EP0634926A1 - Composition a usage therapeutique ou diagnostique, et mode de preparation et d'utilisation - Google Patents

Composition a usage therapeutique ou diagnostique, et mode de preparation et d'utilisation

Info

Publication number
EP0634926A1
EP0634926A1 EP93907890A EP93907890A EP0634926A1 EP 0634926 A1 EP0634926 A1 EP 0634926A1 EP 93907890 A EP93907890 A EP 93907890A EP 93907890 A EP93907890 A EP 93907890A EP 0634926 A1 EP0634926 A1 EP 0634926A1
Authority
EP
European Patent Office
Prior art keywords
ldl
agent
active agent
composition
lysosomotropic
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP93907890A
Other languages
German (de)
English (en)
Inventor
Paavo Kai Johannes Kinnunen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP0634926A1 publication Critical patent/EP0634926A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1275—Lipoproteins; Chylomicrons; Artificial HDL, LDL, VLDL, protein-free species thereof; Precursors thereof
    • 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
    • A61K47/6905—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 the form being a colloid or an emulsion
    • A61K47/6917—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 the form being a colloid or an emulsion the form being a lipoprotein vesicle, e.g. HDL or LDL proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo

Definitions

  • composition for therapeutic or diagnostic use process for its preparation and its use
  • the present invention is based on the use of a carrier selected from the group consisting of lipoproteins, in particular reconstituted LDL (Low Density Lipoprotein) , other types of microemulsion particles, liposomes and micelles, and containing a therapeutically or diagnostical- ly active, lipo- or amphiphilic agent, and associated with a suitable ligand recognizable by its specific (complemen ⁇ tary) cell receptor, together with a lysosomotropic agent, for targeting of the active agent to the site of interest, such as cancerous tissue, and to optimize the effect thereof at the said site.
  • a carrier selected from the group consisting of lipoproteins, in particular reconstituted LDL (Low Density Lipoprotein) , other types of microemulsion particles, liposomes and micelles, and containing a therapeutically or diagnostical- ly active, lipo- or amphiphilic agent, and associated with a suitable ligand recognizable by its specific (complemen ⁇ tary
  • Ligand specific receptors on the cell surface mediate both information on the environment as well as nutrients into the cell.
  • Such ligands to be recognized include a range of molecular structures, e.g. growth factors (for example platelet derived growth factor, endothelial cell growth factor, tumor growth factor, nerve growth factor) , hormones (e.g. insulin, vasopressin etc.), extracellular matrix protein (e.g. collagen) and lipoproteins (e.g. low density lipoprotein) .
  • growth factors for example platelet derived growth factor, endothelial cell growth factor, tumor growth factor, nerve growth factor
  • hormones e.g. insulin, vasopressin etc.
  • extracellular matrix protein e.g. collagen
  • lipoproteins e.g. low density lipoprotein
  • LDL Low Density Lipoprotein
  • apo B apolipoprotein B
  • the interior of LDL is formed by cholesterol in esterified form (compounds of fatty acids and cholesterol) , triacylglycerol, retinol, as well as other hydrocarbon soluble compounds.
  • LDL-receptors which bind to the LDL-particle by specifically recognizing the protein component of the LDL-surface, i.e. apolipopro ⁇ tein B.
  • the density of LDL-receptors is much higher on cancerous cells than on normal cells and cancer cells bind LDL more effectively. It is evident that the lower serum cholesterol level of cancer patients is due to enhanced uptake of LDL by the cancer cells. This is easy to ra ⁇ tionalize in terms of the increased requirement of com- ponents such as cholesterol for the growth of the tumor cells.
  • LDL containing cytotoxic compounds which replace the natural apolar lipids in the particle core has been described.
