Francesco Cilurzo | Università degli Studi di Milano - State University of Milan (Italy) (original) (raw)

Papers by Francesco Cilurzo

Pharmaceutical Sciences Fair and Exhibition, Jun 1, 2009

World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Mar 1, 2014

Three dimensional scaffolds made of silk fibroin (SF) from Bombix mori silkworm require a final c... more Three dimensional scaffolds made of silk fibroin (SF) from Bombix mori silkworm require a final curing to manipulate the protein secondary structure of SF (i.e. the ratio between the \u3b2-sheets and random-coil regions) in order to satisfy the requirements of tissue engineering. However, hydrodynamic environment potentially impacts the functional properties of these structures due to the decreased the pore dimension and limited oxygen and nutrient diffusion. This work aims to evaluate the feasibility of preparing composite PEG/SF scaffold with an enhanced water stability upon incubation in physiologic media over time. Low molecular weight PEG was chosen because the blending with SF induces the formation of \u3b2-sheet domains. Composite scaffolds loaded with a pool of growth factors and micronized hydroxyapatite were subcutaneously implanted in pigs to assess their in vivo performance..

Aaps Journal, 2013

Purpose: This work aims to establish if the assays recently introduced by the EMA and USP to char... more Purpose: This work aims to establish if the assays recently introduced by the EMA and USP to characterize transdermal patches (TP) are suitable for medicated plasters (MP). Indeed, TP are developed using pressure sensitive adhesives and non-deformable backing layers, while MP can also use adhesive hydrogels or wooden-non-wooden or elastic backing layers. Methods: Six commercial MP containing NSAIDs were characterized in terms of adhesive performances by tack, shear adhesion, peel adhesion and release liner removal tests and in vitro skin permeation thought human epidermis. Results: Since the adhesive tests developed for TP were substantially borrowed from the adhesive tape industry, some drawbacks can occur when hydrogels and/or stretchable backing layers are used in MP. The main weakness concerns the use of shear adhesion test. This issue could be overcome by applying a very trivial stress by a lighter weight in place of the standard mass. A general remark concerning both TP and MP is related to the mass balance indicated by the EMA draft for the acceptance of the results of in vitro penetration studies. In the draft the mass balance is considered acceptable without further justification when the recovery of the drug substance is in the 90-110% range. At a first glance, some of our preliminary data failed to comply with this requirement. Nevertheless, the proposed range was narrow than that reported for the determination of drug content in two Eur. Ph. monographs, namely \u201cUniformity of dosage unit\u201d and \u201cUniformity of content of single-dose preparations\u201d. Conclusion: In our opinion, a novel assay should be studied to test the shear adhesion of adhesive hydrogels. Moreover, the recovery range for acceptance of the mass balance reported in the \u201cstudy design\u201d of the \u201cin vitro permeation studies\u201d should be changed according to the requirements of uniformity of content. Finally, the EMA should specify if the reference value for mass balance is the nominal drug content (as chosen in the actual set of experiments) or the drug content of the batch under experiment

Trans)dermal patches are designed to provide a prolonged drug delivery through the skin to achiev... more Trans)dermal patches are designed to provide a prolonged drug delivery through the skin to achieve a local, regional or systemic effect. Usually, they are drug-in-adhesive systems, in which the drug is dispersed and/or dissolved in a pressure-sensitive adhesive (PSA) matrix, generally produced by a solvent casting method. This manufacturing approach requires expansive equipment that is not easily adaptable to the preparation of small or personalized batches. This work demonstrated the feasibility of the extemporaneous preparation of PSA-based (trans)dermal patches by hot-melt ram extrusion 3D printing. This technology allows defining easily both the patch geometry and the dose according to patient's needs avoiding the manipulation (i.e., the dosage form cutting) by the patient or the caregivers. According to the approach proposed for orodispersible film [1], the patch preparation consists of three simple technological operations: i) the drug and the PSA components (at least a polymer and a plasticizer) are mixed in a mortar; ii) the mixture is fed in the chamber of the ram-extruder and heated at a suitable temperature; iii) the melt mixture is printed with the desired geometry (thickness: 50 μm) on the backing layer and coupled with the release liner. Based on a previous experience, Eudragit (Eu) RL, RS or blends thereof plasticized with different amount of triacetin (40-60% w/w range) were tested as components of the PSA [2] while nicotine (NT) and ketoprofen (KP) were chosen as model compounds. The printed patches were characterized in terms of shear adhesion and 180°-peel adhesion, other than drug content and drug release. The results showed that patches with suitable adhesive properties can be printed using 40% w/w of triacetin. Both drugs did not compromise the patch adhesive properties, even if the shear adhesion was significantly reduced. Finally, the in vitro release studies showed that the EuRL/EuRS ratio impacted significantly on the release rate of both the tested drugs. According to the well-known characteristics of the two copolymers, the higher the concentration of EuRL in the matrix, the higher the release rate of both KP and NT.

