EP2026789A2 - Nouvelle formulation d'un cytostatique, en particulier le cis-platine, orientée en fonction de la physiologie tumorale - Google Patents

Nouvelle formulation d'un cytostatique, en particulier le cis-platine, orientée en fonction de la physiologie tumorale

Info

Publication number
EP2026789A2
EP2026789A2 EP07764344A EP07764344A EP2026789A2 EP 2026789 A2 EP2026789 A2 EP 2026789A2 EP 07764344 A EP07764344 A EP 07764344A EP 07764344 A EP07764344 A EP 07764344A EP 2026789 A2 EP2026789 A2 EP 2026789A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
solution
cytostatic
protein
human
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Withdrawn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
EP07764344A
Other languages
German (de)
English (en)
Inventor
Hannsjörg SINN
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.)
AlbuPharm Heidelberg GmbH and Co KG
Original Assignee
AlbuPharm Heidelberg GmbH and Co KG
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 AlbuPharm Heidelberg GmbH and Co KG filed Critical AlbuPharm Heidelberg GmbH and Co KG
Publication of EP2026789A2 publication Critical patent/EP2026789A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/28—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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a pharmaceutical composition containing a conjugate of a low molecular weight cytostatic with a human-compatible protein, optionally galenical additives and / or adjuvants and water, the use of such a pharmaceutical composition for the manufacture of a medicament for the treatment of a disease, which is ill with a changed metabolism Cells, a process for producing such a pharmaceutical composition and a treatment method using such a drug.
  • RES reticuloendothelial system
  • drugs with two or more reactive groups can cause further complications. For example, if you put a conjugate of cis-platinum and albumin and performs a Sice-Exclusion Chromatogrphy (SEC) at different times, shows that the dimeric protein content increases with time. So z. For example, the dimeric portion of a 10% cis-platinum HSA solution exceeds 20% after about two weeks, even when stored at +4 to + 6 ° C, which prohibits stock production of the conjugate by itself, for albumin solution. for clinical use may contain a maximum of 5% dimeric product.
  • SEC Sice-Exclusion Chromatogrphy
  • HSA human serum albumin
  • fluorescent dyes in vivo, in a targeted manner and at a low loading level, reveal completely new behaviors in vivo, as exemplified by Sinn, H., Schrenk, HH, et al. (1990): Design of Compounds Having Enhanced Tumor Uptake, Using Serum
  • Cytostatic agents lose their general toxicity and only act in the tumor tissue, because normal, healthy cells no macromolecular proteins such.
  • B. albumin The biological half-lives of the drugs are no longer in the range of a few hours but at 18 - 20 days. Thus, at any time, if a tumor cell would like to share sufficient drug available.
  • the distribution of the drug is ubiquitous d.
  • H. the distribution space is now identical to the distribution of albumin, which is present in the extravasal space with about 60% of its total amount and is continuously returned to the circulation via the lymphatics. Lymphoid metastases are automatically treated by albumin-bound drugs, as these cells absorb albumin for their growth.
  • Conjugates of cis-platinum (II) derivatives equipped with the above pharmacological advantages, processes for their preparation and their uses are described, for example, in the document DE 199 57 688 A1. That the production and in particular storage of albumin conjugates but also problems z. B. the shelf life is particularly given for drugs with at least two reactive groups such as cis-platinum, melphalan, etc. This dual reactivity leads to the duration of storage of the conjugates, even if it takes place at +4 0 C, too Increased production of di- and oligomeric HSA products that are no longer allowed for clinical use when the dimer content exceeds 5%. This often happens within 24 hours.
  • the invention is therefore based on the technical problem of providing a pharmaceutical composition with a conjugate of a cytostatic with a human tolerated protein, which has an improved tolerance time, in particular a reduced rate of formation of protein dimers or oligomers shows.
  • the invention teaches a pharmaceutical composition
  • a pharmaceutical composition comprising: a) 0.01 to 4 wt .-% of a conjugate of a low molecular weight cytostatic with a human-compatible protein, wherein the weight ratio of protein to cytostatic in the conjugate at 20: 1 or higher, b) 0 to 0.9 wt .-% NaCl, c) 0 to 5 wt .-% of a stabilizing additive, d) 0 to 5 wt .-% of galenic additives and / or auxiliaries, which of the components b) and c ), e) 0 to 5 wt .-% of a different of the component a) pharmacologically and / or diagnostically active substance or a mixture of different such substances, f) 19.9 to 99.9 wt .-% water, wherein the components a) to e) always add up to 100%, in particular consisting of these components
  • the reduced proportion of protein in the composition (about 4% by weight and less compared to about 5% by weight in the prior art) in the composition at substantially the same ratio of protein to cytostatic leads to one compared to the state significantly reduced rate of formation of dimers or oligomers of the protein.
  • the pharmaceutical composition can be administered to a patient far longer than known compositions containing cis-platinum / albumin conjugates, calculated from the preparation of the composition.
  • the tolerance time is thus improved.
  • the expression of the tolerance time means in this case the time which elapses until the formation of an impermissible fraction (5% by weight and more) of dimers or oligomers.
  • a cytostatic agent which can be used according to the invention typically has a molecular weight of 1000 Da and less.
