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TEFARCO ed ADRITELF presentano:
Workshop AFI – Simposio annuale 2015
Sistemi di rilascio di farmaco, prodotti di combinazione e dispositivi medici: nuove
tecnologie farmaceutiche e formulazioni innovative
Drug Delivery Sistems, combination products and medical devices: novel pharmaceutical
technologies and innovative formulations
Le nuove tecnologie e le formulazioni innovative sono basilari per lo sviluppo farmaceutico per quelle
aziende che vogliono immettere sul mercato nuovi prodotti, anche solo per migliorare quelli esistenti o
aumentare la copertura di mercato di marchi consolidati mediante estensioni di linea. I sistemi di rilascio di
farmaco (drug delivery systems) sono quindi più che mai attuali in uno scenario farmaceutico in cui è sempre
più difficile e costoso lo sviluppo di nuove molecole e dove le nuove sostanze biotecnologiche richiedono
soluzioni formulative di elevata specializzazione.
Inoltre la combinazione di più farmaci in una sola forma farmaceutica (combinazioni a dosi fisse) è prassi
sempre più frequente per migliorare l’aderenza alla prescrizione nella politerapia. Essa richiede strategie
tecnologiche innovative per superare i problemi di compatibilità e di modulazione delle cinetiche di rilascio.
La capacità di combinare farmaci, eccipienti, polimeri e dispositivi in modo originale ed inventivo è la base
dei nuovi sistemi terapeutici.
Inoltre la continua ricerca di innovazioni tecnologiche coinvolge la categoria dei dispositivi medici, che copre
un mercato importante e molto dinamico. I prodotti di combinazione farmaco-dispositivo e dispositivo-
farmaco, per la disponibilità di brevetti tecnologici assicurano vantaggi economici. Nel campo dei dispositivi
medici anzi uno sviluppo farmaceutico ben fatto può in alcuni casi surrogare la necessità di test clinici.
Lo scopo dello workshop è di presentare alle aziende le attività di ricerca e sviluppo tecnologico di nuovi
prodotti in atto presso le sedi consorziate di TEFARCO Innova ed in generale presso i Dipartimenti
farmaceutici universitari. Il confronto con le aziende e il contatto costante con le necessità industriali e
regolatorie è essenziale per i gruppi di ricerca accademici.
***
New technologies and innovative formulations are fundamental for the development of pharmaceutical
companies to market new products, improve existing or increase their market share with line extensions. The
drug delivery systems are now more relevant than ever in a scenario in which is difficult and expensive to
develop new molecules and where biopharmaceuticals require highly specialized formulative solutions.
Furthermore the combination of multiple drugs in a single dosage form (fixed-dose combinations) is
becoming a common practice to improve the adherence to the prescription in polypharmacy. This requires
innovative technologies to overcome the problems of compatibility and modulation of kinetics release. The
ability to combine drugs, excipients, polymers and devices in an useful, inventive and patentable way is the
basis of new therapeutic systems.
In addition, the ongoing search for technological innovations involves medical devices, an important and very
dynamic market. The combination products of drug-device and device-drug, due to new intellectual property
on the technology, provide economic benefits. In the field of medical devices a thorough pharmaceutical
development, sometimes can even substitute the need for clinical trials.
The purpose of this workshop is to showcase to the companies research and technological development of
new products developed by consortium TEFARCO Innova and in the Pharmaceutical Departments of our
Italian Universities. The meeting, exchange with the companies and the constant understanding of industrial
and regulatory needs is essential for academic research groups.
