# US 11,433,135 B2 · High capacity diketopiperazine microparticles and methods

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- Number: US 11,433,135 B2
- Document ID: US11433135B2
- Status: Granted
- Kind: B2
- Application number: 16/739,506
- Filed: 2020-01-10
- Published: 2020-05-14
- Granted: 2022-09-06
- Earliest claimed: 2011-06-17
- Assignees: MannKind Corporation
- Applicants: MannKind Corporation
- Inventors: Marshall Grant; Paul Menkin; Grayson W. Stowell
- Web page: https://patentgrep.com/patent/US11433135B2

## CPC

- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61K 9/0075: {for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles}
- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 9/50: Microcapsules {having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals (A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167)}
- A61K 38/28: Insulins
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/18: of the parathyroid hormones
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- Y10T 428/2982: Particulate matter [e.g., sphere, flake, etc.]
- 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
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

Disclosed herein are diketopiperazine microparticles having high capacity for adsorbing a drug or active agent. In particular, the diketopiperazine microparticle are formed using fumaryl diketopiperazine and can comprise a drug in large doses for the treatment of disease or disorders by pulmonary delivery via oral inhalation.

## Claims

### Claim 1

A drug deliverable agent for pulmonary inhalation for treating disease, the drug deliverable agent comprising:
diketopiperazine microparticles; wherein said diketopiperazine microparticles comprise
a specific surface area greater than about 70 m2/g,
a mass-weighted average particle size of about 33,000 to about 216,000 voxels measured by X-ray tomography for particle size measuring about 0.5 μm to about 4 μm in geometric diameter,
a plurality of structural domains having one or more cores surrounded by layers of a porous crystalline material, and
a concentration of an active ingredient, or analog thereof, of about 18% to about 25% by weight of said microparticle.

### Claim 2 (depends on 1)

The drug deliverable agent of claim 1, wherein said diketopiperazine microparticles comprise a voxel-weighted average domain size of about 300 nm to about 400 nm.

### Claim 3 (depends on 1)

The drug deliverable agent of claim 1, wherein said diketopiperazine is fumaryl diketopiperazine (3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; or salt thereof.

### Claim 4 (depends on 1)

The drug deliverable agent of claim 1, wherein said active ingredient is a small organic molecule.

### Claim 5 (depends on 1)

The drug deliverable agent of claim 1, wherein said active ingredient is a neurotransmitter, pain relief agent, vasoactive agent, immunosuppressing agent, anti-cancer agent, vaccine, nucleic acid molecule or prophalactive agent.

### Claim 6 (depends on 1)

The drug deliverable agent of claim 1, wherein said active ingredient is a triptan selected from sumatriptan, rizatriptan and salts thereof.

### Claim 7 (depends on 1)

The drug deliverable agent of claim 1, wherein said active ingredient is a peptide wherein the peptide is insulin, glucagon, glucagon-like peptide-1, oxyntomodulin, peptide YY(3-36), ghrelin, vasoactive intestinal peptide, oxytocin or CCK.

### Claim 8 (depends on 1)

The drug deliverable agent of claim 1, wherein said active ingredient is insulin.

### Claim 9 (depends on 8)

The drug deliverable agent of claim 8, wherein said fumaryl diketopiperazine comprises an insulin content greater than about 4 U/mg.

### Claim 10 (depends on 1)

The drug deliverable agent of claim 1, wherein the diketopiperazine microparticles comprise structural domains ranging in number-weighted size from about 250 voxels to about 1,400 voxels.

### Claim 11 (depends on 1)

The drug deliverable agent of claim 1, wherein the diketopiperazine microparticles comprise structural domains ranging in voxel-weighted size from about 500 voxels to about 2,000 voxels.

### Claim 12 (depends on 1)

The drug deliverable agent of claim 1, wherein the plurality of structural domains have an average size from about 300 nm to about 450 nm as measured by radius of gyration.

### Claim 13 (depends on 1)

The drug deliverable agent of claim 1, further comprising a surfactant.

### Claim 14 (depends on 13)

The drug deliverable agent of claim 13, wherein the surfactant is polysorbate 80.

### Claim 15 (depends on 1)

The drug deliverable agent of claim 1, wherein the deliverable agent is in an inhalable dry powder form.

### Claim 16 (depends on 15)

The drug deliverable agent of claim 15, wherein the deliverable agent is capable of delivery to a patient in a single inhalation to the deep lung using a dry powder inhaler.