WO1995000177A1 - Preparation pharmaceutique et procede permettant d'inhiber la replication de differents virus - Google Patents

Preparation pharmaceutique et procede permettant d'inhiber la replication de differents virus Download PDF

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Publication number
WO1995000177A1
WO1995000177A1 PCT/CA1994/000343 CA9400343W WO9500177A1 WO 1995000177 A1 WO1995000177 A1 WO 1995000177A1 CA 9400343 W CA9400343 W CA 9400343W WO 9500177 A1 WO9500177 A1 WO 9500177A1
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WO
WIPO (PCT)
Prior art keywords
dextran
solution
dissolving
pharmaceutical preparation
azt
Prior art date
Application number
PCT/CA1994/000343
Other languages
English (en)
Inventor
Thomas C. Usher
Natu Patel
Chhagan Tele
I. Louis Wolk
Original Assignee
Dextran Products Limited
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 Dextran Products Limited filed Critical Dextran Products Limited
Publication of WO1995000177A1 publication Critical patent/WO1995000177A1/fr

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Classifications

    • 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
    • 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
    • A61K47/6951—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 using cyclodextrin

Definitions

  • This invention relates to a pharmaceutical preparation and method for inhibiting reverse transcriptase enzyme and the replication of a family of viruses known as human immunodeficiency virus (HIV) by the use of a novel conjugate of dextran, modified dextran, dextran sulphate or other polysaccharides with AZT. It also relates to a method for modifying Dextran so that it is prepared for conjugation with such a drug having a primary or secondary hydroxy group.
  • HIV human immunodeficiency virus
  • HTLV family of retroviruses A group of these viruses designated as HTLV- III has been isolated from patients with Acquired Immune Deficiency Syndrome (AIDS) and has become considered to be responsible for the development of this condition in humans. These are also known as HIV, particularly HIV-1 and HIV-2.
  • Azidothymidine a drug that inhibits reverse transcriptase was expected to prolong the lives of patients with AIDS but this is now in doubt.
  • Many patients who receive AZT have temporary increases in the number of circulating helper (CD4+) T-lymphocytes.
  • CD4+ circulating helper
  • zidovudine (3'-azido-2' , 3'-dideo- zythymidine, AZT, azidothymidine, Retrovir) is the FDA- approved drug, it has undesirable toxicity in the host (e.g. myelosuppression, neuropathy).
  • the invention provides for a pharmaceutical preparation for inhibiting in vivo the reverse transcriptase enzyme and the replication of viruses, which comprises a conjugate of Dextran, Modified Dextran, Dextran Sulphate or Polysaccharides and AZT in appropriate pharmaceutical dosage form.
  • the invention also provides a method for inhibiting in vivo the replication of HIV viruses comprising the different routes of administration of the aforesaid conjugates in a pharmaceutically appropriate dosage form, regimen and quantity.
  • a method for modifying Dextran so that it is prepared for conjugation with a drug having a primary or secondary hydroxy group comprising the steps of:
  • step 5 adding about 0.5 ml of each of the solution of step #3 and of step #4 to the Dextran solution of step #2;
  • a method for modifying Dextran so that it is prepared for conjugation with a drug having a primary or secondary hydroxy group comprising the steps of:
  • a method for modifying Dextran so that it is prepared for conjugation with a drug having a primary or secondary hydroxy group comprising the steps of:
  • Modified Dextran may be substituted, oxidised, cationic, anionic, spacer or activated Dextran.
  • the Dextran conjugated with AZT may have a molecular weight within the range of 4,000 to 1,000,000.
  • the Dextran Sulphate conjugated with AZT may have a molecular weight within the range of 8,000 to 1,000,000.
  • Examples of polysaccharides which may be conjugated with AZT are cyclodextrin and cellulose sulphate. A useful conjugate of AZT and a polysaccharide will be one exhibiting a slow release mechanism.
  • the aforesaid conjugates may include a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical preparations the subject of this invention are not only useful in the treatment of AIDS and other viral diseases, but are also useful in the treatment of AIDS-related complex (A.R.C.).
  • the present invention also contemplates a pharmaceutical preparation useful for the treatment of AIDS comprising a conjugate of a known anti-AIDS agent with (a) Dextran (b) Modified Dextran (c) Dextran Sulphate or, (d) a polysaccharide exhibiting a slow release mechanism.
  • the drug-Dextran conjugate as a macromolecular compound has excellent metabolic stability, resulting in a more effective treatment.
