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International Journal of Molecular... Oct 2023The administration of therapeutic drugs through dermal routes, such as creams and ointments, has emerged as an increasingly popular alternative to traditional delivery...
The administration of therapeutic drugs through dermal routes, such as creams and ointments, has emerged as an increasingly popular alternative to traditional delivery methods, such as tablets and injections. In the context of drug development, it is crucial to identify the optimal doses and delivery routes that ensure successful outcomes. Physiologically based pharmacokinetic (PBPK) models have been proposed to simulate drug delivery and optimize drug formulations, but the calibration of these models is challenging due to the multitude of variables involved and limited experimental data. One significant research gap that this article addresses is the need for more efficient and accurate methods for calibrating PBPK models for dermal drug delivery. This manuscript presents a novel approach and an integrated dermal drug delivery model to address this gap that leverages virtual in vitro release (IVRT) and permeation (IVPT) testing data to optimize mechanistic models. The proposed approach was demonstrated through a study involving Desoximetasone cream and ointment formulations, where the release kinetics and permeation profiles of Desoximetasone were determined experimentally, and a computational model was created to simulate the results. The experimental studies showed that, even though the cumulative permeation of Desoximetasone at the end of the permeation study was comparable, there was a significant difference seen in the lag time in the permeation of Desoximetasone between the cream and ointment. Additionally, there was a significant difference seen in the amount of Desoximetasone permeated through human cadaver skin at early time points when the cream and ointment were compared. The computational model was optimized and validated, suggesting that this approach has the potential to bridge the existing research gap by improving the accuracy and efficiency of drug development processes. The model results show a good fit between the experimental data and model predictions. During the model optimization process, it became evident that there was variability in both the permeability and the partition coefficient within the stratum corneum. This variability had a significant and noteworthy influence on the overall performance of the model, especially when it came to its capacity to differentiate between cream and ointment formulations. Leveraging virtual models significantly aids the comprehension of drug release and permeation, mitigating the demanding data requirements. The use of virtual IVRT and IVPT data can accelerate the calibration of PBPK models, streamline the selection of the appropriate doses, and optimize drug delivery. Moreover, this novel approach could potentially reduce the time and resources involved in drug development, thus making it more cost-effective and efficient.
Topics: Humans; Ointments; Desoximetasone; Skin; Skin Absorption; Computer Simulation; Administration, Cutaneous
PubMed: 37894801
DOI: 10.3390/ijms242015118 -
Dermatology Online Journal Aug 2019Topical corticosteroids are available in many vehicles. However, patients' preference for vehicles are variable and could be tailored to maximize patient adherence.... (Review)
Review
BACKGROUND
Topical corticosteroids are available in many vehicles. However, patients' preference for vehicles are variable and could be tailored to maximize patient adherence. Spray vehicles may offer, convenience, and strong efficacy.
METHODS
A literature review was conducted using keywords: clobetasol, desoximetasone, betamethasone, triamcinolone, corticosteroid, topical, spray, vehicles, treatment, and clinical trial.
RESULTS
For moderate-to-severe plaque psoriasis, 87% of subjects achieved an Overall Disease Severity (ODS) Score ≤2 at week two and 78% achieved an ODS ≤1 after four weeks with clobetasol propionate (CP) 0.05% spray compared to 17% and 3% in the control group, respectively (P<0.001). For desoximetasone 0.25% spray, 31%-53% with moderate-to-severe psoriasis achieve Physician's Global Assessment (PGA) score ≤1 at day 28 versus 5%-18% in the vehicle spray group (P<0.01). For betamethasone dipropionate 0.05% spray, 19% with mild-to-moderate plaque psoriasis achieved an Investigator's Global Assessment (IGA) score ≤1 or a 2-grade reduction in IGA versus 2.3% in vehicle group (P≤0.001). For mild-to-severe steroid responsive inflammatory dermatoses, 64% using triamcinolone acetonide 0.2% spray achieved clear or almost clear skin at day 14 (no P value reported). Adverse events including burning, irritation, and dryness were similar across all corticosteroids.
Topics: Administration, Cutaneous; Aerosols; Dermatitis; Glucocorticoids; Humans; Inflammation; Medication Adherence; Patient Preference; Psoriasis
PubMed: 31553858
DOI: No ID Found -
Pharmaceutics Jul 2023(1) Background: Human keratinocytes and murine skin express various cytochrome P450 enzymes. These include cytochrome P450 3A4, which may participate in the metabolism...