  • the lipids are removed from the core of LDL by first lyophilizing the lipoprotein in the presence of starch (Gustafson, A (1965) J. Lipid Res. 20, 254-264) .
  • a slightly modified technique has been described by Krieger (Krieger, M. (1986) Methods Enzymol. 128, 608- 613) .
  • LDL is reconstituted by lyophilizing in the presence of potato starch and extracting the neutral lipids with an organic solvent, such as heptane.
  • the agent to be introdu ⁇ ced is dissolved in an organic solvent and incubated with the extracted LDL.
  • the organic solvent is evaporated and the reconstituted LDL is dissolved in a buffered aqueous solution.
  • the starch is replaced by a saccharide or a sugar alcohol, and according to this publication, a reconstituted LDL is obtained having similar properties as natural LDL, in vitro and in vivo.
  • li ⁇ posomes wherein the active agent is incorporated a) in a core surrounded by a bilayer of a lipid substance, typical ⁇ ly a phospholipid (together with e.g. cholesterol and sphingomyelin) or b) if the desired therapeutic compound is amphiphilic (e.g. an anti-cancer phospholipid) , it is incorporated in the bilayer itself.
  • a lipid substance typical ⁇ ly a phospholipid
  • amphiphilic e.g. an anti-cancer phospholipid
  • microemulsions for example an emulsion of active agent, such as a lipophilic drug surrounded by a monolayer of phosphatidyl choline, are used.
  • the present invention relates to an improvement to the known methods by means of which it is possible to achieve an enrichment of the active agent at the target site.
  • This is made possible by using, in combination, (a) a carrier selected from the group consisting of lipoproteins, other types of microemulsion particles, liposomes and micelles, and containing a therapeutically or a diagnostically effective amount of a lipo- or amphiphilic active agent, associated with at least one ligand which is complementary to and recognizable by specific receptor in the living cells, and (b) a lysosomotropic agent.
  • the invention concerns, on the one hand, a composition for diagnostic or therapeutic use which contains the said combination, and on the other hand a method for the preparation of the said composition.
  • composition according to the invention thus contains at least two components, i.e. a carrier selected from the group of lipoproteins, other types of microemulsion parti ⁇ cles, liposomes and micelles, and which is associated to a suitable ligand.
  • the carrier components are known as such, as is their manner of manufacture. Common for these carriers is that they can contain a therapeutically or diagnostically active agent.
  • the carrier is associated with a ligand which is characte ⁇ rized in that it is complementary to and can be recognized by a specific cell receptor.
  • the term "associated with” is intended to include also the possibility that the carrier incorporates the said ligand, such as in the case of LDL, where the ligand can be the apo B moiety included in the surface film of the LDL.
  • the ligand is thus typically one of the substances mentioned earlier, such as a protein, e.g. growth factor, a hormone, apolipoprotein, viral protein, synthetic peptide etc.
  • the carrier is a reconstituted LDL, the ligand is the apo B-moiety, or a corresponding receptor recognizable synthetic peptide present on its surface.
  • the ligand may also in all cases be a synthetic ligand made lipophilic or amphiphilic to allow for its incorporation with the carrier, into the lipid surface of the carrier particle, provided that the ligand carries the elements recognizable by the cell receptors. Such substances are also well known in the art.
  • the second central component in the composition is the lysosomotropic agent which according to the invention is a lysosomotropic amphiphile, and is characterized as having both lysosomotropic and detergent activity.
  • the lysosomot ⁇ ropic agents exert lysosomal blocking activity and are well known in the art. They may in addition be amphiphilic such as Triton WR-133 (American Roland Corporation, USA, "tyloxapol”) , weak amines (e.g..pK 5 to 9) such as imidazo- les or morpholines containing longer hydrocarbon alkyl or acyl chains, e.g. N-dodecyl imidazole, or chloroquine, see e.g.