  • conjugate is a large molecule and consists of polysaccharide, it is easy to be received and combined by receptors of the cell which consist of polysacharide-protein.
  • Dextran and certain derivatives such as the sulphate are useful not only as a "transfer weapon", but also as an immunologically active material which has now been used in the treatment study of AIDS.
  • the conjugate provides an effective weapon which will be able to attack and kill the harmful cells of several severe diseases including AIDS and Carcinoma.
  • a Dextran-drug conjugate is a carrier or stabilizer frequently resulting in decreased drug toxicity, after biodistribution (due to the slow release of the drug from the conjugate), and mostly increases therapeutic efficacy.
  • a Dextran Sulphate-drug conjugate increases the bioadhesiveness with increase in polyanionic character as it cannot be captured by the first pass effect and also during circulation.
  • Macromolecules like conjugates of Dextran and a drug remain for prolonged periods of time in contact with cell receptors and appear to inhibit contact of certain viruses with cell receptors.
  • Conjugates of Dextran with a drug will be useful as macromolecular pro-drugs in drug delivery systems and suitable as nontoxi ⁇ carriers for more effective drugs for the treatment of viral diseases.
  • Modified Dextran which may- be conjugated with a drug having a primary or secondary hydroxy group are as follows.
  • the PH is adjusted to about 8.0 with 16% sodium carbonate solution and cooled to below freezing temperature.
  • Triethylamine 0.2 to 1.0 ml Triethylamine is dissolved in about 5 ml DMF.
  • the PH is adjusted to about 9.0 with 16% sodium carbonate solution and the reaction mixture is stirred for about 24 hours. 8) The sample is purified with precipitation and dried.
  • step #2 In the Dextran solution of step #2, 0.5 ml of each of solutions #3 and #4 were added.
  • Modified Dextrans may also be conjugated with AZT. Examples in this regard follow.
  • step #2 After cooling the Dextran solution of step #2, 0.5 ml of each solution #3 and #4 were added.
  • Solution was purified by dialysis, filtered with 0.45 micron filter paper and dried.
  • SUBSTITUTE SHEET Dextran Sulphate may also be conjugated with a drug having a primary or secondary hydroxy group.
  • Methods for conjugating Dextran Sulphate with Cytochalasin-D are as follows.
  • the Dextran Sulphate may have a M.W. of about 500,000.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nanotechnology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Epidemiology (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une préparation pharmaceutique et un procédé qui permettent d'inhiber in vivo une enzyme, la transcriptase inverse, ainsi que la réplication du virus de l'immunodéficience humaine (VIH). Dans une variante, cette préparation pharmaceutique est un produit de conjugaison de dextrane, dextrane modifié, sulfate ou polysaccharides de dextrane et de 3'-azido-2',3'-didésoxythymidine (AZT). Cette préparation peut s'administrer par différentes voies selon les formes galéniques, les dosages et les posologies appropriés, à des patients souffrant d'une maladie virale telle que le SIDA et ses pathologies connexes. Ce produit de conjugaison représente une structure nouvelle qui intervient comme une unité structurelle combinant des propriétés additives et synergiques connues du dextrane ou du sulfate de dextrane, avec l'AZT, et qui semble par la même occasion atténuer les effets toxiques de l'AZT.
PCT/CA1994/000343 1993-06-17 1994-06-17 Preparation pharmaceutique et procede permettant d'inhiber la replication de differents virus WO1995000177A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US7751193A 1993-06-17 1993-06-17
US08/077,511 1993-06-17
US10881393A 1993-08-19 1993-08-19
US08/108,813 1993-08-19

Publications (1)

Publication Number Publication Date
WO1995000177A1 true WO1995000177A1 (fr) 1995-01-05

Family

ID=26759353

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA1994/000343 WO1995000177A1 (fr) 1993-06-17 1994-06-17 Preparation pharmaceutique et procede permettant d'inhiber la replication de differents virus

Country Status (1)

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WO (1) WO1995000177A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997021452A2 (fr) * 1995-12-14 1997-06-19 Advanced Magnetics, Inc. Promedicaments macromoleculaires d'analogues de nucleotides
WO2001091742A1 (fr) * 2000-06-02 2001-12-06 Biodex Composition pharmaceutique contenant au moins un polymere associe ou conjugue a au moins un sel d'un acide phenylalkylcarboxylique, polymeres conjugues et leurs applications
US6642365B1 (en) * 1998-12-28 2003-11-04 Yeda Research And Development Co. Ltd. Anti-(retro)viral conjugates of saccharides and acetamidino or guanidino compounds
US9296776B2 (en) 2007-07-09 2016-03-29 Eastern Virginia Medical School Substituted nucleoside derivatives with antiviral and antimicrobial properties