  • a useful cytostatic agent typically has two or more functional groups that are reactive under physiological conditions (in vitro and / or in vivo).
  • a protein which can be used according to the invention typically has a molecular weight of 20,000 Da and more, in particular 30,000 to 100,000 Da.
  • conjugate of a cytostatic with a protein includes covalent bonds, ionic bonds, hydrogen bonds, and other complex-forming bonds between the cytostatic and the protein.
  • a pharmaceutical composition according to the invention generally contains less than 10% by weight, preferably less than 5% by weight, in particular less than 1% by weight, of unbound cytostatic agent, based on the amount of cytostatic agent used and measured by standard HPLC Method, for example according to the measurement conditions, as indicated in the examples.
  • human-compatible protein refers to any proteins whose administration does not cause any disturbing immune reaction of the human organism. So it does not necessarily have to be human or even the body's own proteins, as long as the tolerance is given when given to a human.
  • (native) bovine serum albumin can also be used.
  • the cytostatic agent is selected from the group consisting of "cis-platinum (II) derivatives, in particular cis-platinum (II) diamine chloride, cis-3,4-diaminobenzoic acid platinum dichloride and 4,5,6-triaminopyrimidine platinum dichloride , N-type compounds, in particular carmustine (BCNU), Chlorambucil and melphalan.
  • the human tolerated protein may be transferrin, preferably albumin, more preferably serum albumin, most preferably human serum albumin.
  • a further improvement in the tolerance time can be achieved by the addition of a stabilizing additive.
  • a suitable stabilizing additive is, for example, ascorbic acid.
  • Suitable galenical additives and / or auxiliaries are, for example, mono- or polyhydric C 1-6 alcohols, such as glycerol.
  • analgesics for example, analgesics, sedatives, or therapeutic agents may be used.
  • the expert can easily select these from the specialist literature if such additional means are to be used.
  • various diagnostically active substances for example conjugates of planar aromatic polycyclic compounds and a human-compatible protein in question, as described in the document DE 198 47 362 Al, or conjugates with diagnostically customary fluorophores.
  • planar aromatic polycyclic compounds it is also possible to use any other contrast agents which differentiate in imaging processes between diseased cells and healthy cells per se or as a conjugate with the protein (because of its accumulation in diseased cells).
  • the protein used in the different component is either different from the protein used in component a), or that the total amount of the protein according to component a), added over all components with the protein, in the composition does not exceed 4 wt .-%.
  • a pharmaceutical composition according to the invention may consist of the components a) to f), for example with the following preferred proportions: a) 0.5 to 3 wt .-%, preferably 1 to 2.5 wt .-%, of the conjugate of the cytostatic with the protein-compatible protein, wherein the weight ratio of protein to cytostatic in the conjugate is 50: 1, in particular 80: 1, and higher, b) 0.4 to 0.9 wt.% NaCl, c) 0 to 3 wt. a stabilizing additive; d) 0 to 3% by weight of galenical additives and / or auxiliaries which are different from components b) and c); f) the remainder water.
  • a preferably usable component a) is obtainable by a coupling reagent-free direct reaction of the cytostatic with an aqueous solution of the human-compatible protein.
  • the pharmaceutical composition may be obtainable, that a) the cytostatic agent in an aqueous solution of NaCl is dissolved, b) the solution from step A) with an aqueous solution of human-compatible protein at a temperature between 0 0 C and 30 0 C. C) optionally the components c) to e) are added in any order of the solution from step B).
  • the pharmaceutical composition may be obtainable by: A) the
  • Cytostatic in solid form directly to an aqueous solution of human-compatible protein at a temperature between 0 0 C and 30 0 C is added and reacted, B) the solution from step A) an aqueous NaCl solution is added, C) optionally components c) to e) are added in any order of the solution from step B).
  • the molar ratio of the cytostatic agent used to the human-compatible protein used can be in the range 0.5: 1 to 5: 1, preferably 1: 1 to 2: 1.
  • the invention further teaches the use of a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment of a disease which is accompanied by an altered metabolism, in particular an increased consumption of human-tolerated protein, of diseased cells.
  • the disease can be, for example, a tumor disease or a be inflammatory disease.
  • Specific diseases for which the invention can be used are, for example: diseases which are characterized by hyperproliferation and lacking cell differentiation, for example tumor diseases and precancerous conditions, such as intestinal tumors,
  • Gastric tumors pancreatic tumors, bladder tumors, lung tumors, breast carcinoma, prostate carcinoma, leukemia, T-cell lymphoma, melanoma, betazeil carcinoma, squamous carcinoma, actinic keratosis, cervical dysplasia, metastatic tumors of any kind or disease, hyperproliferative
  • Skin disorders such as psoriasis, pituriasis subia pilasis, acne, ichthyosis, pruritus, disorders characterized by dysregulation of the immune system, in particular eczema and atopic dermatitis disorders and inflammatory diseases such as rheumatoid arthritis, respiratory diseases such as asthma.
