EP1320368A1 - Solution pour perfusion de ciprofloxacine stable au stockage et a teneur reduite en acide - Google Patents

Solution pour perfusion de ciprofloxacine stable au stockage et a teneur reduite en acide

Info

Publication number
EP1320368A1
EP1320368A1 EP01983507A EP01983507A EP1320368A1 EP 1320368 A1 EP1320368 A1 EP 1320368A1 EP 01983507 A EP01983507 A EP 01983507A EP 01983507 A EP01983507 A EP 01983507A EP 1320368 A1 EP1320368 A1 EP 1320368A1
Authority
EP
European Patent Office
Prior art keywords
active ingredient
mol
infusion solutions
acid
solutions according
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Withdrawn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
EP01983507A
Other languages
German (de)
English (en)
Inventor
Klaus Sommermeyer
Hans-Jörg Müller
Tilo Hniopek
Bernd Eschenbach
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.)
Fresenius Kabi Deutschland GmbH
Original Assignee
Fresenius Kabi Deutschland GmbH
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 Fresenius Kabi Deutschland GmbH filed Critical Fresenius Kabi Deutschland GmbH
Publication of EP1320368A1 publication Critical patent/EP1320368A1/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Withdrawn legal-status Critical Current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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock

Definitions

  • the present invention relates to storage-stable infusion solutions of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (l -piperazinyl) -quinoline-3-carboxylic acid, obtainable by mixing 0.015 to 0.5 g of the active ingredient mentioned to 100 ml of aqueous solution with a sufficient amount of a physiologically compatible compound to dissolve the active ingredient and to stabilize the solution. Furthermore, the invention relates to the method for producing and using such infusion solutions.
  • the invention describes ready-to-use infusion solutions as well as other dosage forms which are introduced into such infusion solutions prior to application, the active ingredient 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl ) -quinoline-3-carboxylic acid is known as ciprofloxacin.
  • EP-A-0049 355 protects i.a. Medicines containing 7-amino-l-cyclopropyl-4-oxo-l, 4-dihydronaphtyridine-3-carboxylic acid.
  • EP-A-0 078 362 protects 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids.
  • the active ingredients known from the two EPs have high antibacterial effects and are suitable as medicaments for combating bacterial infections in humans and animals.
  • the known compounds are not or only very little suitable for producing infusion and or injection solutions because, for example, the pH and / or the solubility and / or the shelf life, in particular with regard to Excretions, the ready-to-use infusion and / or injection solutions do not meet the pharmaceutical requirements for such solutions.
  • DE 33 33 719 AI discloses solutions of the lactic acid salts of piperazinyl-quinolonic and / or -azaquinolonecarboxylic acids which, in addition to the lactic acid salts mentioned and optionally conventional auxiliaries, additionally contain at least one acid which does not lead to precipitation.
  • acids which do not lead to precipitation include lactic acid, methanesulfonic acid, propionic acid or succinic acid, although lactic acid is by far preferred.
  • the lactic acid content of the infusion solutions according to DE 33 33 719 AI can carry 0.1 to 90%.
  • the lactic acid content of the solution to be applied can be 0.1 to 10%.
  • EP-A-0 219 784 The problems occurring according to DE 33 33 719 AI (corresponds to EP-A 0 138 018) are tried to be avoided by EP-A-0 219 784 by providing infusion solutions of ciprofloxacin which contain 0.015 to 0.5 g of the active ingredient per 100 ml of aqueous solution and, depending on the active substance concentration, 0.9 to 5.0 mol, based on 1 mol of active substance, of one or more physiologically tolerated acids.
  • the infusion solutions according to EP-A 0 219 784 contain, in addition to the active ingredient, water and other customary formulation auxiliaries, a sufficient amount of one or more acids from the group consisting of hydrochloric acid, methanesulfonic acid, propionic acid, succinic acid, glutaric acid to dissolve the active ingredient and stabilize the solution.
  • a sufficient amount of one or more acids from the group consisting of hydrochloric acid, methanesulfonic acid, propionic acid, succinic acid, glutaric acid to dissolve the active ingredient and stabilize the solution.