Background: Hot melt ram extrusion 3D printing was recently proposed to prepare small batches of ... more Background: Hot melt ram extrusion 3D printing was recently proposed to prepare small batches of orodispersible films (ODF), but the feasibility of loading thermosensitive drugs with low palatability has not been investigated. Among the possible candidates, diclofenac sodium (DNa) at a dose of 25 mg could be loaded in ODF, despite the limited formulative space, when an immediate release is required. However, the addition of taste masking agents (TMA) should be carefully evaluated as they can compromise the ODF processability and handling. Purpose: This study aims to design ODF loaded by DNa and TMA by hot melt ram extrusion 3D printing and to study their influence on the mechanical and physico-chemical properties of ODF. Methods: ODF made of maltodextrins with a dextrose equivalent of 6 containing DNa and TMA (i.e. mint, licorice-mint and sucralose) or a combination thereof were characterized in terms of drug content, disintegration time, in vitro dissolution test and tensile properties. Results: All ODF disintegrated within 2 min complying the compendial specification. Impurity A of DNa was detected below the Ph. Eur. limits (< 0.2%). The in vitro dissolution profiles of DNa from ODF with and without TMA were superimposable (t 80%~3 min) in deionized water; t 80% decreased about 1-fold for ODF containing TMA in artificial saliva at pH=5.7 (t 80%~2 min). Independently of the presence of TMA, drug loaded ODF were flexible and easy to handle without fracture, even if the presence of DNa significantly increased the tensile strength (placebo ODF=0.17±0.03 MPa vs DNa loaded ODF=2.21±0.54 MPa). Conclusion: Hot melt ram extrusion 3D printing can be also proposed to prepare palatable ODF loaded by a thermosensitive drug.

Current Drug Delivery, 2021

The recent increased interest in orodispersible films (ODF) stems from their ideal potential to c... more The recent increased interest in orodispersible films (ODF) stems from their ideal potential to circumvent several pharmacotherapy-related problems, such as improved medication compliance and adherence, especially in children, elderly and uncooperative patients. Their administration is well accepted by the majority of patients because ODF dissolve upon contact with the saliva in the oral cavity without the need for water intake. ODF application in personalized pharmacotherapy is currently being exploited. Moreover, innovative preparation methods and characterization technologies have been evolving in recent years, highlighting a promising future both from the technological and clinical standpoints. However, the key obstacles to the attainment of full potential of ODF in the pharmaceutical field is the lack of harmonized and well-defined quality characterization procedures, standard evaluation parameters, guidance on appropriate final product properties and specifications. This revie...

Section 3: Production and Compounding, 2019

The dose of oxybutynin was maintained in one patient with the initial dose and, in another, rose ... more The dose of oxybutynin was maintained in one patient with the initial dose and, in another, rose to 0.1 mg/kg/8 hour (the maximum 0.2 mg/kg/8 hour). Pharmaceutical care was performed by the explanation of the doses in milliliters adjusted to the weight and monitoring of possible adverse effects. Strawberry essence was incorporated into the suspension to improve flavour. Since birth, the number of catheters has decreased, with an improvement in the patient's symptoms. Regarding safety, no adverse reactions attributable to the drugs have been observed. Conclusion Both oral suspensions were appropriated for the pathology of our patients, which continue in treatment. They are well tolerated, for an age range not included in the bibliography, with good response. Pharmaceutical care was given from the beginning to the family and the paediatric service. REFERENCES AND/OR ACKNOWLEDGEMENTS To Rosa Millán García for the review of the work and her contribution to it. No conflict of interest.

Section 2: Selection, Procurement and Distribution, 2020

Data in Brief, 2020

The COVID-19 outbreak is now one of the most critical crises to manage for most of the national h... more The COVID-19 outbreak is now one of the most critical crises to manage for most of the national healthcare systems in the world. In the absence of authorised pharmacological treatments, many antiretrovirals, including darunavir/cobicistat fixed combination, are used off-label in the hospital wards as life-treating medicines for COVID-19 patients. Unfortunately, for most of them, the drug products available on the market are not designed to be administered by a nasogastric tube to inpatients of intensive care units. Therefore, their manipulation, even if it can strongly affect the product quality, is necessary for the preparation of suspension to meet patients' need. In this situation, it is urgent to provide data and guidance to support hospital pharmacists and clinicians in their activity. The data in this article indicate that darunavir/cobicistat suspensions compounded by pharmacists using as active ingredient a commercially available tablet can be stable at least for one week.

International Journal of Pharmaceutics, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Regenerative medicine, Jan 21, 2017

This in vitro and in vivo study reports on silk fibroin (SF) scaffold, functionalized for in situ... more This in vitro and in vivo study reports on silk fibroin (SF) scaffold, functionalized for in situ delivery of GABA and/or allopregnanolone (ALLO), as biomaterial for potential application in tissue engineering and nerve regeneration. We evaluated the feasibility to design 2D scaffolds (films) made of regenerated Bombyx mori SF, functionalized with GABA and/or ALLO to enhance in vitro biological functions, health, survival and growth of Schwann cells and sensitive neurons of the dorsal root ganglia. Our 2D-SF film showed an efficient loading and controllable release of drugs promoting nerve regeneration. SF functionalized film may be helpful for the development of bioengineered conduits and, in principle, have great potential for long-gap nerve injury repair.

