EP-4739283-A1 - PEPTIDE STEREOCOMPLEXATION WITH BIODEGRADABLE STEREOREGULAR POLYESTERS IN WATER AND HYDROGEL FORMS THEREOF

Abstract

The application discloses a stereocomplex of a hydrophilic stereoregular biodegradable polyester and a peptide active agent or a protein for delivery of peptides or proteins in vivo.

Inventors

• DOMB, Abraham Yaacov

Assignees

• Yissum Research Development Company of The Hebrew University of Jerusalem Ltd.

Dates

Publication Date

20260513

Application Date

20240703

Claims (20)

1. 1. A stereocomplex of a hydrophilic stereoregular biodegradable polyester and a peptide active agent or a protein, the stereocomplex having outwardly extending hydrophilic functional groups.
2. 2. The stereocomplex according to claim 1, being a solid composite of a polyester and a peptide active agent, wherein the composite is a hydrolysable stereocomplex of the polymer and the peptide active agent.
3. 3. The stereocomplex according to claim 1 or 2, being a particulate material having surface-extending (or surface-exposed) plurality of hydrophilic functionalities, wherein the hydrophilic functionalities are functionalities present on the polymer and/or the peptide active agent.
4. 4. The stereocomplex according to any one of the preceding claims, being a water- dispersible material.
5. 5. The stereocomplex according to any one of the preceding claims, formed in water or in an aqueous medium.
6. 6. The stereocomplex according to any one of the preceding claims, formed by a method comprising combining a solution of the peptide active agent of a given spatial configuration and a solution of the polymer of an opposite spatial configuration under conditions permitting complexation of the polymer and the peptide active agent, wherein one or both of the solutions is an aqueous solution.
7. 7. The stereocomplex according to claim 6, wherein a solution of the polymer is added onto a solution of the peptide active agent.
8. 8. The stereocomplex according to claim 6, the method comprises treating a solution of the peptide active agent of a given spatial configuration with a solution of the polymer of an opposite spatial configuration under conditions permitting complexation of the polymer and the peptide active agent, wherein both the solution comprising the peptide active agent and the solution comprising the polymer are aqueous solutions.
9. 9. The stereocomplex according to any one of the preceding claims, wherein the weight ratio of the peptide active agent: polymer is between 1:100 and 100:1, or between 1: 1 and
10. 10. The stereocomplex according to any one of the preceding claims, wherein the polymer is a D-configured polyester.
11. 11. The stereocomplex according to any one of the preceding claims, wherein stereocomplex is in a form of a nanoparticle.
12. 12. The stereocomplex according to any one of the preceding claims, in a form of a hydrogel with a protein.
13. 13. The stereocomplex according to claim 1, wherein the polyester is a water soluble homopolymer or block copolymer containing at least one stereoregular block that is of the opposite configuration to the L-configured peptide or protein.
14. 14. The stereocomplex according to claim 13, wherein the polyester contains a stereoregular block chain of at least 7 monomer units.
15. 15. The stereocomplex according to claim 14, wherein the monomer units are selected from D-lactic acid and D-oc-hydroxy acids derived from hydrophilic amino acids or tartaric acid and combinations thereof.
16. 16. The stereocomplex according to claim 15, wherein the D-oc-hydroxy acids are derived from serine, glutamine, glutamic acid, lysine, threonine, aspartic acid, cysteine, asparagine, histidine, tyrosine and methionine.
17. 17. The stereocomplex according to any one of the preceding claims, wherein the peptide active agent comprises a chain of at least three L-amino acids.
18. 18. The stereocomplex according to any one of the preceding claims, wherein the polyester is a stereoregular polymer having a stereochemical regularity in the sequential repeating units.
19. 19. The stereocomplex according to any one of the preceding claims, wherein the polyester is a block copolymer of a stereoregular homopolymer and a hydrophilic polymer.
20. 20. The stereocomplex according to any one of the preceding claims, wherein the polyester is a D-polylactic acid (D-PLA).