  • EP-A-0287 926 relates to parenterally administrable solutions of quinolonecarboxylic acids, i.a. Ciprofloxacin, where it is proposed to use particularly pure main active ingredient components to improve storage stability.
  • EP-A-0 287 926 relates to such parenterally administrable solutions in which no more than 1 to 10 ppm, based on the main active ingredient (ciprofloxacin) of the solution, are present on secondary components (“impurities” of the active ingredient)
  • secondary components carried in by the main active ingredient in the infusion solution succeed in reducing the excretions from the infusion solutions (cloudiness during storage) in accordance with EP-A-0 287 926.
  • reducing the secondary components is a relatively complex operation.
  • the publication DE 197 03 023 A discloses that the number of detectable particles is reduced by using glass bottles which have a silicone coating on the inner surface. This can further improve the shelf life of high-purity infusion solutions. It can therefore be assumed that the formation of precipitates is due to the number of particles that are inherently present. The more particles there are, the more particles are formed. This accelerates the formation of particles over time.
  • EP-A-0 219 784 lists, inter alia, lactic acid, phosphoric acid, adipic acid, hydroxyacetic acid and sulfuric acid as possible auxiliaries in an amount of 0.9 to 5 mol per 1 mol of active ingredient, these alternatives are completely missing in EP 0 219 784 B1 , wherein the amount of acid (s) according to EP 0 219 784 B should be between 1.04 and 2.2 moles per 1 mole. Hydroxyacetic acid and phosphoric acid in substoichiometric amounts do not give usable results. In this respect, the successful use of sulfuric acid was not obvious, at least not in the amount according to the invention of 0.96 mol or less per 1 mol of active ingredient.
  • such infusion solutions are of particular interest, which are characterized in that the total content of Sulfuric acid is 0.9 mol or less based on 1 mol of ciprofloxacin (active ingredient).
  • Infusion solutions whose total sulfuric acid content is 0.8 mol or less are even more expedient.
  • Also very particularly preferred are infusion solutions in which the total sulfuric acid content is 0.6 mol or less than 0.6 mol per 1 mol of active ingredient.
  • a derivative of sulfuric acid has also proven itself as an acid auxiliary.
  • This is sodium hydrogen sulfate.
  • This can be used, for example, as an aqueous solution for dissolving the ciprofloxacin, and the aqueous solution of the sodium bisulfate can be prepared in situ.
  • infusion solutions according to the invention are obtainable by introducing sulfuric acid in an amount of 0.96 mol or less per 1 mol of active ingredient sufficient to dissolve the active ingredient and to stabilize the solution and an amount of NaOH which is equimolar to the amount of sulfuric acid and with the Active ingredient mixed.
  • the amount of sulfuric acid present is preferably in the range from 0.96 mol to 0.93 mol per 1 mol of the active ingredient.
  • the amount of sodium hydrogen sulfate presented is in the range from 0.96 mol to 0.93 mol per 1 mol of the active ingredient. An optimum results when the amount of sodium bisulfate present in the solution is less than 0.95 mol per 1 mol of the active ingredient.
  • the acid to be used for additional stabilization of the infusion solutions of ciprofloxacin is particularly preferably glycerol esters of orthophosphoric acid. Are particularly preferred
  • Monoglycerinorthophosphorklareester Of very great interest are infusion solutions in which, in addition to sulfuric acid, the acid (s) is glycerol 1-phosphate, glycerol 2-phosphate or a mixture of the glycerol phosphoric acid monoesters.
  • Diphosphates are also particularly suitable acids. These include in particular glucose diphosphate and fructose 1,6-diphosphate. The acids mentioned are about as strong as phosphoric acid.
  • additions of glycerol 1-phosphate, glycerol 2-phosphate, glucose diphosphate and / or fructose 1,6-diphosphate significantly exceed phosphoric acid in terms of improving the storage stability.
  • the minimum amount of acid required per mole of active ingredient to dissolve naturally also depends on the active ingredient concentration and the acid (s) used and is therefore not constant. It should also be noted that the information in the amounts of acid relates only to the amounts which, according to generally known basic chemical rules, do not result from the addition of bases in the corresponding ⁇ ) salt (s) are implemented. Dissociation of the acids was not taken into account in the quantities, so that they relate to the dissociated and undissociated amount of acid.