  • the presence of the lysosomotropic amphiphile does not interfe ⁇ re with the recognition of the ligand by the receptor, but the carrier with active agent is taken up from the extra- cellular space into the cells according to their contents of receptors and the activity of the endocytic pathway.
  • the carrier particles carrying the lysosomot ⁇ ropic agent enters the lysosomes, the processing of the particles is blocked. In other words, the cycling of the active agent containing particle back to the cell surface (retro-endocytosis) does not take place, and an accumu ⁇ lation of the active agent in the target site is obtained.
  • composition according to the invention is preferably an aqueous solution for parenteral use, such as for injection purposes (iv) , containing a therapeutically or diagnosti- cally effective amount of active agent containing carrier particles together with the lysosomotropic agent.
  • the ratio (weight) of carrier particles to the lysosomotropic agent is suitably such that in each particle approximately 2 to 40 mole-% of its surface active compounds is constituted by the said lysosomotropic agents.
  • composition according to the invention is made by combining the active agent containing carrier with the lysosomotropic agent in a pharmaceutically suitable vehicle, together with possible pharmaceutically acceptable adjuvants.
  • vehicle is normally sterile water.
  • adjuvants may be any substances known per se and suitable for the purpose, the choice thereof being within the knowledge of a person skilled in the art.
  • the dosage used naturally depends on the drug or diagnostic agent used, as well as the condition to be treated or diagnozed.
  • the amount to be administered for any specific purpose can readily be determined by a person skilled in the art.
  • the carrier is comprised of reconstituted LDL.
  • Such reconstitu ⁇ ted LDL is made by a method comprising the steps of lyophilizing LDL in the presence of a protecting substan ⁇ ce, extracting the lyophilized LDL with an organic solvent, incubating a therapeutically or diagnostically effective lipo- or amphiphilic agent in an organic solvent with the extracted LDL, evaporating the solvent and dissolving the product in an aqueous buffered solution to remove any non- included active agent and separating the LDL e.g. by ultracentrifugation.
  • the LDL to be reconstituted is usually isolated from human serum by differential ultracentrifugational flotation in the density range of 1.019 ⁇ d ⁇ 1.063 g/ml.
  • Alternative techniques include, for instance, rate-zonal ultracentrifu- gation.
  • the protecting substance may be any of the substances known for the purpose, such as starch, in particular potato starch, but also a sugar derivative as is disclosed in the WO-publication 86/07540.
  • the solvent used for the extraction of the neutral lipids from the lyophilized LDL is suitably a non-polar solvent, such as heptane, hexane, pentane, petroleum ether, octane, or their mixtures.
  • the solvent used for dissolving the active agent and for incubating with the lyophilized and extracted LDL is also preferably a non-polar solvent such as the ones listed above.
  • the carrier particle can be a liposome.
  • the techniques for making liposomes and for including active agents, such as a drug therein, are very well known in the art.
  • the ligand can comprise a suitable substance recognizable by a specific cell surface receptor, such as those listed earlier, and which is incorporated in the liposome shell during the manufacture thereof.
  • microemulsion can be used, the preparation of which is known in the art (e.g. Walsh, M. T. et al. Methods in Enzymology, vol. 128 582
  • the active agent is an agent for diagnostic or therapeutic purposes. It can be lipophilic or amphiphilic, although the border line between these two types is diffuse.
