IP Library › Granted Patent US 12,233,416
Granted Patent B2
US 12,233,416 · App. 18/296,954 · Granted Feb 25, 2025

Limit size lipid nanoparticles and related methods

Inventors: Pieter R. Cullis (Vancouver, CA); Igor V. Jigaltsev (Vancouver, CA); Robert James Taylor (Vancouver, CA); Timothy Leaver (Delta, CA); Andre Wild (Vancouver, CA); Nathan Maurice Belliveau (Weymouth, CA)
Assignee: The University of British Columbia
B01L3/50273A61J3/00A61K9/1075A61K9/127A61K9/1271A61K9/1277A61K9/14A61K31/704A61K47/44A61K49/0002B01F23/41B01F25/4317B01F25/4331B01F33/30B01L3/502715B01F25/431971B01L2200/0605B01L2200/0647B01L2300/06B01L2300/0848B01L2300/0867B01L2300/18Y10T428/2982
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Quick Facts
Patent No.
US 12,233,416
App. No.
18/296,954
Granted
Feb 25, 2025
Kind
B2
Abstract

Limit size lipid nanoparticles, methods for using the lipid nanoparticles, and methods and systems for making limit size lipid nanoparticles.

Claims (36)

1. A device for producing limit size lipid nanoparticles having a diameter from 10 nm to 50 nm, comprising:

(a) a first inlet for receiving a first solution comprising a first solvent;

(b) a first inlet microchannel in fluid communication with the first inlet to provide a first stream comprising the first solvent;

(c) a second inlet for receiving a second solution comprising lipid particle-forming materials in a second solvent;

(d) a second inlet microchannel in fluid communication with the second inlet to provide a second stream comprising the lipid particle-forming materials in the second solvent; and

(e) a third microchannel for receiving the first and second streams, wherein the third microchannel has a first region adapted for flowing the first and second streams and a second region adapted for mixing the contents of the first and second streams to provide a third stream comprising limit size lipid nanoparticles,

wherein the third microchannel is configured to receive the first and second streams at a flow rate ratio greater than 1.0, and wherein the second region is configured to provide a fluid flow rate from 1 ml/min to 40 ml/min.

2. The device of claim 1 , wherein the second region of the third microchannel has a height of 79 microns to 130 microns.

3. The device of claim 1 , wherein the second region of the third microchannel comprises a micromixer.

4. The device of claim 1 , wherein the second region of the third microchannel comprises bas-relief structures.

5. The device of claim 4 , wherein the bas-relief structures comprise a plurality of herringbone bas-relief structures.

6. The device of claim 1 , wherein the second region of the third microchannel has a principal flow direction and one or more surfaces having at least one groove or protrusion defined therein, the at least one groove or protrusion having an orientation that forms an angle with the principal direction.

7. The device of claim 1 , wherein the first inlet microchannel and the second inlet microchannel each include at least a portion that has a hydraulic diameter of 20 microns to 300 microns.

8. A method of producing limit size lipid nanoparticles having a diameter from 10 nm to 50 nm, the method comprising:

flowing a first stream through a first inlet microchannel of a fluidic device, the first stream comprising a first solvent;

flowing a second stream through a second inlet microchannel of the fluidic device to provide a second stream comprising lipid particle-forming materials in a second solvent; and

flowing the first stream and the second stream through a first region of a third microchannel of the fluidic device, the third microchannel in fluidic communication with the first inlet microchannel and the second inlet microchannel, wherein a flow ratio of the first stream and the second stream is greater than 1.0;

mixing the first stream and the second stream in a second region of the third microchannel, the second region in fluidic communication with the first region, wherein a combined flow rate of the first stream and the second stream in the second region is from 1 ml/min to 40 ml/min; and

flowing a third stream from the second region, the third stream comprising limit size lipid nanoparticles formed by the mixing of the first stream and the second stream.

9. The method of claim 8 , wherein the second region of the third microchannel has a height of 79 microns to 130 microns.

10. The method of claim 8 , wherein the second region of the third microchannel comprises a micromixer.

11. The method of claim 8 , wherein the second region of the third microchannel comprises bas-relief structures.

12. The method of claim 11 , wherein the bas-relief structures comprise a plurality of herringbone bas-relief structures.

13. The method of claim 8 , wherein the second region of the third microchannel has a principal flow direction and one or more surfaces having at least one groove or protrusion defined therein, the at least one groove or protrusion having an orientation that forms an angle with the principal direction.

