WO2001036656B1 - A complex between hyaluronic acid and a biomolecule and its use - Google Patents

A complex between hyaluronic acid and a biomolecule and its use

Info

Publication number
WO2001036656B1
WO2001036656B1 PCT/SE2000/002245 SE0002245W WO0136656B1 WO 2001036656 B1 WO2001036656 B1 WO 2001036656B1 SE 0002245 W SE0002245 W SE 0002245W WO 0136656 B1 WO0136656 B1 WO 0136656B1
Authority
WO
WIPO (PCT)
Prior art keywords
hyaluronic acid
complex
kda
acid
biomolecule
Prior art date
Application number
PCT/SE2000/002245
Other languages
French (fr)
Other versions
WO2001036656A2 (en
WO2001036656A3 (en
Inventor
Gustaf Jederstroem
Original Assignee
Gustaf Jederstroem
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.)
Filing date
Publication date
Application filed by Gustaf Jederstroem filed Critical Gustaf Jederstroem
Priority to AU17481/01A priority Critical patent/AU1748101A/en
Priority to AT00980185T priority patent/ATE287720T1/en
Priority to EP00980185A priority patent/EP1231926B1/en
Priority to CA002391647A priority patent/CA2391647C/en
Priority to DE60017783T priority patent/DE60017783T2/en
Priority to DK00980185T priority patent/DK1231926T3/en
Publication of WO2001036656A2 publication Critical patent/WO2001036656A2/en
Publication of WO2001036656A3 publication Critical patent/WO2001036656A3/en
Publication of WO2001036656B1 publication Critical patent/WO2001036656B1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • 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
    • A61K38/27—Growth hormone [GH] (Somatotropin)
    • 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
    • A61K47/30—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
    • A61K47/50—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
    • A61K47/61—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 the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
    • A61K48/0041—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being polymeric
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Abstract

A new complex between a pharmacologically active biomolecule and hyaluronic acid makes possible the oral administration of peptides and other biomolecules, normally not suited for oral administration. The inventive complex is also suited for parenteral administration, in which case it exhibits other advantages. The present invention also makes available novel therapeutic formulations and methods of treatment according to the attached claims.