  • the invention further teaches a process for the preparation of a pharmaceutical composition according to the invention comprising the following process steps: A) the cytostatic is dissolved in an aqueous NaCl solution, B) the solution from step A) is treated with an aqueous solution of the human-compatible protein, preferably in a Temperature between O 0 C and 40 0 C, in particular between 4 0 C and 2O 0 C, reacted, C) optionally the components c) to e) are added in any order of the solution from stage B), or alternatively: A) the Cytostatic agent is added in solid form directly to an aqueous solution of the human-compatible protein, preferably at a temperature between 0 0 C and 40 0 C, in particular between 4 0 C and 20 0 C, and implemented herein, B) the solution of step A) is an aqueous NaCl solution added, C) optionally components c) to e) added in any order of the solution from step B).
  • the invention relates to a method for the treatment of a disease which is associated with an altered metabolism, in particular an increased consumption of human-tolerated protein, diseased cells, wherein a person suffering from or a person suffering from sick, a physiologically effective dose of a pharmaceutical composition according to the invention is presented.
  • the area of diseased cells can be irradiated with electromagnetic radiation or particle radiation for which the cis-platinum (II) derivative has hyperthermia-inducing absorption.
  • the electromagnetic radiation may in particular be X-radiation.
  • administration units doses of 0.05 to 5 mg cytostatic per kg body weight are possible. However, a range of 0.5 to 2.0 mg cytostatic / kg body weight is preferred. Such administration units can be presented once to a patient. However, it is also possible to administer such administration units from once to twice a month.
  • the preferred dosage forms are i.V. injection.
  • Example 1 Preparation of a pharmaceutical composition according to the invention
  • II cis-diaminoplatinum
  • HSA human serum albumin
  • the covalent binding of cis-platinum to albumin takes place via the direct addition of an infusion solution of cis-platin approved for clinical application to a 5% HSA solution approved for clinical administration.
  • the mixing ratio is constant and is 1.5 moles of cis-platinum per mole of albumin.
  • a standard laboratory scale approach is as follows. 10.5 mg of cis-platinum (about 35 ⁇ mol) dissolved in 19.3 ml of 0.9% NaCl and 66 ⁇ l of 1N HCl. The solution is water clear and colorless, the concentration and the pH value (2.33) of cis-platinum corresponds to the commercially available infusion solutions (0.5 mg / ml). 31 ml of 5% HSA solution [Octapharma] (about 23.3 ⁇ mol) are introduced and the 20 ml cis-platinum solution is added rapidly. The pH of the resulting solution drops to 6.65 within a few seconds. There is no clouding or flocculation of albumin. The ratio of cis-platinum to albumin is about 1.5: 1.
  • Example 2 alternative preparation of a pharmaceutical composition according to the invention
  • a standard laboratory scale approach is as follows. 10.5 mg of cis-platinum (about 35 .mu.mol) are presented in solid form in a sterile vessel. 31 ml of 5% HSA solution [Octapharma] (about 23.3 ⁇ mol) are added rapidly (the molar ratio is about 1.5 cis-platinum: 1 albumin). The solid cis-platinum dissolves within a few minutes and gives a clear solution. There is no clouding or flocculation of albumin at any time. Immediately after dissolving cis-platinum, the HSA solution will be diluted to a 2% level with 0.9% NaCl solution to keep the level of dimeric HSA below 5% for at least 3-4 days.
  • the tolerance time of this 2% cis-platinum-HSA solution may be extended by a few days when ascorbic acid is added to the solution in amounts of 0.5 to 1.0 mg / ml.
  • An upscaling is readily possible as long as the molar ratios are kept constant.
  • the storage or transport should take place at +4 to +6 0 C.
  • the resulting solution was subjected to a control by HPLC / SEC.
  • 12.5 ⁇ L of the 2% cis-platinum HSA solution is diluted with 987.5 ⁇ L of water. This corresponds to a concentration of 0.2 mg albumin / ml, which can be given up directly for analysis.
  • the chromatogram shows practically no difference to the starting product albumin. There is no further peak to recognize. As the protein peak increases, with no change in retention time over pure HSA, the cis-platinum peak completely disappears. 3 days after preparation and storage at 4 0 C, the proportion of albumin dimers was well below 5%.
  • dimeric SA fraction ca. 9,042 - 9,175 min.
  • monomeric SA fraction about 9.908 - 9.975 min.
  • free cis-platinum ca. 12,65 min.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne une composition pharmaceutique contenant : a) de 0,01 à 4 % en poids d'un conjugué d'un agent cytostatique de faible masse moléculaire possédant deux groupes réactifs ou plus et d'une protéine compatible avec l'homme, le ratio en poids de la protéine sur l'agent cytostatique dans le conjugué étant de 20:1 ou supérieur ; b) de 0 à 0,9 % en poids de NaCl ; c) de 0 à 5 % en poids d'un additif stabilisateur ; d) de 0 à 5 % en poids d'additifs et/ou auxiliaires galéniques différents des composants b) et c) ; e) 0 à 5 % en poids d'une substance, différente du composant a), ayant une activité pharmacologique et/ou diagnostique, ou d'un mélange de substances de ce type ; f) de 19,9 à 99,9 % en poids d'eau ; la somme des composants a) à e) étant toujours égale à 100 %. L'invention concerne en outre des utilisations de ces compositions, ainsi que des procédés pour les préparer.
EP07764344A 2006-05-23 2007-05-23 Nouvelle formulation d'un cytostatique, en particulier le cis-platine, orientée en fonction de la physiologie tumorale Withdrawn EP2026789A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006024528A DE102006024528A1 (de) 2006-05-23 2006-05-23 Neue, an der Tumorphysiologie orientierte Formulierung eines Zytostatikums, insbesondere von cis-Platin
PCT/DE2007/000940 WO2007134595A2 (fr) 2006-05-23 2007-05-23 Nouvelle formulation d'un cytostatique, en particulier le cis-platine, orientée en fonction de la physiologie tumorale

