scholarly journals Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1110
Author(s):  
Kunal Jhunjhunwala ◽  
Charles W. Dobard ◽  
Sunita Sharma ◽  
Natalia Makarova ◽  
Angela Holder ◽  
...  
Keyword(s):  
Hiv Prevention ◽  
Antiretroviral Drugs ◽  
Water Soluble ◽  
Fixed Dose ◽  
Receptive Anal Intercourse ◽  
On Demand ◽  
Dose Combination ◽  
Rectal Suppositories

Receptive anal intercourse (RAI) contributes significantly to HIV acquisition underscoring the need to develop HIV prevention options for populations engaging in RAI practices. We explored the feasibility of formulating rectal suppositories with potent antiviral drugs for on-demand use. A fixed-dose combination of tenofovir (TFV) and elvitegravir (EVG) (40 mg each) was co-formulated in six different suppository bases (three fat- and three water-soluble). Fat-soluble witepsol H15 and water-soluble polyethylene glycol (PEG) based suppositories demonstrated favorable in vitro release and were advanced to assess in vivo pharmacokinetics following rectal administration in macaques. In vivo drug release profiles were similar for both suppository bases. Median concentrations of TFV and EVG detected in rectal fluids at 2 h were 1- and 2-logs higher than the in vitro IC50, respectively; TFV-diphosphate levels in rectal tissues met or exceeded those associated with high efficacy against rectal simian HIV (SHIV) exposure in macaques. Leveraging on these findings, a PEG-based suppository with a lower dose combination of tenofovir alafenamide (TAF) and EVG (8 mg each) was developed and found to achieve similar rectal drug exposures in macaques. This study establishes the utility of rectal suppositories as a promising on-demand strategy for HIV PrEP and supports their clinical development.

Postmarketing In Vitro/In Vivo Assessment of Fixed Dose Combination Products of First Line Antiretrovirals

2010 ◽  
Vol 99 (6) ◽  
pp. 2655-2663 ◽  
Author(s):  
A. Joshi ◽  
F. Esseku ◽  
L. Silva ◽  
C. Igwilo ◽  
D. Oqua ◽  
...  
Keyword(s):  
Fixed Dose Combination ◽  
Fixed Dose ◽  
First Line ◽  
Dose Combination ◽  
In Vivo Assessment

scholarly journals Bioavailability of the Common Cold Medicines in Jellies for Oral Administration

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1073
Author(s):  
Ki Hyun Kim ◽  
Minju Jun ◽  
Mi-Kyung Lee
Keyword(s):  
Oral Administration ◽  
Geometric Mean ◽  
Immediate Release ◽  
In Vitro Dissolution ◽  
Fixed Dose ◽  
Chlorpheniramine Maleate ◽  
Patient Centered ◽  
Dose Combination

Jellies for oral administration have been suggested as alternative dosage forms to conventional tablets for improved palatability and compliances for pediatric and geriatric patients. To evaluate the effect of jelly formulation on the bioavailability of cold medicines, two types of jellies were prepared for a fixed-dose combination of acetaminophen (AAP), chlorpheniramine maleate (CPM), dextromethorphan hydrobromide (DMH), and dl-methylephedrine hydrochloride (MEH). Jelly-S and Jelly-H were fabricated using carrageenan and locust bean gum in the absence and presence of xanthan gum, respectively. In vitro dissolution and in vivo absorption of the four drugs in the jellies were compared with other conventional formulations, a syrup and two types of immediate-release (IR) tablets with different hardness, Tablet-S (15 kPa) and Tablet-H (20 kPa). All the formulations exhibited more than 80% dissolution rate within 2 h even though the syrup, Jelly-S, and Tablet-S showed higher 30-min dissolution compared to Jelly-H and Tablet-H. The dissolution rates from the jellies decreased with increasing pH, which resulted in the slowest dissolution in pH 6.8 compared to the syrup and IR tablets. When administered orally to beagle dogs, all five formulations were determined not to be bioequivalent. However, Jelly-S and Jelly-H showed 0.82–1.05 of the geometric mean ratios (GMRs) of AUC0-t for all four drugs compared to the syrup suggesting comparable absorption. In two IR tablets, GMRs of AUC0-t were in a range of 0.55–0.95 indicating a tendency of lower absorption than the syrup and jellies. In conclusion, jelly can be a patient-centered formulation with comparable bioavailability to syrup.

