1,721,069 research outputs found
On the preparation of opioid-loaded cutaneous patches
No full textPurpose - The aim of the present study was i) to evaluate the feasibility of opioid-loaded cutaneous patches made of methacrylic-based adhesive matrix and ii) to rationalize the selection of the best compounds to be loaded into patches intended to act locally for assuring local skin analgesia.
Methods - Dihydromorphine (DM), oxymorphone (OM), hydromorphone (HM), dihydrocodeine (DC), oxycodone (OC) and hydrocodone (HC) were used as free bases and loaded (1% w/w) in cutaneous patches, made of Eudragit NE 40® and triacetin (50/50% w/w of dried weight). Patches were prepared by casting using a laboratory-coating unit Mathis LTE-S(M) (Mathis, CH) and they were characterized in terms of drug release rate (Kr), permeation flux (J) and drug amount retained in the HE (Qret). The dissolution studies were performed using an adapted disk assembly method. In vitro permeation and retention studies were carried out with the Franz diffusion cells using human epidermis (HE) as model membrane.
Results - The compounds with hydroxyl group in position 14 (i.e., OM, OC) resulted in the highest Kr-values (p=0.02). Furthermore, the codeine derivatives exhibited higher Qret values than the morphine ones, except for HM. Among all the opioid derivatives investigated, no statistical differences were observed in terms of J, with the only exception of DM (p=0.0177) that showed the highest J-value.
Table 1. Kr, J, Qret values and the Qret normalized by μ-receptor binding potency [1] of the opioid-loaded patches (Mean ± St.Dev.; n=3).
Form. Kr (h-0,5) Qret (μg/mg) J (μg/cm2h) Normalized Qret
DM 0.10±0.01 0.27±0.09 0.31±0.16 1.10*10-1
OM 0.11±0.01 0.29±0.09 0.07±0.02 3.00*10-1
HM 0.09±0.03 1.38±0.43 0.16±0.09 4.93
DC 0.07±0.01 1.14±0.20 0.09±0.03 3.51*10-3
OC 0.10±0.01 1.40±0.24 0.07±0.01 8.00*10-2
HC 0.08±0.02 1.32±0.18 0.01±0.00 1.20*10-1
Aiming to rationalize the selection of suitable candidates for local analgesia by application of opioid-loaded cutaneous patch, the major features to be considered are both a high tendency to be retained in HE and a high binding affinity for the opioid receptors. In the light of this consideration, the HM was selected as the most promising candidate from the comparison of the normalized Qret.
Conclusions - The methacrylic matrix resulted effective in loading and controlling the release profiles of six morphine derivatives as well as in promoting the drug retention in the HE. Furthermore, the experimental studies confirmed the selection of HM for the design of a cutaneous patch intended to assure local analgesia.
References
1. Musazzi, U.M. et al. Int. J. Pharm. (2015) 489: 177-185
Polymeric micelles for cutaneous delivery of resveratrol
No full textPurpose: The efficacy of resveratrol (RES) in preventing skin aging and protecting epidermis from damages induced by UVA and UVB has been recently demonstrated (Soeur et al., 2015). Considering the low skin penetration of UV rays, the design of delivery systems able to promote the RES localization into the epidermis resulted of interest to guarantee skin protection. The present study aimed to evaluate the feasibility of poloxamer micelles for enhancing the RES penetration in the upper skin layers.
Methods: 0.1% w/v RES-loaded polymeric micelles were prepared using solvent diffusion method (acetone solution/water: 1/10 v/v). Poloxamer 118 (P118) and 407 (P407) were selected as excipients because of their high solubility in water, other than the different molecular weight and HLB value. To study the impact of polymer composition on the physical properties and stability of RES-loaded polymeric micelles, different formulations were prepared using different concentrations of polymers (0.1-1.0% w/v), as single polymer or 1:1 mixture. The resulting nanosystems were characterized in terms of particle size, ζ-potential and apparent solubility of RES in water. Their physical stability was also checked over 1 month at room temperature. Release studies through artificial membrane (i.e., Cuprophan®) and in vitro permeation studies through full-thickness porcine ear skin were performed over 24 h by using Franz cells.
Results: Poloxamers can auto-assemble in nano-micelles when RES was added to the formulation. The size of micelles ranged from 30 to 300 nm, as function of their compositions; ζ-potential was almost neutral for all formulations. In micellar systems containing P407, the RES apparent solubility significantly increased (1.05±0.7 mg/mL) with respect to a saturated solution (0.04±0.00 mg/mL). Similar results were observed with P118, but it had a lower solubilizing efficiency (0.36±0.33 mg/mL). The release study suggested that micelles could act as nano-reservoir systems for RES. Indeed, the RES amount diffused through Cuprophan® membrane within 8h (<5%) was six-time lower for polymeric micelles in comparison to the control solution (≈30%). Among micellar systems, the diffused RES amounts increased in the order: P407 < P118/P407 (1:1) ≈ P118. In vitro permeation study demonstrated that the RES permeation through full-thickness porcine skin was negligible for all tested formulations and the RES retention in the deep epidermal and dermal layers resulted lower than 1% of total RES loaded. Nevertheless, the stripping technique revealed that micellar formulations were more efficient in promoting the penetration and retention of RES than control (p < 0.01) in the upper epidermal layers. Interestingly, micelles made of P188 and P407 (1:1) could enhance the permeation of RES in the lower epidermal layers more than other micellar systems and control (p < 0.05).
