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..
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
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...
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.
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(...
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'-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.
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..
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
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...
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.
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(...
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'-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.
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