(1) Background: Human keratinocytes and murine skin express various cytochrome P450 enzymes. These include cytochrome P450 3A4, which may participate in the metabolism of cytochrome P450 3A4 substrate drugs. Desoximetasone, a topical corticosteroid and cytochrome P450 3A4 substrate, is used to treat skin conditions such as skin allergies, atopic dermatitis, and psoriasis. In this study, we aimed to investigate the anti-psoriatic effect of a low dose of desoximetasone by inhibiting cytochrome P450 3A4 metabolism in the epidermis. (2) Methods: Psoriasis-like skin was induced in BALB/c mice via the topical administration of imiquimod. The mice were then topically treated with 0.01-0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient microemulsion, 0.25% commercial desoximetasone ointment, or 0.5 mg/gm clobetasol ointment. (3) Results: The topical application of 0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation restored the imiquimod-induced skin barrier disruption and resulted in fewer severe clinical and pathological features compared with the treatments with 0.25% commercial desoximetasone ointment and 0.5 mg/gm clobetasol ointment. (4) Conclusions: The cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation improved and prolonged the therapeutic effect of cytochrome P450 3A4 substrate drugs and may be a promising approach for psoriasis treatment.
PubMed: 37631230
DOI: 10.3390/pharmaceutics15082016 -
Turkish Journal of Pharmaceutical... Sep 2021Desoximetasone (DMS) is a widely recommended drug for the topical treatment of plaque psoriasis. However, low water solubility and short half life of DMS present major...
OBJECTIVES
Desoximetasone (DMS) is a widely recommended drug for the topical treatment of plaque psoriasis. However, low water solubility and short half life of DMS present major obstacles in the development of an effective topical formulation. Thus, there is a demand for the development of a safe and effective topical system to deliver hydrophobic DMS. The present study aimed to develop an -based emulgel formulation to ensure enhanced skin deposition of DMS for effective treatment of plaque psoriasis.
MATERIALS AND METHODS
Different formulations (DE1-DE4) of emulgel were prepared using dispersion technique, wherein varying concentrations of propylene glycol (6-14% w/w) and carbopol 934 (0.5-1.0% w/w) were used.
RESULTS
Zetasizer measurements revealed that the globule size of the formulations ranged from 10.34 µm±0.9 to 14.60 µm±1.4 (n=50). Extrudability analysis for the DE3 and DE2 formulations revealed an extrudability of 5.6±0.11 g/cm and 5.8±0.13 g/cm, respectively. The pH of the formulations was recorded in the range of 5.8-6.8. Among these formulations, DE3 showed a maximum drug content of 94.64%±0.29 (n=3), and thus was used for further evalutions. A texture analyzer showed that an optimized DE3 formulation was firmer and exhibited optimal spreadability in comparison with the DE2 formulation. For DE3, the mean max force that represented "firmness" was recorded to be 833.37 g, where as the mean area, denoting "work of shear", was 324.230 g.sec. The DE3 formulation exhibited DMS permeation of 95.40±1.6% over a period of 7 h, as detrmined using an in house fabricated Franze diffusion cell. Evaluation of release kinetics revealed that the release of DMS fitted into the Korsmeyer-Peppas model.
CONCLUSION
Physicochemical characteristics and enhanced permeation of DMS from emulgel highlight its suitability to be efficiently employed for the topical treatment of skin ailments.
PubMed: 34496553
DOI: 10.4274/tjps.galenos.2020.33239 -
International Journal of Molecular... Feb 2021Psoriasis is a chronic autoimmune skin disease impacting the population globally. Pharmaceutical products developed to combat this condition commonly used in clinical...
