PROGRAM: PNCDI III - Programul 2: Increasing economic competitiveness through Romanian research, development and innovation; Subprogram 2.1. Research, development and innovation
PROJECT TYPE: Experimental demonstration project, Health domain (including Science of drug)
CONTRACT NO.: 160 PED / 03.01.2017
PROJECT COD: PN-III-P2-2.1-PED-2016-0813
CONTRACT VALUE: 600000 lei
FINANCING SOURCE: State Budget
CONTRACT DURATION: 18 months (03.01 2017-30.06.2018)
CONTRACTING AUTHORITY: Executive Agency for Higher Education, Research, Development and Innovation Funding (UEFISCDI) - Romania
CONTRACTOR (CO): “Carol Davila” University of Medicine and Pharmacy, Bucharest; Project manager / director: Prof. Dr. Mihaela Violeta GHICA
PARTENER 1 (P1): The National Research & Development Institute for Textiles and Leather, Division of Leather and Footwear Research Institute, Bucharest; Project Responsible: Dr. Chem Mădălina Georgiana ALBU KAYA (03.01.2017 – 02.10.2017), respectively starting with 02.10.2017 – onwards, Project responsible: Dr. Chem. Gheorghe COARĂ (according to the validated Amendment PN-III-P2-2.1-PED-2016-0813/NJ-1)
TOPMULTINOV project is a new and modern concept for the development of biomaterial-based smart supports usable in burn skin repair. Efficient regeneration of burn skin is still a clinical challenge, obtaining an adequate drug release support being a top approach in the field of biomaterials. The general objective of this project consists in the design, evaluation and modeling of an anti-inflammatory drug release mechanism from topical multiparticulate systems that will ensure a controlled release for burns healing. As a novelty element of the project, ensuring a proper anti-inflammatory drug delivery from spongious collagen-based supports using different techniques that allow a gradual degradation of collagen support and a slow release of drug is mentioned. The results generated by the preparation, physico-chemical and morphological characterization as well as the in vitro studies of drug release and testing of the designed topical systems on animal model will be disseminated at conferences and in specialty articles. The pluridisciplinarity and complementarity of both teams (“Carol Davila” University of Medicine and Pharmacy, Bucharest and INCDTP - Division of Leather and Footwear Research Institute, Bucharest) provide high level of scientific/technical experiences to ensure a successful project achievement. TOPMULTINOV is perfectly integrated in the national and European strategies with respect to the impact on human health for improved health and life quality.
Year 2017 – Phase I (unique), 03.01.2017-31.12.2017
Obtaining and characterization of the microcapsules and the topical multiparticulate delivery systems under the form of spongious matrices with anti-inflammatory drug and modeling of the drug release kinetics
The general objective of project Phase I consists in preparation and characterization of some microcapsules and topical delivery systems under the form of collagenic spongious matrices with anti-inflammatory drug incorporated in various forms (drug in free form, drug in free form and encapsulated, and encapsulated drug), and modeling of the drug release kinetics. To achieve the main objective of this phase, the following activities were performed:
Activity 1.1: Setting the structured program for experimental design and statistical analysis of microcapsules with anti-inflammatory drug (CO)
Activity 1.2: Microencapsulation of the anti-inflammatory drug in biodegradable polymeric supports, using experimental factorial design (CO, P1)
Activity 1.3: Physico-chemical, morphological and biopharmaceutical characterization of microcapsules and setting of optimal formulations (CO, P1)
Activity 1.4: Preparation of the topical multiparticulate delivery systems under the form of spongious matrices based on collagen, anti-inflammatory drug and microcapsules (P1)
Activity 1.5: Physico-chemical, morphological and biological characterization of the topical delivery systems (CO, P1)
Activity 1.6: Modeling of the drug release kinetics from topical multiparticulate delivery systems (CO)
Activity 1.7: Dissemination of the results through participation to technical-scientific meetings
Expected results: (1) Setting of the experimental factorial design; (2) Experimental model of microcapsules with anti-inflammatory drug; (3) Physico-chemical, morphological and biopharmaceutical characterization report; (4) Experimental model – spongious matrices; (5) Physico-chemical, morphological and biological characterization report; (6) Kinetic models and setting of the anti-inflammatory drug kinetic release mechanism; (7) Functional model – optimal anti-inflammatory drug release supports; (8) Participation at conference / symposia; (9) 1 article submitted for publication; (10) Scientific and financial report.
