# US 10,765,634 B2 · Controlled release formulations for the induction and proliferation of blood cells

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- Number: US 10,765,634 B2
- Document ID: US10765634B2
- Status: Granted
- Kind: B2
- Application number: 14/372,977
- Filed: 2013-01-22
- Published: 2015-03-19
- Granted: 2020-09-08
- Earliest claimed: 2012-01-24
- Assignees: University of Pittsburgh—Of the Commonwealth System of Higher Education
- Applicants: University of Pittsburgh—Of the Commonwealth System of Higher Education
- Inventors: Steven R. Little; Giorgio Raimondi; Angus W. Thomson; Siddharth Jhunjhunwala
- Web page: https://patentgrep.com/patent/US10765634B2

## CPC

- A61K 9/16: Agglomerates; Granulates; Microbeadlets {; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction (A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51)}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1641: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers}
- A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/1658: {Proteins, e.g. albumin, gelatin}
- A61K 31/203: Retinoic acids {; Salts thereof}
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 38/1841: {Transforming growth factor [TGF]}
- A61K 38/2013: {IL-2}
- A61K 38/2278: {Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)}
- A61K 39/0008: {Antigens related to auto-immune diseases; Preparations to induce self-tolerance}
- A61K 39/001: {Preparations to induce tolerance to non-self, e.g. prior to transplantation}
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The absence of regulatory T cells (Treg) may underlie disorders including but not limited to autoimmunity, dermatitis, periodontitis and even transplant rejection. Enhancing local numbers of Treg through in situ Treg expansion or induction is contemplated herein as a treatment option for these disorders. Current methods for in vivo Treg expansion are not Treg specific and are associated with many adverse side-effects. The data presented herein provides in vitro testing of a Treg-inducing microparticle providing a predictable controlled release for combinations of cytokines and drugs (e.g., IL-2, TGF-β, and/or rapamycin) resulting in targeted Treg migration. These controlled release microparticles are also capable of inducing FoxP3+ Treg in human cells in vitro suggesting that these compositions be developed into an in vivo Treg induction and expansion therapy.

## Claims

### Claim 1

A method for inducing folate receptor 4 expressing regulatory T-cells at a tissue of a subject having an inflammatory disorder, wherein the tissue exhibits at least one symptom of the inflammatory disorder, comprising:
administering a formulation locally to said target the tissue, wherein the formulation comprises a first sustained release microparticle population comprising transforming growth factor beta, a second sustained release microparticle population comprising rapamycin, and a third sustained release microparticle population comprising IL-2;
wherein the transforming growth factor beta, the rapamycin, and IL-2 are released at the tissue to induce the folate receptor 4 expressing regulatory T-cells.

### Claim 2 (depends on 1)

The method of claim 1, wherein one or more microparticle population comprises a polymer, and wherein the weight ratio of a therapeutic agent to the polymer is between about 1:100000 and about 1:1.

### Claim 3 (depends on 2)

The method of claim 2, wherein the weight ratio of a therapeutic agent to the polymer is between about 1:20000 and about 1:500.

### Claim 4 (depends on 3)

The method of claim 3, wherein the weight ratio of a therapeutic agent to the polymer is between about 1:10000 and about 1:500.

### Claim 5 (depends on 1)

The method of claim 1, wherein the IL-2 microparticle has an initial release burst.