Pharmaceutical formulations for the treatment of pulmonary arterial hypertension

• US 10,245,244 B2
• Filed: 01/09/2015
• Issued: 04/02/2019
• Est. Priority Date: 01/10/2014
• Status: Active Grant

• Current Assignee: Heart Biotech Pharma Limited
• Original Assignee: Heart Biotech Pharma Limited
• Inventors: Yacoub, Magdi Habib, El Sherbiny, Ibrahim M
• Primary Examiner(s): Shin, Monica A
• Application Number:
  US14/593,604
• Publication Number:
  US 20150196516A1
• Time in Patent Office: 1,544 Days
• Field of Search: None
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/5036 Polysaccharides, e.g. gums, alginate; Cyclodextrin
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5161 Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 9/12 Antihypertensives

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

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.

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

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

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

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

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

7. The formulation of claim 6, wherein the crosslinked polymeric microparticles have a mean particle diameter ranging from 1 to 5 μ

m for inhalable formulations, and ranging from 1 to 500 μ

m for oral formulations.

8. 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%.

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

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

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

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

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

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

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

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

17. 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.

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

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

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

21. 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.