Description

PEPTIDE STEREOCOMPLEXATION WITH BIODEGRADABLE STEREOREGULAR POLYESTERS IN WATER AND HYDROGEL FORMS THEREOF FIELD OF INVENTION The technology disclosed herein generally concerns stereocomplexes of peptides and proteins with water soluble stereoregular polymers for controlled peptide delivery. Of particular interest are water soluble block copolymers of D-PLA with water-soluble polymers, including polyethylene glycol (PEG) and polysaccharides and compositions thereof for use in therapeutic peptides delivery and hydrogel formation. BACKGROUND Over one hundred peptide drugs, including insulin, LHRH, somatostatin and TRH, have been clinically used for treating various diseases. Advances in the synthesis of recombinant peptides, proteins, DNA and RNA, as well as the exquisite specificity and reduced side effects inherent in their use have raised interest in their clinical development. Peptides present multiple benefits as potential drugs. These include high selectivity, high potency, low toxicity and low accumulation in tissue. However, due to large size, low stability, enzymatic degradation and poor permeability through biological membranes, getting appropriate extended release for days and weeks after subcutaneous or intramuscular injection, absorption and high bioavailability whether by oral or mucosal routes of administration is still a challenge. Biodegradable polymers such as poly(lactic-glycolic acid) PLGA have been used for the extended delivery of leuprolide (Lupron Depot® and Zoladex), exenatide (Bydureon®), and octreotide (Sandostatin® LAR). Other strategies explored oral and nasal spray formulations (Miacalcin), inhalation devices (Afrezza), and transdermal patches but they did not lead to lasting commercial products. Beside the above mentioned few formulations for the delivery of peptides, most peptides are delivered by injection for immediate action and no other delivery systems for extended delivery, oral delivery or nasal and pulmonary delivery of peptide drugs are known. Biodegradable protein-based gels have been reported for medical and other applications. They are usually made by chemical crosslinking gelatin and other types of natural proteins to form gels. SUMMARY OF INVENTION Peptide therapeutics have gained interest in recent years due to their high specificity and reduced side effects. However, poor stability and low bioavailability by an administration mode other than injection has been proven limited; consequently, limiting development of slow or sustained release modalities. To improve delivery of peptide drugs and similar active agents, two practical limitations had to be overcome. The first limitation was the limited control over the release profile of the drug entity; and the second its presentation as a stable drug entity that could sustain different administration modes and formulations. The technology disclosed herein provides means for overcoming both limitations by providing solid forms of peptides which are stable, can be administered by a variety of administration modes and importantly enable quantified sustained or delayed release in vivo. The solid forms of the invention are stereocomplexes of two complementing materials, one being a peptide and the other a polymer that due to their opposite configurations interlock to form a stable composite, demonstrating improved physical and pharmaceutical properties. These solid forms may be caused to shed off the polymeric component or decompose to release the peptide in a controlled manner. The composite materials of the invention may be characterized by presence of a properly selected polymer that contributes to the stability of the composite and which is also susceptible to hydrolysis in a controlled manner. The composite materials are further unique in having a surface charge or a surface polarity that is derived from surface-exposed hydrophilic functionalities making up the polymer and/or the peptide agent. The presence of the surface-exposed functionalities not only contributes to improving the solubilization of the peptide in a variety of formulations, but also protects the composite from early or spontaneous degradation. In exemplified systems disclosed herein, water-soluble D-PLA-based copolymers, such as D-PLA-PEG di- and tri-block copolymers and D-PLA grafted dextran, were treated with insulin, LHRH, somatostatin and semaglutide, separately, to form particles (e.g., of a size between 100 and 400 nm) of the corresponding stereocomplexes composites. The process leading to the formation of the stereocomplexes was characterized by yield, DSC and turbidity. The affinity between the polymer, e.g., D-PLA-PEG and the peptide, e.g., insulin, was demonstrated by Micro Scale Thermophoresis (MST). In vitro release of insulin from the formed stereocomplex in PBS pH 7.4 solution, showed sustained release over a period of 80 days. Subcutaneous administration of the stereocomplex particles to diabetic mice exhibited reduced blood glucos