scholarly journals A Survey of the Regulatory Requirements for BCS-Based Biowaivers for Solid Oral Dosage Forms by Participating Regulators and Organisations of the International Generic Drug Regulators Programme

2018 ◽  
Vol 21 (1) ◽  
pp. 27 ◽  
Author(s):  
Joy Elizabeth Van Oudtshoorn ◽  
Alfredo García-Arieta ◽  
Gustavo Mendes Lima Santos ◽  
Christopher Crane ◽  
Clare Rodrigues ◽  
...  
Keyword(s):  
Generic Drug ◽  
Oral Dosage ◽  
Fixed Dose ◽  
Scientific Model ◽  
Regulatory Requirements ◽  
Regulatory Guidance ◽  
Dose Combination ◽  
Oral Dosage Forms

Purpose:  The Biopharmaceutics Classification System (BCS) based biowaiver is a scientific model which enables the substitution of in vivo bioequivalence studies with in vitro data as evidence of therapeutic equivalence subject to certain conditions. Despite being based on the same principles, BCS-based biowaivers are interpreted and regulated differently among international regulatory agencies. In this survey, the Bioequivalence Working Group (BEWG) of the International Generic Drug Regulators Programme (IGDRP) compared the criteria for BCS-based biowaivers applied by the participating regulators and organisations. Methods:  Differences and similarities regarding solubility, permeability, dissolution, excipients and fixed-dose combination products, were identified and compared in a detailed survey of each participant’s criteria for BCS-based biowaivers. These criteria were determined based upon the participants’ respective regulatory guidance documents, policies and practices. Results: This review has, with the exception of two participants who do not accept BCS-based biowaivers, revealed that most IGDRP participants interpret the BCS principles and conditions similarly but notable differences exist in the application of these principles.  Conclusion: Although many similarities exist, this review identifies several opportunities for greater convergence of regulatory requirements amongst the surveyed jurisdictions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page

Multi-kinetics and site-specific release of gabapentin and flurbiprofen from oral fixed-dose combination: in vitro release and in vivo food effect

2017 ◽  
Vol 262 ◽  
pp. 296-304 ◽  
Author(s):  
Fabio Sonvico ◽  
Chiara Conti ◽  
Gaia Colombo ◽  
Francesca Buttini ◽  
Paolo Colombo ◽  
...  
Keyword(s):  
Food Effect ◽  
In Vitro Release ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Site Specific ◽  
Dose Combination ◽  
Vitro Release

Fenofibrate Solid Dispersion for Improving Oral Bioavailability: Preparation, and Characterization and in vivo Evaluation

2020 ◽  
Vol 13 (5) ◽  
pp. 5102-5109
Author(s):  
Venu Madhav K ◽  
Somnath De ◽  
Chandra Shekar Bonagiri ◽  
Sridhar Babu Gummadi
Keyword(s):  
Oral Bioavailability ◽  
Oral Delivery ◽  
Solid Dispersions ◽  
In Vitro Release ◽  
Aqueous Solubility ◽  
Water Soluble ◽  
Scanning Calorimetry ◽  
In Vivo Evaluation

Fenofibrate (FN) is used in the treatment of hypercholesterolemia. It shows poor dissolution and poor oral bioavailability after oral administration due to high liphophilicity and low aqueous solubility. Hence, solid dispersions (SDs) of FN (FN-SDs) were develop that might enhance the dissolution and subsequently oral bioavailability. FN-SDs were prepared by solvent casting method using different carriers (PEG 4000, PEG 6000, β cyclodextrin and HP β cyclodextrin) in different proportions (0.25%, 0.5%, 0.75% and 1% w/v). FN-SDs were evaluated solubility, assay and in vitro release studies for the optimization of SD formulation. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) analysis was performed for crystalline and morphology analysis, respectively. Further, optimized FN-SD formulation evaluated for pharmacokinetic performance in Wistar rats, in vivo in comparison with FN suspension.  From the results, FN-SD3 and FN-SD6 have showed 102.9 ±1.3% and 105.5±3.1% drug release, respectively in 2 h. DSC and PXRD studies revealed that conversion of crystalline to amorphous nature of FN from FT-SD formulation. SEM studies revealed the change in the orientation of FN when incorporated in SDs. The oral bioavailability FN-SD3 and FN-SD6 formulations exhibited 2.5-folds and 3.1-folds improvement when compared to FN suspension as control. Overall, SD of FN could be considered as an alternative dosage form for the enhancement of oral delivery of poorly water-soluble FN.