Psoriasis is a chronic autoimmune skin disease impacting the population globally. Pharmaceutical products developed to combat this condition commonly used in clinical settings are IV bolus or oral drug delivery routes. There are some major challenges for effectively developing new dosage forms for topical use: API physicochemical nature, the severity of the disease state, and low bioavailability present challenges for pharmaceutical product developers. For non-severe cases of psoriasis, topical drug delivery systems may be preferred or used in conjunction with oral or parenteral therapy to address local symptoms. Elastic vesicular systems, termed "niosomes", are promising drug delivery vehicles developed to achieve improved drug delivery into biological membranes. This study aimed to effectively incorporate a corticosteroid into the niosomes for improving the drug bioavailability of desoximetasone, used to treat skin conditions via topical delivery. Niosomes characterization measurements were drug content, pH, spreadability, specific gravity, content uniformity, rheology, and physicochemical properties. Formulations used a topical gelling agent, Carbomer 980 to test for in vitro skin permeation testing (IVPT) and accelerated stability studies. The developed niosomal test gel provided approximately 93.03 ± 0.23% to 101.84 ± 0.11% drug content with yield stresses ranging from 16.12 to 225.54 Pa. The permeated amount of desoximetasone from the niosomal gel after 24 h was 9.75 ± 0.44 µg/cm compared to 24.22 ± 4.29 µg/cm released from the reference gel tested. Furthermore, a drug retention study compared the test gel to a reference gel, demonstrating that the skin retained 30.88 ng/mg of desoximetasone while the reference product retained 26.01 ng/mg. A controlled drug release profile was obtained with a niosomal formulation containing desoximetasone for use in a topical gel formulation showing promise for potential use to treat skin diseases like psoriasis.
Topics: Administration, Cutaneous; Administration, Topical; Chemical Phenomena; Chemistry, Pharmaceutical; Desoximetasone; Dose-Response Relationship, Drug; Drug Carriers; Drug Delivery Systems; Drug Stability; Gels; Humans; Hydrogen-Ion Concentration; Kinetics; Nanostructures; Permeability; Skin; Skin Absorption; Surface-Active Agents; Viscosity
PubMed: 33546426
DOI: 10.3390/ijms22041535 -
The Journal of Clinical and Aesthetic... May 2018The goal of this study was to evaluate efficacy and safety of desoximetasone spray 0.25%, a topical corticosteroid, in the management of scalp and body psoriasis. This...
The goal of this study was to evaluate efficacy and safety of desoximetasone spray 0.25%, a topical corticosteroid, in the management of scalp and body psoriasis. This was an open-label, observational study. Twenty adults aged 18 years or older with chronic scalp psoriasis present on at least 30 percent of the scalp surface area and an Investigator Global Assessment (IGA) scale score of scalp disease of at least 2 on a scale of 0 to 4 were included in the study. Study spray was applied twice daily for four weeks, followed by 12 weeks of twice-daily application for two consecutive days weekly. At Week 4, the mean Physician Global Assessment (PGA) scale score had decreased 54.8 percent, from moderate disease to almost clear. Body surface area (BSA) had decreased by 51.2 percent, BSA × PGA had decreased by 63 percent, and scalp IGA had decreased by 64.5 percent from moderate to almost clear. Additionally, mean Psoriasis Scalp Severity Index (PSSI) score was 27.3±10.0 at baseline and decreased 82.4 percent to 4.8±5.2 and scalp surface area (SSA) was reduced by 70.7 percent at Week 4. The initial Scalp Index score was a mean of 65.7±15.0 at baseline and was reduced by 44.3 percent and 40.8 percent at Weeks 4 and 16, respectively. The initial response was maintained after a change to twice-weekly, twice-daily dosing, with a 48.4-percent decrease in PGA, a 17.1-percent decrease in BSA, a 31.5-percent decrease in BSA × PGA, a 51.6-percent decrease in scalp IGA, a 63.4 percent decrease in PSSI, and a 42.3-percent decrease in SSA seen at Week 16. Minimal adverse events were experienced by seven subjects. Desoximetasone spray 0.25% produced rapid improvements in PGA, BSA, BSA×PGA, scalp IGA, PSSI, SSA.
PubMed: 29785235
DOI: No ID Found -
Skin Pharmacology and Physiology 2008We report on a double-blind, vehicle-controlled, single-center confirmatory study with random assignment. The purpose of the study was to investigate the topical... (Comparative Study)
Comparative Study Randomized Controlled Trial
INTRODUCTION
We report on a double-blind, vehicle-controlled, single-center confirmatory study with random assignment. The purpose of the study was to investigate the topical bioavailability of different topical corticosteroid formulations in healthy human beings focussing on desoximetasone (DM).
MATERIALS AND METHODS
Two DM 0.25% formulations [ointment (DM-o) and fatty ointment (DM-fo, water-free); class III corticosteroids], the corresponding active ingredient-free vehicles and three comparators of different strength [clobetasol propionate 0.05% (CP 0.05%), fatty ointment, class IV; hydrocortisone (HC) 1%, fatty ointment, class I, and betamethasone (BM) 0.05%, fatty ointment, class III] were tested using the vasoconstriction assay. The degree of vasoconstriction (blanching) in the treatment field was compared to the one found in untreated control fields using chromametric measurements and clinical assessment.