  • a diagnostic agent e.g. light sensitizers, such as hemato- porphyrins, radiosensitizers, such as boronated fatty acid esters, or x-ray contrast agents can be used.
  • a thera ⁇ Therapeutic agent preferably anti-cancer drugs are used, such as doxorybicin, daunomycin, l-hexadecyl-2-methyl-3-phospho- choline etc.
  • LDL was isolated by differential ultracentrifugational flotation in the density range 1.1019 ⁇ d ⁇ 1.063 g/ml. Subsequently, KBr used for the adjustment of appropriate densities was removed by extensive dialysis against 0.3 mM EDTA, pH 7.0 at 4 °C. Thereafter the lipoprotein was concentrated by ultrafiltration using an A icon XM-300 membrane and the concentration of cholesterol was measured. Pure potato starch (60 mg from Sigma) was dissloved in the LDL-solution containing 16 ⁇ moles of cholesterol in a total volume of 1.5 ml. The resulting solution was then frozen in liquid nitrogen and lyophilized.
  • the core lipids of the lyophilized LDL were then extracted with 4 x 10 ml of ice- cold heptane.
  • the core lipids were replaced with a cytoto- xic compound, namely cholesteryl ester of chlorambucil (15 mg dissolved in 1.5 ml of heptane) which contained a 3 H- cholesteryl moiety as a marker for the quantitation of tissue distribution of the cytotoxic compound.
  • the solution was first incubated at -10 °C for 90 minutes, whereafter the solvent was removed under a gentle stream of nitrogen while keeping the sample on an ice-water bath.
  • the dry residue was then dissolved in 3.5 ml of 10 mM Tricine buffer, pH 8.4, and incubated at + 4 °C for 48 hours.
  • the solution was centrifuged at 2000 rpm and the superna ⁇ tant collected.
  • To the supernatant solution containing the cytostat-LDL particles was then added 50 ⁇ L of Triton WR- 1339, and the mixture was incubated at + 4 °C overnight. In this manner an injectable preparation was obtained. This can be used as such, or if necessary, it can be irradiated by bath type sonication to speed up the dispersion into small particles.
  • test animals designated A to E are compared to the values from a control rat (killed at 1 hr) without the implanted sarcoma.
  • Fig. 1 illustrates similar tests and it shows the level of chlorambucil ester-LDL in the blood and in the tumor, respectively, when injected as described above but in the absence of a lysosomotropic agent (Triton WR 1339) .
  • the abscissa indicates the time and the ordinate the amount (in promille) in blood and tumor respectively, calculated from that injected.
  • Fig.2 shows in graphic form the mean values for the levels obtained above, when the same LDL has been injected in the presence of the lysosomotropic agent. From the Figures it is evident that in the absence of a lysosomotropic agent, after an initial transient decrease, the level in the blood increases rapidly, whereas the opposite is true for the level in the tumour.
  • the level of reconstituted LDL in the blood decreases, and the level thereof in the tumour increases, indicating that retro-endocytosis is prevented by the incorporation of the lysosomotropic agent according to the invention.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition comprenant un vecteur choisi dans le groupe comprenant des lipoprotéines, et notamment des lipoprotéines LDL (à faible densité) reconstituées, d'autres particules à microémulsion, des liposomes et des micelles, qui contiennent un agent lipophile ou amphophile utile pour la thérapie ou le diagnostic, et associé avec un ligand approprié reconnaissable par son récepteur cellulaire spécifique (complémentaire), ainsi qu'un agent lysosomotrope, destiné à cibler un site présentant un intérêt, tel qu'un tissu cancéreux, pour y amener l'agent actif.
EP93907890A 1992-04-08 1993-04-07 Composition a usage therapeutique ou diagnostique, et mode de preparation et d'utilisation Withdrawn EP0634926A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US865256 1986-05-20
US86525692A 1992-04-08 1992-04-08
PCT/FI1993/000149 WO1993020800A1 (fr) 1992-04-08 1993-04-07 Composition a usage therapeutique ou diagnostique, et mode de preparation et d'utilisation