Journal of Nanobiotechnology, 2017

Background: This work aimed to provide useful information on the incidence of the choice of formu... more Background: This work aimed to provide useful information on the incidence of the choice of formulation in semisolid preparations of iron-oxide nanoparticles (IONs). The appropriate analytical methods to assess the IONs physical stability and the effect of the semi-solid preparations on IONs human skin penetration were discussed. The physical stability of IONs (D h = 31 ± 4 nm; ζ = −65 ± 5 mV) loaded in five semi-solid preparations (0.3% w/v), namely Carbopol gel (CP), hydroxyethyl cellulose gel (HEC), carboxymethylcellulose gel (CMC), cetomacrogol cream (Cet) and cold cream was assessed by combining DLS and low-field pulsed NMR data. The in vitro penetration of IONs was studied using human epidermis or isolated stratum corneum (SC). Results: Reversible and irreversible IONs aggregates were evidenced only in HEC and CMC, respectively. IONs diffused massively through SC preferentially by an intercellular pathway, as assessed by transmission electron microscopy. The semi-solid preparations differently influenced the IONs penetration as compared to the aqueous suspension. Cet cream allowed the highest permeation and the lowest retained amount, while cold cream and CP favored the accumulation into the skin membrane. Conclusion: Basic cutaneous semi-solid preparations could be used to administer IONs without affecting their permeation profile if they maintained their physical stability over time. This property is better discriminated by low-field pulsed NMR measurements than the commonly used DLS measurements.

International journal of pharmaceutics, Jan 11, 2016

The possible use of regenerated silk fibroin gels as in situ film forming formulations for cutane... more The possible use of regenerated silk fibroin gels as in situ film forming formulations for cutaneous administration of drugs was studied. Ethanol was selected as volatile and skin tolerant solvent to favor the sol-gel transition of silk fibroin solutions. Glycerin was chosen to ameliorate the gel texture profile. Eighteen placebo formulations were prepared to individuate the optimal component ratios as a function of the texture analysis, spreadability and drying time. The in vitro biopharmaceutical performance was investigated by in vitro permeation test through human epidermis on formulations loading caffeine as a model drug. The data evidenced that the optimal technological performances were achieved using gels containing 70% ethanol and silk fibroin/glycerin ratio from 0.18 to 0.36. The caffeine flux (J) through the skin was significantly improved due to an increase of the drug thermodynamic activity (hydro-alcoholic solution: J∼0.8μg/cm(2)/h; in situ formed film: J∼1.4-1.7μg/cm(...

Biomacromolecules, 2016

This study aimed to identify a new skin penetrating peptide (SPP) able to enhance unfractionated ... more This study aimed to identify a new skin penetrating peptide (SPP) able to enhance unfractionated heparin (UFH) permeation through human epidermis by screening a phage display peptide library. The effects of the synthesized heptapeptide (DRTTLTN) on human stratum corneum organization were investigated by ATR-FTIR spectroscopy and molecular dynamics simulation. The DRTTLTN penetration within the human epidermis caused both a fluidization of the stratum corneum lipids and the extension of keratins due to the increase of the contribution of α-helices. The coadministration of DRTTLTN with UFH resulted ineffective in increasing skin penetration due to UFH affinity for keratins. The conjugation of DRTTLTN to UFH by N-(3-(dimethylamino)propyl)-N&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-ethylcarbodiimide hydrochloride and sodium N-hydroxysulfosuccinimide led to an increase of the flux of 24-36-fold with respect to raw UFH, depending on the adopted synthetic procedure. The new compounds showed a decrease of the antifactor Xa activity of about 4-5 times. DRTTLTN also permitted to increase the fluxes of small model molecules. In conclusion, these data support the use of SPP to enhance the skin penetration of poorly absorbed compounds even in the case of macromolecules as polysaccharides.

Journal of Drug Delivery Science and Technology, 2016

Mucosa of the buccal cavity is considered a convenient and easily accessible site for the adminis... more Mucosa of the buccal cavity is considered a convenient and easily accessible site for the administration of drugs intended for both local and systemic delivery. Aiming to optimize the pharmacokinetic, buccal mucoadhesive drug delivery systems are proposed. Mucoadhesion is a complex process involving chemical interactions between mucin and polymers. The success and degree of mucoadhesion bonding is based on various polymer-based features. The evolution of such systems has moved from first-generation hydrophilic polymers, able to form unspecific interactions, to more specific second-generation systems based on lectins, or on novel materials obtained by modification of polymers with various functional groups such as thiol groups. A wide range of formulations has been proposed for the delivery of small molecules, but comparatively few have found their way onto the market. The article reviews the information regarding the most promising mucoadhesive polymers and their application in the design and development of buccal mucoadhesive dosage forms.