Polymeric micelle mediated follicular delivery of spironolactone: Targeting the mineralocorticoid receptor to prevent glucocorticoid-induced activation and delayed cutaneous wound healing.

Impaired wound healing in patients receiving glucocorticoid therapy is a serious clinical concern: mineralocorticoid receptor (MR) antagonists can counter glucocorticoid-induced off-target activation of MR receptors. The aim of this study was to investigate the cutaneous delivery of the potent MR antagonist, spironolactone (SPL), from polymeric micelle nanocarriers, prepared using a biodegradable copolymer, methoxy-poly(ethylene glycol)-di-hexyl-substituted-poly(lactic acid). Immunofluorescent labelling of the MR showed that it was principally located in the pilosebaceous unit (PSU), justifying the study rationale since polymeric micelles accumulate preferentially in appendageal structures. Cutaneous biodistribution studies under infinite and finite dose conditions, demonstrated delivery of pharmacologically relevant amounts of SPL to the epidermis and upper dermis. Preferential PSU targeting was confirmed by comparing amounts of SPL in PSU-containing and PSU-free skin biopsies: SPL nanomicelles showed 5-fold higher delivery of SPL in the PSU-containing biopsies, 0.54 ± 0.18 ng/mm2vs. 0.10 ± 0.03 ng/mm2, after application of a hydrogel in finite conditions. Canrenone, an active metabolite of SPL, was also quantified in skin samples. In addition to being used for the treatment of delayed cutaneous wound healing by site-specific antagonism of the MR, the formulation might also be used to treat pilosebaceous androgen-related skin diseases, e.g. acne vulgaris, since SPL is a potent androgen receptor antagonist.

Poly-Lactic Acid-Based Biopolymer Formulations Are Safe for Sustained Intratympanic Dexamethasone Delivery.

HYPOTHESIS AND BACKGROUND: The clinical treatment of sudden sensorineural hearing loss currently relies on the administration of steroids, either systemically or via intratympanic injections. Intratympanic injections bypass the hemato-cochlear barrier, reducing its systemic side effects. The efficacy of the injections is limited through rapid drug clearance via the Eustachian tube, and through nonoptimal properties of slow-release drug carriers. A new slow-release drug delivery vehicle based on hexyl-substituted-poly-lactic-acid (HexPLA), with the highest possible safety profile and complete bio-degradability, has been evaluated for safety and efficacy in a standardized guinea pig model of intratympanic injection. METHODS: A total of 83 animals received through retrobullar injection either empty Nile-red-colored HexPLA vehicle, 5%-dexamethasone-HexPLA, 5%-dexamethasone suspension, or a sham operation. Long-term residence time of vehicle, biocompatibility, click- and pure-tone hearing thresholds, and dexamethasone levels in the perilymph were prospectively assessed. RESULTS: At 1 week after injection, HexPLA vehicle was morphologically present in the middle ear and perilymph levels in the 5%-dexamethasone-HexPLA were on average 2 to 3 µg/ml and one order of magnitude higher compared with those of the 5%-dexamethasone suspension group. No significant postoperative morphological or functional changes were observed up to 3 months postdelivery. CONCLUSIONS: HexPLA is safe, fully biocompatible, and efficient for sustained high-dose, intratympanic delivery of dexamethasone at least for 1 week and therefore of high interest for the treatment of sudden sensorineural hearing loss and other acute inner ear diseases. Due to the favorable chemical properties, a wide range of other drugs can be loaded into the vehicle further increasing its potential value for otological applications.

Topical Administration of Spironolactone-Loaded Nanomicelles Prevents Glucocorticoid-Induced Delayed Corneal Wound Healing in Rabbits.

