Improved Safety and Anti-Glioblastoma Efficacy of CAT3-Encapsulated SMEDDS through Metabolism Modification

13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma. 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403) is the active in vivo lipase degradation metabolite of CAT3. Both CAT3 and PF403 can penetrate the blood–brain barrier to cause an anti-glioma effect. However, PF403, which is produced in the gastrointestinal tract and plasma, causes significant gastrointestinal side effects, limiting the clinical application of CAT3. The objective of this paper was to propose a metabolism modification for CAT3 using a self-microemulsifying drug delivery system (SMEDDS), in order to reduce the generation of PF403 in the gastrointestinal tract and plasma, as well as increase the bioavailability of CAT3 in vivo and the amount of anti-tumor substances in the brain. Thus, a CAT3-loaded self-microemulsifying drug delivery system (CAT3-SMEDDS) was prepared, and its physicochemical characterization was systematically carried out. Next, the pharmacokinetic parameters of CAT3 and its metabolite in the rats’ plasma and brain were measured. Furthermore, the in vivo anti-glioma effects and safety of CAT3-SMEDDS were evaluated. Finally, Caco-2 cell uptake, MDCK monolayer cellular transfer, and the intestinal lymphatic transport mechanisms of SMEDDS were investigated in vitro and in vivo. Results show that CAT3-SMEDDS was able to form nanoemulsion droplets in artificial gastrointestinal fluid within 1 min, displaying an ideal particle size (15–30 nm), positive charge (5–9 mV), and controlled release behavior. CAT3-SMEDDS increased the membrane permeability of CAT3 by 3.9-fold and promoted intestinal lymphatic transport. Hence, the bioavailability of CAT3 was increased 79% and the level of its metabolite, PF403, was decreased to 49%. Moreover, the concentrations of CAT3 and PF403 were increased 2–6-fold and 1.3–7.2-fold, respectively, in the brain. Therefore, the anti-glioma effect in the orthotopic models was improved with CAT3-SMEDDS compared with CAT3 in 21 days. Additionally, CAT3-SMEDDS reduced the gastrointestinal side effects of CAT3, such as severe diarrhea, necrosis, and edema, and observed less inflammatory cell infiltration in the gastrointestinal tract, compared with the bare CAT3. Our work reveals that, through the metabolism modification effect, SMEDDS can improve the bioavailability of CAT3 and reduce the generation of PF403 in the gastrointestinal tract and plasma. Therefore, it has the potential to increase the anti-glioma effect and reduce the gastrointestinal side effects of CAT3 simultaneously.

Download Full-text

Enhanced Dissolution and Oral Bioavailability of Cyclosporine A: Microspheres Based on αβ-Cyclodextrins Polymers

Pharmaceutics ◽

10.3390/pharmaceutics10040285 ◽

2018 ◽

Vol 10 (4) ◽

pp. 285 ◽

Cited By ~ 2

Author(s):

Malika Lahiani-Skiba ◽

Francois Hallouard ◽

Frederic Bounoure ◽

Nicolas Milon ◽

Youness Karrout ◽

...

Keyword(s):

Drug Delivery ◽

Secondary Structure ◽

Oral Administration ◽

Drug Delivery System ◽

Delivery System ◽

Cyclosporine A ◽

Polymer Mixture ◽

Pharmacokinetic Parameters

Cyclosporine (CsA) has a selective property of suppressing various T-lymphocyte functions. This is of utmost importance in preventing allograft rejection by several organ transplantations, as well as in the treatment of systemic and local autoimmune disorders. However, the poor water solubility of CsA can be a major hurdle for its absorption into the blood stream, which leads to low bioavailability and thus less efficacy. The aim of this study was to prepare, characterize, and evaluate in vitro as well as in vivo, the potential of the innovative CsA drug delivery system. The latter contains CsA in spherical amorphous solid dispersion (SASD) which is embedded in an original α-cyclodextrin and β-cyclodextrin polymer mixture (Poly-αβ-CD) as a multifunctional amorphous carrier. The new developed SASD formulation showed that CsA was molecularly dispersed in αβ-cyclodextrins in an amorphous form, as was confirmed by physicochemical characterization studies. Interestingly, the peptide secondary structure, and thus, the drug activity was not impacted by the preparation of SASD as was shown by circular dichroism. Furthermore, the in vitro CsA release profile kinetics was almost identical to the commercially available product Neoral®. This study presents the first in vivo proof-of-concept for a novel drug delivery system based on Poly-αβ-CD containing CsA, with SASD allowing for increased bioavailibility. The pharmacokinetic parameters of cyclosporine A from the spherical spray-dried dispersion formulation was demonstrated in a “rat” animal model. For comparison, the commercially available Neoral® was studied. Importantly, the pharmacokinetic parameters were improved by extending Tmax from 2 to 3 h after the oral administration in rats, and eventually preventing the enterohepatic circulation. All these results clearly demonstrate the improved pharmacokinetic parameters and enhanced bioavailability of CsA in the new developed drug delivery system. These data demonstrated the superiority of the newly developed Poly-αβ-CD formulation for oral administration of the poorly soluble CsA in vivo without altering its secondary structure. Poly-αβ-CD can be a very useful tool for the oral administration of poorly water-soluble drugs.

