Pulmonary delivery of active agents

• US 6,693,073 B2
• Filed: 06/14/2002
• Issued: 02/17/2004
• Est. Priority Date: 07/27/1998
• Status: Expired due to Term

• Current Assignee: NOVO Nordisk North America Operations A/S (Novo Nordisk A/S)
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Gschneidner, David, Sarubbi, Donald J., Milstein, Sam J., Smart, John E., Leipold, Monica, OʼToole, Doris, Flanders, Elizabeth, Leone-Bay, Andrea
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US10/172,582
• Publication Number:
  US 20030072740A1
• Time in Patent Office: 613 Days
• Field of Search: 514/2, 514/3, 514/11, 514/12, 514/21, 514/56, 514/563
• US Class Current: 514/6.5
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: A61K 38/30 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 insulin-like growth factor binding protein A61K38/1754
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: C07C 235/64 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring

Abstract

The present invention provides methods for administering an active agent to an animal in need of the agent by the pulmonary route. This method comprises administering via the pulmonary route, a composition comprising (a) an active agent and (b)(i) an acylated amino acid, (ii) a sulfonated amino acid, or (iii) a combination of (i) and (ii). Administration of the compositions of the present invention provide improved pulmonary delivery and greater bioavailability of the active agent than administration of the active agent alone. As a result, lesser amounts of the active agent may be administered to obtain a desired result when contained in the composition of the present invention than when administered alone.

Claims

1. A method for administering a biologically-active agent to an animal in need of said agent, said method comprising administering via the pulmonary route to said animal a composition comprising:

(a) insulin; and

(b) a carrier comprising an acylated amino acid, a sulfonated amino acid, a polyamino acid which includes an acylated amino acid, a polyamino acid which includes a sulfonated amino acid, or any combination of any of the foregoing.

2. The method of claim 1, wherein the carrier is an acylated amino acid.

3. The method of claim 1, wherein the carrier comprises a compound having the formula

wherein

R¹ is C₁-C₇ alkyl, C₃-C₁₀ cycloalkyl, cycloalkenyl, aryl, thienyl, phenyl, naphthyl, pyrrolo, or pyridyl;

R¹ is optionally substituted with one or more C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₆-C₁₀ cycloalkyl, phenyl, phenoxy, F, Cl, Br, —

OH, —

SO₂, —

SO₃H, —

NO₂, —

SH, —

PO₃H, oxazolo, isoxazolo, alkoxy having the formula —

OR⁶, —

COOR⁷, —

N(R⁵)₂, —

N⁺(R⁵)3X, or any combination thereof;

X is halogen, hydroxide, sulfate, tetrafluoroborate, or phosphate;

R² is hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, or —

(CH2)_n—

COOH where n is 1 to 10;

R³ is C₁-C₂₄ alkyl, C₂-C₄ alkenyl, C₂-C₂₄ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, phenyl, naphthyl, (C₁-C₁₀ alkyl)phenyl, (C₂-C₁₀ alkenyl)phenyl, (C₁-C₁₀ alkyl)naphthyl, (C₂-C₁₀ alkenyl)naphthyl, phenyl(C₁-C₁₀ alkyl), phenyl(C₂-C₁₀ alkenyl), naphthyl(C₁-C₁₀ alkyl), or naphthyl(C₂-C₁₀ alkenyl);

R³ being optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy, —

OH, —

SH, halogen, —

NH₂, —

CO₂R⁴, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, heterocyclic having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S or any combination thereof, aryl, (C₁-C₁₀alk)aryl, ar(C₁-C₁₀ alkyl), or any combination thereof;

R⁴ is hydrogen, C₁-C₄ alkyl or C₂-C₄ alkenyl;

R⁵ is hydrogen or C₁-C₁₀ alkyl;

R⁶ is C₁-C₁₀ alkyl, alkenyl, alkynl, aryl or cycloalkyl; and

R⁷ is hydrogen, C₁-C₁₀ alkyl, alkenyl, alkynl, aryl or cycloalkyl.

4. The method of claim 1, wherein the carrier comprises a compound having the formula Ar—

Y—

(R⁸)_n—

OH, wherein Ar is a substituted or unsubstituted phenyl or naphthyl;

R⁸ has the formula

R⁹ is C₁-C₂₄ alkyl, C₂-C₄ alkenyl, phenyl, naphthyl, (C₁-C₁₀ alkyl) phenyl, (C₂-C₁₀ alkenyl)phenyl, (C₁-C₁₀ alkyl)naphthyl, (C₂-C₁₀ alkenyl)naphthyl, phenyl(C₁-C₁₀ alkyl), phenyl(C₂-C₁₀ to alkenyl), naphthyl(C₁-C₁₀ alkyl), or naphthyl(C₂-C₁₀ alkenyl);

R⁹ is optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ alkoxy, —

OH, —

SH, —

CO₂R¹¹, cycloalkyl, cycloalkenyl, heterocyclic alkyl, alkaryl, heteroaryl, heteroalkaryl, or any combination thereof;

R⁹ is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof;

R¹⁰ is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl; and

R¹¹ is hydrogen, C₁-C₂₄ alkyl, or C₂-C₄ alkenyl.

5. The method of claim 4, wherein Ar is a substituted or unsubstituted 2-OH phenyl.

6. The method of claim 1, wherein the carrier comprises a compound having the formula

or a salt thereof.

7. The method of claim 1, wherein the carrier comprises a compound having the formula

or a salt thereof.

8. The method of claim 1, wherein the carrier comprises a compound having the formula

or a salt thereof.