Publications (1)

Publication Number Publication Date
EP2026789A2 true EP2026789A2 (fr) 2009-02-25

Family

ID=38521760

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07764344A Withdrawn EP2026789A2 (fr) 2006-05-23 2007-05-23 Nouvelle formulation d'un cytostatique, en particulier le cis-platine, orientée en fonction de la physiologie tumorale

Country Status (3)

Country Link
EP (1) EP2026789A2 (fr)
DE (1) DE102006024528A1 (fr)
WO (1) WO2007134595A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014020171A1 (fr) * 2012-08-03 2014-02-06 Boehringer Ingelheim International Gmbh Capacité tampon d'anticorps
CN117159705A (zh) * 2015-01-19 2023-12-05 锡拉莱斯科技有限公司 金属-糖蛋白复合物及其作为化学治疗化合物的用途
US10111936B2 (en) 2015-01-19 2018-10-30 Theralase Technologies, Inc. Metal-glycoprotein complexes and photodynamic therapy of immune privileged sites with same

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19926154A1 (de) * 1999-06-09 2000-12-14 Ktb Tumorforschungs Gmbh Verfahren zur Herstellung einer injizierbaren Arzneimittelzubereitung
EA200200234A1 (ru) * 1999-08-09 2002-06-27 Фармация Энд Апджон С.П.А. Препараты для парентерального применения эстрамустин фосфата и альбумина
DE19957688A1 (de) * 1999-11-30 2001-06-13 Deutsches Krebsforsch Konjugate von cis-Platin(II)-Derivaten, Verfahren zu ihrer Herstellung und ihre Verwendung
DE102004016355A1 (de) * 2004-04-02 2005-11-03 Rösner Research GmbH & Co.KG Herstellung und Verwendung des Konjugats Methotrexat-Albumin als Mittel zur Immunosuppression bei GVHD

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007134595A2 *

Also Published As

Publication number Publication date
DE102006024528A1 (de) 2007-11-29
WO2007134595A3 (fr) 2008-10-16
WO2007134595A2 (fr) 2007-11-29

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