14. The method of claim 8 , wherein the first inlet microchannel and the second inlet microchannel each include at least a portion that has a hydraulic diameter of 20 microns to 300 microns.

15. A system, comprising:

a first inlet microchannel configured to receive a first solution and provide a first stream comprising the first solution;

a second inlet microchannel configured to receive a second solution and provide a second stream comprising the second solution;

a third microchannel configured to receive the first stream and the second stream, wherein the third microchannel has a first region adapted for flowing the first stream and the second stream and a second region adapted for mixing the first stream and the second stream to provide a third stream comprising a mixture of the first solution and the second solution;

a first pump configured to provide the first solution to the first inlet microchannel at a first flow rate; and

a second pump configured to provide the second solution to the second inlet microchannel at a second flow rate;

wherein the ratio of the first flow rate to the second flow rate is greater than 1.0, and wherein the second region is configured to provide a fluid flow rate from 1 ml/min to 40 ml/min.

16. The system of claim 15 , wherein the second region of the third microchannel comprises a micromixer.

17. The system of claim 15 , wherein the second region of the third microchannel comprises bas-relief structures.

18. The system of claim 15 , wherein the second region of the third microchannel has a principal flow direction and one or more surfaces having at least one groove or protrusion defined therein, the at least one groove or protrusion having an orientation that forms an angle with the principal direction.

19. The system of claim 15 , wherein the first inlet microchannel and the second inlet microchannel each include at least a portion that has a hydraulic diameter of 20 microns to 300 microns.