Claims

38AMENDED CLAIMS[received by the International Bureau on 14 June 2001 ( 14.06 01 ), original claims 1 -50 replaced by amended claims 1-48 (5 pages)]
1 . A complex between a biomolecule and hvaluronic acid, characterized in that the biomolecule is reversibly compressed and that the complex is formed by means ot hydrophobic interactions between the components in an acid electrolyte solution
2. A complex between a biomolecule and hvaluronic acid according to claim 1. characterized in that the biomolecule is rev ersibly compressed to less than about 10 " » ot its original size.
3. A complex according to claim 1 . characterized in that said hvaluronic acid i hvaluronic acid having a molecular weight of less than about 400 kDa. preferably in the interval ot about 60 to about 360 kDa.
4. A complex according to claim 1. characterized in that said hvaluronic acid is hv aluronic acid having a molecular weight of about 150 kDa.
5. A complex according to claim 1. characterized in that said biomolecule is a peptide
6. A complex according to claim 1. characterized in that said biomolecule is a protein
7. A complex according to claim 1. characterized in that said biomolecule is a glycoprotein
8. A complex according to claim 1 . characterized in that said biomolecule is a polynucleotide.
9. A complex according to claim 5, characterized in that said peptide is chosen among the following groups of substances: hormones, neuropeptides, signal peptides, peptide antibiotics, peptide antigens, antibodies and naturally occurring or synthetic amino acid polymers.
10. A complex according to claim 5. characterized in that said peptide is chosen among the following substances: insulin, growth hormone, human growth hormone, glucagon. corticotropin, oxytocin, bradykinin. thyrotropin-release factor and thyrotropin. enkephalins, and peptide antibiotics.
1 1. A complex according to claim 8, characterized in that said polynucleotide is chosen among the following: plasmides, DNA, RNA, cDNA, mRNA, recombinant DNA, recombinant RNA. and combinations thereof.
12. A method for oral delivery of biomolecules, characterized in that the biomolecule is reversibly compressed and incorporated in a complex with hyaluronic acid by hydrophobic interaction between the components, and the resulting complex administered orally to a patient.
13. A method according to claim 12. characterized in that the size of the biomolecule is reversibly compressed to less than about 10 % of its original size.
14. A method according to claim 12, characterized in that said biomolecule is a peptide.
15. A method according to claim 12. characterized in that said biomolecule is a protein.
16. A method according to claim 12, characterized in that said biomolecule is a glycoprotein.
17. A method according to claim 12, characterized in that said biomolecule is a polynucleotide.
18. A method according to claim 14, characterized in that said peptide is chosen among the following groups of substances: hormones, neuropeptides, signal peptides, peptide antibiotics, peptide antigens and naturally occurring or synthetic amino acid polymers.
19. A method according to claim 14, characterized in that said peptide is chosen among the following substances: insulin, growth hormone, human growth hormone, glucagon, corticotropin, oxytocin, bradykinin, thyrotropin-release factor and thyrotropin, enkephalins, and peptide antibiotics.
20. A method according to claim 17, characterized in that said polynucleotide is chosen among the following: plasmides, DNA, RNA, cDNA, mRNA, recombinant DNA, recombinant RNA, and combinations thereof.
21. A method according to claim 12, characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of less than about 400 kDa, preferably in the interval of about 60 to about 360 kDa.
A method according to claim 12, characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of about 150 kDa
A method for the treatment of insulin dependent diabetes, characterized in that insulin is administered orally, incorporated in a complex with hyaluronic acid
A method according to claim 23. characterized in that the size of the insulin molecule is reversibly compressed, preferably to less than 10 % ot its oπginal size
A method according to claim 23, characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of less than about 400 kDa, preferably in the interval of about 60 to about 360 kDa
A method according to claim 23 characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of about 150 kDa
A method tor the treatment of hormone deficiencies characterized in that a hormone is administered orally, incorporated in a complex with hyaluronic acid
A method according to claim 27. characterized in that the size of the hormone molecule is reversibly compressed, preferably to less than 10 % ot its oπginal size
A method according to claim 27. characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of less than about 400 kDa, preferably in the interval of about 60 to about 360 kDa
A method according to claim 27, characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of about 150 kDa
A method for use in gene therapy, characterized in that a polynucleotide reversibly compressed to less than 10 % of its oπginal size and incorporated m a complex with hyaluronic acid
A method according to claim 31 , characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of less than about 400 kDa, preferably in the interval of about 60 to about 360 kDa 41
33 A method according to claim 31 , characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of about 150 kDa
34 A method for the prevention of transplant rejections in a patient receiving a transplanted organ, tissue or cells, characterized in that growth hormone is administered to said patient, incoprorated in a complex with hyaluronic acid
35 A method according to claim 34. characterized in that the size of the hormone molecule is reversibly compressed, preferably to less than 10 % of its oπginal size
36 A method according to claim 34, characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of less than about 400 kDa, preferably in the interval ot about 60 to about 360 kDa
37 A method according to claim 34, characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of about 150 kDa
38 A method for the administration of hepaπn, characterized in that hepaπn is administered orally to a patient, incorporated in a complex with hyaluronic acid
39 A method for manufactuπng a complex of a biomolecule and hyaluronic acid, characterized in that the method compπses the following steps
a) dissolving hyaluronic acid in a solution containing an acid and an electrolyte solution,
b) dissolving the biomolecule in the dissolved hyaluronic acid and an acid solution, and
c) dialysing the solution formed in b) at about neutral pH
40 A method according to claim 39, characterized in that the acid in step a) and b) is chosen among hydrochloπc acid, sulphuπc acid, phosphoπc acid and acetic acid and the pH is in the range of about 1 0 to about 3 0
41 A method according to claim 39, characterized in that the electrolyte solution of step a) contains cations chosen among NH4 +, K+, Na+, Ca +, Mg2+, Zn2+, Fe2+, Fe3+ and anions such as sulphate, nitrate, chloπde, hydroxide and acetate
42 A method according to claim 39, characterized in that the pH in step c) is dialysed in the interval of about 5 5 to about 7 5 42
43. A method according to claim 39, characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of less than about 400 kDa, preferably in the interval of about 60 to about 360 kDa.
44. A method according to claim 39, characterized in that said hyaluronic acid is hyaluronic acid having a molecular weight of about 150 kDa.
45. The use of insulin for the manufacture of a complex of reversibly compressed insulin and hyaluronic acid, for use as a medicament for the treatment of diabetes.
46. The use of growth hormone for the manufacture of a complex of reversibly compressed growth hormone and hyaluronic acid, for use as a medicament for the treatment of growth hormone deficiencies.
47. The use of growth hormone for the manufacture of a complex of reversibly compressed growth hormone and hyaluronic acid, for use as a medicament for the prevention of transplant rejections.
48. The use of heparin or bioactive derivatives thereof for the manufacture of a complex of reversibly compressed heparin or derivatives thereof and hyaluronic acid, for use as a medicament.
PCT/SE2000/002245 1999-11-15 2000-11-15 A complex between hyaluronic acid and a biomolecule and its use WO2001036656A2 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU17481/01A AU1748101A (en) 1999-11-15 2000-11-15 New complex, and methods for its production and use
AT00980185T ATE287720T1 (en) 1999-11-15 2000-11-15 BIOMOLECULAR COMPLEX FORMED FROM HYALURONIC ACID AND A BIOMOLECULE, PRODUCTION PROCESS THEREOF AND THEIR THERAPEUTIC USE
EP00980185A EP1231926B1 (en) 1999-11-15 2000-11-15 Biomolecular complex formed between hyaluronic acid and a biomolecule, its method of manufacture and medical uses thereof
CA002391647A CA2391647C (en) 1999-11-15 2000-11-15 Biomolecular complex formed between hyaluronic acid and a biomolecule
DE60017783T DE60017783T2 (en) 1999-11-15 2000-11-15 BIOMOLECULAR COMPLEX MADE FROM HYALURONIC ACID AND A BIOMOLECULAR, METHOD OF MANUFACTURING THEREOF AND THEIR THERAPEUTIC USE
DK00980185T DK1231926T3 (en) 2000-11-15 2000-11-15 Biomolecular complex formed by hyaluronic acid and a biomolecule, a process for its preparation and medical use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9904121-2 1999-11-15
SE9904121A SE9904121D0 (en) 1999-11-15 1999-11-15 Hydrophobic biomolecular structure

