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EP2879660A1 - Resiniferatoxin solution - Google Patents

Resiniferatoxin solution

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Publication number
EP2879660A1
EP2879660A1 EP12746257.0A EP12746257A EP2879660A1 EP 2879660 A1 EP2879660 A1 EP 2879660A1 EP 12746257 A EP12746257 A EP 12746257A EP 2879660 A1 EP2879660 A1 EP 2879660A1
Authority
EP
European Patent Office
Prior art keywords
resiniferatoxin
solution according
solution
protective gas
solvent
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Withdrawn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
EP12746257.0A
Other languages
German (de)
French (fr)
Inventor
Thomas Giller
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.)
Mestex AG
Original Assignee
Mestex AG
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 Mestex AG filed Critical Mestex AG
Publication of EP2879660A1 publication Critical patent/EP2879660A1/en
Withdrawn legal-status Critical Current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
    • 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
    • A61K47/02—Inorganic 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
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D85/00—Containers, packaging elements or packages, specially adapted for particular articles or materials
    • B65D85/70—Containers, packaging elements or packages, specially adapted for particular articles or materials for materials not otherwise provided for

Definitions

  • the invention relates to a Resiniferatoxin solution according to the preamble of patent claim 1.
  • Resiniferatoxin can be used for a variety of purposes, primarily in medicine and medical or pharmacological research. It comes from the plant Euphorbia resinifera and has the desired property of being effective even in lowest doses at the TRPV1 receptor and presumably other sites. It is biologically related to capsaicin and chemically it is a diterpene from the family of Daphnan structures. The molecule also shows similarities to the phorbol-ester family but without detectable tumor-suppressive effects. However, a difficulty in dealing with RTX is that it is commonly used in amounts where it is invisible to the naked eye and is particularly difficult to detect, especially when used with other substances.
  • RTX has the tendency to easily bind to a variety of surfaces and substances.
  • Another property of RTX is that it is only partially stable as a powder or in a dissolved state even frozen (-20 ° C) and is very sensitive to oxidation by atmospheric oxygen or hydrolysis.
  • the molecular weight is 628.7 gr / mol, the empirical formula is C37H oO 9 .
  • the storage is still mostly in powder form, at -20 ° C. In unfrozen state, it remains unstable and readily breaks down into ROPA (Resiniferanol-9,13,14-ortho-pentylacetate) and other fragments.
  • ROPA Resiniferanol-9,13,14-ortho-pentylacetate
  • the invention aims to remedy this situation.
  • the object of the invention is to provide a resiniferatoxin solution in which the dissolved resiniferatoxin:
  • the saturation amount for each eligible inert gas in each selected solvent can be easily taken from the relevant manuals, or can also be determined by a simple measurement.
  • One liter of alcohol dissolves, for example, 120 ml of nitrogen gas at 19 ° and atmospheric pressure (Rompps Chemie-Lexikon, 8th ed., 1979, pag. 3984).
  • the saturation amount of argon was determined to be 0.07 wt% at room temperature and normal pressure.
  • compositions given below relate to RTX RTX stock solutions which are diluted appropriately prior to use (eg with hyaluronic acid, water or mixtures thereof) and optionally added with buffer solutions for injection into the patient.
  • RTX RTX stock solutions which are diluted appropriately prior to use (eg with hyaluronic acid, water or mixtures thereof) and optionally added with buffer solutions for injection into the patient.
  • example 1 RTX RTX stock solutions which are diluted appropriately prior to use (eg with hyaluronic acid, water or mixtures thereof) and optionally added with buffer solutions for injection into the patient.
  • DMSO dimethylsulfoxide
  • another suitable biocompatible solvent or mixtures thereof, may be chosen.
  • inert gases or gas mixtures may also be used, for example nitrogen N 2 , CO 2 , helium, neon, krypton, xenon or mixtures thereof.
  • the shielding gas is introduced under elevated pressure into a capsule (glass clear or brown or otherwise colored, metal, coated or not) with the RTX stock solution or directly into the RTX stock solution. This increases the measured in the liquid concentration of the protective gas over its share at atmospheric pressure.
  • the gas can in principle be introduced into the RTX stock solution using all methods familiar to the person skilled in the art.
  • the Resiniferatoxin solution according to the invention is used to prepare injectable single doses or multiple doses. These contain an amount RTX of 1 ng to 10 micrograms, preferably 50ng to 2 micrograms prepared from the inventive Resiniferatoxin solution (stock solution) at a concentration of 1 ug / ml to 50 ug / ml.
  • the resiniferatoxin solution according to the invention can also be used for the preparation of mixtures for external treatment, for example ointments or creams or for solutions which are applied only temporarily (eg bladder or mucous membranes).
  • the preferred uses concern painful loci of the musculoskeletal system, in particular intraarticular use in synovial joints.
  • Other preferred sites include synovial spaces and the vicinity of tendons, use in the nucleus pulposus, in and around the disc, on ligaments and their attachment sites, and in and around joint capsules, as well as use in and around painful teeth.
  • Other applications concern the nervous system, eg intra- or periganglionic as well as intra-epi- and peridural as well as intraarachnoidal applications on the spine and the cerebrum.
  • the application includes humans and animals.
  • Resiniferatoxin solution Another positive property of the inventive Resiniferatoxin solution is that the substance even in dilute, ready-to-use solution (ie diluted with buffer solution and hyaluronic acid) is so stabilized that you can use them in combination with commercial, plastic plastic syringes, which usually made of polypropylene, polyethylene, polyurethane and other materials. So far, it has been considered essential that the RTX solution does not come in contact with polymer as it binds to it immediately. However, in the preparation shown here, it can be mounted in a polypropylene syringe, stored there for 10 minutes and then injected into the patient with no measurable loss of RTX.
