WO1998024425A1 - Produit pharmaceutique contenant du cis-platinum - Google Patents

Produit pharmaceutique contenant du cis-platinum Download PDF

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Publication number
WO1998024425A1
WO1998024425A1 PCT/NL1997/000661 NL9700661W WO9824425A1 WO 1998024425 A1 WO1998024425 A1 WO 1998024425A1 NL 9700661 W NL9700661 W NL 9700661W WO 9824425 A1 WO9824425 A1 WO 9824425A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
compound
neoplasms
complex
Prior art date
Application number
PCT/NL1997/000661
Other languages
English (en)
Inventor
Ben De Kruijff
Gelske Speelmans
Rutger Willibrordus Hendricus Maria Staffhorst
Jan Reedijk
Original Assignee
Rijksuniversiteit Utrecht
Seed Capital Investments-2 B.V.
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 Rijksuniversiteit Utrecht, Seed Capital Investments-2 B.V. filed Critical Rijksuniversiteit Utrecht
Priority to AU54168/98A priority Critical patent/AU5416898A/en
Publication of WO1998024425A1 publication Critical patent/WO1998024425A1/fr

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Classifications

    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • 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
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids

Definitions

  • Examples are C1-, (HPO ⁇ ) 2" , 0H-, H 2 0, His, Met, Cys, gluthathione, metallothionein, ATP, amino acids and polyphosphates .
  • the sites at proteins are believed to be the most likely origin of the several toxic side effects of cis-Pt and its several derivatives [111.5,10 and 14]. Significant amounts of administered cis-Pt are lost due to binding to proteins .
  • the cis platinum family of compounds comprises compounds of the structural class cis- [PtX 2 (amine) 2 ] , wherein X is the leaving anionic group and amine is any primary or secondary amine. It has been possible to formulate structure- activity relationships for platinum compounds.
  • the cis-geometry of two amines and the presence of at least one N-H group on the amine as well as the leaving groups with a weaker trans effect than the amine have been found to be necessary.
  • the amines can be symmetric, asymmetric, chelating or nonchelating. Water solubility should be good and toxic side effects should be minimised. Possible reactions in the blood with ligands containing S donor atoms should be suppressed [I].
  • the second generation platinum drug carboplatin [Pt(C 6 H 6 0 / ,) (NH 3 ) 2 ] has been developed and is in routine use. This compound has less toxic side effects than cisplatin. It has a lower reactivity which allows a higher dose to be delivered.
  • the dosage of carboplatin can be up to 2000mg/dose[1.2] .
  • the cisplatin dosage is usually around 100 mg/day for up to five consecutive days.
  • the second generation drugs are generally referred to as CBDCA derivatives after the parent compound.
  • third generation derivatives In order to reduce development of resistance to the cytostatic further derivatives, the socalled third generation derivatives have evolved. These include platinum(IV) derivatives that can be administered orally.
  • Treatment to try and prevent resistance occurring comprises administering a number of chemotherapeutic agents rather than one and applying a varied scheme of administration. In particular upon treatment of ovarian cancer a major limitation of cisplatin is acquired resistance. The dose escalation required to overcome even a small increase in cellular resistance can cause severe toxicity.
  • the pharmaceutical composition according to the invention is a pharmaceutical composition for use in treatment of a subject having neoplasms with a view to reducing size and/or number of neoplasms, said pharmaceutical composition comprising a complex of a cytostatic compound of the cis platinum family and an anionic organic compound as complexed form of the active pharmaceutical component, said complex having the following general formula 1
  • Zl , Z2 independently 0 or NR' ;
  • cisplatin is a small hydrophilic molecule which is not expected to remain trapped in such a liposome structure as taught in the document for a sufficient length of time to provide a suitable slow release medicament.