1
Sistemi di rilascio di farmaco, prodotti di combinazione e dispositivi medici:
nuove tecnologie farmaceutiche e formulazioni innovative
Drug Delivery Sistems, combination products and medical devices: novel
pharmaceutical technologies and innovative formulations
Rimini, 10 Giugno 2015, 9:00-12:30
PROGRAMMA
09:00-09:15 Registrazione partecipanti
Moderatori: Prof. Maurizio Cini (Direttore TEFARCO) e Prof. Franco Alhaique (Presidente ADRITELF)
09:15- 09:30 Technological innovation and efficacy evaluation of a medical device: hyaluronic acid
mucoadhesive gel compared to solid lipid nanoparticle loaded gel formulation
Priscilla Capra – Università degli Studi di Pavia
09:30- 09:45 Anticancer drug-loaded quantum dots engineered PLGA NPS: therapy/diagnosis
combined approach
Giovanni Tosi – Università di Modena e Reggio
09:45- 10:00 Malt-o Fast technology for nutraceutical and drug delivery purpose
Francesca Selmin – Università degli Studi di Milano
10:00 –10:15 Therapeutic spray paint combining topical drug delivery and wound healing action
Gaia Colombo – Università degli Studi di Ferrara
10:15 -10:30 Tobramycin dry powder inhaler: dose and respirability
Anna Giulia Balducci Università degli Studi di Parma
10:30- 10:45 Pegylated polylactide-CO-glicolide gentamicin loaded microparticulate gel for the local
antibiotic delivery to bone.
Rossella Dorati - Università degli Studi di Pavia
10:45 – 11:00 Versatile mucoadhesive patches aimed for buccal delivery: clonazepam experience for local
and systemic release
Francesca Maestrelli - Università degli Studi di Firenze
11:00 -11:15 Liposomes for vitamin K1 nebulization on the skin
Giuseppe De Rosa - Università degli Studi di Napoli Federico II
11:15 -11:30 Oral pulsatile delivery systems based on functional polymeric barriers: from coated units to
capsular devices obtained by injection molding and 3D printing
Alice Melocchi – Università di Milano
11:30 -11:45 Pectin-chitosan particulate systems for the delivery of manuka honey components effective
in wound healing
Marika Tenci - Università degli Studi di Pavia
11:45-12:00 Conclusioni
2
Technological innovation and efficacy evaluation of a medical device: hyaluronic acid mucoadhesive
gel compared to solid lipid nanoparticle loaded gel formulation.
1* 2 1 1 1,2
Priscilla Capra , M. Bleve , F. Pavanetto , G. Musitelli , P.Perugini
1
Dipartimento di Scienza del Farmaco, Università degli Studi di Pavia, Via Taramelli 12, 27100 Pavia, Italy.
2
EticHub s.r.l, academic spin-off, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy
email: *priscilla.capra@unipv.it
Short Description of the Technology
Medical devices can be considered a viable alternative strategy to traditional drug therapies administered for
the treatment and prevention of mucosa disorders, such as oral recurrent aphthous stomatitis [1]. Yet for the
medical device can compete with several oral drug therapies (antibiotics, antineoplastic and anti acids),
currently in use, must prove to have a therapeutic effect and opportune technological performance. In this
regard, device must be able to remain for a long time in the site of action in order to ensure a prolonged
effect, enhancing, at the same time, a rapid regeneration of the damaged tissue [2].
it is the impairment of non-keratinized oral mucosa, in fact, the main cause of the symptoms that occur in
patients with disorders borne oral.
For this reason, in this research work is proposed the application of a system based on hyaluronic acid or its
derivative. In particular, N-acetyl glucosamine (NAG), a constituent of hyaluronic acid, if appropriately loaded
in nano particle systems, such as solid-lipid particles (SLN), might be able to effectively reach the site of
action promoting tissue regeneration [3,4] .
According to what is said there are two aspects to be addressed in the project: i) to compare the
performance of a technological mucoadhesive gel based on hyaluronic acid, similar to what is currently on
the market, with solid lipid nanoparticle gel, properly loaded with NAG; ii) to develop a working protocol with
which it is possible to discern the performance of one or more products in comparison. Three parameters will
be considered in the study: mucoadhesion [5], biocompatibility and barrier properties. Another interesting
aspect of the study is represented by the use of reconstituted oral epithelium to ensure standardization and
reproducibility of the method.
References
[1] Karavana, Gokce et al. International J. of Nanomedicine 7:5693-5704, 2012.
[2] Andrews, Laverty et al., European J. of Pharmaceutics and biopharmaceutics, 71: 505-518, 2009.
[3] Chen, Abatangelo et al. Wound repair and re generation, 7(2): 79-89, 1999.
[4] Perugini et al. Skin Research and Technology, 18: 45-54, 2012.