  • the single figure shows a graph showing the time in months on the x-axis and the stability of the dissolved RTX on the y-axis.
  • Three measurement series are shown, the first (diamond measurement points) shows the results for RTX dissolved in ethanol at 5 ° C without additional protective gas (argon), the second (square measurement points) shows the results for RTX dissolved in ethanol at 5 ° C containing 0.07 wt.% Argon and the third (triangle measuring points) shows the results for RTX dissolved in ethanol at 25 ° C and containing 0.07 wt.% Argon.
  • the first set of measurements for the unstabilized RTX solution shows a continuous drop in RTX content.
  • the second and third series of measurements prove that even at a relatively high temperature of 25 ° C, the RTX content remains unchanged at 100% for months.
  • the amount of inert gas is at least 2 wt .-%, preferably at least 4 wt .-% of the saturation amount of the protective gas in the solvent at room temperature and atmospheric pressure.
  • the amount of inert gas may advantageously be at least 10 wt .-%, preferably at least 30 wt .-% of the saturation amount of the protective gas in the solvent at room temperature and atmospheric pressure.
  • the solvent comprises ethanol or dimethyl sulfoxide or mixtures thereof.
  • the solution may additionally contain one or more of the following solvents:
  • heptane preferably at most 1, 0 wt.%
  • the solution contains 0.00010 - 3.0000% by weight, preferably 0.000375 - 0.01000% by weight of resiniferatoxin.
  • the solution contains 1 to 60 pg / ml, preferably 3 to 50 pg / ml of resiniferatoxin.
  • the shielding gas may be selected from the group consisting of argon, nitrogen, carbon dioxide, helium, neon, krypton, xenon or mixtures thereof.
  • the solution contains not more than 0.03% by weight, preferably not more than 0.01% by weight, of oxygen.
  • the resiniferatoxin solution has a pH of from 7.0 to 9.0, preferably from 7.3 to 8.2.
  • the resiniferatoxin solution additionally contains one or more of the following substances: sodium chloride, calcium chloride or potassium chloride.
  • the quantitative ratio between RTX and shielding gas MRTX / Mschutzgas in the range of 0.04 to 10.0, preferably from 0.1 to 2.0.
  • the resiniferatoxin solution additionally comprises a tricyclic antidepressant.
  • the inventive resiniferatoxin solution can be used in particular for the treatment of intra-articular pain.
  • the Resiniferatoxin solution is filled in a container containing the inert gas.
  • a container containing the inert gas.
  • At least the inner wall of the container may be made of polymeric material.
  • the polymeric material may be selected from the group consisting of polypropylene, polyethylene, polyurethane or combinations thereof.
  • the container may be designed as a syringe.
  • a method for producing the inventive Resiniferatoxin solution is that the Resiniferatoxin is dissolved in the solvent and then the resulting solution is enriched with the protective gas.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Mechanical Engineering (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to a resiniferatoxin solution having an enhanced storage stability, in which the resiniferatoxin is dissolved in a body-compatible solvent which contains a protective gas in solution, wherein the amount of the protective gas is at least 1 wt% of the saturation amount of the protective gas in the solvent at ambient temperature and normal pressure. The resiniferatoxin dissolved in the resiniferatoxin solution remains stable for a relatively long period and exhibits a reduced tendency to cling to polymeric surfaces.

Description

Resiniferatoxin-Lösung  Resiniferatoxin solution
Die Erfindung bezieht sich auf eine Resiniferatoxin-Lösung gemäss dem Oberbegriff des Patentanspruchs 1. The invention relates to a Resiniferatoxin solution according to the preamble of patent claim 1.
Resiniferatoxin (RTX) kann für verschiedenste Zwecke, in erster Linie in der Medizin und medizinischen oder pharmakologischen Forschung verwendet werden. Es stammt aus der Pflanze Euphorbia resinifera und hat die erwünschte Eigenschaft bereits in geringsten Dosierungen am TRPV1 Rezeptor und vermutlich anderen Orten wirksam zu sein. Es ist damit biologisch zu Capsaicin verwandt und chemisch handelt es sich um ein Diterpen aus der Familie der Daphnan Strukturen. Das Molekül zeigt auch Ähnlichkeiten zur Phorbol-Ester Familie jedoch ohne nachweisbare tumor-suppressive Wirkung. Eine Schwierigkeit im Umgang mit RTX ist aber, dass es üblicherweise in Mengen verwendet wird, in denen es von blossem Auge nicht sichtbar ist und insbesondere in Verwendung mit anderen Substanzen sehr schwer nachweisbar ist. Dies liegt einerseits an der extrem kleinen benötigten Dosierung, welche den Nachweis per se schwierig macht und andererseits hat RTX die Tendenz sich leicht an verschiedenste Oberflächen und Substanzen zu binden. Eine weitere Eigenschaft von RTX ist, dass es als Pulver oder in gelöstem Zustand auch tiefgekühlt (-20° C) nur beschränkt stabil ist und sehr anfällig auf Oxidation durch Luftsauerstoff oder Hydrolyse reagiert. Das Molekulargewicht beträgt 628.7 gr/mol, die Summenformel lautet C37H oO9. Die Lagerung erfolgt dennoch meist pulverförmig, bei -20°C. In ungefrorenem Zustand bleibt es instabil und zerfällt leicht zu ROPA (Resiniferanol-9,13,14-ortho- pentylacetat) und anderen Fragmenten. Aus diesen Gründen wird RTX unmittelbar vor dem Gebrauch aufgetaut und bei Raumtemperatur mit einem Lösungsmittel, typischerweise Ethanol oder Dimethylsulfoxid (DMSO) aufgelöst, um dann so weiterverwendet zu werden. Resiniferatoxin (RTX) can be used for a variety of purposes, primarily in medicine and medical or pharmacological research. It comes from the plant Euphorbia resinifera and has the desired property of being effective even in lowest doses at the TRPV1 receptor and presumably other sites. It is biologically related to capsaicin and chemically it is a diterpene from the family of Daphnan structures. The molecule also shows similarities to the phorbol-ester family but without detectable tumor-suppressive effects. However, a difficulty in dealing with RTX is that it is commonly used in amounts where it is invisible to the naked eye and is particularly difficult to detect, especially when used with other substances. This is partly due to the extremely small dosage required, which makes the detection per se difficult and on the other hand, RTX has the tendency to easily bind to a variety of surfaces and substances. Another property of RTX is that it is only partially stable as a powder or in a dissolved state even frozen (-20 ° C) and is very sensitive to oxidation by atmospheric oxygen or hydrolysis. The molecular weight is 628.7 gr / mol, the empirical formula is C37H oO 9 . The storage is still mostly in powder form, at -20 ° C. In unfrozen state, it remains unstable and readily breaks down into ROPA (Resiniferanol-9,13,14-ortho-pentylacetate) and other fragments. For these reasons, RTX is thawed immediately before use and dissolved at room temperature with a solvent, typically ethanol or dimethylsulfoxide (DMSO), to be reused.