  • W096/15774 a process and apparatus for making liposomes containing hydrophobic drugs is disclosed using critical, supercritical or near critical fluids. Such structures comprise the drug enclosed within the liposome structure not as a structural component of the liposome itself.
  • the description mentions a large number of potentially useful hydrophobic drugs and includes in this list the compound B cisplatin.
  • the pharmaceutical composition according to the invention suitably comprises as substituents R1,R2,R3 and R4 substituents common to what are generally known in the art as belonging to the cisplatinum family of compounds. These have been described in the introductory part of the description and are all incorporated herein by reference. In particular the first and second generation derivatives are suitable.
  • Preferable compounds comprise cisplatinum substituents in combinations already in use clinically.
  • Such chains can be alkyl, alkenyl, optionally substituted by amino, hydroxy and/or acyloxy or a mixture thereof.
  • Such hydrophobic chains may comprise one or more fatty acid chains. These can vary in length or be of the same length.
  • naturally occurring fatty acids can be used. The use of natural fatty acids is preferred as tolerance to such a compound will be higher upon release of the active Pt, whereby the ligands are also released.
  • anionic organic complexant examples include amino acid residues (-0C0-CHR"-NR' -) , malonic acid derivatives (-0C0-CHR"-C00-) , ⁇ - phosphonocarboxylic acid derivatives (-0C0-CHR"-P0(0 ⁇ )-0-) and the corresponding amides.
  • a pharmaceutical composition wherein the anionic organic compound comprises a phosphorylated tyrosine, serine, homoserine or threonine structure is a preferred embodiment of the invention.
  • the presence of the structures corresponding to other amino acids either natural or derived i.e. comprising an amino and carboxyl group also falls within the scope of the invention.
  • a pharmaceutical composition according to the invention preferably releases the active cytostatic compound upon contact with gluthathione .
  • the complex is more stable in the bloodstream than in the cell.
  • a pharmaceutical composition according to the invention comprises the complex in a pharmaceutically acceptable dosage form.
  • dosage forms are immediately apparent to a person skilled in the art.
  • the dosage form will depend on the patient, the severity of the malignancy, the dosage regime selected by the physician and can have numerous embodiments as is well known in the art. A number are provided here.
  • a pharmaceutically acceptable dosage form can be selected from the group comprising tablets, lozenges etc, ingestible liquids, injectable solutions or freezedried products to be solubilised that can be administered via infusion i.a.
  • the amount of active compound in a single bolus dosage form according to the invention can surpass that common to the prior art compositions comprising the corresponding cisplatinum derivative, due to the reduced toxicity of the subject compositions vis a vis the prior art compositions.
  • a pharmaceutical composition must be sterile. It is preferably isotonic upon administration and should be free of undesirable compounds e.g. toxic compounds other than a cytostatic compound and impurities .
  • a method of treating a subject having neoplasms with a compound of the cisplatinum family of cytostatic compounds comprising application of a pharmaceutical composition in any embodiment described above as the invention in a pharmaceutically acceptable dosage and form to said subject in order to reduce the number and/or size of neoplasms also falls within the scope of the invention.
  • neoplasms that can be treated are those which are already known in the prior art susceptible to treatment with cis platinum derivatives. Other forms may also be treated due to the higher dosages now possible in a more effective manner.
  • a method according to the invention can reduce the number and/or size of neoplasms with reduced side effects related to treatment with said cytostatic compound were it to be applied as a direct release pharmaceutical composition per se.
  • a method according to the invention can reduce the number and/or size of neoplasms with reduced nephrotoxicity related to treatment with said cytostatic compound were it to be applied as a direct release pharmaceutical composition per se.