[5] H.gerstrom et Edsman, J. of Pharmacy and Pharmacology, 53:1589-1599, 2001
3
ANTICANCER DRUG-LOADED QUANTUM DOTS ENGINEERED PLGA NPS:
THERAPY/DIAGNOSIS COMBINED APPROACH
*a,c a,c a c a b c
Giovanni. Tosi , F. Pederzoli , M.A. Vandelli , E. Pracucci , F. Forni , A. Tombesi , G. Ratto , B.
a
Ruozi *
a
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
b
CIGS, University of Modena and Reggio Emilia, Modena, Italy
c
National Enterprise for nanoScience and nanoTechnology, Scuola Normale Superiore, Pisa, Italy
*e-mail of presenting author: barbara.ruozi@unimore.it; giovanni.tosi@unimore.it
Short Description of the Technology
Combinations of different nanostructured materials are considered promising tools to allow the
development of multifunctional nanomedicines for multimodal imaging and drug delivery [1]. QDs and
polymeric nanotechnology revealed to be a good binomial for these applications. In fact, by sensitive and
fast responsive fluorescent imaging approach with exploitation of QDs as probes, the behavior of labeled
nanocarriers in both cells and animals can be dynamically monitored. By assessing the chemico-physical,
morphological and photophysical features of QD/NPs obtained by different coupling strategies, we tested
the ability of the combined anticancer drug delivery.
By setting up two different strategies to modify biodegradable and biocompatible PLGA NPs with QDs-
PEG-NH2 (PRE-FORMUATION and POST-FORMUATION STRATEGIES), we demonstrated changes in
morphological and photo-physical properties of different multifunctional QDS-modified NPs. We figured out
that NPs modified with QDs-PEG-NH2 after the formulation process (POST-FORMUATION QDs-
MODIFIED NPs) nicely maintained the photophysical features of QDs-PEG-NH2 probe. On the other hand,
using PLGA (as polymer) modified with QDs (PLGA-PEG-QDs) in the formulation process, we obtained
pre-formulation QDs-modified NPs. The photophysical characterization demonstrated that a significant
quenching of QDs-PEG-NH2 fluorescence and a blue-shift in its emission spectra, due to the packaging of
QDs-PEG-NH2 into the polymeric matrix took place. These findings evidenced for the first time the
importance of considering polymeric influence using QDs probe and may induce a new way for different
NPs characterization by analyzing QD fluorescence spectrum. Moreover, since these nanodevices are
aimed to be used for theranostic goals, the choice of the route of administration should be strongly taken
into consideration, as we figured out that it impacts hardly on the photophysical profiles of QDs-modified
NPs.
Curcumin (CUR), is a natural diphenol, has shown potent anti-cancer efficacy in various types of cancers,
including lymphoma [2]. However, suboptimal pharmacokinetics and poor bioavailability limit its effective
use in cancer therapeutics. Several successful CUR nanoformulations have recently been reported which
improve upon these features [3,4]. Starting from these bases, we synthesized polymeric NPs encapsulating
curcumin (NPs-CUR) and polymeric NPs encapsulating curcumin and engineered on their surface with QD
(QD-NPs-CUR). Physico-chemical and photophysical characterization of samples (by dynamic laser light
scattering, TEM, SEM and confocal and 2-photon microscopies, respectively) described the size
distribution, the surface properties, the morphology and the architecture of samples along with their
photophysical features. Then, the therapeutic efficacy of combined drug/diagnostic agents was evaluated,
by using cytofluorimetric assay and confocal analysis in in vitro cancer model. The impact of the strategy of
nanoformulations on both curcumin bioavailability and on the tracking/imaging potential of QDs-conjugated
NPs was deeply investigated.
References
[1]. Kim, Lee, et al. Adv. Mat. 20 (3):478, 2008.
[2]. Uddin, Khan, et al. Exp. Opin Investig Drugs, 18(1): 57-67, 2009.
[3]. Yallapu, Dobberpuhl, et al. Curr. Drug Metab. 13(1):120-8, 2012.
[4]. Bisht, Feldmann, et al. J. Nanobiotech. 5:3, 2007
4
Malt-o Fast technology for nutraceutical and drug delivery purposes
Francesca Selmin, C.G.M. Gennari, F. Cilurzo, P. Minghetti, L. Montanari
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via G. Colombo, 71 - 20133 Milano.
email: francesca.selmin@unimi.it
Short Description of the Technology
Fast-dissolving oral delivery systems are commonly referred as solid dosage forms readily disintegrate or
dissolve (i.e. < 1 min.) in the oral cavity without drinking or chewing. Initially, fast-dissolving tablets
manufactured by special technologies or formulations were proposed as efficient drug release formulations.