Conclusions: Poloxamers can auto-assemble in presence of RES to form micellar systems, enhancing significantly its apparent solubility in water. Micelles made of P188 and P407 resulted promising nanocarriers for enhancing the skin partition of RES and its localization in the upper skin layers.
References
Soeur J et al. Skin resistance to oxidative stress induced by resveratrol: From Nrf2 activation to GSH biosynthesis. Free Radical Biology and Medicine 2015, 78, 213-223
Improved skin penetration of resveratrol from polymeric micelles
No full textThe efficacy of resveratrol (RES) in preventing skin aging and protecting epidermis from damages induced by UVA and UVB has been recently demonstrated (Soeur et al., 2015). Considering the low skin penetration of UV rays, the design of delivery systems able to promote the RES localization into the epidermis resulted of interest to guarantee skin protection. The present study aimed to evaluate the feasibility of poloxamer micelles for enhancing the RES penetration in the upper skin layers.
0.1% w/v RES-loaded polymeric micelles were prepared using solvent diffusion method (acetone solution/water: 1/10 v/v). Poloxamer 118 (P118) and 407 (P407) were selected as excipients because of their high solubility in water, other than the different molecular weight and HLB value. To study the impact of polymer composition on the physical properties and stability of RES-loaded polymeric micelles, different formulations were prepared using different concentrations of polymers (0.1-1.0% w/v), as single polymer or 1:1 mixture. The resulting nanosystems were characterized in terms of particle size, ζ-potential and apparent solubility of RES in water. Their physical stability was also checked over 1 month at room temperature. Release studies through artificial membrane (i.e., Cuprophan®) and in vitro permeation studies through full-thickness porcine ear skin were performed over 24 h by using Franz cells.
Poloxamers can auto-assemble in nano-micelles when RES was added to the formulation. The size of micelles ranged from 30 to 300 nm, as function of their compositions; ζ-potential resulted almost neutral for all formulations.
In micellar systems containing P407, the RES apparent solubility significantly increased (1.05±0.7 mg/mL) with respect to a saturated solution (0.04±0.00 mg/mL). Similar results were observed with P118, but it had a lower solubilizing efficiency (0.36±0.33 mg/mL). The release study suggested that micelles could act as nano-reservoir systems for RES. Indeed, the RES amount diffused through Cuprophan® membrane within 8h (<5%) was six-time lower for polymeric micelles in comparison to the control solution (≈30%). Among micellar systems, the diffused RES amounts increased in the order: P407 < P118/P407 (1:1) ≈ P118. In vitro permeation study demonstrated that the RES permeation through full-thickness porcine skin was negligible for all tested formulations and the RES retention in the deep epidermal and dermal layers resulted lower than 1% of total RES loaded. Nevertheless, the stripping technique revealed that micellar formulations were more efficient in promoting the penetration and retention of RES than control (p < 0.01) in the
upper epidermal layers. Interestingly, micelles made of P188 and P407 (1:1) could enhance the permeation of RES in the lower epidermal layers more than other micellar systems and control (p < 0.05).
In conclusions, poloxamers can auto-assemble in presence of RES to form micellar systems, enhancing significantly its apparent solubility in water. Micelles made of P188 and P407 resulted promising nanocarriers for enhancing the skin partition of RES and its localization in the upper skin layers
TRANSDERMAL AND TRANSMUCOSAL PHARMACEUTICAL DOSAGE FORMS FOR PALLIATIVE CARE IN CANCER THERAPY
Full text linkPain is recognized as one of the most distressing cancer-related syndromes and treatment side effects and is linked to decreased quality of life among patients. Despite the improvements of pain management guidelines proposed in the last decades, therapeutic issues are still unsolved, above all in the treatment of loco-regional painful symptoms. For example, a proper pharmacological therapy to treat cisplatin-induced ototoxicity is not currently available. Pain associated to cutaneous wounds is treated by an off-label use of systemic analgesics with high incidence of related side effects. Conventional dosage forms applied in the buccal cavity are unable to achieve suitable efficacy in the case of oral mucositis.
Hence, there is a need to design novel drug delivery systems, which can be easily used in the clinical practice for an effective treatment of loco-regional painful syndromes.