RESULTS/CONCLUSION
DM-o 0.25%, DM-fo 0.25% and BM 0.05% showed similar vasoconstrictive potential, i.e., clear blanching. In fact, both DM preparations were proven to be noninferior to BM 0.05%, while CP 0.05% was found a little less active. HC 1.0% and the DM vehicles showed no clear-cut vasoconstrictive effect. No adverse events related to the study medications were observed. Good topical bioavailability of both DM formulations was detected by chromametric measurement and clinical assessment.
Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Betamethasone; Biological Availability; Clobetasol; Desoximetasone; Double-Blind Method; Female; Humans; Hydrocortisone; Male; Middle Aged; Pharmaceutical Vehicles; Skin; Skin Absorption; Vasoconstriction; Vasoconstrictor Agents
PubMed: 18523415
DOI: 10.1159/000131082 -
SAGE Open Medical Case Reports 2021The article description and significance to dermatologists: bleomycin flagellate dermatitis is a rare cutaneous manifestation, believed to be due to the lack of...
The article description and significance to dermatologists: bleomycin flagellate dermatitis is a rare cutaneous manifestation, believed to be due to the lack of bleomycin hydrolase enzyme in the skin, which inactivates bleomycin, resulting in its accumulation. This is thought to be a dose-dependent reaction, and doses over 200 U and higher may increase risk. This case describes a male developing a pruritic, erythematous linear flagellated dermatitis to the lower back after his third cycle of bleomycin, etoposide and cisplatin for a stage 3 seminoma. Pruritis resolved and erythema improved with the treatment of bilastine and desoximetasone cream. It is important to recognize this condition because untreated pruritis may lead to increased impairment of the skin barrier in already immunocompromised patient populations. This may also give further evidence to having ongoing and continuing collaboration between Dermatology and Medical Oncology for any patients presenting with a new rash undergoing chemotherapy treatments.
PubMed: 34484791
DOI: 10.1177/2050313X211039476 -
Experimental Cell Research Oct 2020SARS-CoV2, the agent responsible for the current pandemic, is also causing respiratory distress syndrome (RDS), hyperinflammation and high mortality. It is critical to...
BACKGROUND
SARS-CoV2, the agent responsible for the current pandemic, is also causing respiratory distress syndrome (RDS), hyperinflammation and high mortality. It is critical to dissect the pathogenetic mechanisms in order to reach a targeted therapeutic approach.
METHODS
In the present investigation, we evaluated the effects of SARS-CoV on human bronchial epithelial cells (HBEC). We used RNA-seq datasets available online for identifying SARS-CoV potential genes target on human bronchial epithelial cells. RNA expression levels and potential cellular gene pathways have been analyzed. In order to identify possible common strategies among the main pandemic viruses, such as SARS-CoV, SARS-CoV1, MERS-CoV, and H1N1, we carried out a hypergeometric test of the main genes transcribed in the cells of the respiratory tract exposed to these viruses.
RESULTS
The analysis showed that two mechanisms are highly regulated in HBEC: the innate immunity recruitment and the disassembly of cilia and cytoskeletal structure. The granulocyte colony-stimulating factor (CSF3) and dynein heavy chain 7, axonemal (DNAH7) represented respectively the most upregulated and downregulated genes belonging to the two mechanisms highlighted above. Furthermore, the carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM7) that codifies for a surface protein is highly specific of SARS-CoV and not for SARS-CoV1, MERS-CoV, and H1N1, suggesting a potential role in viral entry. In order to identify potential new drugs, using a machine learning approach, we highlighted Flunisolide, Thalidomide, Lenalidomide, Desoximetasone, xylazine, and salmeterol as potential drugs against SARS-CoV infection.
CONCLUSIONS
Overall, lung involvement and RDS could be generated by the activation and down regulation of diverse gene pathway involving respiratory cilia and muscle contraction, apoptotic phenomena, matrix destructuration, collagen deposition, neutrophil and macrophages recruitment.
Topics: Bronchi; COVID-19; Carcinoembryonic Antigen; Coronavirus Infections; Drug Discovery; Dyneins; GPI-Linked Proteins; Gene Regulatory Networks; Granulocyte Colony-Stimulating Factor; Humans; Immunity, Innate; Machine Learning; Pandemics; Pneumonia, Viral; Respiratory Mucosa; Transcriptome; Up-Regulation
PubMed: 32735892
DOI: 10.1016/j.yexcr.2020.112204