CA2510058A1 - Improved pharmaceutical botulinum toxin compositions - Google Patents

Improved pharmaceutical botulinum toxin compositions Download PDF

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Publication number
CA2510058A1
CA2510058A1 CA002510058A CA2510058A CA2510058A1 CA 2510058 A1 CA2510058 A1 CA 2510058A1 CA 002510058 A CA002510058 A CA 002510058A CA 2510058 A CA2510058 A CA 2510058A CA 2510058 A1 CA2510058 A1 CA 2510058A1
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Prior art keywords
composition
botulinum toxin
units
albumin
sequestration agent
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Granted
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CA002510058A
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French (fr)
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CA2510058C (en
Inventor
Gary E. Borodic
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Revance Therapeuticals Inc
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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
    • A61K38/38—Albumins
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A61K38/4893—Botulinum neurotoxin (3.4.24.69)
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Botulinum toxin, a well know systemic poison, produces favorable therapeutic effect by virtue of regionally attaching to nerves within the myoneural junction and possibly other tissues in a target region of a particular tissu e. The present invention provides compositions of botulinum toxin and a sequestration agent that increase sequestration and delivery of the botulinu m toxin to neural and associated tissues, as compared with available formulations of botulinum toxins, and thereby produce a beneficial clinical effect. The sequestration agents of the present invention include proteins, lipids and carbohydrates. A preferred composition of the present invention comprises a botulinum toxin and an albumin. The present invention also provides methods of treating neuromuscular diseases and pain using the disclosed compositions and methods of making the disclosed compositions.</SD OAB>

Claims (60)