This doctoral thesis aimed to investigate the critical aspects of drug delivery correlated to three loco-regional syndromes and propose technological solutions to rationalize drug delivery. In particular, the experimental work focused on:
(1) the development of a mucoadhesive microparticle suspension intended for treating oral mucositis and designed to combine the peculiarities of prolonged release mucoadhesive systems with those of an immediate release oromucosal solution;
(2) the optimization of a biodegradable nanoparticle system intended to deliver resveratrol to cochlea in the therapy of cisplatin-induced ototoxicity;
(3) the rationalization of the use of morphine derivatives, according to their chemical structure, in the management of cutaneous painful syndromes
Innovative pharmaceutical approaches for the management of inner ear disorders
Full text linkThe sense of hearing is essential for permitting human beings to interact with the environment, and its dysfunctions can strongly impact on the quality of life. In this context, the cochlea plays a fundamental role in the transformation of the airborne sound waves into electrical signals, which can be processed by the brain. However, several diseases and external stimuli (e.g., noise, drugs) can damage the sensorineural structures of cochlea, inducing progressive hearing dysfunctions until deafness. In clinical practice, the current pharmacological approaches to treat cochlear diseases are based on the almost exclusive use of systemic steroids. In the last decades, the efficacy of novel therapeutic molecules has been proven, taking advantage from a better comprehension of the pathological mechanisms underlying many cochlear diseases. In addition, the feasibility of intratympanic administration of drugs also permitted to overcome the pharmacokinetic limitations of the systemic drug administration, opening new frontiers in drug delivery to cochlea. Several innovative drug delivery systems, such as in situ gelling systems or nanocarriers, were designed, and their efficacy has been proven in vitro and in vivo in cochlear models. The current review aims to describe the art of state in the cochlear drug delivery, highlighting lights and shadows and discussing the most critical aspects still pending in the field
Resveratrol-loaded nanocarrier for inner ear delivery
No full textPurpose: The aim of the work is to develop resveratrol-loaded nanocarriers (RES-NCs) for inner ear delivery and to evaluate in vitro toxicity on cochlear cell lines.
Materials and methods: RES-NCs are prepared by solvent-diffusion technique without surfactant. Resveratrol (RES), poly(D,L-lactide-co-glycolide) (PLGA) and poly(ε-caprolactone)–poly(ethylene glycol) diblock (PCL-PEG) are mixed in different ratios, dissolved in acetone and added dropwise to aqueous phase under constant stirring (acetone/water ratio 1/10). RES-NCs are washed and freeze-dried. Box-Behnken design (BBD) is used to study influence of RES-NCs composition on Z-size, PDI, Zeta-potential, drug encapsulation efficiency (EE%) and ratio between RES-NCs Z-size before and after freeze-drying (Sf/Si). In order to increase RES-NC stability during freeze-drying, lactose, mannitol, sucrose and trehalose are tested at different concentrations (1%, 5%, 10%, 15%, 20%w/v). Finally, MTS and LDH assays are carried out to check RES and Blank NCs toxicity after 24h incubation on two different cell lines: an organ of Corti model (HEI-OC1) and a stria vascularis one (SVK-1).
Results: BBD model is validated since all experimental responses fit with predicted values. Checkpoint analyses (bias NMT 10%) and Montecarlo simulation (response defect values NMT 10%) show good robustness in model capability to predict RES-NCs properties. The optimal formulation (desirability: 0.86), made of 7.4mg of RES, 3mg of PLGA and 5.3mg of PCL-PEG, correspond to Z-size of 136.2nm, PDI of 0.127, Z- potential of -26.80mV, EE% of 100.09% and Sf/Si of 3.30. All cryoprotectants increase RES-NCs stability during freeze-drying, disaccharides are more effective than mannitol. However, only trehalose in concentration higher than 15%w/v maintains Z-size and PDI in model space. In vitro toxicity studies show that RES can decrease cell viability only at concentration higher than 500μM, whereas blank NCs are toxic on HEI-OC1 in concentration more than 800μg/mL.
Conclusion: RES-NCs are successfully prepared by emulsion-diffusion technique and optimized by BBD. Moreover, threalose at 15%w/v guarantees RES-NCs stability during freeze-drying process.
Finally, in vitro studies show that RES and NCs are not toxic for cochlear cell lines in concentration lower than 500μg/mL and 800μg/mL respectively
I farmaci innovativi: disciplina nazionale attesa, per il 2017, per la copertura del fondo
No full text
Alternatives when an authorized medicinal product is not available
Full text linkThe industrialization of medicinal products has permitted us to reach important results in terms of quality, efficacy, safety, and availability of drugs; however, not all the legitimate expectations of patients are met. When an authorized medicinal product is not available on the market, the physician can prescribe other pharmacological treatments in the following scenario: off-label prescriptions, extemporaneous preparations, compassionate use of medicinal products, and medicinal products authorized in foreign countries. The best solution among these alternatives should be evaluated case-by-case on the basis of good scientific evidence, expert medical judgement, and published literature, also keeping an eye on the availability, the cost, and the regulatory requirements at a national level
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