Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
PROCESS FOR BUILDING ARTIFICIAL MULTIFUNCTIONAL INJECTABLE FILLER
Document Type and Number:
WIPO Patent Application WO/2019/171366
Kind Code:
A1
Abstract:
This process for engineering nanoporous biodegradable artificial multifunctional injectable bio-composite filler is designed aiming the prevention of body immune reaction when integrated with host tissue. This nanoporous biodegradable artificial multifunctional filler is compounded as follow: First ingredient is a bio-composite of alpha- or beta-tricalcium phosphate (a- or β-TCP) mixed with polycaprolactone (PCL) composite powder. Second ingredient, phospholipid - phosphatidilcholine (PC) which is worldwide known as the leader of lysolecithin produced under various names by different factories around the world. Third ingredient, any product of microbiological synthesis of exopolysaccharides (EPS) using bacteria Xanthomonas Campestris and Bacillus Amyloliquefacience such as Xanthan, Levan, Pullulan, Kurdlan etc. Fourth Ingredient, any connective collagen tissue. Fifth Ingredient, gelatine powder. Sixth ingredient, recombinant Human Vascular Endothelial Growth Factor A165. After injection, the final processing of all this bio-composite is acquired immediately by ultrasound treatment at a frequency between 24 and 32 Khz applied for a very short period of time under 60s.

Inventors:
NAZIR PALI (IL)
Application Number:
PCT/IL2019/050119
Publication Date:
September 12, 2019
Filing Date:
January 31, 2019
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
NAZIR PALI (IL)
International Classes:
A61K9/00; A61L27/00; A61K9/06; A61L27/18; A61L27/46; A61L27/56; A61L27/58; C08L67/04
Domestic Patent References:
WO2018158760A12018-09-07
WO2012176224A12012-12-27
WO2010148229A12010-12-23
Foreign References:
CN103251983B2014-09-17
US4699788A1987-10-13
IL25088117A2017-03-01
IL2018050096W2018-01-29
Other References:
MICHAEL BERNSTEIN ET AL: "Low Temperature Fabrication of [beta]-TCP-PCL Nanocomposites for Bone Implants", ADVANCED ENGINEERING MATERIALS., vol. 12, no. 8, 1 August 2010 (2010-08-01), DE, pages B341 - B347, XP055577441, ISSN: 1438-1656, DOI: 10.1002/adem.201080027
M. MILAS; M. RINAUDO: "Conformational investigation on the bacterial polysaccharide xanthan", CARBOHYDR. RES., no. 76, 1979, pages 189
JOHN STREET; MIN BAO; LEO DE GUZMAN; STUART BUNTING; FRANKLIN V. PEALE, JR.; NAPOLEONE FERRARA; HOPE STEINMETZ; JOHN HOEFFEL; JEFF: "Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 99, no. 15, August 2002 (2002-08-01), pages 9656 - 61, XP002539331, DOI: doi:10.1073/PNAS.152324099
P. RUAS-MADIEDO; J. HUNGENHOLTZ; P. ZOON: "An overview of the functional of exopolysaccharides produced by lactic acid bacteria", INTERNATIONAL DAIRY JOURNAL, vol. 12, 2002, pages 163 - 171, XP027377901, DOI: doi:10.1016/S0958-6946(01)00160-1
MIRONESCU, M.: "Microbial polisaccharides production, characterization and properties", ACTA UNIVERSITATIS CIBINIENSIS SERIES E: FOOD TECHNOLOGY, vol. VII, no. 2, 2003, pages 26 - 38
ANN HOEBEN; BART LANDUYT; MARTIN S. HIGHLEY; HANS WILDIERS; ALLAN T. VAN OOSTEROM; ERNST A. DE BRUJIN: "Vascular Endothelial Growth Factor and Angiogenesis", PHARMACOLOGICAL REVIEWS, vol. 56, no. 4, December 2004 (2004-12-01), pages 549 - 580, XP002493205, DOI: doi:10.1124/pr.56.4.3
MIN WANG: "Composite Scaffolds for Bone Tissue Engineering", AMERICAN JOURNAL OF BIOCHEMISTRY AND BIOTECHNOLOGY, vol. 2, no. 2, 2006, pages 80 - 84
LAVERTU M; FILION D; BUSCHMANN MD: "Heat-induced transfer of protons from chitosan to glycerol phosphate produces chitosan precipitation and gelation", BIOMACROMOLECULES, vol. 79, 2008, pages 640 - 650
JAYACHANDRAN VENKATESAN; SE-KWON KIM: "Chitosan Composites for Bone Tissue Engineering - An Overview", MARINE DRUGS, vol. 8, 2010, pages 2252 - 2266
BERNSTEIN, M.; MAKAROV. C.; GOTMAN, I.; PHADKE, A.; RADIN, S.; DUCHEYME, P.; GUTMANAS, E. Y.: "Low temperature fabrication of 0-TCP-PCL nanocomposites for bone implants", ADV. ENG. MATER., vol. 12, 2010, pages B341 - B347, XP055577441, DOI: doi:10.1002/adem.201080027
ARTOUM RAKOVSKY; IRENA GOTMAN; EUGEN RABKIN; ELAZAR Y. GUTMANAS: "Strong bioresorbable Ca phosphate-PLA nanocomposites with strong phase distribution by attrition milling and high pressure consolidation", JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS, vol. 18, 2013, pages 37 - 46, XP055577766, DOI: doi:10.1016/j.jmbbm.2012.11.004
KAI HU; BJORN R; OLSEN. BONE, THE ROLES OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN BONE REPAIR AND REGENERATION, vol. 91, October 2016 (2016-10-01), pages 30 - 38
Download PDF:
Claims:
Claims