Chemosensitizing Activity of Histone Deacetylases Inhibitory Cyclic Hydroxamic Acids for Combination Chemotherapy of Lymphatic Leukemia

2018 ◽  
Vol 18 (4) ◽  
pp. 365-371 ◽  
Author(s):  
Denis V. Mishchenko ◽  
Margarita E. Neganova ◽  
Elena N. Klimanova ◽  
Tatyana E. Sashenkova ◽  
Sergey G. Klochkov ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Acute Toxicity ◽  
Histone Deacetylases ◽  
Hydroxamic Acids ◽  
Water Soluble ◽  
Male Rat ◽  
Hybrid Male ◽  
Cyclic Hydroxamic Acids

Background: Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis. Objective: The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents. Method: Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study. Results: Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine < Alanine < Valine < Leucine < Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a-e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro-tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg. Conclusion: It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c.

scholarly journals Reductions of copper ion-mediated low-density lipoprotein (LDL) oxidations of trypsin inhibitors, the sweet potato root major proteins, and LDL binding capacities

2020 ◽  
Vol 61 (1) ◽  
Author(s):  
Yeh-Lin Lu ◽  
Chia-Jung Lee ◽  
Shyr-Yi Lin ◽  
Wen-Chi Hou
Keyword(s):  
Sweet Potato ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Trypsin Inhibitors ◽  
Water Soluble ◽  
Affinity Column ◽  
Low Density ◽  
Native Page

Abstract Background The root major proteins of sweet potato trypsin inhibitors (SPTIs) or named sporamin, estimated for 60 to 80% water-soluble proteins, exhibited many biological activities. The human low-density lipoprotein (LDL) showed to form in vivo complex with endogenous oxidized alpha-1-antitrypsin. Little is known concerning the interactions between SPTIs and LDL in vitro. Results The thiobarbituric-acid-reactive-substance (TBARS) assays were used to monitor 0.1 mM Cu2+-mediated low-density lipoprotein (LDL) oxidations during 24-h reactions with or without SPTIs additions. The protein stains in native PAGE gels were used to identify the bindings between native or reduced forms of SPTIs or soybean TIs and LDL, or oxidized LDL (oxLDL). It was found that the SPTIs additions showed to reduce LDL oxidations in the first 6-h and then gradually decreased the capacities of anti-LDL oxidations. The protein stains in native PAGE gels showed more intense LDL bands in the presence of SPTIs, and 0.5-h and 1-h reached the highest one. The SPTIs also bound to the oxLDL, and low pH condition (pH 2.0) might break the interactions revealed by HPLC. The LDL or oxLDL adsorbed onto self-prepared SPTIs-affinity column and some components were eluted by 0.2 M KCl (pH 2.0). The native or reduced SPTIs or soybean TIs showed different binding capacities toward LDL and oxLDL in vitro. Conclusion The SPTIs might be useful in developing functional foods as antioxidant and nutrient supplements, and the physiological roles of SPTIs-LDL and SPTIs-oxLDL complex in vivo will investigate further using animal models.

scholarly journals Activity of Indenoisoquinolines against African Trypanosomes

2008 ◽  
Vol 53 (1) ◽  
pp. 123-128 ◽  
Author(s):  
Rahul P. Bakshi ◽  
Dongpei Sang ◽  
Andrew Morrell ◽  
Mark Cushman ◽  
Theresa A. Shapiro
Keyword(s):  
Anticancer Agents ◽  
Mammalian Cells ◽  
Sleeping Sickness ◽  
Water Soluble ◽  
African Trypanosomes ◽  
In Vivo Experiments ◽  
Topoisomerase Ib ◽  
Topoisomerase Poisons

ABSTRACT African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill T. brucei. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.

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