In situ forming nimodipine depot system based on microparticles for the treatment of posthemorrhagic cerebral vasospasm

Bege, Nadja; Renette, Thomas; Endres, Thomas; Beck-Broichsitter, Moritz; Hänggi, Daniel; Kissel, Thomas

doi:10.1016/j.ejpb.2012.12.016

Cited by 32 publications

(20 citation statements)

References 26 publications

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“…In order to evaluate the influence of the polymer on the performance of the semisolid formulation, non-polymeric particles (SNP) were also prepared and work SEM images with a 5,000 fold magnification were used and more than 300 particles were counted. This method has been employed for size analysis of powders, including those obtained by vibrational spray-drying [24,28,40,41].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to traditional spray-drying, in which very small particles (< 2 µm) are lost during the drying process, this new equipment allows collecting particles in the submicron scale [22,23]. Vibrational atomization spray-drying has been studied to produce polymeric or nonpolymeric particles with a range from 300 nm to 5 μm intended for several pharmaceutical applications, including cerebral [24], oral [25], ophthalmic [26] and pulmonary administration [27][28][29].…”

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confidence: 99%

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Submicron polymeric particles prepared by vibrational spray-drying: Semisolid formulation and skin penetration/permeation studies

Beber¹,

Andrade²,

Kann³

et al. 2014

European Journal of Pharmaceutics and Biopharmaceutics

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Topical glucocorticoids (TG) such as dexamethasone (DEX) have been used for decades for the treatment of skin diseases. However, TG present welldocumented side effects and their delivery to the skin is often insufficient.Therefore, many efforts have been undergone to improve the amount of drug delivered to the skin and to reduce side effects at the same time. In this work, the feasibility of DEX-submicron polymeric particles (SP) prepared by vibrational spray-drying as an approach to overcome the challenges associated with the topical administration of this drug class was evaluated. DEX was homogeneously dispersed in the SP matrix, according to confocal Raman microscopy analysis. Drug-loaded SP were incorporated into the oil phase of oil-in-water emulsions (creams). The formulation containing polymeric submicron particles (C-SP) showed controlled drug release kinetics and a significant drug accumulation in skin compared to formulations containing nonpolymeric particles or free drug. DEX accumulation in the stratum corneum was evaluated by tape stripping and a depot effect over time was observed for C-SP, while the formulation containing the free drug showed a decrease over time.Similarly, C-SP presented higher drug retention in epidermis and dermis in skin penetration studies performed on pig skin in Franz diffusion cells, while drug permeation into the receptor compartment was negligible. It was demonstrated, for the first time, the advantageous application of submicron polymeric particles obtained by vibrational spray-drying in semisolid formulations for cutaneous administration to overcome challenges related to the therapy with TG such as DEX.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Submicron polymeric particles prepared by vibrational spray-drying: Semisolid formulation and skin penetration/permeation studies

Beber¹,

Andrade²,

Kann³

et al. 2014

European Journal of Pharmaceutics and Biopharmaceutics

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“…For these reasons, the use of a carrier that would improve the solubility of NM in body fluids and enhance drug delivery, seems much promising. In the recent decades, nanospheres [8-12, 15, 16, 18] or microspheres [11,13,14,17] were widely used as drug carriers. A few reports have been published on the use of liquid and solid microemulsions [19,20], solid dispersions [21][22][23] or drug-loaded type systems based on cyclodextrins [24][25][26] and lipid [27][28][29] or phospholipid micelles [30,31].…”

Section: Introductionmentioning

confidence: 99%

Mesoporous drug carrier systems for enhanced delivery rate of poorly water-soluble drug: nimodipine

et al. 2015

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Two mesoporous silica materials: MCM-41 and SBA-15 were applied as potential nanocarriers for poorly soluble drug-nimodipine. Drug incorporation was performed using modified adsorption from the solution method and loaded samples before and after washing procedure were studied. The physical properties were verified by: differential scanning calorimetry, X-ray powder diffraction, electron microscopies (SEM/TEM) and Fourier-transform infrared spectroscopy (FT-IR). FT-IR results for bulk nimodipine were interpreted on the basis of first principles calculations (DFT). As a result of encapsulation process, in both matrices nimodipine appeared simultaneously in two forms: crystalline and amorphous, but the first one turned out to be easily removable during washing procedure. The in vitro dissolution and release tests were performed with ultra pure water under supersaturating conditions. The release rate of the amorphous nimodipine from mesoporous silica materials was at least 70 times higher than dissolution rate of bulk drug, thus revealed a potential usefulness of such carrier in future pharmaceutical applications in terms of delivery of poorly soluble drugs.

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“…There have been prior reports of sustained-release formulations of dihydropyridines and other drugs administered into the subarachnoid space for SAH [12,13,29,30]. While there has been some evidence that these may be effective, these formulations have had limitations, including lack of characterization of pharmacokinetics, stability, and injectability, use of materials with known or unknown toxicity, and limited data on efficacy of the active drug.…”

Section: Discussionmentioning

confidence: 99%

“…They are prepared with dichloromethane, a neurotoxin that may not be optimal for human use [11]. Given that nimodipine is effective at improving outcome, we sought to develop a formulation that could be administered either intracisternally after neurosurgical clipping of ruptured aneurysms, or intraventricularly to patients with a ventricular catheter who undergo endovascular aneurysm repair, or even neurosurgical clipping [13]. A sustained-release formulation was developed because intracranial access may be limited to the early phase after SAH, while nimodipine must be administered for 14-21 days [14].…”

Section: Introductionmentioning

confidence: 99%

A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage

et al. 2016

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Nimodipine is the only drug approved for use by the Food and Drug Administration for improving outcome after aneurysmal subarachnoid hemorrhage (SAH). It has less than optimal efficacy, causes dose-limiting hypotension in a substantial proportion of patients, and is administered enterally 6 times daily. We describe development of site-specific, sustainedrelease nimodipine microparticles that can be delivered once directly into the subarachnoid space or cerebral ventricles for potential improvement in outcome of patients with aneurysmal SAH. Eight injectable microparticle formulations of nimodipine in poly(DL-lactide-co-glycolide) (PLGA) polymers of varying composition were tested in vitro, and 1 was advanced into preclinical studies and clinical application. Intracisternal or intraventricular injection of nimodipine-PLGA microparticles in rats and beagles demonstrated dose-dependent, sustained concentrations of nimodipine in plasma and cerebrospinal fluid for up to 29 days with minimal toxicity in the brain or systemic tissues at doses <2 mg in rats and 51 mg in beagles, which would be equivalent of up to 612-1200 mg in humans, based on scaling relative to cerebrospinal fluid volumes. Efficacy was tested in the double-hemorrhage dog model of SAH. Nimodipine-PLGA microparticles significantly attenuated angiographic vasospasm. This therapeutic approach shows promise for improving outcome after SAH and may have broader applicability for similar diseases that are confined to body cavities or spaces, are self-limited, and lack effective treatments.

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In situ forming nimodipine depot system based on microparticles for the treatment of posthemorrhagic cerebral vasospasm

Cited by 32 publications

References 26 publications

Submicron polymeric particles prepared by vibrational spray-drying: Semisolid formulation and skin penetration/permeation studies

Submicron polymeric particles prepared by vibrational spray-drying: Semisolid formulation and skin penetration/permeation studies

Mesoporous drug carrier systems for enhanced delivery rate of poorly water-soluble drug: nimodipine

A Site-Specific, Sustained-Release Drug Delivery System for Aneurysmal Subarachnoid Hemorrhage

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