Publications (1)

Publication Number Publication Date
EP0634926A1 true EP0634926A1 (fr) 1995-01-25

Family

ID=25345059

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93907890A Withdrawn EP0634926A1 (fr) 1992-04-08 1993-04-07 Composition a usage therapeutique ou diagnostique, et mode de preparation et d'utilisation

Country Status (6)

Country Link
EP (1) EP0634926A1 (fr)
JP (1) JPH07505408A (fr)
KR (1) KR950700726A (fr)
AU (1) AU3892593A (fr)
CA (1) CA2117749A1 (fr)
WO (1) WO1993020800A1 (fr)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5756067A (en) * 1993-11-08 1998-05-26 Peptide Delivery Systems Pty Ltd Labelled diagnostic compositions and method of their use
DE19500665A1 (de) * 1995-01-12 1996-07-18 Axel Prof Dr Haase Verfahren zur ortsauflösenden Abbildung eines Bereiches eines biologischen Objektes mit Hilfe elektromagnetischer Strahlen unter Applikation von Kontrastmittel
GB2321455A (en) * 1997-01-24 1998-07-29 Norsk Hydro As Lipophilic derivatives of biologically active compounds
US5827533A (en) 1997-02-06 1998-10-27 Duke University Liposomes containing active agents aggregated with lipid surfactants
IL161498A0 (en) 2001-10-24 2004-09-27 Univ California Measurement of protein synthesis rates in humans and experimental system by use of isotopically labeled water
WO2003068919A2 (fr) 2002-02-12 2003-08-21 The Regents Of The University Of California Mesure de vitesses de biosynthese et de degradation de molecules biologiques inaccessibles ou peu accessibles a un echantillonnage direct, de maniere non invasive, par incorporation d'etiquettes dans des derives metaboliques et des produits cataboliques
EP1546364A4 (fr) 2002-07-30 2006-09-06 Univ California Procede de mesure automatique a grande echelle des taux de flux moleculaire proteomique ou organeomique par spectrometrie de masse
ATE415486T1 (de) 2002-09-13 2008-12-15 Univ California Verfahren zur messung der geschwindigkeiten des cholesterinrückwärtstransports in vivo als index für anti-artherogenese
US7504233B2 (en) 2002-11-04 2009-03-17 The Regents Of The University Of California Methods for determining the metabolism of sugars and fats in an individual
US7262020B2 (en) 2003-07-03 2007-08-28 The Regents Of The University Of California Methods for comparing relative flux rates of two or more biological molecules in vivo through a single protocol
US20050202406A1 (en) 2003-11-25 2005-09-15 The Regents Of The University Of California Method for high-throughput screening of compounds and combinations of compounds for discovery and quantification of actions, particularly unanticipated therapeutic or toxic actions, in biological systems
TW200538738A (en) 2004-02-20 2005-12-01 Univ California Molecular flux rates through critical pathways measured by stable isotope labeling in vivo, as biomarkers of drug action and disease activity
JP2014526685A (ja) 2011-09-08 2014-10-06 ザ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア 代謝流量測定、画像化、および顕微鏡法
EP2788772B1 (fr) 2011-12-07 2018-02-14 GlaxoSmithKline LLC Procédés de détermination de la masse musculaire squelettique totale du corps
US9134319B2 (en) 2013-03-15 2015-09-15 The Regents Of The University Of California Method for replacing biomarkers of protein kinetics from tissue samples by biomarkers of protein kinetics from body fluids after isotopic labeling in vivo
KR102387248B1 (ko) 2021-07-06 2022-04-15 (주)효림세울 난연 사이로필 방적사 제조 설비 및 이를 사용하여 제조된 난연 사이로필 방적사 및 난연 사이로필 방적사 제조 방법
KR20230145752A (ko) 2022-04-11 2023-10-18 (주)효림세울 몰토 자스페 원사 제조설비 및 이를 사용한 몰토 자스페 원사 제조 방법

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE456136B (sv) * 1985-06-17 1988-09-12 Oncholab Ab Forfarande for framstellning av en med ett lipofilt biologiskt aktivt emne bemengd berare pa basis av rekonstituerat ldl (lagdensitetslipoprotein)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9320800A1 *

Also Published As

Publication number Publication date
CA2117749A1 (fr) 1993-10-28
WO1993020800A1 (fr) 1993-10-28
AU3892593A (en) 1993-11-18
JPH07505408A (ja) 1995-06-15
KR950700726A (ko) 1995-02-20

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