Phase I/2017 abstract:
The project phase I presents a new approach concerning the preparation of release supports like collagen-based spongious matrices with an anti-inflammatory drug incorporated in free form, in free and encapsulated form, and in encapsulated form respectively, to model and control its release rate. The vehicle formulation in the drug delivery sciences is a critical quality attribute which needs special attention for tailor made design in order to rationalize the system development. Thus, for the design and characterization both of microcapsules and collagen spongious supports, a novel methodology, based on the combination of classical techniques of experimental statistical design with the response surface analysis and Taguchi approach is used. This modern method offers several advantages such as a reduced number of experiments to get useful information on the targeted response, product quality optimization and process robustness, and from a practical point of view determines time and money savings, reduced costs and quality preservation to a constant technological level
Dissemination of the results for execution Phase I:
- V. Ghica, M.G. Albu Kaya, C.E. Dinu-Pîrvu, D. Lupuleasa, D.I. Udeanu, Development, Optimization and In Vitro/In Vivo Characterization of Collagen-Dextran Spongious Wound Dressings Loaded with Flufenamic Acid, Molecules, 2017, 22, 1552; doi:10.3390/molecules22091552, ISBN: 1420-3049, FI 2016/2017 = 2.861 (journal in yellow zone position 17 according to impact factor and position 22, respectively, according to the influence score).
- V. Ghica, D.A. Kaya, M.G. Albu Kaya, C. Dinu-Pîrvu, L. Popa, Flufenamic acid-collagen-dextran spongious burn dressings: optimization and characterization, poster presented at Wound Care: From Innovations To Clinical Trials (WCICT2017), Manchester, UK, 20-21 June 2017, p. 9, abstract book.
- Ș. Marin, M.G. Albu Kaya, D.Alpaslan Kaya, Z. Moldovan, E. Dănilă, C. Chelaru, The influence of laurel oil microcapsules embedded into collagen wound dressings, poster presented at 20th Romanian International Conference on Chemistry and Chemical Engineering (RICCCE), Poiana Brașov, Romania, 6-9 September 2017 (S6-310), abstract book.
Value of Phase I / 2017: 450000 lei
CO: “Carol Davila” University of Medicine and Pharmacy, Bucharest: 250000 lei
P1: The National Research & Development Institute for Textiles and Leather, Division of Leather and Footwear Research Institute, Bucharest: 200000 lei
Year 2018 – Phase II (unique), 01.01.2018-30.06.2018
Validation of the optimal topical multiparticulate delivery systems using animal model
The main objectives of project Phase II consist in: (i) the setting of the release mechanism from topical release supports like collagen spongious matrices of an anti-inflammatory drug incorporated in various forms as free form, free and encapsulated form, and encapsulated form respectively (obtained in the first Execution phase); (ii) in vivo preclinical studies on animal model for the evaluation of the therapeutical potential in burn healing for the anti-inflammatory drug release supports, with the selection of optimal topical supports with some release characteristics according to the therapeutical indication; (iii) Validation in the laboratorial environment of optimal topical systems. To achieve these objectives the following activities were performed:
Activity 2.1: Setting of the release mechanism for the support model in accordance with the therapeutical indication (CO)
Activity 2.2. Testing of the topical multiparticulate delivery systems with anti-inflammatory drug on animal model (CO)
Activity 2.3: Selection of the topical systems and setting of the model support with some release characteristics according to the therapeutical indication (CO, P1)
Activity 2.4: Validation in the laboratorial environment of the optimal topical multiparticulate delivery systems with anti-inflammatory drug (CO, P1)
Activity 2.5: Dissemination of the results through participation to scientific meetings and articles publication in specialty journals (CO, P1)
Expected results: (1) Protocol to obtain topical multiparticulate delivery systems; (2) Functional model of topical multiparticulate delivery systems; (3) Product samples; (4) Test report on animal model; (5) Participation at conference / symposia; (6) 1 article submitted for publication; (7) Scientific and financial report.
