proportionate with the targeted species. Antioxidant activity is related to α-terpinene, α-terpinolene and γ-terpinene. Hypersensitivity may occur as mild dermatitis or being aggravated to hepatitis and central nervous system reactions due to chronic or acute poisoning. Acne treatment prognosis shows significant improvement after TTO application proceeding by Propionibacterium acnes colony destruction. Plus, TTO usage psoriasis is also possible. Further investigations have premised TTO’s insecticidal effects performed by anticholinesterase activity. Destructive ability of the oil on Pityrosporum ovale is also indisputable and including TTO as the active ingredient has been highly beneficial for curing scalp dandruff. Expeditious antiviral activity is also considered as the promising characteristic suggested for this oil. Still, little information is available about feasibility of in vivo utilization.

Formulation and Characterization of Phytophospholipid Complex of Andrographis Paniculata Extract

Active constituents extracted from various parts of the plants have wide therapeutic potential for the treatment of diseases. Number of these compounds obtained elicits positive in vitro pharmacological effect; however poor in vivo absorption of polyphenolic compounds limited the widespread applicability. One of the novel strategies to improve the bioavailability and thereby oral absorption of these compounds is the use of phytophospholipid complexes. The present work is aimed to formulate and characterize phytophospholipid complex of methanolic extract of leaves of Andrographis paniculata by anti-solvent precipitation technique. Four different formulation batches (F1-F4) were prepared by combining the phospholipid and Andrographis paniculata leaves extract in different molar ratios. Formulated batches were characterized for particle size, polydispersity index, entrapment efficiency, FTIR, SEM, XRD, and in vitro drug release characteristic. On the basis of various experimental resulted the formulation batch (F4) with molar ratio of extract and phospholipids 1:2 was found to be stable giving highest drug loading and sustained drug release for prolonged period of time.

Absolute Quantitation of N-Nitrosamines by Coulometric Mass Spectrometry without Using Standards.

Carcinogenic N-nitrosamines were recently found in the sartan family of drugs and caused many drug recalls. Both of their detection and quantification are therefore important. Methods reported for N-nitrosamine quantitation rely on the use of standards and are just applicable to simple N-nitrosamines. There is an urgent need to quantify N-nitrosamines derived from drugs with a complicated structure that lack standards. To tackle the issue, this study describes a novel absolute quantitation strategy for N-nitrosamines using coulometric mass spectrometry (CMS) without standards. In our approach, N-nitrosamine is first converted into electrochemically active hydrazine via zinc reduction under acidic condition and the resulting hydrazine can then be easily quantified using CMS. To validate our method, six simple N-nitrosamines, N-nitrosodiethylamine (NDEA), N-nitroso-4-phenylpiperidine (NPhPIP), N-nitrosodiphenylamine (NDPhA), N-nitrosodibutylamine (NDBA), N-nitrosodipropylamine (NDPA), and N-nitrosopiperidine (NPIP), were chosen as test samples, and they all were quantified with excellent measurement accuracy (quantitation error ≤1.1%). Taking this one step further, as a demonstration of the method utility, a drug-like N-nitrosamine, (R)-N-(2-(6-chloro-5-methyl-1'-nitroso-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)propan-2-yl)acetamide (VII), was also synthesized and successfully quantified using our method at 15 ppb level in a complex formulation matrix, following solvent extraction, N-nitrosamine isolation, and reductive conversion. Because of the feature of requiring no standards, CMS provides a simple and powerful approach for N-nitrosamine absolute quantitation and has great potential for analysis of other drug impurities or metabolites.

Application of bioengineered elastin-like polypeptide-based system for targeted gene delivery in tumor cells

Successful gene delivery depends on the entry of negatively charged DNAs and oligonucleotides across the various barriers of the tumor cells and localization into the nucleus for its transcription and protein translation. Here, we have reported a thermal responsive self-assemble and highly biocompatible, targeted ELP-based gene delivery system. These systems consist of cell-penetrating peptides, Tat and single or multiple repeats of IL-4 receptor targeting peptide AP-1 along the backbone of ELP. Cell-penetrating peptides were introduced for nuclear localization of genes of interest, AP-1 for targeting IL-4R highly expressed tumor cells and ELP for stable condensation favoring protection of nucleic acids. The designed multidomain fusion ELPs referred to as Tat-ELP, Tat-A1E28 and Tat-A4V48 were employed to generate formulation with pEGFP-N1. Profound formulation of stable complexes occurred at different molar ratios owing to electrostatic interactions of positively charged amino acids in polymers with negatively charged nucleic acids. Among the complexes, Tat-A4V48 containing four copies of AP-1 showed maximum complexation with pEGFP-N1 in lower molar ratio. The polymer-pEGFP complexes were further analyzed for its transfection efficiency in different cancer cell lines. Both the targeted polymers, Tat-A4V48 and Tat-A1E28 upon transfection displayed significant EGFP-expression with low toxicity in different cancer cells. Therefore, both Tat-A4V48 and Tat-A1E28 can be considered as novel transfection system for successful gene delivery with therapeutic applications.