Diese Vorgehensweise ist aufwendig und wegen der sehr kleinen Dosierungen unpräzise oder aber sehr teuer.  This procedure is complicated and because of the very small dosages imprecise or very expensive.
Hier will die Erfindung Abhilfe schaffen. Aufgabe der Erfindung ist es eine Resiniferatoxin-Lösung bereitzustellen, in welcher das gelöste Resiniferatoxin: The invention aims to remedy this situation. The object of the invention is to provide a resiniferatoxin solution in which the dissolved resiniferatoxin:
(a) über längere Zeit stabil bleibt; und  (a) remains stable over time; and
(b) eine reduzierte Haftungstendenz an polymere Oberflächen aufweist. Die Erfindung löst die gestellte Aufgabe mit einer Resiniferatoxin-Lösung, welche die Merkmale gemäss dem Anspruch 1 aufweist. (b) has a reduced adhesion tendency to polymeric surfaces. The invention solves this problem with a Resiniferatoxin solution having the features according to claim 1.
Die Sättigungsmenge für jedes in Frage kommende Schutzgas im jeweils gewählten Lösungsmittel (bei Raumtemperatur und Normaldruck) lässt sich leicht aus den einschlägigen Handbüchern entnehmen, bzw. kann auch durch eine einfache Messung bestimmt werden. Ein Liter Alkohol löst beispielsweise 120 ml Stickstoffgas bei 19° und Normaldruck (Römpps Chemie-Lexikon, 8. Aufl., 1979, pag. 3984). Die Sättigungsmenge für Argon wurde bei Raumtemperatur und Normaldruck zu 0,07 Gew. % bestimmt. The saturation amount for each eligible inert gas in each selected solvent (at room temperature and atmospheric pressure) can be easily taken from the relevant manuals, or can also be determined by a simple measurement. One liter of alcohol dissolves, for example, 120 ml of nitrogen gas at 19 ° and atmospheric pressure (Rompps Chemie-Lexikon, 8th ed., 1979, pag. 3984). The saturation amount of argon was determined to be 0.07 wt% at room temperature and normal pressure.
Es hat sich überraschend gezeigt, dass das Resiniferatoxin gelöst im mit Schutzgas angereicherten Lösungsmittel sehr stabil bleibt und sogar bei Raumtemperatur (Temperaturbereich bis +25°C) über mehrere Monate gelagert werden kann (siehe die Figur). Interessanter und unerwarteter Weise genügt es nicht, gefrorenes RTX unter Schutzgas, z.B. Argon zu lagern und danach mit Ethanol zu lösen. In dieser Konstellation tritt ein Verlust des in Ethanol gelösten RTX in der Grössenordnung von 10% in 3 Monaten auf. Wird das RTX zusammen mit Argon jedoch in Ethanol oder anderen körperverträglichen Lösungsmitteln gelöst, bleibt der Verlust bei Raumtemperatur sehr gering. Wie unten näher beschrieben verliert RTX in der erfindungsgemässen Resiniferatoxin-Lösung sogar seine unerwünschte Tendenz an polymeren Oberflächen zu haften. It has surprisingly been found that the Resiniferatoxin dissolved in inert gas-enriched solvent remains very stable and even at room temperature (temperature range to + 25 ° C) can be stored for several months (see the figure). Interestingly and unexpectedly, it is not enough to use frozen RTX under inert gas, e.g. Store argon and then dissolve with ethanol. In this constellation, a loss of RTX dissolved in ethanol of the order of 10% occurs in 3 months. However, when the RTX together with argon is dissolved in ethanol or other biocompatible solvents, the loss at room temperature remains very low. As further described below, RTX even loses its undesirable tendency to adhere to polymeric surfaces in the inventive resiniferatoxin solution.