More recently, fast-dissolving films emerged as a very promising dosage form in a field subdued to tablets to
definitely eliminate patients’ fear of chocking.
Malt-o Fast is a fast-dissolving film platform, which dissolves within few seconds in the mouth. The basic
formula comprises of maltodextrin and glycerol; additional Pharmacopeia excipients or food additives can be
incorporated in order to tailor the product profile. Malt-o Fast is actually produced by solvent-casting
evaporation method, even if hot-melt extrusion allowed to obtain film with good characteristics.
The drug loading capacity was proven by incorporating several pharmaceutical active ingredients also at the
2
nanoscale, as well as food supplements up to 75 mg on a 6 cm surface.
Depending on the physical-chemico characteristics of the active ingredient loaded and its strength in the
formulation, modifications of the mechanical and texture properties can occur resulting in films too flexible or
brittle to guarantee the dosage form integrity during packaging process. These effects can be
counterweighted by using non-traditional plasticizers, e.g. aminoacids, and/or nanofillers.
To develop palatable and cost-effective formulation, flavours and/or sweeteners can be directly incorporated
into basic formula without decreasing the drug loading capacity with respect to other technique, such as
complexation and microencapsulation. The flavours and/or sweeteners suitable for the final purpose can be
preliminary defined by means an electronic tongue and confirmed by a human panel testing.
References
1. Cilurzo F, Cupone IE, Minghetti P, Selmin F, Montanari L. Fast dissolving films made of maltodextrins.
(2008) Eur. J. Pharm. Biopharm. 70(3): 895-900.
2. Cilurzo F, Cupone IE, Minghetti P, Buratti S, Selmin F, Gennari CGM, Montanari L. Nicotine fast dissolving
films made of maltodextrins: a feasibility study. (2010) AAPS PharmSciTech 11(4): 1511-1517.
3. Cilurzo F, Cupone IE, Minghetti P, Buratti S, Selmin F, Montanari L. Diclofenac fast-dissolving film:
suppression of bitterness by a taste-sensing system. (2011) Drug Dev. Ind. Pharm. 37(3): 252-259.
4. Selmin F, Franceschini I, Cupone IE, Minghetti P, Cilurzo F. Aminoacids as non-traditional plasticizers of
maltodextrins fast-dissolving films. (2015) Carbohydrate Pol. 115: 613-616.
5. Lai F, Franceschini I, Corrias F, Sala MC, Cilurzo F, Pini E, Sinico C. Maltodextrin fast dissolving films for
quercetin nanocrystal delivery. A feasibility study. (2015) Carbohydrate Pol. 121: 217-223.
Patent Application Status
Cilurzo F, Di Grigoli M, Pagani S, Minghetti P. (2014) Orodispersible films having quick dissolution times for
therapeutic and food use. WO2014049548.
Cilurzo F, Minghetti P, Montanari L. (2006). Self-supporting films for pharmaceutical and food use.
EP04791317 B1.
5
Therapeutic spray paint combining topical drug delivery and wound healing action
1 * 1 2 2 2 3 3
Gaia Colombo , F. Bortolotti, A.G. Balducci, F. Sonvico, P. Colombo, L. Gallina, A. Scagliarini
1
Dipartimento di Scienze della Vita e Biotecnologie, Università di Ferrara, Via Fossato di Mortara 17/19,
44121 Ferrara
2
Dipartimento di Farmacia, Università di Parma, 43124 Parma
3
Dipartimento di Scienze Mediche Veterinarie, Università di Bologna, 40064 Ozzano Emilia (BO)
E-mail: *clmgai@unife.it
Short Description of the Technology
Veterinary skin infections caused by viruses such as Orf virus (contagious ecthyma) and Papillomavirus
(equine sarcoid) can be treated topically. However, conventional topical semisolid formulations (creams,
ointments) hinder drug application on a large scale (in the field), due to the need of touching the lesion (and
the animal) for product application. Hence, a bioadhesive spray dosage form was manufactured with
sucralfate gel as vehicle for the drug cidofovir delivery to animals. The formulation, prepared by simply
dissolving cidofovir within the sucralfate gel suspension, combines the antiviral activity of cidofovir to the
wound-healing properties of sucralfate gel.