1. A composition comprising botulinum toxin and a sequestration agent, wherein the sequestration agent is present in an amount between 550 and 550,000 µg sequestration agent per 100 LD50 units botulinum toxin.
2. The composition of claim 1, wherein the sequestration agent is present in an amount between 550 and 5,500 µg sequestration agent per 100 LD50 units botulinum toxin.
3. The composition of claim 1, wherein the sequestration agent is present in an amount between 5,500 and 13,000 µg sequestration agent per 100 LD50 units botulinum toxin.
4. The composition of claim 1, wherein the sequestration agent is present in an amount between 13,000 and 50,500 µg sequestration agent per 100 LD50 units botulinum toxin.
5. The composition of claim 1, wherein the sequestration agent is present in an amount between 50,500 and 505,000 µg sequestration agent per 100 LD50 units botulinum toxin.
6. The composition of claim 1, wherein the sequestration agent is formulated as encapsulated microspheres in an amount between 50,500 and 90,500 µg sequestration agent per 100 LD50 units botulinum toxin.
7. The composition of claim 1, wherein the botulinum toxin is selected from the group consisting of: botulinum toxin types A, B, C, D, E, F and G.
8. The composition of claim 7, wherein the botulinum toxin is botulinum toxin type A
from Hall strain Clostridium botulinum.
9. The composition of claim 1, wherein the botulinum toxin comprises fractionated-light-chain botulinum toxin.
10. The composition of claim 1, wherein the botulinum toxin consists essentially of fractionated light chain botulinum toxin.
11. The composition of claim 1, wherein the botulinum toxin consists essentially of a mixture of hybrid and chain-translocated forms of botulinum toxin.
12. The composition of claim 1, wherein the botulinum toxin consists essentially of chimeric forms of botulinum toxin.
13. The composition of claim 1, wherein the botulinum toxin has a specific activity greater than or equal to 20 LD50 units per nanogram botulinum toxin.
14. The composition of claim 1, wherein the ratio of LD50 units of botulinum toxin to µg sequestration agent is less than or equal to 0.2 for botulinum toxin type A.
15. The composition of claim 1 wherein the ratio of LD50 units of botulinum toxin to µg sequestration agent is less than or equal to 10 for botulinum toxin type B.
16. The composition of claim 1 further comprising a pharmaceutically acceptable carrier.
17. The composition of claim 1, wherein the botulinum toxin is noncovalently bound to the asequestration agent.
18. The composition of claim 1, wherein the botulinum toxin is covalently bound to the sequestration agent.
19. A composition of claim 1 further comprising zinc or a zinc salt.
20. The composition of claim 1, wherein the sequestration agent is albumin.
21. The composition of claim 1, wherein albumin is present in an amount between 550 and 5,500 µg albumin per 100 LD50 units botulinum toxin.
22. The composition of claim 1, wherein albumin is present in an amount between 5,500 and 13,000 µg albumin per 100 LD50 units botulinum toxin.
23. The composition of claim 1, wherein albumin is present in an amount between 13,000 and 50,500 µg albumin per 100 LD50 units botulinum toxin.
24. The composition of claim 1, wherein albumin is present in an amount between 50,500 and 505,000 µg albumin per 100 LD50 units botulinum toxin.
25. The composition of claim 1, wherein albumin is formulated as encapsulated microspheres in an amount between 50,500 and 90,500 µg albumin per 100 LD50 units botulinum toxin.
26. The composition of claim 1, wherein the albumin is formulated as a solid albumin particle.
27. The composition of claim 1, wherein the albumin is recombinantly produced.
28. The composition of claim 20 further comprising one or more additional sequestration agents.
29. The composition of claim 1, wherein the sequestration agent is selected from the group consisting of: proteins, lipids and carbohydrates.
30. The composition of claim 29, wherein the sequestration agent is collagen.
31. The composition of claim 29, wherein the sequestration agent is hyaluronate.
32. The composition of claim 29, wherein the sequestration agent is epinephrine.
33. A method of localized denervation in a subject in need thereof, comprising administering an effective amount of the composition of claim 1.
34. The method of claim 33, wherein the subject suffers from a neuromuscular disease associated with increased muscle tone or involuntary movement.
35. The method of claim 34, wherein the neuromuscular disease associated with increased muscle tone with involuntary. movement is blepharospasm or torticollis.
36. The method of claim 35, wherein the neuromuscular disease associated with increased muscle tone with involuntary movement is blepharospasm.
37. The method of claim 36, wherein the effective amount is between 10-200 LD50 units.
38. The method of claim 35, wherein the neuromuscular disease associated with increased muscle tone with involuntary movement is torticollis.
39. The method of claim 38, wherein the effective amount is between 10 and units.
40. A method of treating a condition selected from the group consisting of facial wrinkles, rhytides and cosmetic alteration of lip and brow, in a subject in need thereof, comprising administering an effective amount of the composition of claim 1.
41. The method of claim 40, wherein the effective amount is between 2.5 and units.
42. A method of treating human headache disorders in a subject in need thereof, comprising administering an effective amount of the composition of claim 1.
43. The method of claim 42, wherein the effective amount is between 5 and 1,000 LD50 units.
44. A method of treating human migraine headache disorders in a subject in need thereof, comprising administering an effective amount of the composition of claim 1.
45. The method of claim 44, wherein the effective amount is between 5 and 1,000 LD50 units.
46. A method of treating human inflammatory conditions in a subject in need thereof, comprising administering an effective amount of the composition of claim 1.
47. The method of claim 46, wherein the effective amount is between 5 and 4,000 LD50 units.
48. A method of treating myopathic or neuropathic pain in a subject in need thereof, comprising administering an effective amount of the composition of claim 1.
49. The method of claim 48, wherein the effective amount is between 5 and 4,000 LD50 units.
50. A method of treating back pain or arthritic pain in a subject in need thereof, comprising administering an effective amount of the composition of claim 1.
51. The method of claim 50, wherein the effective amount is between 5 and 4,000 LD50 units.
52. A method of treating gastrointestinal spasm and strictures in a subject in need thereof, comprising administering an effective amount of the composition of claim 1.
53. The method of claim 52, wherein the effective amount is between 5 and 4,000 LD50 units.
54. A method of treating a hyperhyrosis syndrome in a subject in need thereof, comprising administering of the composition of claim 1.
55. The method of claim 54, wherein the effective amount is between 5 and 4,000 LD50 units.
56. A method of producing the composition of claim 1, comprising mixing albumin to botulinum toxin in a weight to weight ratio which exceeds 100 µg albumin to 1 ng of botulinum toxin.
57. A method of producing the composition of claim 1, comprising freeze drying or flash drying a mixture of a botulinum toxin and albumin in a weight to weight ratio of 100 µg albumin to 1 ng of botulinum toxin.
58. A method of producing the composition of claim 1, comprising lyophilizing a mixture of a botulinum toxin and albumin in a weight to weight ratio of 100 µg to 1 ng of botulinum toxin.
59. A composition comprising botulinum toxin and a sequestration agent, wherein the sequestration agent is present in an amount between 550 and 900,500 µg sequestration agent per 100 LD50 units botulinum toxin.
60. The composition of claim 59, wherein the albumin is formulated as a solid albumin particle.
CA2510058A 2002-12-20 2003-12-22 Improved pharmaceutical botulinum toxin compositions Expired - Lifetime CA2510058C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US43590102P 2002-12-20 2002-12-20
US60/435,901 2002-12-20
PCT/IB2003/006145 WO2004060384A2 (en) 2002-12-20 2003-12-22 Pharmaceutical botulinum toxin compositions

Publications (2)

Publication Number Publication Date
CA2510058A1 true CA2510058A1 (en) 2004-07-22
CA2510058C CA2510058C (en) 2010-03-16

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CA2510058A Expired - Lifetime CA2510058C (en) 2002-12-20 2003-12-22 Improved pharmaceutical botulinum toxin compositions

Country Status (17)

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US (2) US7491403B2 (en)
EP (1) EP1594523B1 (en)
JP (1) JP2006519761A (en)
KR (1) KR20050094817A (en)
CN (1) CN100525831C (en)
AT (1) ATE426408T1 (en)
AU (2) AU2003300666A1 (en)
BR (1) BR0316871A (en)
CA (1) CA2510058C (en)
CR (1) CR9813A (en)
DE (1) DE60326887D1 (en)
IL (1) IL168745A0 (en)
MX (1) MXPA05006690A (en)
NO (1) NO20053424L (en)
NZ (1) NZ540425A (en)
WO (1) WO2004060384A2 (en)
ZA (1) ZA200504982B (en)

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