Die nachstehend angegebenen beispielhaften Zusammensetzungen beziehen auf hochkonzentrierte Vorratslösungen (Stammlösungen) von RTX, welche vor Gebrauch entsprechend verdünnt werden (z.B. mit Hyaluronsäure , Wasser oder Mischungen davon) und gegebenenfalls mit Pufferlösungen versetzt werden damit sie dem Patienten injiziert werden können. Beispiel 1 The exemplary compositions given below relate to RTX RTX stock solutions which are diluted appropriately prior to use (eg with hyaluronic acid, water or mixtures thereof) and optionally added with buffer solutions for injection into the patient. example 1
Substanz Bereich in Gew.%  Substance range in% by weight
RTX 0,000375RTX 0,000,375
Ethylacetat 0,00049 Heptan 0,00131Ethyl acetate 0.00049 heptane 0.00131
Methylcyclohexan 0,00001Methylcyclohexane 0.00001
Ethylalkohol 99,92819Ethyl alcohol 99.92819
Argon 0,07Argon 0.07
Total 100,000000 % Total 100.000000%
Beispiel 2 Example 2
Substanz Bereich in Gew.%  Substance range in% by weight
RTX 0,0006RTX 0.0006
Ethylacetat 1 ,0 Heptan 3,0Ethyl acetate 1, 0 heptane 3.0
Methylcyclohexan 0,04Methylcyclohexane 0.04
Dimethylsulfoxid 95,844Dimethyl sulfoxide 95,844
Stickstoff 0,1 1Nitrogen 0.1 1
Total 100,0000 % Total 100.0000%
Beispiel 3 Example 3
Substanz Bereich in Gew.%  Substance range in% by weight
RTX 0,001RTX 0.001
Heptan 3,0Heptane 3.0
Methylcyclohexan 0,05Methylcyclohexane 0.05
Ethylalkohol 96,749Ethyl alcohol 96.749
Kohlenstoffdioxid 0,2Carbon dioxide 0.2
Total 100,000 % Überraschenderweise genügt es bereits, eine Mischung von RTX, Ethanol und gelöstem Argon allein zu verwenden, dabei wurde eine RTX Konzentration von 3,75,Total 100,000% Surprisingly, it is sufficient to use a mixture of RTX, ethanol and dissolved argon alone, while an RTX concentration of 3.75,
12,00 und 60,00 μg/ml etabliert. Als Alternative zu Ethanol kann Dimethylsulfoxid (DMSO) oder ein anderes geeignetes körperverträgliches Lösungsmittel, bzw. Mischungen davon gewählt werden. 12.00 and 60.00 μg / ml established. As an alternative to ethanol, dimethylsulfoxide (DMSO) or another suitable biocompatible solvent, or mixtures thereof, may be chosen.
Als Alternative zu Argon können auch andere inerte Gase oder Gasgemische verwendet werden, z.B.: Stickstoff N2, CO2, Helium, Neon, Krypton, Xenon oder Mischungen davon. As an alternative to argon, other inert gases or gas mixtures may also be used, for example nitrogen N 2 , CO 2 , helium, neon, krypton, xenon or mixtures thereof.
Besonders hilfreich hat es sich erwiesen, dass das Schutzgas unter erhöhtem Druck in eine Kapsel (Glas durchsichtig oder braun oder anders gefärbt, Metall, beschichtet oder nicht) mit der RTX- Vorratslösung oder direkt in die RTX-Vorratslösung eingebracht wird. Dabei erhöht sich die in der Flüssigkeit gemessene Konzentration des Schutzgases gegenüber seinem Anteil bei Normaldruck. Das Gas kann aber grundsätzlich mit allen dem Fachmann geläufigen Verfahren in die RTX-Vorratslösung eingebracht werden. It has been found to be particularly beneficial that the shielding gas is introduced under elevated pressure into a capsule (glass clear or brown or otherwise colored, metal, coated or not) with the RTX stock solution or directly into the RTX stock solution. This increases the measured in the liquid concentration of the protective gas over its share at atmospheric pressure. However, the gas can in principle be introduced into the RTX stock solution using all methods familiar to the person skilled in the art.
Verwendung der Vorratslösung: Use of the stock solution:
Die erfindungsgemässe Resiniferatoxin-Lösung wird nach entsprechender Verdünnung (z.B. mit Hyaluronsäure, Wasser oder Mischungen davon) dazu verwendet um injizierbare Einzeldosierungen oder Mehrfachdosierungen herzustellen. Diese enthalten eine Menge RTX von 1 ng bis 10 Mikrogramm, vorzugsweise 50ng bis 2 Mikrogramm hergestellt aus der erfindungsgemässen Resiniferatoxin-Lösung (Stammlösung) mit einer Konzentration von 1 μg/ml bis 50 μg/ml. Die erfindungsgemässe Resiniferatoxin- Lösung kann aber auch für die Herstellung von Mixturen zur äusserlichen Behandlung verwendet werden, z.B. Salben oder Cremes oder für Lösungen, welche nur temporär (z.B. Blase oder Schleimhäute) appliziert werden. Die bevorzugten Verwendungen betreffen schmerzhafte Stellen am Bewegungsapparat, insbesondere die intraartikuläre Verwendung in synovialen Gelenken. Andere bevorzugte Stellen sind synoviale Räume und die Umgebung von Sehnen, die Verwendung im Nucleus pulposus, in und um die Bandscheibe, an Bändern und deren Ansatzstellen sowie in und um Gelenkkapseln, sowie die Verwendung in und um schmerzhafte Zähne. Andere Anwendungen betreffen das Nervensystem, z.B. intra- oder periganglionäre sowie intra- epi- und peridurale sowie intraarachnoidale Anwendungen an der Wirbelsäule und am Grosshirn. Die Anwendung umfasst Mensch und Tier. The Resiniferatoxin solution according to the invention, after appropriate dilution (eg with hyaluronic acid, water or mixtures thereof), is used to prepare injectable single doses or multiple doses. These contain an amount RTX of 1 ng to 10 micrograms, preferably 50ng to 2 micrograms prepared from the inventive Resiniferatoxin solution (stock solution) at a concentration of 1 ug / ml to 50 ug / ml. However, the resiniferatoxin solution according to the invention can also be used for the preparation of mixtures for external treatment, for example ointments or creams or for solutions which are applied only temporarily (eg bladder or mucous membranes). The preferred uses concern painful loci of the musculoskeletal system, in particular intraarticular use in synovial joints. Other preferred sites include synovial spaces and the vicinity of tendons, use in the nucleus pulposus, in and around the disc, on ligaments and their attachment sites, and in and around joint capsules, as well as use in and around painful teeth. Other applications concern the nervous system, eg intra- or periganglionic as well as intra-epi- and peridural as well as intraarachnoidal applications on the spine and the cerebrum. The application includes humans and animals.
