WO2003017975A2 - Procedes pour produire des solutions - Google Patents

Procedes pour produire des solutions Download PDF

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Publication number
WO2003017975A2
WO2003017975A2 PCT/EP2002/009776 EP0209776W WO03017975A2 WO 2003017975 A2 WO2003017975 A2 WO 2003017975A2 EP 0209776 W EP0209776 W EP 0209776W WO 03017975 A2 WO03017975 A2 WO 03017975A2
Authority
WO
WIPO (PCT)
Prior art keywords
water
substance
solution
insoluble
substances
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.)
Ceased
Application number
PCT/EP2002/009776
Other languages
German (de)
English (en)
Other versions
WO2003017975A3 (fr
Inventor
Ralph E. Eckert
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.)
Molecular and Clinical Drug Research
Original Assignee
Molecular and Clinical Drug Research
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 Molecular and Clinical Drug Research filed Critical Molecular and Clinical Drug Research
Priority to AU2002340848A priority Critical patent/AU2002340848A1/en
Publication of WO2003017975A2 publication Critical patent/WO2003017975A2/fr
Publication of WO2003017975A3 publication Critical patent/WO2003017975A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K47/06—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine

Definitions

  • the invention relates to processes for the preparation of aqueous solutions of poorly water-soluble or substantially water-insoluble substances.
  • the invention further relates to aqueous solutions which are produced on the basis of such a method and the use of such solutions.
  • the type of dosage form and the galenical formulation must ensure that the active ingredient is used over a defined period of time in a defined area of activity (e.g. on a specific organ or the entire blood circulation system).
  • the aim is to achieve the lowest possible side effects through the galenical formulation and additives used.
  • water-soluble drugs does not generally pose any major problems, since their bioavailability is also guaranteed when given in solid form (e.g. as a dragee or tablet) and, on the other hand, liquid water-based formulations of such drugs are biocompatible with the human or animal organism are so that no solvent-related side effects (e.g. venotoxicity when injected) are to be expected during their application.
  • a large part of the known medicinally active substances is essentially insoluble in water or is so insoluble in water that aqueous solutions of such substances do not have a sufficient concentration of substances in order to obtain a sufficient medicinal effect in the target organism.
  • Liquid formulations based on organic solvents or solubilizers are also known, for. B. in ethanol, oils or fats or in organic solubilizers. It is also known to use mixtures of different organic solvents and / or solubilizers in order to produce liquid or viscous formulations of water-insoluble active substances.
  • such formulations can predominantly be administered orally (e.g. in gelatin capsules).
  • oral administration is not suitable for all indications.
  • liquid organic solvent-based formulations e.g. ethanol
  • injections of such formulations are associated with severe pain due to tissue damage caused by the solvent.
  • This object is achieved according to the invention by a process for the preparation of aqueous solutions of sparingly water-soluble and essentially water-insoluble substances, in which the substance is first dissolved in at least one water-miscible solubilizer and then converted into aqueous solution by adding water and / or an aqueous buffer solution becomes.
  • the invention is based on the surprising result that, using at least one solubilizer which is miscible with H 2 O, aqueous, Highly concentrated formulations of sparingly water-soluble or essentially water-insoluble substances which are soluble in the water-miscible solubilizer are available.
  • the sparingly water-soluble or essentially water-insoluble substances remain in solution even after the aqueous dilution of the substance-solubilizer mixture and do not precipitate out even with strong dilution (and thus low concentration of solubilizer in the final dilution).
  • the substances remain pharmacologically active even after aqueous dilution.
  • aqueous solutions prepared in this way can be used to produce a wide variety of pharmaceuticals based on known and previously unknown substances.
  • the new formulation of known substances is expected to improve efficacy in known indications.
  • pharmaceuticals can be manufactured on the basis of known active substances, which are used for a much wider range of indications. For example, in the case of essentially water-insoluble or sparingly water-soluble active substances which have hitherto been predominantly used in solid form, it can now also be assumed that these can be used for the production of eye drops or injection solutions.
  • Substances which are practically insoluble in water are understood as essentially water-insoluble substances of these substances (because, for example, the medicinal effect of such solutions is too low due to the low concentration of active substance).
  • the term "poorly water-soluble substance” includes substances that are poorly soluble in water and more readily soluble in organic solvents (eg moxaverine hydrochloride). With these substances, the method according to the invention enables the production of highly concentrated aqueous solutions of the respective substance for the first time.
  • the term "substance” includes the respective active substance in pure form, for. B. as a free base, free acid or as a pharmaceutically acceptable salt, ester or amide.
  • Pharmaceutically acceptable salts are salts which are produced from pharmaceutically acceptable, non-toxic acids of the respective active substance.
  • Solubilizers are substances that improve the solubility of other substances.
  • the solution can be mediated on the basis of complexation, by molecular variation and salt formation, by micelle formation (solubilization) or by improving the solution conditions as a result of structural changes in the solvent (cosolvation).
  • cosolvents of water i.e. organic solvents which can be mixed with water as desired
  • solubilizers are preferably used as solubilizers, with the exception of ethanol.
  • solubilizers suitable for the production of pharmaceuticals in which the water-insoluble substances are readily soluble (i.e. more soluble than in water) and which are miscible with water can be used as solubilizers.
  • aqueous polyvinylpyrrolidone (PVP) solutions with PVP concentrations suitable for the production of medicaments can also be used as solubilizers.
  • the content of solubilizer in the finished aqueous solution is reduced to such an extent that it does not exceed 50% by volume
  • solubilizers are suitable as stock solutions for the manufacture of medicinal products which have to be further diluted, since only small concentrations of solubilizers (e.g. a maximum of 30 vol. % of polyethylene glycols) are allowed.
  • Aqueous dilutions with less than 30% by volume of solubilizer can be used as a medicament or for the production of medicaments without further dilution.
  • one or a mixture of different polyalkylene glycols are used as solubilizers. Because of their physiological compatibility, polypropylene glycols or polyethylene glycols are particularly suitable. The use of polyethylene glycols is particularly preferred. Polyethylene glycols are characterized by good solubility with unlimited miscibility with water and good compatibility.
