OA13136A - Pulmonary administration of chemically modified insulin. - Google Patents

Pulmonary administration of chemically modified insulin. Download PDF

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Publication number
OA13136A
OA13136A OA1200300305A OA1200300305A OA13136A OA 13136 A OA13136 A OA 13136A OA 1200300305 A OA1200300305 A OA 1200300305A OA 1200300305 A OA1200300305 A OA 1200300305A OA 13136 A OA13136 A OA 13136A
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OA
OAPI
Prior art keywords
insulin
composition
peg
polyethylene glycol
administration
Prior art date
Application number
OA1200300305A
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English (en)
Inventor
John S Patton
Mei-Chang Kuo
Milton J Harris
Chester Leach
Kimbery Perkins
Blaine Bueche
Original Assignee
Nektar Therapeutics
Nektar Therapeutics Al Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Nektar Therapeutics, Nektar Therapeutics Al Corp filed Critical Nektar Therapeutics
Publication of OA13136A publication Critical patent/OA13136A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)

Claims (75)

1 3136 · -62- IT rs CLAIMED:
1. An irssulin composition for puimonary administration, said compositioncoroprising a conjugale of insulin covaientîy coupled to one or more molécules of a non-naturally occurring hydrophilic polymer.
2. The insulin composition of claim 1, whercin said conjugate is absent a lipophiliemoiety.
3. The insulin composition of claim i, wherein said non-naturally occurringhydrophilic polymer is a polyalkyene glycol.
4. The insulin composition of claim i, wherein said non-naturally occurringhydrophilic polymer is polyethylene glycol.
5. The insulin composition of claim 2, wherein said non-naturally occurringhydrophilic polymer is polyethylene glycoi.
6. The composition of claim 4, characterized by an absolute puimonary bioavailability thaï is greater than that of native insulin.
7. The composition of claim 6, characterized by an absolute puimonary bioavailability that is at least twice that of native insulin. S. The composition of claim 4, characterized by an absolute puimonary bioavailability greater than 15%.
9. The composition of claim 8, characterized by an absolute puimonary bioavailability greater than 30%.
10. The composition of claim 4, which when administered to the lung, is characterizedby a Tmax that is at least three times that of native insulin. DUPLICATA 1 3136 · -63-
1 - The composition of daim 10, which when administered to the iung, ischaracterized by a Tmax that is at least five limes that of native insulin.
12. The composition of ciaim 4, wherein said polyethylene giycol is end-capped.
13. The composition of ciaim 12, wherein said polyethylene giycol is end-capped withan alkoxy group.
14. The composition of daim 4, wherein said polyethylene giycol is selected from thegroup consisting of linear polyethylene giycol, branched polyethylene giycol, forkedpolyethylene giycol, and dumbbell polyethylene giycol.
15. The composition of daim 14, wherein said polyethylene giycol comprises abiodégradable linkage. ·
16. The composition of ciaim 14, wherein said polyethylene giycol comprises anumber of (OCH2CH2) subunits selected from the group consisting of from about 2 to 300subunits, from about 4 to 200 subunits, and from about 10 to 100 subunits.
17. The composition of ciaim 14, wherein said polyethylene giycol has a nominalaverage molecular weight from about 200 to about 10,000 daltons.
18. The composition of ciaim 14, wherein said polyethylene giycol is linear.
19. The composition of daim 17, wherein said polyethylene giycol has a nominalaverage molecular weight from about 200 to about 5,000 daltons.
20. The composition of ciaim 17, wherein said polyethylene giycol has a nominalaverage molecular weight from about 200 to about 2,000 daltons.
21. The composition of ciaim 17, wherein said polyethylene giycol has a nominalaverage molecular weight from about 200 to about 1,000 daltons. DUPLICATA -64- 1 3136
22. The composition of claim 4, wherein said insulin is native insulin.
23. The composition of claim 4, wherein said conjugate has a purity of greater than90 %. 5
24. The composition of claim 4, wherein said insulin is covalently coupled topolyethyiene glycol at one or more of its amino sites.
25. The composition of claim 24, wherein at least about 75% of the B-lPhe sites on 10 insulin are covalently coupled to polyethyiene glycol.
26. The composition of claim 25, wherein at least about 90% of the B-lPhe sites oninsulin are covalently coupled to polyethyiene glycol.
27. The composition of claim 24, comprising a mixture of monomer and dimer conjugales of insulin.
28. The composition of claim 27, further comprising a trimer insulin conjugate.
29. The composition of claim 4, wherein said insulin is covalently coupled to polyethyiene glycol via a iinking moiety positioned at a terminus of said polyethyieneglycol.
30. The composition of claim 4, wherein said polyethyiene glycol, prior to coupling 25 with insulin, possesses an activated Iinking moiety at one terminus suitable for covaient coupling with insulin.
31. The composition of claim 30, wherein said activated Iinking moiety is suitable forcoupling with reactive insulin amino groups. 30
32. The composition of claim 31, wherein said activated Iinking moiety comprises areactive functional group selected from the group consisting of N-hydroxysuccinimideactive esters, active carbonates, aldéhydes, and acetais. DUPLICATA -65- 13136,
33. The composition of claim 29, wherein insulin is covalently coupled to poiyethylene glycol via an amide linkage.
34. The composition of claim 4 in aerosolized form.
35. The composition of claim 4 in Iiquid or dry form.
36. The composition of claim 4 further comprising a pharmaceutically acceptableexcipient.
37. The composition of claim 4 in spray-dried form.
38. A method for delivering insulin to a mammalian subject in need thereof, saidmethod comprising: aerosolizing the insulin composition of claim 4, and administering said aerosolized insulin composition by inhalation for déposition inand absorption from the lung of said subject.
39. A method for providing a substantially non-immunogenic insulin composition foradministration to the lung of a subject in need thereof, said method comprising: covalently coupîing insulin to one or more molécules of a non-naturally occurringhydrophilic polymer to provide a composition comprising an insulin-hydrophilic polvmerconjugate, and administering said composition to the lung of a subject in need thereof byinhalation, whereby as a resuit of said administering, said insulin passes through the lungand enters into the blood circulation.