  • cis-Diamminedichloroplatinum(II) (cisplatin) 1 is a commonly used anti-cancer drug. It is a reactive compound which can occur in various species in aqueous solution depending on the pH and chloride ion concentration (1-4). It is well established that cisplatin interacts with DNA and thereby causes inhibition of DNA synthesis which might be a primary therapeutic action (5-7) • In addition the molecule interacts with proteins (8, 9)- Whether cisplatin has an affinity for cellular lipids is not known.
  • Phospholipids were purchased from Avanti Polar Lipids, Inc. (Birmingham, AL, USA) and contained two oleoyl fatty acyl chains, except cardiolipin, derived from bovine heart, sphingomyelin, derived from egg, and phosphatidylinositol, derived from soybean.
  • Cisplatin incubations with, phospholipids dispersions - Lipid dispersions (2 mM phospholipid) were prepared by adding buffer containing no or 5 mM cisplatin to a dry lipid film followed by 10 times freeze- thawing and agitation with a Vortex mixer. In all cases cisplatin solutions were always freshly prepared by dissolving the compound in the appropriate buffer which was facilitated by warming to 4 ⁇ 50 °C.
  • mM cisplatin final concentration was added to the membranes (2 mM phospholipid-Pi) and incubation was performed at 37 °C, in 10 mM Mes, 50 mM Na2S04, 1 mM egta, pH 6.0. Since these ghosts are open structures, cisplatin is able to reach both the inner and outer leaflet of the membrane. Samples were taken at different time points and phospholipids were extracted according to (18).
  • TMS TMP (trimethyl phosphate) and K 2 PtCl (-1600 ppm) , respectively.
  • Cisplatin specifically complexes with phosphatidylserine in mode l membranes -
  • a chloride-ion free buffer of pH 6.0 10 mM MES, 50 mM Na j SO/,, 1 mM egta
  • X a new species can be observed by TLC (Fig. 1A) .
  • X has a lower R F value then DOPS in an acidic eluens, it is phosphorus positive and in contrast to DOPS it does not stain purple (but brownish) when stained with the amino-group-specific ninhydrin reagent (data not shown).
  • Dispersions of DOPE, DOPC and sphingomyelin representatives of the other major mammalian plasma membrane phospholipids, do not show the appearance of new reaction products upon incubation with cisplatin under these conditions (Fig. 1A) . This is also not observed for a D0PE/D0PC (1:1, molar) mixed dispersion (data not shown) which is organized in a lamellar phase at room temperature (pure DOPE forms a H phase [21]). Furthermore, new reaction products are also absent when the negatively charged phospholipids cardiolipin, phosphatidylglycerol and phosphatidylinositol are incubated with cisplatin (data not shown) .
  • the (M+H) + ions at m/z 1014, 1015, and 1016 were subjected to MS-MS.
  • MS-MS spectra two dominant fragments ion clusters are observed m/z 412, 413, and 4l4, and m/z 314, 315, and 316 (Fig. 5).
  • product ion spectrum of m/z 1014 only m/z 4l2 and m/z 314 are observed (Fig. 5A) .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition pharmaceutique destinée à être utilisée dans le traitement d'un sujet présentant des néoplasmes afin de réduire la taille et/ou le nombre de ces néoplasmes; cette composition pharmaceutique comprend un complexe d'un composé cytostatique de la famille du cis-platinum, ainsi qu'un composé organique anionique comme forme complexée du composant pharmaceutique actif, ledit complexe présentant la formule générale 1 dans laquelle Q = -CO- ou -PO(O-)-; Y = -CHR'-, -CO-, -PO(O-)- ou une liaison directe; Z1, Z2 = de manière indépendante O ou NR', R1, R2 = H ou un groupe hydrocarbure éventuellement substitués, éventuellement liés l'un à l'autre ou à R3 et/ou à R4, dans laquelle R3, R4 = H ou un groupe hydrocarbure éventuellement substitués, éventuellement liés l'un à l'autre ou à R1 et/ou R2, dans laquelle R' = H, ou un groupe hydrocarbure éventuellement substitués et dans laquelle R''= un groupe hydrocarbure substitué par un groupe capable de former des liposomes.
PCT/NL1997/000661 1996-12-03 1997-12-03 Produit pharmaceutique contenant du cis-platinum WO1998024425A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54168/98A AU5416898A (en) 1996-12-03 1997-12-03 Cisplatinum comprising pharmaceutical