  • polyethylene glycols with an average molecular weight (weight average) between 200 and 2000 are particularly suitable, since they are essentially liquid at room temperature.
  • polyethylene glycols in this molecular weight range are distinguished by the fact that they are particularly suitable for the preparation of highly concentrated solutions of poorly water-soluble substances. It is possible with polyethylene glycols with an average molecular weight in the range from 200 (PEG 200) to 1000 (PEG 1000) to produce particularly highly concentrated substance solutions.
  • PEG 400 as a solubilizer is particularly preferred.
  • the process according to the invention includes a process step in which a desired pH value is set.
  • a desired pH value depends on the type of use of the aqueous solution to be prepared.
  • the pH is expediently adjusted by adding a suitable buffer (usually in
  • the addition of other substances which do not serve as active substances is also expedient, for example in addition to the substances mentioned further customary formulations and additives (depending on the particular determination of the aqueous solution) are added. Since the use of the smallest possible number of additives minimizes the risk of side effects, the number of additives is kept as low as possible.
  • the aqueous solution according to the invention contains only a single solubilizer, preferably polyethylene glycol (in particular PEG 400).
  • the addition of active ingredient stabilizers may be necessary in order to increase the stability of the essentially water-insoluble or sparingly water-soluble substances (for example physiologically compatible dyes in the case of light-sensitive substances).
  • the type of such formulations and additives is generally known to the person skilled in the art.
  • the finished aqueous solution has an essentially isotonic and preferably isotonic setting (ie an at least essentially isotonic electrolyte concentration and / or an at least essentially isotonic electrolyte composition.
  • an essentially isotonic and preferably isotonic setting ie an at least essentially isotonic electrolyte concentration and / or an at least essentially isotonic electrolyte composition.
  • buffer substances or buffer solutions which serve to set a suitable pH value and a suitable electrolyte concentration. It has been found that the solution of the water-insoluble substance or substances in the undiluted solubilizer in the temperature range between 15 and 50 ° C and preferably between 20 and 40 ° C, particularly preferably between 35 and 39 ° C and in particular at about 37 ° C is useful is. At these temperatures, the difficult to dissolve or essentially water-insoluble substances dissolve particularly well in the solubilizer, which is particularly true for polyethylene glycols and especially for polyethylene glycols in the range of average molecular weight between 200 and 600.
  • the temperatures are low enough so as not to have a negative effect on the stability of most substances which are poorly or substantially water-insoluble, so that a loss of activity in the end product is avoided.
  • a solution of the water-insoluble substances at temperatures above 20 ° C is advisable due to their higher and temperature-dependent viscosity.
  • the process is particularly suitable for the preparation of aqueous solutions of sparingly or substantially water-insoluble substances which are soluble in alcohols, preferably in ethanol, for example alkaloids and their salts.
  • Isoquinoline derivatives, in particular moxaverine are particularly suitable here.
  • Dihydropyridine derivatives, in particular nifedipine or nifedipine analogs, preferably nitrendipine, nimodipine, nisoldipine or felodipine, are also particularly suitable.
  • the invention further relates to aqueous solutions of poorly or substantially water-insoluble substances which are produced by the process according to the invention. " '' In a preferred embodiment, the invention relates • • aqueous solutions of isoquinoline derivatives and / or dihydropyridine DerivHenceen relates, in particular those listed above.
  • the invention also relates to the use of the aqueous solutions according to the invention for the production of medicaments.
  • a mixture of several poorly or substantially water-insoluble substances or a mixture of one or several poorly or substantially water-insoluble substances are contained with one or more water-soluble substances as active ingredients.
  • the medicinally active constituents can (eg in the case of gel capsules which contain, inter alia, an aqueous formulation of poorly or substantially water-soluble and / or water-soluble substances) be contained in a formulation other than the aqueous formulation.
  • all of the pharmaceutical constituents are preferably present in the aqueous formulation.
  • the invention also relates to the use of the aqueous solutions according to the invention for the production of injection solutions.
  • Nitrendipine was completely dissolved as a pure substance in increasing proportions in 10 ml of commercially available polyethylene glycol with an average molecular weight of 200 or 400 (Sigma company, ⁇ 1% H 2 O) with constant stirring at a temperature of 37 ° C. Nitrendipine concentrations of up to 60 mg / ml could be achieved in undiluted polyethylene glycol. (For comparison: A maximum of 5 mg / ml can be dissolved in EtOH. Nitrendipine is practically insoluble in H 2 O, ⁇ 1 mg / ml.) The results are summarized in Table 1.
  • the dissolved nitrendipine was then transferred into aqueous solution with constant stirring by adding 1 x Tyrode solution with normal extracellular electrolyte composition and concentration.
  • the solutions could be diluted as desired without the dissolved nitrendipine failing.
  • pH-neutral nitrendipine solutions prepared in this way could also be diluted as desired.
  • the nitrendipine did not precipitate even at low PEG concentrations of 5% or less.
  • the nitrendipine dissolved in it was active.
  • the solutions remained stable for 3 months without the nitrendipine failing.
  • Moxaverin hydrochloride was used as a pure substance in increasing proportions (see Table 1) in 10 ml of commercially available polyethylene glycol with an average molecular weight of 200 or 400 (PEG 200 or PEG 400, Sigma company, ⁇ 1% H 2 0) with constant stirring at Temperature of 37 ° C completely dissolved. Moxaverin concentrations of up to 40 mg / ml could be achieved in undiluted polyethylene glycol.
  • the moxaverin-HCl dissolved in PEG 200 precipitated at concentrations of 35 mg / ml and more after neutralization.
  • the moxaverin dissolved in PEG 400 remained in solution even at high concentrations even after pH neutralization.
  • the pH-neutral moxaverin solutions prepared in this way could also be diluted as desired.
  • the moxaverin did not precipitate even at low PEG concentrations of 5% or less.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des procédés pour produire des solutions aqueuses de substances insolubles dans l'eau par dissolution d'au moins une substance pure dans au moins un agent de solubilisation miscible avec l'eau et dilution aqueuse de la solution ainsi obtenue par addition d'eau et/ou d'une solution tampon aqueuse.
PCT/EP2002/009776 2001-08-31 2002-09-02 Procedes pour produire des solutions Ceased WO2003017975A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002340848A AU2002340848A1 (en) 2001-08-31 2002-09-02 Method for producing solutions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10142416.7 2001-08-31
DE2001142416 DE10142416A1 (de) 2001-08-31 2001-08-31 Verfahren zur Herstellung von Lösungen