Combined Action of Hyper-Harmonized Hydroxylated Fullerene Water Complex and Hyperpolarized Light Leads to Melanoma Cell Reprogramming In Vitro.

(1) Background: Their unique structure and electron deficiency have brought fullerenes into the focus of research in many fields, including medicine. The hyper-harmonized hydroxylated fullerene water complex (3HFWC) formulation has solved the limitations of the poor solubility and bioavailability of fullerenes. To achieve better antitumor activity, 3HFWC was combined with short-term irradiation of cells with hyperpolarized light (HPL) generated by the application of a nanophotonic fullerene filter in a Bioptron® device. The benefits of HPL were confirmed in the microcirculation, wound healing and immunological function. (2) Methods: B16, B16-F10 and A375 melanoma cells were exposed to a wide spectrum of 3HFWC doses and to a single short-term HPL irradiation. (3) Results: Apart from the differences in the redox status and level of invasiveness, the effects of the treatments were quite similar. Decreased viability, morphological alteration, signs of melanocytic differentiation and cellular senescence were observed upon the successful internalization of the nanoquantum substance. (4) Conclusions: Overall, 3HFWC/HPL promoted melanoma cell reprogramming toward a normal phenotype.

IDF21-0121 NDMA Analytics in Metformin Products: Comparison of Methods and Pitfalls

Background: Since late 2019 concerns regarding trace levels of the N-nitrosamine NDMA in metformin-containing pharmaceuticals have been an issue, as they exceeded the maximum allowable intake of 96 ng/day for a medicine with long-term intake. This has resulted in thorough assessment of the safety of metformin products in this regard by manufactures worldwide. From the early focus on trace NDMA levels in drug substance, the scope of concern quickly expanded to drug products, associated excipients, and the potential for nitrosamine formation in packaging processes. As the scope expanded, the trace analysis challenge has grown. Metformin is made from the starting materials 2-cyanoguanidine and DMA, hence low residual amounts of DMA in the API are unavoidable. Inorganic nitrite is present in trace amounts in many excipients and can react with DMA to form the mutagenic N-nitrosamine NDMA, which needs to be measured in complex drug product formulations. The methods developed in the pharmaceutical industry are validated according to the applicable guidelines. Nevertheless, incorrect measurements can never be fully excluded. In food analysis, environmental analysis and in medical diagnostics, proficiency tests are a common tool to identify and eliminate systematic errors by comparing measurement results from individual laboratories. Aim: Here, we describe the outcome of an across-industry method comparison study for determination of NDMA in metformin-containing drug products between four labs, employing orthogonal mass spectroscopic methods, and discuss how it has helped to identify and mitigate artefactual results due to NDMA in-situ formation in the analytical process. Method: Proficiency testing employing orthogonal mass spectrometric methods was performed between four laboratories in three countries through analysis of different branded metformin-containing products. To exclude bias from sample inhomogeneity, fine powders of test tablets were prepared by one of the participating laboratories. To avoid bias from sample aging, experiments were performed contemporarily. Results: A risk of overestimating NDMA levels has been identified. Notably, special attention must be given to the sample preparation to prevent artefactual formation of NDMA in the extracted sample. Metformin medicines contain DMA in the ppm range, and nitrite in the ppb range, which react in the standard organic solvent DCM to form elevated levels of NDMA. This study has demonstrated that both removal of DMA and nitrite via solvent extraction, and “quenching” the reaction by addition of a nitrosation scavenger are effective remedies. Discussion: Without proper mitigation, NDMA in-situ formation causes overestimation of the NDMA content, which may in turn lead to an overestimation of affected batches and, ultimately, the risk to patients.

Characterization of Complex Drug Formulations Using Cryogenic Scanning Electron Microscopy (Cryo-SEM).

The physicochemical properties of complex drug formulations, including liposomes, suspensions, and emulsions, are important for understanding drug release mechanisms, quality control, and regulatory assessment. It is ideal to characterize these complex drug formulations in their native hydrated state. This article describes the characterization of complex drug formulations in a frozen-hydrated state using cryogenic scanning electron microscopy (cryo-SEM). In comparison to other techniques, such as optical microscopy or room-temperature scanning electron microscopy, cryo-SEM combines the advantage of studying hydrated samples with high-resolution imaging capability. Detailed information regarding cryo-fixation, cryo-fracture, freeze-etching, sputter-coating, and cryo-SEM imaging is included in this article. A multivesicular liposomal complex drug formulation is used to illustrate the impact of different cryogenic sample preparation conditions. In addition to drug formulations, this approach can also be applied to biological samples (e.g., cells, bacteria) and soft-matter samples (e.g., hydrogels). © Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Basic Protocol 1: Cryo-fixation to preserve the native structure of samples using planchettes Alternate Protocol: Cryo-fixation to preserve the native structure of biological samples on sapphire disks Basic Protocol 2: Sample preparation for cross-sectional cryo-SEM imaging Basic Protocol 3: Cryo-SEM imaging and microanalysis.