40. The method of claim 39, wherein said non-naturally occurring hydrophilicpolymer is a polyalkylene glycol. DUPLICATA -66- 13136
41. A method for providing a prolonged-effect insulin composition for administrationto the lung of a subject in need thereof, said method comprising: covalently coupiing insulin to one or more molécules of a non-naturally occurringhydrophilic polymer to provide a composition comprising an insulin-hydrophilic polymerconjugate, administering said composition to the lung of a subject in need thereof byinhalation, whereby as a resuit of said administering, (i) said insulin passes through thelung and enters the blood circulation, and (ii) elevated blood levels of insulin aresustained for at least 8 hours post administration.
42. The method of claim 41, wherein said non-naturally occurring hydrophilicpolymer is a polyalkylene glycol.
43. The method of claim 42, wherein said non-naturally occurring hydrophilicpol ymer i s pol yeth ylene gl ycol.
44. The method of claim 43, whereby elevated levels of insulin are sustained for atleast 10 hours post-administration.
45. The method of claim 43, whereby elevated levels of insulin are sustained for atleast 12 hours post-administration.
46. The method of claim 43, whereby further as a resuit of said administering, glucoselevels in said subject are suppressed for at least 10 hours post administration.
47. The method of claim 46, whereby further as a resuit of said administering, glucoselevels in said subject are suppressed for at least 12 hours post administration.
48. The method of claim 43, wherein said administering step comprises administeringsaid composition in aerosolized form.
49. The method of claim 43, further comprising the step of aerosolizing saidcomposition prior to administering. DUPLICATA 13136·
50. The method of claim 43, wherein said coupling step comprises covalentlycoupling insulin to polyethylene glycoi in a site-specific fashion.
51. The method of claim 43, wherein said coupling step comprises covalentlycoupling insulin to polyethylene glycoi in a random fashion.
52. The method of claim 43, wherein said conjugate when administered to the lung isfurther characterized by an absolute pulmonary bioavailability that is greater than that ofnative insulin.
53. The method of claim 43, wherein said coupling step comprises covalentlycoupling insulin to one or more molécules of end-capped polyethylene glycoi.
54. The method of claim 43, wherein said coupling step comprises covalentlycoupling insulin to one or more molécules of polyethylene glycoi selected from the groupconsisting of linear, branched, forked, and dumbbell polyethylene glycoi.
55. The method of claim 43, wherein said conjugate is absent a lipophilie moiety.
56. The method of claim 43, wherein said composition is absent a lipophiliecomponent.
57. The method of claim 43, wherein said coupling step comprises covalentlycoupling insulin to one or more molécules of polyethylene glycoi comprising abiodégradable linkage.
58. The method of claim 43, wherein said polyethylene glycoi comprises a number of(OCH7CH2) subunits selected from the group consisting of from about 2 to 300 subunits,from about 4 to 200 subunits, and from about 10 to 100 subunits.
59. The method of claim 43, wherein said polyethylene glycoi has a nominal averagemolecular weighl from about 200 to about 10,000 daltons. DUPLICATA 1 3136·* -68-
60. The method of daim 43, wherein said poiyethylene glycol has a nominal averagemolecular weight from about 200 to about 5,000 daltons.
61. The method of daim 43, wherein said poiyethylene glycol has a nominal averagemolecular weight from about 200 to about 2,000 daltons.
62. The method of daim 43, wherein said poiyethylene glycol has a nominal averagemolecular weight from about 200 to about 1,000 daltons.
63. The method of daim 43, wherein said coupling comprises coupling poiyethyleneglycol to insulin at one or more of its reactive amino sites.
64. The method of daim 63, wherein said poiyethylene glycol is coupled to insulin atmore or more of its reactive amino sites via a bond selected from the group consisting ofamide, urethane, and methylene amino.
65. The method of daim 63, wherein said coupling comprises reacting a poiyethyleneglycol having a terminal reactive group selected from the group consisting of N-hydroxysuccinimide active esters, active carbonates, aldéhydes, and acetals with one ormore reactive amino sites on insulin.
66. The method of daim 43, wherein said coupling results in a composition whereinat least about 75% of the B-lPhe sites on insulin are covalently coupled to poiyethyleneglycol.
67. The method of daim 43, wherein said coupling results in a composition whereinat least about 90% of the B-lPhe sites on insulin are covalently coupled to poiyethyleneglycol.
68. The method of daim 43, wherein said coupling results in a compositioncomprising a mixture of monomer and dimer conjugates of insulin. DUPLICATA -69- 13136·
69. The method of claim 68, wherein said coupiing results in a composition furthercomprising a trimer conjugate of insulin.
70. The method of ciaim 43, wherein said poiyethylene glycol comprises an activatedS linking moîety at one terminus suitable for covalent coupiing with insulin.
71. The method of claim 43, wherein said activated linking moiety comprises areactive functional group selected from the group consisting of N-hydroxysuccinimideactive esters, active carbonates, aldéhydes, and acetals. 10
72. The method of claim 70, wherein said linking moiety has a length of from about 2to about 20 atoms.
73. The method of claim 43, wherein said administering step comprises administering15 said composition by dry powder inhaler.
74. The method of claim 43, wherein said administering step comprises administeringsaid composition by a metered dose inhaler.
75. The method of claim 43, wherein said administering step comprises administering said composition by a nebulizer.
76. The method of ciaim 43, wherein said composition further comprises apharmaceutically acceptable excipient. 25
77. The method of claim 43, whereby as a resuit of administering said conjugatecomposition, sérum levcls of insulin that are at least 2 times greater than basai levels areachieved within 1 hour post administration. DUPLICATA
OA1200300305A 2001-05-21 2002-05-21 Pulmonary administration of chemically modified insulin. OA13136A (en)