Sucralfate gel is a suitable vehicle owing to its colloidal properties, which lead to stable suspensions that
are bioadhesive to the mucosa. In fact, the suspension per se is fluid enough to be directly sprayed on the
lesions. Spraying facilitates the application with no need for the caregiver of touching the treated site (less
risk of contamination). The sprayed product strongly adheres to skin and mucosae. It forms a layer on the
lesion that dries quickly leaving a protective crust [1].
In equine sarcoid, as horses are treated surgically to remove the tumor mass, the product is applied during
surgery and then used as a follow-up therapy, reducing the likelihood of relapses [2].
Worldwide, the industrial application of this product can provide farmers and veterinarians with a drug
product suitable for the treatment of cutaneous viral infections in sheep and goats (orf virus infection) and
horses (equine sarcoid). At present, there are no products on the market to counteract two veterinary
diseases responsible of significant economic loss due to their impact on the agricultural sector as well as
on veterinary and public health.
References
[1] Sonvico F. et al. AAPS J 11: 242-9, 2009.
[2] Scagliarini A. et al. Vet Rec. 171: 330, 2012.
Patent Application Status
US2013274209 (A1) ― 2013-10-17
6
Tobramycin dry powder inhaler: dose and respirability
1 2 2 3 3 3 .
Anna Giulia Balducci*, M. Di Cuia, D. Frascio, P. Colombo, R. Bettini, F. Buttini
1
PlumeStars srl, via Lago Scuro 11, 43124, Parma (Italy)
2
Interdipartimental Biopharmanet-TEC Centro, University of Parma (Italy)
3
Department of Pharmacy, University of Parma, 43124 Parma (Italy)
E-mail: *annagiulia.balducci@plumestars.com
Short Description of the Technology
The standard therapy for the treatment of lung infections in cystic fibrosis is represented by a tobramycin
inhalation solution [1]. The administration of antibiotic powder has introduced a significant advantage for the
compliance and the quality of life of the patients. Recently, a powder formulation of tobramycin (TOBI
Podhaler, Novartis, Switzerland) has been authorized. The treatment involves the administration of a high
amount of powder, 200 mg, of which only 112 mg of tobramycin are divided into four capsules [2, 3].
In this presentation is proposed an innovative product as tobramycin dry powder with only 1% w/w of an
excipient. 120 mg of powder equivalent to 112 mg of tobramycin were agglomerated, loaded into a capsule
size 0 able to contain the dose and aerosolized with a device for dry powders (RS01, Plastiape, I) [4].
The agglomerates of tobramycin allow to significantly reduce the mass of powders that enters into the patient
lung at the same dose of tobramycin.
References
[1] Balducci, A.G., Bettini, R., Colombo, P., Buttini, F., 2014. Drug delivery strategies for pulmonary
administration of antibiotics. In: Nokhodchi, A., Martin, G.P. (Eds.), Pulmonary Drug Delivery: Advances and
Challenges. Wiley-Blackwell, Chichester, West Sussex, UK (in press).
[2] Geller DE, Konstan MD, Smith MWJ, Noonberg SB, and Conrad C, 2007. Novel Tobramycin Inhalation
Powder in Cystic Fibrosis Subjects: Pharmacokinetics and Safety Pediatric Pulmonology. 42:307–313
[3] Parkins MD, Elborn JS. 2011. Tobramycin Inhalation Powder™: a novel drug delivery system for treating
chronic Pseudomonas aeruginosa infection in cystic fibrosis. Expert Rev Respir Med. Oct;5 (5):609-22.
[4] Parlati C, Colombo P, Buttini F, Young PM, Adi H, Ammit AJ, Traini D, 2009. Pulmonary spray dried
powders of tobramycin containing sodium stearate to improve aerosolization efficiency. Pharm Res 26,
1084–1092.
Patent Application Status
Buttini F, Colombo P, Parlati C, 2010. A drug powder for inhalation administration and a process thereof.
