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US-12622873-B2 - Composition of matter comprising liposomes embedded in a polymeric matrix and methods of using same

US12622873B2US 12622873 B2US12622873 B2US 12622873B2US-12622873-B2

Abstract

The present disclosure provides a composition of matter comprising liposomes encapsulating in their intraliposomal aqueous compartment at least one active agent, the liposomes having a diameter of at least 200 nm and being embedded in a water insoluble, water absorbed cross-linked polymeric matrix. In one embodiment, the composition of matter is held within an aqueous medium, preferably being in iso-osmotic equilibrium with the intraliposomal aqueous compartments of the liposomes. The present disclosure also provides a method of removal of non-encapsulated active agent from the composition of matter, a method of preparing said composition of matter, a pharmaceutical composition comprising said composition of matter, use of such composition of matter; a method of providing prolonged delivery of an active agent to a subject in need thereof by administering to said subject the composition of matter disclosed herein as well as a package comprising said composition of matter held within said aqueous medium and instructions for use thereof.

Inventors

  • Yechezkel Barenholz
  • Rivka Cohen

Assignees

  • YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY OF JERUSALEM LTD.

Dates

Publication Date
20260512
Application Date
20231102

Claims (18)

  1. 1 . A method of treating pain in a patient comprising: (i) providing a composition comprising (a) an external storage solution having a first osmolality comprising at least one water-soluble lipid permeable analgesic drug having a first concentration, wherein the water-soluble lipid permeable analgesic drug has a molecular weight of less than or equal to 500 Da, and a log P of greater than 2.2; and (b) particles contained within the external storage solution wherein the particles comprise (i) a water insoluble water absorbed cross-linked polymeric matrix and (ii) liposomes contained within the water insoluble water absorbed cross-linked polymeric matrix, wherein the liposome comprises cholesterol and a liposome forming lipid having a Tm greater than or equal to 41° C.; wherein the liposomes have an intraliposomal aqueous compartment containing an intraliposomal solution having a second osmolality, comprising the at least one water soluble, lipid permeable active agent having a molecular weight of less than or equal to 500 Da, and a log P of greater than 2.2 at a second concentration; wherein the first osmolality is not more than 50 mOsmoles higher than the second osmolality; and wherein the second concentration is at least three times greater than the first concentration; (ii) removing the external storage solution to provide a solution containing the particles; and (iii) administering the particle containing solution to the patient.
  2. 2 . The method of claim 1 wherein the analgesic drug is selected from the group consisting of benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, propoxycaine, procaine, proparacaine, tetracaine, articaine, bupivacaine, carticaine, cinchocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimecaine, saxitoxin and tetrodotoxin.
  3. 3 . The method of claim 2 , wherein the analgesic drug is bupivacaine.
  4. 4 . The method of claim 1 , wherein the analgesic drug is a non-steroidal anti-inflammatory drug.
  5. 5 . The method of claim 1 , wherein the pain is due to osteoarthritis.
  6. 6 . The method of claim 1 , wherein the pain is due to rheumatoid arthritis.
  7. 7 . The method of claim 1 , wherein said administering is by either parenteral injection or infusion.
  8. 8 . The method of claim 7 where in said administering is selected from the group consisting of intravenous, intraarterial, intramuscular, intracerebral, intracerebroventricular, intracardiac, subcutaneous, intraosseous, intradermal, intratheacal, intraperitoneal, intravesical, and intracavernosal and epidural injection or infusion.
  9. 9 . The method of claim 8 , wherein the administration is intramuscular.
  10. 10 . The method of claim 1 , wherein said administering is selected from the group consisting of transdermal, transmucosal, inhalation or intravitreal administration.
  11. 11 . The method of claim 1 , wherein said administering is local administration.
  12. 12 . The method of claim 1 , wherein the liposome forming lipid is selected from the group consisting of glyercophospholipid, monocationic lipid, polycationic lipids and sphingomyelin.
  13. 13 . The method of claim 12 , wherein the glycerophospholipid is selected from the group consisting of glycerophospholipid, phosphatidylglycerols (PG), phosphatidylcholine (PC), phosphatidic acid (PA), phosphatidylinositol (PD), and phosphatidylserine (PS).
  14. 14 . The method of claim 13 , wherein the glycerophospholipid is phosphatidylcholine.
  15. 15 . The method of claim 12 , wherein the monocationic lipid is selected from the group consisting of 1,2-dimyristoyl-3-trimethylammonium propane (DMTAP) 1,2-dioleyloxy-3-(trimethylamino) propane (DOTAP); N-[1-(2,3,-ditetradecyloxy) propyl]-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE); N-[1-(2,3,-dioleyloxy) propyl]-N,N-dimethyl-N-hydroxy ethyl-ammonium bromide (DORIE); N-[1-(2,3-dioleyloxy) propyl]-N,N,N-trimethylammonium chloride (DOTMA); 3P [N—(N,N′-dimethylaminoethane) carbamoly]cholesterol (DC-Chol); and dimethyl-dioctadecylammonium (DDAB).
  16. 16 . The method of claim 12 , wherein the polycationic lipid is selected from the group consisting of N-[2-[2,5-bis [3-aminopropyl)amino]-1-oxopentyl] amino] ethyl]-N,N-dimethyl-2,3-bis [(1-oxo-9-octadecenyl)oxy]-1-propanaminium (DOSPA), and ceramide carbamoyl spermine (CCS).
  17. 17 . The method of claim 13 , wherein said phosphatidylglycerols is dimyristoyl phosphatidylglycerol (DMPG).
  18. 18 . The method of claim 14 , wherein said phosphatidylcholine (PC) is selected from the group consisting of egg yolk phosphatidylcholine, dimyristoyl phosphatidylcholine (DMPC), 1-palmitoyl-2-oleoylphosphatidyl choline (POPC), hydrogenated soy phosphatidylcholine (HSPC), and distearoylphosphatidylcholine (DSPC).