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982000251A1 (fr) * 1980-07-21 1982-02-04 Commerce Us Forme soluble dans l'eau de retinoides
EP0190464A2 (fr) * 1984-12-31 1986-08-13 Yeda Research And Development Company Limited Médicaments contre le cancer
EP0327766A2 (fr) * 1987-12-30 1989-08-16 University Of Florida Système rédox pour l'administration de médicament à action sur le cerveau
WO1990005534A1 (fr) * 1988-11-23 1990-05-31 Genentech, Inc. Derives de polypeptides
EP0506431A1 (fr) * 1991-03-28 1992-09-30 Wako Pure Chemical Industries Ltd Enzyme modifié
CA2057289A1 (fr) * 1991-12-09 1993-06-10 Lionel Resnick Preparations pharmaceutiques inhibant la replication de divers virus
WO1993011763A1 (fr) * 1991-12-09 1993-06-24 Usher Thomas C Utilisation de cytochalasines pour inhiber la replication virale

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982000251A1 (fr) * 1980-07-21 1982-02-04 Commerce Us Forme soluble dans l'eau de retinoides
EP0190464A2 (fr) * 1984-12-31 1986-08-13 Yeda Research And Development Company Limited Médicaments contre le cancer
EP0327766A2 (fr) * 1987-12-30 1989-08-16 University Of Florida Système rédox pour l'administration de médicament à action sur le cerveau
WO1990005534A1 (fr) * 1988-11-23 1990-05-31 Genentech, Inc. Derives de polypeptides
EP0506431A1 (fr) * 1991-03-28 1992-09-30 Wako Pure Chemical Industries Ltd Enzyme modifié
CA2057289A1 (fr) * 1991-12-09 1993-06-10 Lionel Resnick Preparations pharmaceutiques inhibant la replication de divers virus
WO1993011763A1 (fr) * 1991-12-09 1993-06-24 Usher Thomas C Utilisation de cytochalasines pour inhiber la replication virale

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
R. ANAND ET AL.: "SULPHATED SUGAR ALPHA-CYCLODEXTRIN SULPHATE, A UNIQUELY POTENT ANTI-HIV AGENT, ALSO EXHIBITS MARKED SYNERGISM WITH AZT, AND LYMPHOPROLIFERATIVE ACTIVITY", ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, vol. 1, no. 1, 1990, pages 41 - 46 *
R. UENO ET AL.: "DEXTRAN SULPHATE, A POTENT ANTI-HIV AGENT IN VITRO HAVING SYNERGISM WITH ZIDOVUDINE", LANCET, vol. 8546, 1987, pages 1379 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997021452A2 (fr) * 1995-12-14 1997-06-19 Advanced Magnetics, Inc. Promedicaments macromoleculaires d'analogues de nucleotides
WO1997021452A3 (fr) * 1995-12-14 1997-10-09 Advanced Magnetics Inc Promedicaments macromoleculaires d'analogues de nucleotides
US5981507A (en) * 1995-12-14 1999-11-09 Advanced Magnetics, Inc. Polymeric carriers linked to nucleotide analogues via a phosphoramide bond
US6642365B1 (en) * 1998-12-28 2003-11-04 Yeda Research And Development Co. Ltd. Anti-(retro)viral conjugates of saccharides and acetamidino or guanidino compounds
WO2001091742A1 (fr) * 2000-06-02 2001-12-06 Biodex Composition pharmaceutique contenant au moins un polymere associe ou conjugue a au moins un sel d'un acide phenylalkylcarboxylique, polymeres conjugues et leurs applications
FR2809735A1 (fr) * 2000-06-02 2001-12-07 Biodex Composition pharmaceutique contenant au moins un polymere associe ou conjugue a au moins un sel d'un acide phenylalkycarboxylique, polymeres conjugues et leurs applications
US9296776B2 (en) 2007-07-09 2016-03-29 Eastern Virginia Medical School Substituted nucleoside derivatives with antiviral and antimicrobial properties
US9738678B2 (en) 2007-07-09 2017-08-22 Eastern Virginia Medical School Substituted nucleoside derivatives with antiviral and antimicrobial properties

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