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US (3) US6838076B2 (fr)
EP (1) EP1395294A4 (fr)
JP (1) JP2004535401A (fr)
KR (1) KR20030097876A (fr)
CN (2) CN1314445C (fr)
AP (1) AP1763A (fr)
AR (1) AR033903A1 (fr)
AU (1) AU2002303869B2 (fr)
BG (1) BG108494A (fr)
BR (1) BR0209896A (fr)
CA (1) CA2447236A1 (fr)
CO (1) CO5540371A2 (fr)
CZ (1) CZ20033182A3 (fr)
EA (1) EA007408B1 (fr)
EC (1) ECSP034855A (fr)
GE (1) GEP20063917B (fr)
HR (1) HRP20030949A2 (fr)
HU (1) HUP0400442A2 (fr)
IL (2) IL158862A0 (fr)
IS (1) IS7043A (fr)
LT (1) LT5153B (fr)
LV (1) LV13197B (fr)
MA (1) MA26185A1 (fr)
MX (1) MXPA03010649A (fr)
MY (1) MY137181A (fr)
NO (1) NO20035157D0 (fr)
NZ (1) NZ529572A (fr)
OA (1) OA13136A (fr)
PL (1) PL366911A1 (fr)
SK (1) SK15532003A3 (fr)
TN (1) TNSN03116A1 (fr)
TR (1) TR200400295T2 (fr)
WO (1) WO2002094200A2 (fr)
YU (1) YU98503A (fr)
ZA (1) ZA200309085B (fr)

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