Description

RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 17/066,034, filed Oct. 8, 2020, which is a continuation of U.S. application Ser. No. 16/254,084, filed Jan. 22, 2019, now U.S. Pat. No. 10,842,745 which is a continuation of U.S. application Ser. No. 15/626,836, filed Jun. 19, 2017, which is a continuation of U.S. application Ser. No. 13/123,130, filed Jun. 22, 2011, now U.S. Pat. No. 9,713,591, which is a national phase filing under 35 U.S.C. 371 of International Application No. PCT/IL2009/000967, filed on Oct. 11, 2009, and claims the benefit of U.S. Provisional Application Ser. No. 61/103,440, filed Oct. 7, 2008, the entirety of these applications are hereby incorporated herein by reference for the teachings therein. FIELD OF THE INVENTION The present disclosure is in the field of biochemistry and in particular to compositions of matter comprising a combination of polymers and liposomes for carrying active agents. BACKGROUND OF THE INVENTION Among other applications, liposomes are used as carriers of drugs for delivery via a plurality of mechanisms. To this end, various types of liposomes are used, from small unilamellar vesicles (SUV), large unilamellar vesicles (LUV), multilamellar vesicles (MLV), multivesicular vesicles (MVV), large multivesicular vesicles (LMVV, also referred to, at times, by the term giant multivesicular vesicles, “GMV”), oligolamellar vesicles (OLV), and others. It is appreciated by those versed in the art that LMVV are somewhat different from unilamellar vesicles of various sizes and of the “onion like” MLV structure. In LMVV the amount of aqueous medium forming the aqueous phase per the amount of lipid is greater than that in MLV, this potentially allowing higher amount of drug to be loaded into the aqueous phase, namely, higher drug to lipid mole ratio in the LMVV when compared to MLV system of similar size distribution. This difference was exemplified by Grant et al. 2004 [Anesthesiology 101(1):133-7, 2004] and in U.S. Pat. No. 6,162,462. It has been found that the difference in structure between MLV an LMVV not only allows higher loading of the drug into the liposomes but also a prolonged release of the drug from the LMVV system. Specifically, U.S. Pat. No. 6,162,462 discloses liposomal bupivacaine compositions in which the bupivacaine is loaded by a transmembrane ammonium sulfate gradient, the liposomes being giant multivesicular vesicles (GMV, a synonym for LMVV) having a mole ratio of encapsulated drug to lipid in said liposomal composition of at least 1.0. A specific drug encapsulated in the liposomes of U.S. Pat. No. 6,162,462 is the amphipathic analgesic drug bupivacaine (BUP). These bupivacaine loaded LMVV have shown to be provide superior analgesia in mice and humans [Grant et al. 2004, ibid. and U.S. Pat. No. 6,162,462]. However, a phenomenon that still remains unresolved with these LMVV relates to leakage of bupivacaine from the LMVV during storage at 4° C. or room temperature. Thus, after time, free drug is contained in the composition of matter (the amount may be above drug MTD) and the administration of the composition of matter containing such free drug may result in toxicity and unwanted side effects (from exposure high amounts of free drug), unfavorable pharmacokinetics and shorter duration of the therapeutic effect. Thus, there is a need in the art to provide a composition of matter where leakage of drug from liposomes encapsulating same during storage is reduced or prevented. SUMMARY OF THE INVENTION The present disclosure provides, in accordance with a first of its aspects, a composition of matter comprising liposomes encapsulating in their intraliposomal aqueous compartment at least one active agent, the liposomes having a diameter of at least 200 nm and being embedded in a water insoluble, water absorbed cross-linked polymeric matrix. In one embodiment, this composition of matter is held in an aqueous medium, e.g. a storing medium. It has been found and shown herein that keeping the composition of matter in a suitable aqueous medium, as further defined herein, significantly reduces the amount of material that leaks from the liposomes. Also provided by the present disclosure is a method of preparing a composition of matter comprising liposomes encapsulating in their intraliposomal aqueous compartment at least one active agent, the liposomes having a diameter of at least 200 nm and being embedded in a cross-linked water insoluble and water absorbed polymeric matrix, the method comprising mixing (i) liposomes encapsulating in their intraliposomal aqueous compartment at least one active agent, the liposomes having a diameter of at least 200 nm; (ii) at least one cross-linkable polymer; and (iii) an aqueous solution comprising a cross-linker capable of forming with said cross-linkable polymer a water insoluble, water absorbed cross-linked polymer having embedded therein said liposomes. Also provided herein is a method for remov