On the ambiguity of mechanical power

Introduction. Mechanical vibrations are widespread in the production processes. The drives of machines and mechanisms are mainly electromechanical, so mechanical reactive power is transformed into electrical reactive power of the network, impairing the quality of electricity. This explains the significance of considering the mechanical reactive power, and, as a consequence, the urgency of the presented study. The research objective is to detail the types of mechanical power under harmonic vibrations.Materials and Methods. The literature on the issues of dynamics, kinematics, vibrations, transformation of motion in oscillatory systems, etc., has been studied. Theoretical, mainly mathematical methods of research are used.Results. The powers developed under elastic deformations, forced harmonic vibrations of an inert body, and vibrations associated with gravitational influence, as well as reactive, active, full powers in the complex formulation, and mechanical powers in the vector representation are mathematically interpreted.Discussion and Conclusions. Under the mechanical harmonic vibrations, along with the sign-positive thermal power, sign-variable reactive powers develop, characterizing the reversibility of kinetic and potential energies. The total mechanical power satisfies the Pythagorean formula. The concept of mechanical reactive, active, and total powers generalizes the corresponding concepts of power from electrical engineering, and thus manifesting electromechanical dualism.

Formulation and Characterization of Stimuli-Responsive Lecithin-Based Liposome Complexes with Poly(acrylic acid)/Poly(N,N-dimethylaminoethyl methacrylate) and Pluronic® Copolymers for Controlled Drug Delivery.

Polymer–liposome complexes (PLCs) can be efficiently applied for the treatment and/or diagnosis of several types of diseases, such as cancerous, dermatological, neurological, ophthalmic and orthopedic. In this work, temperature-/pH-sensitive PLC-based systems for controlled release were developed and characterized. The selected hydrophilic polymeric setup consists of copolymers of Pluronic®-poly(acrylic acid) (PLU-PAA) and Pluronic®-poly(N,N-dimethylaminoethyl methacrylate) (PLU-PD) synthesized by atom transfer radical polymerization (ATRP). The copolymers were incorporated into liposomes formulated from soybean lecithin, with different copolymer/phospholipid ratios (2.5, 5 and 10%). PLCs were characterized by evaluating their particle size, polydispersity, surface charge, capacity of release and encapsulation efficiency. Their cytotoxic potential was assessed by determining the viability of human epithelial cells exposed to them. The results showed that the incorporation of the synthesized copolymers positively contributed to the stabilization of the liposomes. The main accomplishments of this work were the innovative synthesis of PLU-PD and PLU-PAA by ATRP, and the liposome stabilization by their incorporation. The formulated PLCs exhibited relevant characteristics, notably stimuli-responsive attributes upon slight changes in pH and/or temperature, with proven absence of cellular toxicity, which could be of interest for the treatment or diagnosis of all diseases that cause some particular pH/temperature change in the target area.

Topical bioequivalence: Experimental and regulatory considerations following formulation complexity

Documenting topical bioequivalence can be an extremely complex process, which is intrinsically dependent on the formulation technological features. According to EMA guideline, for simple formulations, BE may be demonstrated by documenting the qualitative (Q1), quantitative (Q2), microstructure (Q3) and performance (Q4) equivalence. Nevertheless, when addressing complex semisolids, equivalence regarding local availability should also be demonstrated. The purpose of this study is to pursue this strategy using two opposite scenarios: a simple dimetindene maleate 1 mg/g gel formulation and a diclofenac diethylammonium 23.2 mg/g emulgel, representing a complex formulation. For both formulations, Q1/Q2 test (TP) and reference products (RP) were used. Rheology, in vitro release (IVRT) and in vitro permeation methods (IVPT) were developed and validated for both products.For the dimetindene formulation, equivalence pertaining to Q4 was established. However, high variability was observed for some rheology endpoints, especially for the different RP batches. Therefore, equivalence could not be established for Q3 as per EMA requirements. Can some rheology endpoints be waived? Can we establish reasonable criteria that are overall feasible for generic manufacturers and at the same time safe for the patient? An attempt was made to propose a wider acceptance range based on the inter-batch variability of the RP. For that, the rationale presented in the EMA guideline on bioequivalence for highly variable products was used.For the diclofenac formulation, Q3 equivalence was likewise not established. Q4 equivalence was only found for some batch combinations and when applying a wider acceptance criterion (75–133%). Furthermore, IVPT equivalence also failed to be demonstrated. Nevertheless, since the TP displays an equivalent pharmacokinetic profile compared to the RP, the observed Q3, Q4 and local availability differences are not expected to be clinically significant. This study draws attention to an effective search to determine the most appropriate strategy for assessing topical bioequivalence on a case-by-case basis.