Phase II/2018 abstract:
Drug delivery collagen spongious matrices with anti-inflammatory drug incorporated in free form and multiparticulate systems based on collagen spongious matrices with drug incorporated in free and encapsulated form, and in encapsulated form respectivelly, already obtained in the first Execution phase of the project, proved proper physical-chemical, morphological, biological and biopharmaceutical properties, indicated for their use in burn treatment. Spongious matrices showed kinetic profiles characterized by (i) an initial phase of fast drug release (less evident in case of multiparticulate systems) reducing the post-traumatic local pain and the amount of pro-inflammatory mediators released at the burn site, followed by (ii) a slow and gradual drug release (up to 48 hours for multiparticulate systems) ensuring an anti-inflammatory and analgesic effect for a longer period of time required for the burn healing. Such kinetic profiles with drug biphasic release are suitable for the local control of the inflammation and the pain associated to a burn wound because the first 12-48 hours are critical for the healing process. Testing on animal model (Wistar rats), within the second Execution phase of the project, of the optimal topical delivery collagen supports loaded with anti-inflammatory drug in different forms in the spongious matrix, is very important and frequently used in the preclinical in vivo studies to assess the pharmacological effect and therapeutic potential in burns treatment. Based on the studies performed, the delivery systems with drug loaded in different forms in the spongious biopolymeric matrix having beneficial effects in the healing process of the burns with different severity degrees (low and medium) were selected, the biopolymers offering a support for local tissue regeneration. The anti-inflammatory drug presence as free form, incorporated within the multiparticulate systems as free form and encapsulated and respectively only as encapsulated form in the biopolymeric matrix, proved a positive effect on the the healing process evolution during the first days without secondary systemic or topical effects. Sustained by the in vitro test results, the use in burns treatment of the multiparticulate systems with anti-inflammatory drug demonstrated significant pharmacological effects with no secondary reactions and an accelerated healing process in case of burns with medium degree of severity. The results obtained concerning the therapeutic potential of these new designed pharmaceutical formulations recommend the use of the multiparticulate systems for the treatment of medium severity burns with important benefits in the tissue homeostasis and post-traumatic inflammation and favorable long term consequences in the cicatrizing process. To validate in laboratorial environment the optimal topical delivery systems of the anti-inflammatory drug, following the testing on animal model the multiparticulate systems that showed an accelerated evolutionary process compared to the control group, noted especially in the first 7 days for a medium severity burn, were selected These systems were prepared in 3 batches and tested from physico-chemical, morphological, biological and biopharmaceutical point of view, obtaining reproducible results that allow the “zero serial” manufacturing at pilot scale of multiparticulate systems for topical delivery of an antiinflammatory drug, indicated for use in burns healing.
Dissemination of the results for execution Phase II:
- Ghica Mihaela Violeta, Albu Kaya Mădălina Georgiana, Udeanu Denisa Ioana, Marin Minodora Maria, Marin Ștefania, Kaya Durmuș Alpaslan, Dinu-Pîrvu Cristina Elena, Popa Lăcramioara, Dănilă Elena, Topical multiparticulate delivery systems based on biopolymers with controlled release of an anti-inflammatory drug and process for preparing the same, patent application file A / 00388 – 2018 (OSIM).
- I. Udeanu, M.G. Albu Kaya, M.V. Ghica, Ș. Marin, M.M. Marin, D.A. Kaya, L. Popa, C.E. Dinu-Pîrvu, Anti-inflammatory drug-loaded biopolymeric spongious matrices with therapeutic perspectives in burns treatment, Farmacia, in press 2018, IF 2016/2017 = 1.348/2016.
- V Ghica, M.G. Albu Kaya, D.I. Udeanu, Ș. Marin, M.M. Marin, D.A. Kaya, C. Dinu-Pîrvu, L. Popa, Collagen-sodium carboxymethylcellulose spongious matrices loaded with non-steroidal anti-inflammatory drug for burn healing, poster (PC3) presented at International Conference „New trends in applied chemistry” (Chimia 2018), Constanţa, 24-26 May 2018, abstract book, Vol.3, p. 63, ISSN 2360-3941.
- Dănilă, E.Z. Moldovan, M.C. Chifiriuc, M. Bucur, D.A. Kaya, M. Pătrașcu, M.G. Albu Kaya, Dermatocosmetic emulsions based on collagen and essential oils used as a potential treatment for acne, oral communication presented at First International Conference on Chemistry for Beauty and Health, Torun, Poland, 13-16 June 2018, abstract book, p. 44, ISBN 978-83-231-4027-6. The work was awarded: The best presentation in Session for Young Scientist.
Value of Phase II / 2018: 150000 lei
CO: “Carol Davila” University of Medicine and Pharmacy, Bucharest: 70000 lei
P1: The National Research & Development Institute for Textiles and Leather, Division of Leather and Footwear Research Institute, Bucharest: 80000 lei
Mihaela Violeta Ghica
Department of Physical and Colloidal Chemistry,
Faculty of Pharmacy
“Carol Davila” University of Medicine and Pharmacy, Bucharest
6 Traian Vuia, 2nd District, 020956,
Phone: 0213180751 / 0744486250
Email: email@example.com; firstname.lastname@example.org