Publications (3)

Publication Number Publication Date
WO2001036656A2 WO2001036656A2 (en) 2001-05-25
WO2001036656A3 WO2001036656A3 (en) 2001-11-15
WO2001036656B1 true WO2001036656B1 (en) 2002-02-28

Family

ID=20417718

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2000/002245 WO2001036656A2 (en) 1999-11-15 2000-11-15 A complex between hyaluronic acid and a biomolecule and its use

Country Status (9)

Country Link
US (3) US6448093B1 (en)
EP (1) EP1231926B1 (en)
AT (1) ATE287720T1 (en)
AU (1) AU1748101A (en)
CA (1) CA2391647C (en)
DE (1) DE60017783T2 (en)
ES (1) ES2236004T3 (en)
SE (1) SE9904121D0 (en)
WO (1) WO2001036656A2 (en)

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ATE376824T1 (en) 1999-01-13 2007-11-15 Alchemia Oncology Pty Ltd USE OF HYALURONAN FOR PRODUCING A MEDICATION TO INCREASE THE EFFECTIVENESS OF CYTOTOXIC DRUGS
SE9904121D0 (en) * 1999-11-15 1999-11-15 Gustaf Jederstroem Hydrophobic biomolecular structure
US9066919B2 (en) 2000-07-14 2015-06-30 Alchemia Oncology Pty Limited Hyaluronan as a chemo-sensitizer in the treatment of cancer
AUPQ879500A0 (en) 2000-07-14 2000-08-10 Meditech Research Limited Hyaluronan as cytotoxic agent, drug presensitizer and chemo-sensitizer in the treatment of disease
CN1309392C (en) * 2002-02-15 2007-04-11 研究发展基金会 Hyaluronic acid mediated adenoviral transduction
JP4851185B2 (en) 2003-05-16 2012-01-11 ジェレックスインターナショナル株式会社 Allergy symptom suppressant and air filtration filter
JP5465431B2 (en) 2005-07-27 2014-04-09 アルケミア オンコロジー ピーティーワイ リミテッド Treatment protocol with hyaluronan
AU2006289651B2 (en) * 2005-09-07 2012-07-26 Alchemia Oncology Pty Limited Therapeutic compositions comprising hyaluronan and therapeutic antibodies as well as methods of treatment
WO2008136759A1 (en) * 2007-05-07 2008-11-13 Jederstrom Pharmaceuticals Ab Stabilized suspension
FR2925333B1 (en) * 2007-12-19 2012-04-13 Farid Bennis PHARMACEUTICAL COMPOSITIONS COMPRISING AT LEAST ONE PROTEIN ACTIVE INGREDIENT PROTECTS DIGESTIVE ENZYMES
RU2014120626A (en) * 2014-05-22 2015-11-27 Владимир Андреевич Сабецкий INSULIN-CONTAINING MEDICINE OF LONG-TERM ACTION

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Also Published As

Publication number Publication date
US20030096266A1 (en) 2003-05-22
US6448093B1 (en) 2002-09-10
EP1231926A2 (en) 2002-08-21
EP1231926B1 (en) 2005-01-26
CA2391647A1 (en) 2001-05-25
AU1748101A (en) 2001-05-30
WO2001036656A2 (en) 2001-05-25
US6926910B2 (en) 2005-08-09
CA2391647C (en) 2008-03-11
US7338931B2 (en) 2008-03-04
ES2236004T3 (en) 2005-07-16
SE9904121D0 (en) 1999-11-15
US20050255162A1 (en) 2005-11-17
US20070275069A9 (en) 2007-11-29
DE60017783T2 (en) 2006-01-05
ATE287720T1 (en) 2005-02-15
WO2001036656A3 (en) 2001-11-15
DE60017783D1 (en) 2005-03-03

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