Eine weitere positive Eigenschaft der erfindungsgemässen Resiniferatoxin-Lösung besteht darin, dass die Substanz selbst in verdünnter, anwendungsbereiter Lösung (d.h. mit Pufferlösung und Hyaluronsäure verdünnt) so stabilisiert ist, dass man sie auch in Kombination mit handelsüblichen, polymeren Plastik-Spritzen verwenden kann, welche üblicherweise aus Polypropylen, Polyethylen, Polyurethan und anderen Materialien hergestellt werden. Bislang galt es als unabdingbar, dass die RTX-Lösung nicht mit Polymer in Kontakt kommt, da es daran sofort bindet. In der hier dargestellten Herstellungsform kann es aber in eine Polypropylen-Spritze aufgezogen werden, dort für 10 Minuten gelagert und dann in den Patienten ohne messbaren Verlust an RTX gespritzt werden. Another positive property of the inventive Resiniferatoxin solution is that the substance even in dilute, ready-to-use solution (ie diluted with buffer solution and hyaluronic acid) is so stabilized that you can use them in combination with commercial, plastic plastic syringes, which usually made of polypropylene, polyethylene, polyurethane and other materials. So far, it has been considered essential that the RTX solution does not come in contact with polymer as it binds to it immediately. However, in the preparation shown here, it can be mounted in a polypropylene syringe, stored there for 10 minutes and then injected into the patient with no measurable loss of RTX.
Die durch die Erfindung erreichten Vorteile sind somit im Wesentlichen darin zu sehen, dass die erfindungsgemässe Resiniferatoxin-Lösung einerseits eine wesentlich höhere Stabilität und damit Lagerfähigkeit aufweist und andererseits eine reduzierte Haftungstendenz an polymeren Oberflächen aufweist. The advantages achieved by the invention are thus essentially to be seen in that the inventive Resiniferatoxin solution on the one hand has a much higher stability and thus storage stability and on the other hand has a reduced adhesion tendency on polymeric surfaces.
In der einzigen Figur ist eine Graphik gezeigt, welche auf der x-Achse die Zeit in Monaten und auf der y-Achse die Stabilität des gelösten RTX dargestellt. Dabei sind drei Messreihen dargestellt, die erste (Rauten-Messpunkte) zeigt die Resultate für RTX gelöst in Ethanol bei 5°C ohne zusätzliches Schutzgas (Argon), die zweite (Quadrate- Messpunkte) zeigt die Resultate für RTX gelöst in Ethanol bei 5°C mit einem Gehalt von 0,07 Gew.-% Argon und die dritte (Dreieck-Messpunkte) zeigt die Resultate für RTX gelöst in Ethanol bei 25 °C und mit einem Gehalt von 0,07 Gew.-% Argon. The single figure shows a graph showing the time in months on the x-axis and the stability of the dissolved RTX on the y-axis. Three measurement series are shown, the first (diamond measurement points) shows the results for RTX dissolved in ethanol at 5 ° C without additional protective gas (argon), the second (square measurement points) shows the results for RTX dissolved in ethanol at 5 ° C containing 0.07 wt.% Argon and the third (triangle measuring points) shows the results for RTX dissolved in ethanol at 25 ° C and containing 0.07 wt.% Argon.
Die erste Messreihe für die unstabilisierte RTX-Lösung zeigt einen kontinuierlichen Abfall im RTX-Gehalt. Die zweite und dritte Messreihe belegen, dass selbst bei einer relativ hohen Temperastur von 25 °C der RTX-Gehalt über Monate hinweg unverändert bei 100 % liegt. The first set of measurements for the unstabilized RTX solution shows a continuous drop in RTX content. The second and third series of measurements prove that even at a relatively high temperature of 25 ° C, the RTX content remains unchanged at 100% for months.
Weitere vorteilhafte Ausgestaltungen der Erfindung können wie folgt kommentiert werden: Bei einer besonderen Ausführungsform beträgt die Menge des Schutzgases mindestens 2 Gew.-%, vorzugsweise mindestens 4 Gew.-% der Sättigungsmenge des Schutzgases im Lösungsmittel bei Raumtemperatur und Normaldruck. Die Menge des Schutzgases kann vorteilhafterweise mindestens 10 Gew.-%, vorzugsweise mindestens 30 Gew.-% der Sättigungsmenge des Schutzgases im Lösungsmittel bei Raumtemperatur und Normaldruck betragen. Further advantageous embodiments of the invention can be commented on as follows: In a particular embodiment, the amount of inert gas is at least 2 wt .-%, preferably at least 4 wt .-% of the saturation amount of the protective gas in the solvent at room temperature and atmospheric pressure. The amount of inert gas may advantageously be at least 10 wt .-%, preferably at least 30 wt .-% of the saturation amount of the protective gas in the solvent at room temperature and atmospheric pressure.