Patent WO2010003465 (A2).
7
Pegylated polylactide-co-glicolide gentamicin loaded microparticulate gel for the local antibiotic
delivery to bone
Rossella Dorati, A. DeTrizio, I. Genta, G. Grisoli, T. Modena, B. Conti
University of Pavia, Department of Drug Sciences,
Via Taramelli 12, 27100 Pavia
email: rossella.dorati@unipv.it
Short Description of the Technology
Antibiotic local delivery has become increasingly popular for a variety of reasons in the treatment of
musculoskeletal infections,. The high local concentrations of antibiotics facilitate their delivery by
diffusion to the devascularized areas which are poorly reachable through the systemic administration.
Moreover, in many cases the organisms that are resistant to drug concentrations achieved by systemic
antibiotic administration, are susceptible to the extremely high local drug concentrations provided by
local antibiotic delivery. A novel in situ forming composite gel (ISFcSG) was designed and developed for
antibiotic delivery and bone reconstruction suitable to support tissue regeneration in dental, plastic,
cranio-maxillofacial or orthopaedic surgery, while preventing such infections as osteomyelitis. The
proposed ISFcSG consists in a suspension of bovine spongious granules dispersed into an in situ
gelling polymeric solution. The antibiotic agent, loaded into the gel, is formulated in a biodegradable
microparticulate drug delivery system in order to control its release and prolong the therapeutic effect.
The final product can be injected through a cannula in the site of action, thus avoiding systemic
administration of Gentamicin and improving its activity.
The product formulation study, preparation and characterization is here introduced and discussed.
References
Dorati R. et al Eur. Cells Mater. 42:14, 2012.
Zilberman M. et al. J. Control. Rel. 130(3):202-215, 2008.
Ismail AF. et al. Int. J. Pharm. Pharm. Sci. 2012; 4(4):685-691.
8
Versatile mucoadhesive patches aimed for buccal delivery: clonazepam experience for local and
systemic release
*
Francesca Maestrelli
Dept. of Chemistry, University of Florence, via Schiff 6, Sesto Fiorentino 50019, Florence, Italy
email: *francesca.maestrelli@unifi.it
Short Description of the Technology
Mucoadhesive patches can be more effective than conventional dosage forms for both local and systemic
(1)
delivery of drugs . For local delivery to the oral cavity, mucoadhesive patches proved to be more effective
than conventional dosage forms assuring a localized and prolonged release. On the other hand, also for
systemic delivery such patches can be more effective than conventional dosage forms, providing a
prolonged release across the oral mucosa and less collateral disease. Clonazepam (CLZ) was a good
candidate to test such kind of patches since is widely used to treat convulsive disorders and panic attacks
but recently it has been demonstrated its efficacy also in the local therapy of the burning mouth syndrome
(BMS), pathology characterized by a painful burning sensation and/or other dysesthesias of the oral
(2)
mucosa . Due to the CLZ low water solubility, cyclodextrin complexation could be useful to increase its
solubility and dissolution rate, and then enhance its therapeutic efficacy and we previously demonstrated
the performance of some amorphous cyclodextrin (CD) derivatives in terms of complexing and solubilizing
(3)
power toward CLZ . We recently developed patches, simply prepared by direct compression of chitosan
(4)
and Poloxamer 407 with suitable characteristics to be efficient buccal patches for local drug delivery .The
same patches opportunely coated can assure unidirectional release of drug across the mucosa, essential
(5)
for an efficient systemic release . The presented results demonstrated the possibility of obtaining, by
direct compression, buccal patches with suitable technological properties, suitable residence time and a
controlled swelling. These patches can be used for local drug delivery or, if coated for systemic delivery.
Permeation studies across both pig and artificial mucosa and in vivo studies are on progress in order to
confirm our findings. Therefore these patches can be considered as the most effective to use for the future
development of buccal delivery systems of drugs.
References
1. Bruschi, de Freitas. Drug Dev. Ind. Pharm. 31: 293-310, 2005.
2. Grushka et al., Oral Surg. 86:557-561, 1998.
3. Mennini et al., J. Pharm. Biomed. Anal. 89: 142-149 (2014).
4. Maestrelli et al., 9th World Meeting, Lisbon, Portugal (2014)
5. Maestrelli, et al., 7th Workshop of CRS Italy Chapter, Florence 2014
9
Liposomes for vitamin K1 nebulization on the skin.