Download Full-text

Anti-Inflammatory Effect of Very High Dose Local Vessel Wall Statin Administration: Poly(L,L-Lactide) Biodegradable Microspheres with Simvastatin for Drug Delivery System (DDS)

International Journal of Molecular Sciences ◽

10.3390/ijms22147486 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7486

Author(s):

Piotr Wacinski ◽

Mariusz Gadzinowski ◽

Wojciech Dabrowski ◽

Justyna Szumilo ◽

Jakub Wacinski ◽

...

Keyword(s):

Drug Delivery ◽

Side Effects ◽

Drug Delivery System ◽

Delivery System ◽

Vessel Wall ◽

Systemic Side Effects ◽

Anti Inflammatory ◽

Inflammatory Effect

Atherosclerosis involves an ongoing inflammatory response of the vascular endothelium and vessel wall of the aorta and vein. The pleiotropic effects of statins have been well described in many in vitro and in vivo studies, but these effects are difficult to achieve in clinical practice due to the low bioavailability of statins and their first-pass metabolism in the liver. The aim of this study was to test a vessel wall local drug delivery system (DDS) using PLA microstructures loaded with simvastatin. Wistar rats were fed high cholesterol chow as a model. The rat vessels were chemically injured by repeated injections of perivascular paclitaxel and 5-fluorouracil. The vessels were then cultured and treated by the injection of several concentrations of poly(L,L-lactide) microparticles loaded with the high local HMG-CoA inhibitor simvastatin (0.58 mg/kg) concentration (SVPLA). Histopathological examinations of the harvested vessels and vital organs after 24 h, 7 days and 4 weeks were performed. Microcirculation in mice as an additional test was performed to demonstrate the safety of this approach. A single dose of SVPLA microspheres with an average diameter of 6.4 μm and a drug concentration equal to 8.1% of particles limited the inflammatory reaction of the endothelium and vessel wall and had no influence on microcirculation in vivo or in vitro. A potent pleiotropic (anti-inflammatory) effect of simvastatin after local SVPLA administration was observed. Moreover, significant concentrations of free simvastatin were observed in the vessel wall (compared to the maximum serum level). In addition, it appeared that simvastatin, once locally administered as SVPLA particles, exerted potent pleiotropic effects on chemically injured vessels and presented anti-inflammatory action. Presumably, this effect was due to the high local concentrations of simvastatin. No local or systemic side effects were observed. This approach could be useful for local simvastatin DDSs when high, local drug concentrations are difficult to obtain, or systemic side effects are present.

Download Full-text

Glucan particles as anti-inflammatory agent and drug delivery system for natural compounds in experimentally induced intestinal inflammation in vivo

10.1055/s-0037-1608375 ◽

2017 ◽

Author(s):

D Rotrekl ◽

Z Vochyánová ◽

L Paráková ◽

I Saloň ◽

P Šalamúnová ◽

...

Keyword(s):

Drug Delivery ◽

Drug Delivery System ◽

Delivery System ◽

Intestinal Inflammation ◽

Natural Compounds ◽

Inflammatory Agent ◽

Anti Inflammatory ◽

Experimentally Induced

Download Full-text

Development and Evaluation of Floating Pulsatile Drug Delivery System Using Meloxicam

International Journal of Drug Delivery Technology ◽

10.25258/ijddt.v7i04.10647 ◽

2017 ◽

Vol 7 (04) ◽

Author(s):

ShirishaG. Suddala ◽

S. K. Sahoo ◽

M. R. Yamsani

Keyword(s):