Bei einer weiteren Ausführungsform umfasst das Lösungsmittel Ethanol oder Dimethylsulfoxid oder Mischungen davon. Die Lösung kann noch zusätzlich eines oder mehrere der folgenden Lösungsmittel enthalten: In a further embodiment, the solvent comprises ethanol or dimethyl sulfoxide or mixtures thereof. The solution may additionally contain one or more of the following solvents:
a) Heptan, vorzugsweise maximal 1 ,0 Gew. %; a) heptane, preferably at most 1, 0 wt.%;
b) Ethylacetat, vorzugsweise maximal 0,4 Gew. %; b) ethyl acetate, preferably at most 0.4% by weight;
c) Butanol c) butanol
d) Aceton, d) acetone,
e) tert.-Butylmethylether, vorzugsweise maximal 0,2 Gew. %; e) tert-butyl methyl ether, preferably at most 0.2% by weight;
f) Dichlormethan, vorzugsweise maximal 0,2 Gew. %; f) dichloromethane, preferably at most 0.2% by weight;
g) Methylcyclohexan, vorzugsweise maximal 0,01 Gew. %. g) methylcyclohexane, preferably at most 0.01% by weight.
Bei einer besonderen Ausführungsform enthält die Lösung 0,00010 - 3,0000 Gew.-%, vorzugsweise 0,000375 - 0,01000 Gew.-% Resiniferatoxin. In a particular embodiment, the solution contains 0.00010 - 3.0000% by weight, preferably 0.000375 - 0.01000% by weight of resiniferatoxin.
Bei einer weiteren Ausführungsform enthält die Lösung 1 bis 60 pg/ml, vorzugsweise 3 bis 50 pg/ml Resiniferatoxin.  In another embodiment, the solution contains 1 to 60 pg / ml, preferably 3 to 50 pg / ml of resiniferatoxin.
Das Schutzgas kann aus folgender Gruppe ausgewählt werden: Argon, Stickstoff, Kohlendioxid, Helium, Neon, Krypton, Xenon oder Mischungen davon. The shielding gas may be selected from the group consisting of argon, nitrogen, carbon dioxide, helium, neon, krypton, xenon or mixtures thereof.
Bei einer besonderen Ausführungsform enthält die Lösung maximal 0,03 Gew.% , vorzugsweise maximal 0,01 Gew.% Sauerstoff. In a particular embodiment, the solution contains not more than 0.03% by weight, preferably not more than 0.01% by weight, of oxygen.
Vorteilhafterweise weist die Resiniferatoxin-Lösung einen pH-Wert von 7,0 bis 9,0 , vorzugsweise von 7,3 bis 8,2 auf. Bei einer besonderen Ausführungsform enthält die Resiniferatoxin-Lösung zusätzlich eine oder mehrere der folgenden Subtanzen: Natriumchlorid, Kalziumchlorid oder Kaliumchlorid. Advantageously, the resiniferatoxin solution has a pH of from 7.0 to 9.0, preferably from 7.3 to 8.2. In a particular embodiment, the resiniferatoxin solution additionally contains one or more of the following substances: sodium chloride, calcium chloride or potassium chloride.
Vorteilhafterweise liegt das Mengenverhältnis zwischen RTX und Schutzgas MRTX / Mschutzgas im Bereich von 0,04 bis 10,0 , vorzugsweise von 0,1 bis 2,0. Advantageously, the quantitative ratio between RTX and shielding gas MRTX / Mschutzgas in the range of 0.04 to 10.0, preferably from 0.1 to 2.0.
Bei einer besonderen Ausführungsform umfasst die Resiniferatoxin-Lösung zusätzlich ein trizyklisches Antidepressivum. In a particular embodiment, the resiniferatoxin solution additionally comprises a tricyclic antidepressant.
Die erfindungsgemässe Resiniferatoxin-Lösung kann insbesondere zur Behandlung von intraartikulären Schmerzen verwendet werden. The inventive resiniferatoxin solution can be used in particular for the treatment of intra-articular pain.
Bei einer besonderen Ausführungsform ist die Resiniferatoxin-Lösung in einem Behälter abgefüllt, welcher das Schutzgas enthält. Mindestens die Innenwand des Behälters kann aus polymerem Material bestehen. Das polymere Material kann aus folgender Gruppe ausgewählt sein: Polypropylen, Polyethylen, Polyurethan oder Kombinationen davon. Vorteilhafterweise kann der Behälter als Spritze ausgebildet sein. In a particular embodiment, the Resiniferatoxin solution is filled in a container containing the inert gas. At least the inner wall of the container may be made of polymeric material. The polymeric material may be selected from the group consisting of polypropylene, polyethylene, polyurethane or combinations thereof. Advantageously, the container may be designed as a syringe.
Ein Verfahren zur Herstellung der erfindungsgemässen Resiniferatoxin-Lösung besteht darin, dass das Resiniferatoxin im Lösungsmittel aufgelöst wird und anschliessend die erhaltene Lösung mit dem Schutzgas angereichert wird. A method for producing the inventive Resiniferatoxin solution is that the Resiniferatoxin is dissolved in the solvent and then the resulting solution is enriched with the protective gas.
Obwohl wie oben beschrieben verschiedene Ausführungsformen der vorliegenden Erfindung vorliegen, sind diese so zu verstehen, dass die verschiedenen Merkmale sowohl einzeln als auch in jeder beliebigen Kombination verwendet werden können. Diese Erfindung ist daher nicht einfach auf die oben erwähnten, besonders bevorzugten Ausführungsformen beschränkt. While various embodiments of the present invention are described above, it should be understood that the various features may be used both individually and in any combination. This invention is therefore not limited to the above-mentioned, particularly preferred embodiments.

