Abnormal corneal wound healing can compromise corneal transparency and lead to visual impairment. Mineralocorticoid receptor antagonists (MRA) are promising candidates to promote corneal remodeling ...with anti-inflammatory properties and lack gluococorticoids-associated side effects. In this preclinical study, a new polymer-free hydroxypropyl-gamma-cyclodextrin-based eyedrop containing 0.1% spironolactone (SPL), a potent but non-water-soluble MRA, was investigated for its ocular surface tolerance and efficacy in a rat model of corneal wound healing. SPL eyedrops were stable for up to 9 months at 4 °C. The formulation was well-tolerated since no morphological changes or inflammatory reactions were observed in the rat cornea after multiple daily instillations over 7 days. SPL eyedrops accelerated rat corneal wound healing, reduced corneal edema and inflammation, enhanced epithelial integrity, and improved nerve regeneration, suggesting restoration of corneal homeostasis, while potassium canrenoate, an active and soluble metabolite of SPL, had no effect. SPL eyedrops could benefit patients with impaired corneal wound healing, including that secondary to glucocorticoid therapy. Repurposing known drugs with known excipients will expedite translation to the clinic.
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•Overview of colonic drug delivery systems.•Potential for local and systemic delivery.•Key focus on metabolic activity of the colonic microbiota.•Challenges of microbiota-sensitive ...natural polysaccharides.•Laying special emphasize on oral dosage forms of chemical and biological drugs.
Colon targeting is an ongoing challenge, particularly for the oral administration of biological drugs or local treatment of inflammatory bowel disease (IBD). In both cases, drugs are known to be sensitive to the harsh conditions of the upper gastrointestinal tract (GIT) and, thus, must be protected. Here, we provide an overview of recently developed colonic site-specific drug delivery systems based on microbiota sensitivity of natural polysaccharides. Polysaccharides act as a substrate for enzymes secreted by the microbiota located in the distal part of GIT. The dosage form is adapted to the pathophysiology of the patient and, thus, a combination of bacteria-sensitive and time-controlled release or pH-dependent systems can be used for delivery.
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A variety of polymer:polymer blends was used to prepare hot melt extrudates and empty capsules (bodies and caps) by injection-molding using a benchtop extruder (Babyplast). ...KollidonSR:inulin and Carbothane:inulin blends were investigated. The impact of the blend ratio on the water uptake and dry mass loss kinetics upon exposure to 0.1 MHCl, phosphate buffer pH6.8 and culture medium optionally inoculated with fecal samples from Inflammatory Bowel Disease (IBD) patients were studied. Hot melt extrudates were loaded with up to 60% theophylline, capsules were filled with drug powder. Increasing the inulin content led to increased water uptake and dry mass loss rates, resulting in accelerated drug release from the dosage forms, irrespective of the type of polymer blend. This can be attributed to the higher hydrophilicity/water-solubility of this polymer compared to KollidonSR and Carbothane. Interestingly, the presence of fecal samples in culture medium increased the water uptake and dry mass loss of hot melt extrudates to a certain extent, suggesting partial system degradation by bacterial enzymes. However, these phenomena did not translate into any noteworthy impact of the presence of colonic bacteria on theophylline release from the investigated extrudates or capsules. Hence, drug release can be expected to be independent of the location “small intestine vs. colon” from these dosage forms, which can be advantageous for long term release throughout the entire gastro intestinal tract.
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Metoprolol tartrate and metoprolol free base loaded pellet starter cores were coated with Eudragit RS, plasticized with 25% triethyl citrate (TEC). The initial drug loading and ...coating level were varied from 10 to 40 and 0 to 20%, respectively. Drug release was measured in 0.1 N HCl and phosphate buffer pH 7.4. The water uptake and swelling kinetics, mechanical properties and TEC leaching of/from coated pellets and/or thin, free films of identical composition as the film coatings were monitored. The following unusual tendencies were observed: (i) the relative drug release rate from coated pellets increased with increasing initial drug content, and (ii) drug release from pellets was much faster for metoprolol free base compared to metoprolol tartrate, despite its much lower solubility (factor >70). These phenomena could be explained by plasticizing effects of the drug for the polymeric film coatings. In particular: 1) Metoprolol free base is a much more potent plasticizer for Eudragit RS than the tartrate, leading to higher film permeability and overcompensating the pronounced differences in drug solubility. Also, Raman imaging revealed that substantial amounts of the free base migrated into the film coatings, whereas this was not the case for the tartrate. 2) The plasticizing effects of the drug for the film coating overcompensated potential increasing limited solubility effects when increasing the initial drug loading from 10 to 40%. In summary, this study clearly demonstrates how important the plasticization of polymeric controlled release film coatings by drugs can be, leading to unexpected formulation effects.
Different types of hot melt extrudates were prepared based on a variety of blends of ethylcellulose with a 2nd polysaccharide, namely hydroxypropyl methylcellulose (HPMC), pectin, maize starch, ...inulin, maltodextrin, guar gum, and chitosan. In selected cases, the polymer:polymer blend ratio was varied from 80:20, 70:30, 60:40, 50:50, 40:60, 30:70 to 20:80. The addition of appropriate amounts of plasticizers allowed reducing the extrusion temperature to about 100 °C. The impacts of the screw speed, extrusion temperature, amount and type of plasticizer as well as of the amount and type of drug (10–60% theophylline or diprophylline) were studied. Drug release was measured in 0.1 M HCl for 2 h, followed by phosphate buffer pH 6.8 and (optionally) fecal samples to simulate the colon (under anaerobic conditions). DSC measurements and optical microscopy were used to characterize the physical state and morphology of the systems. Interestingly, hot melt extrudates based on ethylcellulose:guar gum blends could be easily prepared at a temperature of 100 °C and offered large spectra of drug release patterns for both: slightly water-soluble theophylline as well as freely water-soluble diprophylline. About constant drug release rates could be obtained during prolonged periods of time. Importantly, the resulting drug release rates from hot melt extrudates based on ethylcellulose:guar gum 80:20 blends were similar in the presence and absence of colonic bacteria, indicating that the ethylcellulose seems to protect the guar gum from degradation upon exposure to fecal samples. Furthermore, these systems were long term stable for at least 1 year under ambient conditions. Thus, they can offer an interesting potential as oral controlled drug delivery systems.
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Synthetic Vascular Graft Infection (SVGI) can be very serious for patients with dramatic consequences (up to 6%). Polyester vascular grafts (PET) were modified with polymerized cyclodextrin ...(Poly-MeβCD) and loaded with ciprofloxacin (CFX) for the prevention of postoperative infections. The aim of this study was to investigate the CFX/Poly-MeβCD interactions and the importance of the type of the dissolution technique. The solubility of CFX was significantly improved upon Poly-MeβCD, and the interaction between CFX and Poly-MeβCD were observed by NMR (Nuclear Magnetic Resonance). Drug release was measured in phosphate buffer saline pH 7.4 at 37 °C using: (i) agitated flasks, (ii) the paddle apparatus, (iii) the conventional flow-through cells, (iv) the modified flow-through cells with agarose gel at different flow rates. Importantly, CFX release depends on the flow rate as well as the experimental set-up in vitro. CFX release from virgin prostheses (PET) was faster than from functionalized prostheses (PET-MeβCD), irrespective of the flow rate, which indicates the superiority of Poly-MeβCD in the control of CFX release. The CFX diffusion from PET-MeβCD into agarose gel showed a continuously progressive diffusion during 7 days. Thus, this test can be highly appropriate for in vitro characterization of such drug delivery systems.
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