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/NL1996/000474 WO1998024424A1 (fr) 1996-12-03 1996-12-03 Produit pharmaceutique contenant du cisplatine
NLPCT/NL96/00474 1996-12-03

Publications (1)

Publication Number Publication Date
WO1998024425A1 true WO1998024425A1 (fr) 1998-06-11

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PCT/NL1997/000661 WO1998024425A1 (fr) 1996-12-03 1997-12-03 Produit pharmaceutique contenant du cis-platinum

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Application Number Title Priority Date Filing Date
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AU (2) AU7711096A (fr)
WO (2) WO1998024424A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1545459A2 (fr) * 2002-08-02 2005-06-29 Transave, Inc. Agregats de platine, et procede de fabrication correspondant
US9107824B2 (en) 2005-11-08 2015-08-18 Insmed Incorporated Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally
US9186322B2 (en) 2002-08-02 2015-11-17 Insmed Incorporated Platinum aggregates and process for producing the same
CN109745338A (zh) * 2019-01-17 2019-05-14 南开大学 包载伏立诺他具有还原响应的Pt(IV)聚合物前药胶束的制备方法及应用
US11291644B2 (en) 2012-09-04 2022-04-05 Eleison Pharmaceuticals, Llc Preventing pulmonary recurrence of cancer with lipid-complexed cisplatin

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2524478A1 (fr) * 2003-05-02 2004-11-18 Aronex Pharmaceuticals, Inc. Complexes de platine a lipides et leurs procedes d'utilisation
CN106572991A (zh) 2014-06-11 2017-04-19 德克萨斯州大学系统董事会 用于克服铂耐受性的德克萨卟啉‑pt(iv)缀合物及组合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990002131A1 (fr) * 1988-08-22 1990-03-08 Board Of Regents, The University Of Texas System Composes cis-platiniques hydrophobes efficacement incorpores a des liposomes
US5059591A (en) * 1983-05-26 1991-10-22 The Liposome Company, Inc. Drug preparations of reduced toxicity
WO1996015774A1 (fr) * 1994-11-18 1996-05-30 Aphios Corporation Procedes et dispositifs de confection de liposome contenant des medicaments hydrophobes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5059591A (en) * 1983-05-26 1991-10-22 The Liposome Company, Inc. Drug preparations of reduced toxicity
US5059591B1 (en) * 1983-05-26 2000-04-25 Liposome Co Inc Drug preparations of reduced toxicity
WO1990002131A1 (fr) * 1988-08-22 1990-03-08 Board Of Regents, The University Of Texas System Composes cis-platiniques hydrophobes efficacement incorpores a des liposomes
WO1996015774A1 (fr) * 1994-11-18 1996-05-30 Aphios Corporation Procedes et dispositifs de confection de liposome contenant des medicaments hydrophobes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
G. SPEELMANS ET AL, BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1283, no. 1, 14 August 1996 (1996-08-14), pages 60 - 66, XP002040390 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1545459A2 (fr) * 2002-08-02 2005-06-29 Transave, Inc. Agregats de platine, et procede de fabrication correspondant
JP2006502233A (ja) * 2002-08-02 2006-01-19 トランセーブ，インク． 白金凝集物およびその製造方法
EP1545459A4 (fr) * 2002-08-02 2007-08-22 Transave Inc Agregats de platine, et procede de fabrication correspondant
US9186322B2 (en) 2002-08-02 2015-11-17 Insmed Incorporated Platinum aggregates and process for producing the same
US9107824B2 (en) 2005-11-08 2015-08-18 Insmed Incorporated Methods of treating cancer with high potency lipid-based platinum compound formulations administered intraperitoneally
US11291644B2 (en) 2012-09-04 2022-04-05 Eleison Pharmaceuticals, Llc Preventing pulmonary recurrence of cancer with lipid-complexed cisplatin
CN109745338A (zh) * 2019-01-17 2019-05-14 南开大学 包载伏立诺他具有还原响应的Pt(IV)聚合物前药胶束的制备方法及应用

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Publication number Publication date
WO1998024424A1 (fr) 1998-06-11
AU7711096A (en) 1998-06-29
AU5416898A (en) 1998-06-29

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