Rheumatoid Arthritis ◽

Drug Delivery ◽

Drug Release ◽

Drug Delivery System ◽

Delivery System ◽

Lag Time ◽

Oral Dosage ◽

Lag Phase ◽

Pulsatile Drug Delivery

Objective: The objective of this research work was to develop and evaluate the floating– pulsatile drug delivery system (FPDDS) of meloxicam intended for Chrono pharmacotherapy of rheumatoid arthritis. Methods: The system consisting of drug containing core, coated with hydrophilic erodible polymer, which is responsible for a lag phase for pulsatile release, top cover buoyant layer was prepared with HPMC K4M and sodium bicarbonate, provides buoyancy to increase retention of the oral dosage form in the stomach. Meloxicam is a COX-2 inhibitor used to treat joint diseases such as osteoarthritis and rheumatoid arthritis. For rheumatoid arthritis Chrono pharmacotherapy has been recommended to ensure that the highest blood levels of the drug coincide with peak pain and stiffness. Result and discussion: The prepared tablets were characterized and found to exhibit satisfactory physico-chemical characteristics. Hence, the main objective of present work is to formulate FPDDS of meloxicam in order to achieve drug release after pre-determined lag phase. Developed formulations were evaluated for in vitro drug release studies, water uptake and erosion studies, floating behaviour and in vivo radiology studies. Results showed that a certain lag time before drug release which was due to the erosion of the hydrophilic erodible polymer. The lag time clearly depends on the type and amount of hydrophilic polymer which was applied on the inner cores. Floating time and floating lag time was controlled by quantity and composition of buoyant layer. In vivo radiology studies point out the capability of the system of longer residence time of the tablets in the gastric region and releasing the drug after a programmed lag time. Conclusion: The optimized formulation of the developed system provided a lag phase while showing the gastroretension followed by pulsatile drug release that would be beneficial for chronotherapy of rheumatoid arthritis and osteoarthritis.

Download Full-text

Design and In Vivo Characterization of Novel Pulsatile Drug Delivery System of Biguanide Anti-Diabetic

International Journal of Pharmaceutical Research ◽

10.31838/ijpr/2020.12.02.0058 ◽

2020 ◽

Vol 12 (02) ◽

Keyword(s):

Drug Delivery ◽

Drug Delivery System ◽

Delivery System ◽

Pulsatile Drug Delivery ◽

In Vivo Characterization

Download Full-text

Management of Glioblastoma Multiforme by Phytochemicals: Applications of Nanoparticle Based Targeted Drug Delivery System

Current Drug Targets ◽

10.2174/1389450121666200727115454 ◽

2020 ◽

Vol 21 ◽

Author(s):

Sayed Md Mumtaz ◽

Gautam Bhardwaj ◽

Shikha Goswami ◽

Rajiv Kumar Tonk ◽

Ramesh K. Goyal ◽

...

Keyword(s):

Drug Delivery ◽

Glioblastoma Multiforme ◽

Drug Delivery System ◽

Delivery System ◽

Genetic Disorder ◽

Drug Regimen ◽

Brain Regions ◽

Radio Therapy ◽

Novel Drug ◽

The Brain

: The Glioblastoma Multiforme (GBM; grade IV astrocytoma) exhort tumor of star-shaped glial cell in the brain. It is a fast-growing tumor that spreads to nearby brain regions specifically to cerebral hemispheres in frontal and temporal lobes. The etiology of GBM is unknown, but major risk factors are genetic disorder like neurofibromatosis and schwanomatosis which develop the tumor in the nervous system. The management of GBM with chemo-radio therapy leads to resistance and current drug regimen like Temozolomide (TMZ) is less efficacious. The reasons behind failure of drugs are due to DNA alkylation in cell cycle by enzyme DNA guanidase and mitochondrial dysfunction. Naturally occurring bio-active compounds from plants known as phytochemicals, serve as vital sources for anti-cancer drugs. Some typical examples include taxol analogs, vinca alkaloids such as vincristine, vinblastine, podophyllotoxin analogs, camptothecin, curcumin, aloe emodin, quercetin, berberine e.t.c. These phytochemicals often act via regulating molecular pathways which are implicated in growth and progression of cancers. However the challenges posed by the presence of BBB/BBTB to restrict passage of these phytochemicals, culminates in their low bioavailability and relative toxicity. In this review we integrated nanotech as novel drug delivery system to deliver phytochemicals from traditional medicine to the specific site within the brain for the management of GBM.