1. The powders size of the components of the first ingredient a- or b-TCP and PCL must be reduced bv any enabling and approved process for this procedure with suitable cooling measures (f. ex. high energy milling attritor etc.).

2. Tissue integration is made possible between numerous kinds of cells: myocites, fibrocites, dermocites etc.

3. Mixed with above §1 compound of any Lysolecithin produced Phospholipid.

4. Mixed with above §3 any product of microbiological synthesis of exopolysaccharides (EPS).

5. Mixed with above §4, grinding of any element containing connective collagen tissue (f. ex. catgut etc.) until obtaining the tiniest particles as possible with the help of a laboratory grinder. Dosage of catgut or any substance composed of any connective collagen tissue is variable and depending to the type of the tissue to be treated.

6. Idem as §5 is the addition of Gelatine powder mixed in distilled water with any laboratory mixer till the transformation of the whole compound into a gel with an ad hoc addition of water to obtain an usable product.

7. Recombinant human Vascular Endothelial Growth Factor A165 (rhVEGF-A165) which is part of this bio-composite is provided and acts as a potent and effective factor for micro-vascular perfusion enhancement and for the development of new micro-vascular capillaries in an organized structural network in living tissues.

8. This artificial multifunctional bio-composite is activator of neovasculogenesis process in the treated tissue.

9. This artificial multifunctional bio-composite filler can be used in plastic, traumatologic and orthopedic surgery.

10. This artificial multifunctional bio-composite is free of any immune reaction, while others may have many reactions and influences on the recipient's body, especially those based on animal tissues or cancerogenic components.

11. This artificial multifunctional bio-composite may be liquid or gel.

12. Process of building of this artificial bio-composite filler is finalized with the ultrasound treatment.

13. It is important to notice that the ultrasound treatment is applied at a frequency between 24 and 32Khz during a very short period of time - under 60s.

14. The ultrasound treatment has to be performed in vivo.

This artificial multifunctional bio-composite can be used to heal various damaged human or animal tissues!

