# US 10,245,244 B2 · Pharmaceutical formulations for the treatment of pulmonary arterial hypertension

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,245,244 B2
- Document ID: US10245244B2
- Status: Granted
- Kind: B2
- Application number: 14/593,604
- Filed: 2015-01-09
- Published: 2015-07-16
- Granted: 2019-04-02
- Earliest claimed: 2014-01-10
- Assignees: Heart Biotech Pharma Limited
- Applicants: Heart Biotech Pharma Limited
- Inventors: Magdi Habib Yacoub; Ibrahim M El Sherbiny
- Web page: https://patentgrep.com/patent/US10245244B2

## CPC

- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61P 11/00: Drugs for disorders of the respiratory system
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 9/5036: {Polysaccharides, e.g. gums, alginate; Cyclodextrin}
- A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/5161: {Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin}
- A61K 31/12: Ketones
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/5575: having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61P 9/12: Antihypertensives
- 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

Pharmaceutical formulations are described for use in the treatment of pulmonary arterial hypertension (PAH). The formulations comprise polymeric nanoparticles encapsulated within crosslinked polymeric hydrogel microparticles, wherein the polymeric nanoparticles carry a therapeutic agent suitable for treatment of PAH loaded within them (for example, prostacyclin synthetic analogs, PPAR β agonists and NO donors). Preferred formulations are inhalable, dry powder pharmaceutical formulations, which are able to swell on administration to the lungs of a patient.

## Claims

### Claim 1

A pharmaceutical formulation comprising polymeric nanoparticles encapsulated within crosslinked polymeric microparticles, wherein the polymeric nanoparticles carry a therapeutic agent suitable for treatment of pulmonary arterial hypertension (PAH) loaded within them, wherein the therapeutic agent is selected from the group consisting of a prostacyclin synthetic analog, PPAR β agonist, and NO donor, wherein the polymeric nanoparticles comprise a chitosan-derivative polymer selected from the group consisting of chitosan-PEG-Cholanic acid, chitosan-PEG-Stearic acid, and chitosan-PEG-Oleic acid, and wherein the PEG component of the polymer is connected to the chitosan component of the polymer by an ester bond, and wherein both the PEG component and the fatty acid component are connected to the same monosaccharide ring of the chitosan.

### Claim 2 (depends on 1)

The formulation of claim 1, which is an inhalable, dry powder pharmaceutical formulation.

### Claim 3 (depends on 1)

The formulation of claim 1, which is an oral pharmaceutical formulation.

### Claim 4 (depends on 1)

The formulation of claim 1, which is an injectable pharmaceutical formulation.

### Claim 5 (depends on 1)

The formulation of claim 1, wherein the nanoparticles have a mean particle diameter ranging from 1 to 500 nm.

### Claim 6 (depends on 5)

The formulation of claim 5, wherein the microparticles comprise a pH responsive carrier.

### Claim 7 (depends on 6)

The formulation of claim 6, wherein the crosslinked polymeric microparticles have a mean particle diameter ranging from 1 to 5 μm for inhalable formulations, and ranging from 1 to 500 μm for oral formulations.

### Claim 8 (depends on 1)

The formulation of claim 1, wherein the formulation is a dry formulation and the polymeric nanoparticles have a moisture content, in the dry formulation, of less than 2%.

### Claim 9 (depends on 8)

The formulation of claim 8, wherein the polymeric nanoparticles are produced via self assembly following sonication of amphiphilic polymer solutions.

### Claim 10 (depends on 9)

The formulation of claim 9, wherein the crosslinked polymeric microparticles are cross-linked hydrogel polymeric microparticles.

### Claim 11 (depends on 10)

The formulation of claim 10, wherein the polymeric hydrogel microparticles are pH-responsive and comprise semi-interpenetrating polymeric networks (semi-IPNs) or full-IPNs.

### Claim 12 (depends on 11)

The formulation of claim 11, wherein the microparticles comprise chitosan or a water soluble chitosan derivative.

### Claim 13 (depends on 12)

The formulation of claim 12, wherein the microparticles further comprise one or more polymers selected from the group consisting of hyaluronate, carrageenan, and oligoguluronate.

### Claim 14 (depends on 13)

The formulation of claim 13, wherein the microparticles incorporating nanoparticles are produced using spray-drying technique, spray gelation, or ionotropic gelation followed by lyophilization.

### Claim 15 (depends on 14)

The formulation of claim 14, wherein the microparticles are swellable.

### Claim 16 (depends on 15)

The formulation of claim 15, wherein the microparticle is able to swell to at least 500% of the original (dry formulation) size.

### Claim 17 (depends on 16)

The formulation of claim 16, wherein the formulation is an inhalable dry powder formulation, and wherein the microparticle is able to swell to a larger diameter within 10 minutes from administration to the lungs of a patient.

### Claim 18 (depends on 17)

The formulation of claim 17, wherein the microparticle comprises less than 7.5% water when in the dry formulation.

### Claim 19 (depends on 1)

The formulation of claim 1, wherein the therapeutic agent is a prostacyclin synthetic analog.

### Claim 20 (depends on 19)

The formulation of claim 19, wherein the analog is treprostinil or selexipag.

### Claim 21 (depends on 1)

A method of treating PAH, the method comprising administering a composition according to claim 1 to a subject, wherein the composition is administered to the subject by inhalation.