Publications (2)

Publication Number Publication Date
WO2003017975A2 true WO2003017975A2 (fr) 2003-03-06
WO2003017975A3 WO2003017975A3 (fr) 2003-12-24

Family

ID=7697053

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/009776 Ceased WO2003017975A2 (fr) 2001-08-31 2002-09-02 Procedes pour produire des solutions

Country Status (3)

Country Link
AU (1) AU2002340848A1 (fr)
DE (1) DE10142416A1 (fr)
WO (1) WO2003017975A2 (fr)

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58131982A (ja) * 1982-02-01 1983-08-06 Tokyo Tanabe Co Ltd 新規なる１．４−ジヒドロピリジン誘導体
DE3307422A1 (de) * 1983-03-03 1984-09-06 Bayer Ag, 5090 Leverkusen Fluessigzubereitungen von dihydropyridinen, ein verfahren zu ihrer herstellung, sowie ihre verwendung bei der bekaempfung von erkrankungen
DE3316510A1 (de) * 1983-05-06 1984-11-08 Bayer Ag Parenterale formulierung von nimodipin, ein verfahren zu ihrer herstellung sowie ihre verwendung bei der bekaempfung von erkrankungen
IT1187751B (it) * 1985-10-15 1987-12-23 Eurand Spa Procedimento per la preparazione di formulazioni solidi di nifedipina ad elevata biodisponibilita' e ad effetto prolungato e formulazioni cosi' ottenute
DE3544692A1 (de) * 1985-12-18 1987-06-19 Bayer Ag Dihydropyridinspray, verfahren zu seiner herstellung und seine pharmazeutische verwendung
GB8629761D0 (en) * 1986-12-12 1987-01-21 Harris Pharma Ltd Capsules
DE3702105A1 (de) * 1987-01-24 1988-08-04 Bayer Ag Parenterale loesung
DE3738236A1 (de) * 1987-11-11 1989-05-24 Euro Celtique Sa Beisskapsel
KR960004019B1 (ko) * 1992-12-10 1996-03-25 보령제약주식회사 니모디핀의 가용화 방법
DE19757224A1 (de) * 1997-12-22 1999-07-01 Bayer Ag Verfahren und Vorrichtung zur in-situ-Formulierung einer Arzneistofflösung zur parenteralen Applikation

Also Published As

Publication number Publication date
DE10142416A1 (de) 2003-03-20
WO2003017975A3 (fr) 2003-12-24
AU2002340848A1 (en) 2003-03-10

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WO2003017975A2 (fr) Procedes pour produire des solutions

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