Continuity (6)
Continuation 17061247 · Oct 1, 2020
Continuation 15927925 · Mar 21, 2018
Continuation 15087721 · Mar 31, 2016
Continuation 14353460
Provisional Application 61551366 · Oct 25, 2011
Related Publication 20230256436A1 · Aug 17, 2023
References Cited (121)
US 5921678A · Desai · 1999 [cited by applicant]
US 5981501A · Wheeler · 1999 [cited by applicant]
US 6479299B1 · Parce · 2002 [cited by applicant]
US 6815432B2 · Wheeler · 2004 [cited by applicant]
US 6843942B2 · Katinger · 2005 [cited by applicant]
US 7005140B2 · Zhang · 2006 [cited by applicant]
US 7160025B2 · Ji · 2007 [cited by applicant]
US 7214348B2 · Desmond · 2007 [cited by applicant]
US 7252928B1 · Hafeman · 2007 [cited by applicant]
US 7507380B2 · Chang · 2009 [cited by applicant]
US 7622509B2 · Tonkovich · 2009 [cited by applicant]
US 7708949B2 · Stone · 2010 [cited by applicant]
US 7745221B2 · Butler · 2010 [cited by applicant]
US 7794136B2 · Yang · 2010 [cited by applicant]
US 7901708B2 · MacLachlan · 2011 [cited by applicant]
US 8058069B2 · Yaworski · 2011 [cited by applicant]
US 8106176B2 · Aurisicchio · 2012 [cited by applicant]
US 8122909B2 · Tonkovich · 2012 [cited by applicant]
US 8137699B2 · Johnson · 2012 [cited by applicant]
US 8273573B2 · Ismagilov · 2012 [cited by applicant]
US 8329070B2 · Maclachlan · 2012 [cited by applicant]
US 8361415B2 · Di Carlo · 2013 [cited by applicant]
US 8367004B2 · Panagiotou · 2013 [cited by applicant]
US 8414182B2 · Paul · 2013 [cited by applicant]
US 8492359B2 · Yaworski · 2013 [cited by applicant]
US 8496961B2 · Hong · 2013 [cited by applicant]
US 8522413B2 · Van'T Oever · 2013 [cited by applicant]
US 8883200B2 · Hong · 2014 [cited by applicant]
US 9005654B2 · Maclachlan · 2015 [cited by applicant]
US 9943846B2 · Cullis · 2018 [cited by examiner]
US 10843194B2 · Cullis · 2020 [cited by examiner]
US 11648556B2 · Cullis · 2023 [cited by examiner]
US 20040262223A1 · Strook · 2004 [cited by applicant]
US 20060108012A1 · Barrow · 2006 [cited by applicant]
US 20060219307A1 · Wang · 2006 [cited by applicant]
US 20070263485A1 · Yang · 2007 [cited by applicant]
US 20100022680A1 · Karnik · 2010 [cited by examiner]
US 20110070292A1 · Javeri · 2011 [cited by applicant]
US 20110182994A1 · Kornfield · 2011 [cited by applicant]
US 20110305734A1 · Edelson · 2011 [cited by applicant]
US 20120276209A1 · Cullis · 2012 [cited by applicant]
US 20130303587A1 · Yaworski · 2013 [cited by applicant]
CA 2427640A1 · 2003 [cited by applicant]
CA 2491164A1 · 2004 [cited by applicant]
CA 2578574A1 · 2006 [cited by applicant]
CA 2579695A1 · 2006 [cited by applicant]
CA 2616877A1 · 2007 [cited by applicant]
CA 2673924A1 · 2008 [cited by applicant]
CA 2781527A1 · 2011 [cited by applicant]
EP 2123260A1 · 2009 [cited by applicant]
JP 2005525815A · 2005 [cited by applicant]
JP 2006082073A · 2006 [cited by applicant]
JP 2007513122A · 2007 [cited by applicant]
JP 2007524604A · 2007 [cited by applicant]
JP 2007533647A · 2007 [cited by applicant]
JP 2009509553A · 2009 [cited by applicant]
JP 2010514708A · 2010 [cited by applicant]
JP 2010180353A · 2010 [cited by applicant]
WO 03097805A2 · 2003 [cited by applicant]
WO 2005039535A1 · 2005 [cited by applicant]
WO 2005053642A1 · 2005 [cited by applicant]
WO 2005120152A2 · 2005 [cited by applicant]
WO 2005120461A2 · 2005 [cited by applicant]
WO 2007150030A2 · 2007 [cited by applicant]
WO 2008053988A1 · 2008 [cited by applicant]
WO 2009086558A1 · 2009 [cited by applicant]
WO 2009127060A1 · 2009 [cited by applicant]
WO 2010055106A1 · 2010 [cited by applicant]
WO 2012000104A1 · 2012 [cited by applicant]
WO 2012016184A2 · 2012 [cited by applicant]
First-Final Office Action mailed Jan. 7, 2020, issued in Japanese Patent Application No. 2019-022341, filed Oct. 25, 2012, 4 pages. [cited by applicant]
Kitazoe, K. et al. “A Microdevice With Chaotic Mixer to Constract Multofunctional Envelope-Type Nanodevice for Delivery System,” 14th International Conference on Miniaturized Systems for Chemistry and Life Sciences, Oct… [cited by applicant]
Jahn, A. et al., “Microfluidic Mixing and the Formation of Nanoscale Lipid Vesicles,” ACS Nano, 4:4; Apr. 27, 2010, pp. 2077-2087. [cited by applicant]
Wheeler, J. J. et al., “Polyethylene Glycol Modified Phospholipids Stabilize Emulsions Prepared from Triacylglycerol,” Journal of Pharmaceutical Sciences, American Chemical Society and American Pharmaceutical Associatio… [cited by applicant]