1,2 2 1 3 1 1
V. Campani M. Pitaro ,M. Biondi , F. Cilurzo , P. Grieco ,G. De Rosa
1 2
Department of Pharmacy, Università degli Studi di Napoli Federico II, Naples, Italy; Xenus Srl,
3
Rome, Italy, Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy.
e-mail: gderosa@unina.it
Short Description of the Technology
Vitamin K1 (VK1) is a very lipophilic and photosensitive molecule contained in some vegetables. In recent
years, creams containing VK1 have been proposed to prevent side effects on the skin in patients with
metastatic tumors of the colon and rectum, treated with cetuximab, a monoclonal antibody directed against
the epidermal growth factor receptor (EGFR) [1,2].
Here, we propose an innovative strategy for the administration of VK1 on the skin. In particular, to overcome
the drawbacks associated with a VK1-containing fatty ointment available on the market, an aqueous
liposome-based formulation suitable to be administered by nebulization was developed. The use of
liposomes encapsulating VK1 allowed overcoming issues due to the lipophilicity of VK1. No alteration of the
vesicle characteristics following the liposome supply through the nebulizer was found. Permeation ex-vivo
studies were carried out on pig-excised skin in Franz cells and the newly developed formulation was
compared to a marketed VK1-containing ointment. These experiments demonstrated an enhanced VK1
accumulation into the skin when using nebulized liposomes.
This newly developed formulation could be a valid alternative to the products for topical administration of
VK1 available on the market today. In particular, the use of liposomes could facilitate the multiple
administrations per day by aerosol, but also increase, compared to a semi-solid preparation, the
accumulation of VK1 into the epidermis and dermis.
References
[1] Ocvirk J. Radiol Oncol. 2010;44:256–266.
[2] Segaert S, Van Cutsem E. Ann Oncol. 2005;16:1425–1433.
[3] Campani V. et al. Int. J. Nanomed. 2014 Apr 10;9:1823-32.
Patent Application Status
Italian patent application - Formulazione liquida micronizzabile per il trattamento terapeutico dell'acne e di
altre patologie cutanee correlate. domanda n. RM2012A000267, - pending.
10
ORAL PULSATILE DELIVERY SYSTEMS BASED ON FUNCTIONAL POLYMERIC BARRIERS: FROM
COATED UNITS TO CAPSULAR DEVICES OBTAINED BY INJECTION MOLDING AND 3D PRINTING
1 2 1 1 1 1
Alice Melocchi , Federico Parietti , Giulia Loreti , Alessandra Maroni , Lucia Zema , Andrea Gazzaniga
1
Dipartimento di Scienze Farmaceutiche, Sezione di Tecnologia e Legislazione Farmaceutiche
“Maria Edvige Sangalli”, Università degli Studi di Milano, 20133 Milano, Italia
2
Mechanical Engineering Department, Massachusetts Institute of Technology, 02139 Cambridge, MA, USA
email: alice.melocchi@unimi.it
Short Description of the Technology
Oral Drug Delivery Systems (DDSs) are based on various formulation strategies that are aimed at enhancing the
bioavailability of the active ingredient conveyed or modifying its release in terms of time, rate and/or site. In particular,
reservoir systems, which consist in a drug-containing core coated with a functional polymeric barrier, represent one of
the most common configuration of oral DDSs. The polymers employed show peculiar properties (pH-dependent
solubility, enzyme degradability, slow interaction with aqueous fluids etc.) that define the release profile of the DDS and,
consequently, its potential application (gastroresistant, prolonged release, pulsatile release systems etc.). From an
industrial point of view, the possibility of an independent development for the polymeric layer and the drug-containing
core would be particularly interesting. As a result, functional containers in the form of capsule shells could be obtained.