Download Full-text

Formulation, Characterization and In Vivo Evaluation of Self-Nanoemulsifying Drug Delivery System for Oral Delivery of Valsartan

Current Nanoscience ◽

10.2174/15734137113096660107 ◽

2014 ◽

Vol 10 (2) ◽

pp. 263-270 ◽

Cited By ~ 3

Author(s):

Maulick Chopra ◽

Usha Y. Nayak ◽

Aravind Kumar Gurram ◽

M. Sreenivasa Reddy ◽

K.B. Koteshwara

Keyword(s):

Drug Delivery ◽

Drug Delivery System ◽

Delivery System ◽

Oral Delivery ◽

In Vivo Evaluation

Download Full-text

A Conceptual Analysis of solid Self-emulsifying drug Delivery System and its Associate Patents for the Treatment of Cancer

Recent Patents on Nanotechnology ◽

10.2174/1872210514666200909155516 ◽

2020 ◽

Vol 14 ◽

Author(s):

Neeraj Singh ◽

Shweta Rai ◽

Sankha Bhattacharya

Keyword(s):

Drug Delivery ◽

Gastrointestinal Tract ◽

Drug Delivery System ◽

Delivery System ◽

Ternary Phase Diagram ◽

Review Article ◽

New Drugs ◽

Systemic Absorption ◽

Hydrophobic Drugs ◽

Drug Bioavailability

Background: About two-third of new drugs reveal low solubility in water due to that; it becomes difficult for formulation scientists to develop oral solid dosage forms with a pharmaceutically acceptable range of therapeutic activity. In such cases, S-SMEEDS are the best carrier used universally for the delivery of hydrophobic drugs. SEDDS were also used, but due to its limitations, S-SMEDDS used widely. These are the isotropic mixtures of oils, co-solvents, and surfactants. S-SMEDDS are physically stable, easy to manufacture, easy to fill in gelatin capsules as well as improves the drug bioavailability by releasing the drug in the emulsion form to the gastrointestinal tract and make smooth absorption of the drug through the intestinal lymphatic pathway. Methods: We took on the various literature search related to our review, including the peer-reviewed research, and provided a conceptual framework to that. Standard tools are used for making the figures of the paper, and various search engines are used for the literature exploration.In this review article the author discussed the importance of S-SMEDDS, selection criteria for excipients, pseudo-ternary diagram, mechanism of action of S-SMEDDS, solidification techniques used for S-SMEDDS, Characterization of SEDDS and S-SMEDDS including Stability Evaluation of both and future prospect concluded through recent findings on S-SMEDDS on Cancer as well as a neoteric patent on S-SMEDDS Results: Many research papers discussed in this review article, from which it was found that the ternary phase diagram is the most crucial part of developing the SMEDDS. From the various research findings, it was found that the excipient selection is the essential step which decides the strong therapeutic effect of the formulation. The significant outcome related to solid-SMEDDS is less the globule size, higher would be the bioavailability. The adsorption of a solid carrier method is the most widely used method for the preparation of solid-SMEDDS. After review of many patents, it is observed that the solid-SMEDDS have a strong potential for targeting and treatment of a different type of Cancer due to their property to enhance permeation and increased bioavailability. Conclusion: S-SMEEDS are more acceptable pharmaceutically as compare to SEDDS due to various advantages over SEDDS viz stability issue is prevalent with SEDDS. A number of researchers had formulated S-SMEDDS of poorly soluble drugs and founded S-SMEDDS as prospective for the delivery of hydrophobic drugs for the treatment of Cancer. S-SMEEDS are grabbing attention, and the patentability on S-SMEDDS is unavoidable, these prove that S-SMEEDS are widely accepted carriers. These are used universally for the delivery of the hydrophilic drugs and anticancer drugs as it releases the drug to the gastrointestinal tract and enhances the systemic absorption. Abstract: Majority of active pharmaceutical ingredients (API) shows poor aqueous solubility, due to that drug delivery of the API to the systemic circulation becomes difficult as it has low bioavailability. The bioavailability of the hydrophobic drugs can be improved by the Self-emulsifying drug delivery system (SEDDS) but due to its various limitations, solid self-micro emulsifying drug delivery systems (S-SMEDDS) are used due to its advantages over SEDDS. S-SMEDDS plays a vital role in improving the low bioavailability of poorly aqueous soluble drugs. Hydrophobic drugs can be easily loaded in these systems and release the drug to the gastrointestinal tract in the form of fine emulsion results to In-situ solubilisation of the drug. In this review article the author's gives an overview of the solid SMEDSS along with the solidification techniques and an update on recent research and patents filled for Solid SMEDDS.

Download Full-text