Extended European Search Report mailed on Sep. 28, 2021. issued in corresponding European Application No. 21169020.1, filed on Jun. 22, 2021, 13 pages. [cited by applicant]
Abrams, M.T., et al., “Evaluation of Efficacy, Biodistribution, and Inflammation for a Potent siRNA Nanoparticle: Effect of Dexamethasone Co-Treatment,” Molecular Therapy 18(1):171-180, Jan. 2010. [cited by applicant]
Avnir, Y., et al., Amphipathic Weak Acid Glucocorticoid Prodrugs Remote-Loaded Into Sterically Stabilized Nanoliposomes Evaluated in Arthritic Rats and in a Beagle Dog: A Novel Approach to Treating Autoimmune Arthritis,… [cited by applicant]
Belliveau, N.M., et al., “Microfluidic Synthesis of Highly Potent Limit-Size Lipid Nanoparticles for In Vivo Delivery of siRNA,” Molecular Therapy-Nucleic Acids 1(8):e37, Aug. 2012, 9 pages. [cited by applicant]
Chen, D., et al., “Rapid Discovery of Potent siRNA-Containing lipid Nanoparticles Enabled by Controlled Microfluidic Formulation,” Journal of the American Chemical Society 134( 16):6948-6951, Apr. 2012. [cited by applicant]
Crawford, R., et al., “Analysis of Lipid Nanoparticles by Cryo-EM for Characterizing siRNA Delivery Vehicles,” Intemational Journal of Pharmaceutics 403(1-2):237-244, Jan. 2011. [cited by applicant]
Deamer, D.W., and P.S. Uster, “Liposome Preparation: Methods and Mechanisms,” in M.J. Ostra (ed.), “Liposomes,” Marcel Dekker, New York, 1983, pp. 27-52. [cited by applicant]
Geusens, B., et al., “Ultradeformable Cationic Liposomes for Delivery of Small Interfering RNA {siRNA) Into Human Primary Melanocytes,” Journal of Controlled Release 133(3):214-220, Feb. 2009. [cited by applicant]
Gindy, M.E., et al., “Mechanism of Macromolecular Structure Evolution in Self-Assembled Lipid Nanoparticles for siRNA Delivery,” Langmuir 30(16):4613-4622, Apr. 2014. [cited by applicant]
Heyes, J., et al., “Lipid Encapsulation Enables the Effective Systemic Delivery of Polyplex Plasmid DNA,” Molecular Therapy 15(4):713-720, Apr. 2007. [cited by applicant]
Hope, M.J., et al., “Generation of Multilamellar and Unilamellar Phospholipid Vesicles,” Chemistry and Physics of Lipids 40(2-4 ):89-107, Jun.-Jul. 1986. [cited by applicant]
Jahn, A., et al., “Preparation of Nanoparticles by Continuous-Flow Microfluidics,” Journal of Nanoparticle Research 10(6):925-934, Aug. 2008. [cited by applicant]
Jeffs, L.B., et al., “A Scalable, Extrusion-Free Method for Efficient Liposomal Encapsulation of Plasmid DNA,” Pharmaceutical Research 22(3):362-372, Mar. 2005. [cited by applicant]
Johnson, B.K., and R.K. Prud'Homme, “Mechanism for Rapid Self-Assembly of Block Copolymer Nanoparticles,” Physical Review Letters 91(11):118302-1-118302-4, Sep. 2003. [cited by applicant]
Kapoor, M., et al., “Physicochemical Characterization Techniques for Lipid Based Delivery Systems for siRNA,” International Journal of Pharmaceutics 427(1 ):35-57, May 2012. [cited by applicant]
Karnik, R., et al., “Microfluidic Platform for Controlled Synthesis of Polymeric Nanoparticles,” Nano Letters 8(9):2906-2912, Sep. 2008. [cited by applicant]
Koh, C.G., et al., “Delivery of Antisense Oligodeoxyribonucleotide Lipopolyplex Nanoparticles Assembled by Microfiuidic Hydrodynamic Focusing,” Journal of Controlled Release 141(1):62-69, Jan. 2010. [cited by applicant]
MacLachlan, I., “Liposomal Formulations for Nucleic Acid Delivery,” in S.T. Crooke (ed.), “Antisense Drug Technology: Principles, Strategies, and Applications,” 2nd ed., Chap. 9, CRC Press, Jul. 2007. [cited by applicant]
Montana, G., et al., “Employment of Cationic Solid-Lipid Nanoparticles as RNA Carriers,” Bioconjugate Chemistry 18:302-308, Published on Web Jan. 25, 2007. [cited by applicant]
Peer, D., and R. Margalit, “Tumor-Targeted Hyaluronan Nanoliposomes Increase the Antitumor Activity of Liposomal Doxorubicin in Syngeneic and Human Xenografl Mouse Tumor Models,” Neoplasia 6(4):343-353, Jul.-Aug. 2004. [cited by applicant]
Rudra, A., et al., “Doxorubicin-Loaded Phosphatidylelhanolamine-Conjugated Nanoliposomes: In Vitro Characterization and Their Accumulation in Liver, Kidneys, and Lungs in Rats,” International Journal of Nanomedicine 5:8… [cited by applicant]
Seo, M., et al., “Microfluidic Assembly of Monodisperse, Nanoparticle-Incorporated Perfluorocarbon Microbubbles for Medical Imaging and Therapy,” Langmuir 26(17):13855-13860, Published on Web Jul. 28, 2010. [cited by applicant]