Description:
Process for Building Artificial Multifunctional Injectable Filler

Description

This process for engineering nanoporous biodegradable artificial multifunctional injectable bio-composite filler is designed aiming the prevention of body immune reaction when integrated with host tissue. This nanoporous biodegradable artificial multifunctional filler is compounded as follow: First ingredient is a bio-composite of alpha- or beta-tricalcium phosphate (a- or b-TCP) mixed with polycaprolactone (PCL) composite powder followed by high pressure consolidation of the blend at room temperature and in proportion not less than 7% and never more than 10% of the final compound product. Second ingredient, phospholipid - phosphatidilcholine (PC) which is worldwide known as the leader of lysolecithin produced under various names by different factories around the world, its proportion being not less than 20% and never more than 25% of the final compound product. Third ingredient, any product of microbiological synthesis of exopolysaccharides (EPS) using bacteria Xanthomonas Campestris and Bacillus Amyloliquefacience such as Xanthan, Levan, Pullulan, Kurdlan etc. In proportion not less than 8% and never more than 10% of the final compound product. Fourth Ingredient, any connective collagen tissue (f. ex. catgut etc.) in proportion not less than 11% and never more than 13% of the final compound product. Fifth Ingredient, gelatine powder in proportion of lg for 5ml of distilled water, this solution being in proportion not less than 42% and never more than 54% of the final compound product. Sixth ingredient, recombinant Human Vascular Endothelial Growth Factor A165 (rhVEGF-A165) with a dosage inferior to 1-3 ng/ml of the final compound measured by the dose-dependant stimulation of the proliferation of Human Vascular Endothelial Cell (HUVEC). After injection, the final processing of all this bio-composite is acquired immediately by ultrasound treatment at a frequency between 24 and 32 Khz applied for a very short period of time under 60s.

References:

1. Milas, M. Conformational investigation on the 5. Composite Scaffolds for Bone Tissue Engineering. bacterial polysaccharide xanthan / M. Milas, M. Min Wang. American Journal of Biochemistry and Rinaudo // Carbohydr. Res. 1979. - N.76. - P.189. Biotechnology 2 (2): 80-84, 2006

2. Vascular endothelial growth factor stimulates 6. Lavertu M, Filion D, Buschmann MD (2008) Heat- bone repair by promoting angiogenesis and bone induced transfer of protons from chitosan to glycerol turnover. John Street, Min Bao, Leo de Guzman, phosphate produces chitosan precipitation and Stuart Bunting, Franklin V. Peale, Jr., Napoleone gelation. Biomacromolecules 79:640-650.

Ferrara, Hope Steinmetz, John Hoeffel, Jeffrey L. 7. Chitosan Composites for Bone Tissue Engineering Cleland, Ann Daugherty, Nicholas van Bruggen, H. - An Overview. Jayachandran Venkatesan and Se- Paul Redmond, Richard A. D. Carano, and Ellen H. Kwon Kim. Marine Drugs 2010, 8, 2252-2266.

Filvaroff. Proceedings of the National Academy of 8. Bernstein, M., Makarov. C., Gotman, I., Phadke, A., Sciences 99(15):9656-61 · August 2002. Radin, S., Ducheyme, P., Gutmanas, E. Y., 2010. Low

3. Ruas-Madiedo, P. An overview of the functional of temperature fabrication of b-TCP-PCL nanocomposi exopolysaccharides produced by lactic acid bacteria / tes for bone implants. Adv. Eng. Mater. 12, B341-B347. P. Ruas-Madiedo, J. Hungenholtz, P. Zoon // 9. Strong bioresorbable Ca phosphate-PLA International Dairy Journal. 2002. - Vol. 12. - P. 163- nanocomposites with strong phase distribution by 171. attrition milling and high pressure consolidation.

4. Mironescu, M. Microbial polisaccharides Artoum Rakovsky, Irena Gotman, Eugen Rabkin, production, characterization and properties / M. Elazar Y. Gutmanas. Journal of the Mechanical Mironescu // Acta Universitatis Cibiniensis Series E: Behavior of Biomedical Materials 18 (2013) 37-46. Food Technology. 2003. - V. VII, N.2 - P.26-38. 10. The roles of vascular endothelial growth factor in bone repair and regeneration. Kai Hu, Bjorn R. Olsen.

5. Vascular Endothelial Growth Factor and

Bone October 2016, vol.91 :30-38.

Angiogenesis. Ann Hoeben, Bart Landuyt, Martin S.

11. US Patent Number 4,699,788.

Highley, Hans Wildiers, Allan T. Van Oosterom, and

Ernst A. De Brujin. Pharmacological Reviews 12. Israeli Patent Application Number 250881 - PCT December 2004, 56 (4) 549-580 Application Number IL2018050096-IB304.