The objective was to investigate whether mineralocorticoid receptor antagonism using a novel topical micellar formulation of spironolactone could prevent glucocorticoid-induced delayed corneal wound healing in New Zealand white rabbits. Spironolactone micelles (0.1%, w/v) with a mean number weighted diameter of 20 nm were prepared using a pegylated copolymer (mPEG-dihexPLA) and showed a preliminary stability of at least 12 months at 5 °C. Preclinical studies in New Zealand white rabbits demonstrated that the 0.1% spironolactone micellar formulation was well-tolerated since no reaction was observed in the cornea following multiple daily instillation over 5 days. As expected, the preclinical studies also confirmed that dexamethasone significantly delayed epithelial wound healing as compared to untreated control (percentage re-epithelialization after day 4: 84.6 ± 13.9% versus 99.5 ± 1.0% for the control, p < 0.05). However, the addition of the 0.1% spironolactone micellar formulation significantly improved the extent of re-epithelialization, countering the dexamethasone induced delayed wound healing with a percentage re-epithelialization that was statistically equivalent to the control (96.9 ± 7.3% versus 99.5 ± 1.0%, p > 0.05). The biodistribution study provided insight into the ocular metabolism of spironolactone and hence the relative contributions of the parent molecule and its two principal metabolites, 7α-thiomethylspironolactone and canrenone, to the observed pharmacological effects. Comparison of the efficacies of spironolactone and potassium canrenoate (a water-soluble precursor of canrenone) in overcoming the dexamethasone-induced delayed wound healing confirmed that the former had greater efficacy. The results pointed to the greater potency of 7α-thiomethylspironolactone over canrenone as a mineralocorticoid receptor antagonist, which explained its superior ability in countering the glucocorticoid-induced overactivation that was responsible for the delayed wound healing. In conclusion, the preliminary results supported the above-mentioned hypothesis suggesting that coadministration of mineralocorticoid receptor antagonists to patients under glucocorticoid therapy might prevent the deleterious effects of glucocorticoids on complex corneal wound healing processes.

Self-assembling polymeric nanocarriers to target inflammatory lesions in ulcerative colitis.

We have developed a self-assembling polymeric nanocarrier to deliver the potent immunosuppressive drug Cyclosporine A (CsA) to inflammatory lesions in ulcerative colitis (UC) patients. Our nanocarrier has a high drug loading capacity and efficiently targets its CsA payload to the diseased tissue after local administration. Tissue drug levels were several orders of magnitude higher in animals suffering from a trinitrobenzene-sulfonic acid (TNBS) - induced colitis, compared to healthy control animals; no drug was detectable in the plasma, underlining the localized delivery strategy. An efficient reduction in inflammation score was obtained with a CsA dose of 1mg/mL. Therapeutic efficacy was comparable to 5-aminosalicylic acid (5-ASA), the positive control treatment in the TNBS-induced colitis model. Repetitive treatment of healthy animals with CsA nanocarriers for seven days was well tolerated with no alterations in colon histology.

Improved topical delivery of tacrolimus: A novel composite hydrogel formulation for the treatment of psoriasis.

We have developed a composite hydrogel for improved topical delivery of the poorly soluble drug Tacrolimus (TAC) to psoriasis lesions. TAC is efficiently solubilized in methoxy poly- (ethylene glycol) hexyl substituted poly-(lactic acid) (mPEGhexPLA) based nanocarriers. For convenient and patient-friendly topical administration, TAC loaded polymeric nanocarriers were incorporated in a Carbopol® based hydrogel, to yield a composite hydrogel formulation (TAC composite hydrogel). TAC composite hydrogel was designed to have superior pharmaceutical formulation properties, delivery efficiency and local bioavailability, compared to currently available paraffin-based TAC ointments. Composite hydrogel formulations had good local tolerance and showed no signs of immediate toxicity after repeated topical administration in healthy mice. Skin delivery of TAC composite hydrogel in an imiquimod-induced psoriasis mouse model was found to be twice as high as for the commercial formulation Protopic™, used as benchmark. TAC composite hydrogel showed significant improvement in the in vivo and histopathological features of the imiquimod-induced psoriasis model.