Szoka, F., Jr., “Comparative Properties and Methods of Preparation of Lipid Vesicles (Liposomes),” Annual Review of Biophysics and Bioengineering 9:467-508, 1980. [cited by applicant]
Vemuri, S., and C.T. Rhodes, “Preparation and Characterization of Liposomes as Therapeutic Delivery Systems: A Review,” Pharmaceutica Acta Helvetiae 70(2):95-111, Jul. 1995. [cited by applicant]
Ku, Y., et al., “Physicochemical Characterization and Purification of Cationic Lipoplexes,” Biophysical Journal 77(1):341-353, Jul. 1999. [cited by applicant]
Yu, B., et al., “Microfluidic Methods for Production of Liposomes,” Methods in Enzymology 465:129-141, 2009. [cited by applicant]
Zhang, J., et al., “Assessing the Heterogeneity Level in Lipid Nanoparticles for siRNA Delivery: Size-Based Separation, Composition at Heterogeneity, and Impact of Bioperformance,” Molecular Pharmaceutics 10(1):397-405,… [cited by applicant]
Zhang, J., et al., “Polydispersity Characterization of Lipid Nanoparticles for siRNA Delivery Using Multiple Detection Size-Exclusion Chromatography,” Analytical Chemistry 84(14):6088-6096, Jul. 2012. [cited by applicant]
Zhigal Tsev, IV., et al., “Bottom-Up Design and Synthesis of Limit Size Lipid Nanoparticle Systems With Aqueous and Triglyceride Cores Using Millisecond Microfluidic Mixing,” Langmuir 28(7):3633-3640, Feb. 2012. [cited by applicant]
First Office Action mailed Jul. 15, 2014, issued in Japanese Patent Application No. 2012-537274, filed Nov. 4, 2010, 5 pages. [cited by applicant]
Decision of Rejection mailed Apr. 7, 2015 (with foreign associate's comments), issued in Japanese Application No. 2012-537274, filed Nov. 4, 2010, 6 pages. [cited by applicant]
International Search Report and Written Opinion mailed Feb. 8, 2011, issued in International Application No. PCT/CA2010/001766, filed Nov. 4, 2010, 17 pages. [cited by applicant]
International Preliminary Report on Patentability mailed May 18, 2012, issued in International Application No. PCT/CA2010/001766, filed Nov. 4, 2010, 11 pages. [cited by applicant]
Notification Concerning Transmittal of International Preliminary Report on Patentability, International Preliminary Report on Patentability and Written Opinion mailed May 18, 2012, issued in International Application No… [cited by applicant]
International Search Report mailed Feb. 18, 2013, issued in International Application No. PCT/CA2012/000991, filed Oct. 25, 2012, 18 pages. [cited by applicant]
Notification of the Second Office Action, issued Jan. 24, 2014, in Chinese Application No. 201080059999.7, filed Nov. 4, 2010, 7 pages. [cited by applicant]
Notification of the Third Office Action, mailed Oct. 15, 2014, issued in Chinese Application No. 201080059999.7, filed Nov. 4, 2010, 7 pages. [cited by applicant]
Notification of the Fourth Office Action mailed Jul. 6, 2015, issued in Chinese Application No. 201080059999.7, filed Nov. 4, 2010, 10 pages. [cited by applicant]
Office Action mailed Oct. 10, 2014, issued in Russian Application No. 2012122776, filed Nov. 4, 2010, 12 pages. [cited by applicant]
Partial Supplementary European Search Report mailed Jun. 1, 2015, issued in corresponding European Application No. 12843980.9, filed Oct. 25, 2012, 5 pages. [cited by applicant]
Extended European Search Report mailed Oct. 6, 2015, issued in corresponding European Application No. 12843980.9, filed Oct. 25, 2012, 7 pages. [cited by applicant]
Supplementary European Search Report mailed Dec. 6, 2013, issued in European Application No. 10 85 1175.9, filed Nov. 4, 2010, 10 pages. [cited by applicant]
Communication Pursuant to Article 94(3) EPC, issued Jul. 18, 2014, in European Application No. 10 85 1175.9, filed Nov. 4, 2010, 7 pages. [cited by applicant]
Extended European Search Report mailed Jul. 8, 2016, issued in corresponding European Patent Application No. 16166730.8, filed Oct. 25, 2012, 6 pages. [cited by applicant]
First Office Action mailed Jul. 20, 2016, issued in corresponding Japanese Application No. 2014-537433, filed Oct. 25, 2012, 8 pages. [cited by applicant]
Examination Search Report mailed Aug. 29, 2017, issued in corresponding Canadian Application No. 2,853,316, filed Oct. 25, 2012, 5 pages. [cited by applicant]
First Japanese Office Action mailed Feb. 9, 2018, issued in corresponding Japanese Application No. 2016-245508, filed Oct. 25, 2012, 3 pages. [cited by applicant]