Such devices, which represent a step forward in the design and production of reservoir systems, could be filled with
different drug preparations and impart the release profile on the basis of composition and design features of the shell
only [1-4]. In this respect, capsule shells intended for pulsatile release of the contents (Chronocap™) were proposed
starting from the Chronotopic™ system, which comprises a drug-containing core and a swellable/erodible polymer
coating. The Chronocap™ platform is currently the functional container at the most advanced development stage and is
manufactured by Injection Molding (IM). This technique, widely employed in other industrial fields and potentially
favorable in terms of versatility (size, shape and composition) and development (patentability, time and costs of
production) of the DDS, consists in the injection, under elevated pressure, of a molten thermoplastic material into a
closed mold, which determines the tridimensional shape of the final object [5].
With the aim of strengthening the potential of the Chronocap™ platform for time- and site-specific release, changes in
the design and composition of the capsule shells would be needed for the fine-tuning of the lag phase. For this purpose,
development of new formulations and molds as well as a revision of molding processes would be required, which may
prove especially challenging. Such critical issues may be overcome by combining IM with three dimensional (3D)
printing, and in particular with Fused Deposition Modeling (FDM) technique, which involves the use of thermoplastic
polymeric filaments for the manufacturing of solid objects using 3D models [6-8]. In fact, 3D printing by FDM, thanks to
its rapid prototyping capability, could speed up the screening of new formulations, their transition to production and
possible changes in the shell design (e.g. thickness), by making prototypes of the final product available in real time.
Moreover, 3D printing may become in the future a preferred tool for the production of small batches of functional
containers potentially useful for the treatment of single patients (personalized therapy) or relatively small groups of them
(e.g. clinical trials, galenic preparations, rare diseases).
Bibliografia
1. Gazzaniga A.et al., AAPS Pharm. Sci.Tech.12: 295-303 (2011).
2. Zema L. et al., J. Pharm. Sci.102: 489-499 (2013).
3. Zema L. et al., Int. J. Pharm.440: 264-272 (2013).
4. Macchi E. et al., Eur. J. Pharm. Sci. 70: 1-11 (2015).
5. Zema L. et al., J. Control. Rel. 159: 324-331 (2012).
6. Melocchi A. et al., US Provisional Patent, EFS ID 19107430 (2014).
7. Melocchi A. et al., Proceedings of CRS Italy Chapter Annual Workshop (2014).
st
8. Melocchi A. et al., 1 European Conference on Pharmaceutics: Drug Delivery, accepted (2015).
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Pectin-chitosan particulate systems for the delivery of manuka honey components effective in
wound healing
M. Tenci*, S. Rossi, M.C. Bonferoni, F. Ferrari, M. Daglia, A. Di Lorenzo, G. Sandri,
C. Boselli, A. Invernizzi, C.M. Caramella
Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100, Pavia
email: *marika.tenci01@ateneopv.it
Short Description of the Technology
Manuka honey (MH), obtained from Leptospermum scoparium, is known for antibacterial properties,
attributed to the high concentration of methylglyoxal (MGO), and, consequently, for potential capability of
promoting wound healing [1].
Particulate systems offer peculiar advantages in the treatment of chronic wounds due to ease of
application, non occlusive properties, improved stability and compatibility, versatile release kinetics.
In this project beads and capsules based on pectin (PEC) and chitosan glutamate low MW (CS) are
proposed for the delivery of Manuka honey (MH) fractions. Two different fractions of MH were examined:
one (Fr1), rich in methylglyoxal, the other (Fr2), rich in other bioactive components, among which
polyphenols. Fr1 proved able to improve human fibroblast proliferation.
Beads were prepared by dropping an aqueous PEC solution into a CS/CaCl2 mixture solution. Optimized
variables were CS concentration and residence time in the cationic solution. Capsules were obtained by
dropping a CaCl2 /CS mixture solution into a PEC solution. Screening and optimization of capsule
formulation was based on a Quality by Design approach using DOEs.
Optimized particles (beads and capsules) (low size, high hydration properties and suitable mechanical
resistance) were loaded with MH Fr1, characterized for loading capacity, for proliferation activity In vitro on
NHDF fibroblasts and for In vivo healing properties in an animal model (rat). The results obtained from in
vitro proliferation test and in vivo studies indicate a synergic effect between CS and MH Fr1 in promoting
wound healing.
The combination of natural products and biopolymers is a feasible alternative to the use of traditional
medications in the treatment of chronic skin lesions.
References
[1] Mavric E., Wittmann S., Barth G., Henle T., Molecular Nutrition & Food Research 52: 483−489 (2008).
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