Claims

Patentansprüche claims
1. Resiniferatoxin-Lösung mit erhöhter Lagerungsstabilität, 1. Resiniferatoxin solution with increased storage stability,
dadurch gekennzeichnet, dass characterized in that
das Resiniferatoxin in einem körperverträglichen Lösungsmittel gelöst ist, welches ein Schutzgas in Lösung enthält, wobei die Menge des Schutzgases mindestens 1 Gew.- % der Sättigungsmenge des Schutzgases im Lösungsmittel bei Raumtemperatur und Normaldruck beträgt. the Resiniferatoxin is dissolved in a biocompatible solvent containing a protective gas in solution, wherein the amount of the protective gas is at least 1% by weight of the saturation amount of the protective gas in the solvent at room temperature and atmospheric pressure.
2. Resiniferatoxin-Lösung nach Anspruch 1 , dadurch gekennzeichnet, dass die Menge des Schutzgases mindestens 2 Gew.-%, vorzugsweise mindestens 4 Gew.-% der Sättigungsmenge des Schutzgases im Lösungsmittel bei Raumtemperatur und Normaldruck beträgt. 2. Resiniferatoxin solution according to claim 1, characterized in that the amount of the protective gas is at least 2 wt .-%, preferably at least 4 wt .-% of the saturation amount of the protective gas in the solvent at room temperature and atmospheric pressure.
3. Resiniferatoxin-Lösung nach Anspruch 2, dadurch gekennzeichnet, dass die Menge des Schutzgases mindestens 10 Gew.-%, vorzugsweise mindestens 30 Gew.-% der Sättigungsmenge des Schutzgases im Lösungsmittel bei Raumtemperatur und Normaldruck beträgt. 3. Resiniferatoxin solution according to claim 2, characterized in that the amount of the protective gas is at least 10 wt .-%, preferably at least 30 wt .-% of the saturation amount of the protective gas in the solvent at room temperature and atmospheric pressure.
4. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass das Lösungsmittel Ethanol oder Dimethylsulfoxid oder Mischungen davon umfasst. 4. Resiniferatoxin solution according to one of claims 1 to 3, characterized in that the solvent comprises ethanol or dimethyl sulfoxide or mixtures thereof.
5. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass die Lösung zusätzlich eines oder mehrere der folgenden Lösungsmittel enthält: a) Heptan, vorzugsweise maximal 1 ,0 Gew. %; 5. Resiniferatoxin solution according to one of claims 1 to 4, characterized in that the solution additionally contains one or more of the following solvents: a) heptane, preferably at most 1, 0 wt.%;
b) Ethylacetat, vorzugsweise maximal 0,4 Gew. %; b) ethyl acetate, preferably at most 0.4% by weight;
c) Butanol c) butanol
d) Aceton, d) acetone,
e) tert.-Butylmethylether, vorzugsweise maximal 0,2 Gew. %; e) tert-butyl methyl ether, preferably at most 0.2% by weight;
f) Dichlormethan, vorzugsweise maximal 0,2 Gew. %; f) dichloromethane, preferably at most 0.2% by weight;
g) Methylcyclohexan, vorzugsweise maximal 0,01 Gew. %. g) methylcyclohexane, preferably at most 0.01% by weight.
6. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass die Lösung 0,00010 - 3,0000 Gew.-%, vorzugsweise 0,000375 - 0,01000 Gew.- % Resiniferatoxin enthält. 6. Resiniferatoxin solution according to one of claims 1 to 5, characterized in that the solution contains 0.00010 - 3.0000 wt .-%, preferably 0.000375 - 0.01000 wt .-% resiniferatoxin.
7. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass die Lösung 1 bis 60 pg/ml, vorzugsweise 3 bis 50 g/ml Resiniferatoxin enthält. 7. Resiniferatoxin solution according to one of claims 1 to 5, characterized in that the solution contains 1 to 60 pg / ml, preferably 3 to 50 g / ml Resiniferatoxin.
8. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass das Schutzgas aus folgender Gruppe ausgewählt ist: Argon, Stickstoff, Kohlendioxid, Helium, Neon, Krypton, Xenon oder Mischungen davon. 8. Resiniferatoxin solution according to one of claims 1 to 7, characterized in that the protective gas is selected from the following group: argon, nitrogen, carbon dioxide, helium, neon, krypton, xenon or mixtures thereof.
9. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass die Lösung maximal 0,03 Gew.% , vorzugsweise maximal 0,01 Gew.% Sauerstoff enthält. 9. Resiniferatoxin solution according to one of claims 1 to 8, characterized in that the solution contains at most 0.03 wt.%, Preferably at most 0.01 wt.% Of oxygen.
10. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 9, dadurch gekennzeichnet, dass die Lösung einen pH-Wert von 7,0 bis 9,0 , vorzugsweise von 7,3 bis 8,2 aufweist. 10. Resiniferatoxin solution according to one of claims 1 to 9, characterized in that the solution has a pH of 7.0 to 9.0, preferably from 7.3 to 8.2.
1 1. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 10, dadurch gekennzeichnet, dass die Lösung zusätzlich eine oder mehrere der folgenden Subtanzen enthält: 1 1. Resiniferatoxin solution according to one of claims 1 to 10, characterized in that the solution additionally contains one or more of the following substances:
Natriumchlorid, Kalziumchlorid oder Kaliumchlorid.  Sodium chloride, calcium chloride or potassium chloride.
12. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 1 1 , dadurch gekennzeichnet, dass das Mengenverhältnis zwischen RTX und Schutzgas MRTX / Mschutzgas im Bereich von 0,04 bis 10,0 , vorzugsweise von 0,1 bis 2,0 liegt. 12. Resiniferatoxin solution according to one of claims 1 to 1 1, characterized in that the quantitative ratio between RTX and protective gas MRTX / Mschutzgas in the range of 0.04 to 10.0, preferably from 0.1 to 2.0.
13. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 12, dadurch gekennzeichnet, dass sie zusätzlich ein trizyklisches Antidepressivum umfasst. 13. Resiniferatoxin solution according to one of claims 1 to 12, characterized in that it additionally comprises a tricyclic antidepressant.
14. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 13, zur Verwendung in der Behandlung von intraartikulären Schmerzen. 14. Resiniferatoxin solution according to any one of claims 1 to 13, for use in the treatment of intra-articular pain.
15. Resiniferatoxin-Lösung nach einem der Ansprüche 1 bis 13, dadurch gekennzeichnet, dass sie in einem Behälter abgefüllt ist, welcher das Schutzgas enthält. 15. Resiniferatoxin solution according to one of claims 1 to 13, characterized in that it is filled in a container containing the inert gas.
16. Resiniferatoxin-Lösung nach Anspruch 15, dadurch gekennzeichnet, dass mindestens die Innenwand des Behälters aus polymerem Material besteht. 16. Resiniferatoxin solution according to claim 15, characterized in that at least the inner wall of the container consists of polymeric material.
17. Resiniferatoxin-Lösung nach Anspruch 15, dadurch gekennzeichnet, dass das polymere Material aus folgender Gruppe ausgewählt ist: Polypropylen, Polyethylen, Polyurethan oder Kombinationen davon. 17. Resiniferatoxin solution according to claim 15, characterized in that the polymeric material is selected from the group consisting of: polypropylene, polyethylene, polyurethane or combinations thereof.
18. Resiniferatoxin-Lösung nach einem der Ansprüche 15 bis 17, dadurch gekennzeichnet, dass der Behälter als Spritze ausgebildet ist. 18. Resiniferatoxin solution according to one of claims 15 to 17, characterized in that the container is designed as a syringe.
19. Verfahren zur Herstellung der Resiniferatoxin-Lösung nach einem der Ansprüche 1 - 13, dadurch gekennzeichnet, dass das Resiniferatoxin im Lösungsmittel aufgelöst wird und anschliessend die erhaltene Lösung mit dem Schutzgas angereichert wird. 19. A process for preparing the Resiniferatoxin solution according to any one of claims 1-13, characterized in that the Resiniferatoxin is dissolved in the solvent and then the resulting solution is enriched with the inert gas.
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WO2018085476A1 (en) 2016-11-02 2018-05-11 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof
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EP3898991A4 (en) 2018-12-21 2022-09-14 Sorrento Therapeutics, Inc. PERINEAL ADMINISTRATION OF RESINIFERATOXIN FOR THE TREATMENT OF MALADAPTIVE PAIN
US11254659B1 (en) 2019-01-18 2022-02-22 Centrexion Therapeutics Corporation Capsaicinoid prodrug compounds and their use in treating medical conditions
US11447444B1 (en) 2019-01-18 2022-09-20 Centrexion Therapeutics Corporation Capsaicinoid prodrug compounds and their use in treating medical conditions
JP7530365B2 (en) 2019-01-22 2024-08-07 ソレント・セラピューティクス・インコーポレイテッド Methods for treating osteoarthritis pain by administering resiniferatoxin - Patent Application 20070123333
WO2021202084A1 (en) 2020-03-30 2021-10-07 Sorrento Therapeutics, Inc. Treating pulmonary inflammatory disease associated with covid-19 by administering resiniferatoxin
CA3182730A1 (en) 2020-06-19 2021-12-23 Sorrento Therapeutics, Inc. Administration of resiniferatoxin for treatment of bladder pain or bladder cancer
JP2024507130A (en) 2021-02-11 2024-02-16 ソレント・セラピューティクス・インコーポレイテッド Administration of resiniferatoxin for the treatment of prostate cancer

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60239415A (en) * 1984-05-15 1985-11-28 Nippon Kayaku Co Ltd Injection containing etoposide
FI883337L (en) * 1987-07-16 1989-01-17 Bristol Myers Co ICKE-VATTENLOESNINGAR AV DOXORUBICIN HYDROCHLORIN.
JPH08333257A (en) * 1995-04-04 1996-12-17 Otsuka Pharmaceut Co Ltd Product holding pharmaceutical preparation of procaterol hydrochloride aqueous solution and pharmaceutical preparation of aqueous solution of procaterol hydrochloride
JP2003261449A (en) * 2002-03-05 2003-09-16 Nisshin Oillio Ltd Famotidine-containing aqueous injection preparation and method for producing the same
PL1838301T3 (en) * 2004-12-28 2015-08-31 Mestex Ag Use of resiniferatoxin (rtx) for the preparation of an agent for the treatment of pain
EP1981547B1 (en) * 2005-12-28 2015-09-30 Alza Corporation Stable therapeutic formulations
WO2008109026A1 (en) * 2007-03-05 2008-09-12 Mt Cook Pharma Pharmaceutical compositions for the localized treatment of neurogenic dysfunction
JP2009143922A (en) * 2007-11-22 2009-07-02 Fujiyakuhin Co Ltd Injection product
JP2011126856A (en) * 2009-12-17 2011-06-30 Takada Seiyaku Kk Liquid medicine containing sumatriptan for internal-use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2014019095A1 *

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