  • the infusion solutions according to the invention can also contain further formulation agents such as complexing agents, antioxidants, isotonizing agents and / or agents for adjusting the pH.
  • the osmolality of the infusion solutions is 0.20 to 0.70 Osm / kg, preferably 0.26 to 0.39 Osm / kg and is adjusted by isotonic agents such as NaCl, mannitol, glucose, sucrose and glycerol or mixtures of such substances. If necessary, substances can also be used that are contained in common, commercially available infusion carrier solutions.
  • the usual infusion carrier solutions include infusion solutions with an electrolyte supply without carbohydrates such as saline, Ringer's lactate solution, etc. and those with carbohydrates and solutions for the supply of amino acids, each with and without carbohydrate content.
  • infusion carrier solutions are in Rote Liste 1998, list of finished medicinal products of the members of the Federal Association of the Pharmaceutical Industry, Editio Cantor, Aulendorf / Württ. listed.
  • infusion solutions which, in addition to water, active ingredient and other formulation auxiliaries, contain such an amount of sodium chloride or other auxiliaries customary for isotonization that a solution which is isotonic or slightly hypotonic or hypertonic with the tissue fluid of the human or animal body is present.
  • the infusion solutions according to the invention have a pH of 2.6 to 5.2, preferably 3.0 to 5.2. pH values of 3.6 to 4.7 and 3.9 to 4.5 are also preferred. PH values in the range from 4.1 to 4.3 are very particularly preferred.
  • the infusion solutions according to the invention can be present in dosage units suitable for infusion with removable contents of 40 to 600 ml, preferably 50 to 120 ml.
  • the present invention also relates to a process for the preparation of infusion solutions according to the independent claim regarding the infusion solutions, which is characterized in that a suitable amount of the active ingredient, optionally in the form of a salt such as alkali or alkaline earth metal salt or addition salt, a hydrate or a hydrate of the salt or in the form of mixtures of these salts or hydrates, with a quantity of sulfuric acid or with a quantity of sulfuric acid and NaOH or with a quantity of sodium hydrogen sulfate and in each case optionally a quantity of a physiologically compatible monoester or diester of orthophosphoric acid or a mixture of several physiologically compatible monoesters - or diester derivatives of orthophosphoric acid are added, the total amount of acid being 0.96 mol or less than 0.96 mol per 1 mol of active ingredient, optionally adding formulation auxiliaries and with water or a conventional infusion agent
  • the solution is filled up in such a way that a concentration range of 0.015 to 0.5 g is obtained for the
  • the solutions correspond to the properties already listed with regard to pH, amounts of acid and osmolality. If the active ingredient is used in salt form, it is expedient to use an acid whose anion corresponds to the anion of the active ingredient salt or of the salt hydrate.
  • the pH of the infusion solutions according to the invention can be adjusted to the above-mentioned values, namely 2.6 to 5.2, expediently 3.0 to 5.2, in particular 3.6 to 4, using (physiologically) compatible acids and / or bases. 7 set.
  • the solutions or only a part thereof can be slightly warmed, preferably to temperatures between 20 ° C and 80 ° C.
  • the solutions according to the invention can be produced particularly economically via concentrated solutions.
  • the amount of active ingredient required for one batch with the main amount of acid required for the complete batch e.g. 95% based on molar basis
  • This concentrate is then diluted.
  • any other auxiliary substances - such as Table salt for isotonization - added, as well as the possibly still missing amount of acid.
  • the solution After filtering the solution, it can be filled into suitable containers. Without being restricted thereby, glass bottles or bags made of plastic films are generally used for this purpose, which are suitable for medical use. PVC-free bags based on polyolefins are particularly preferred. To improve the shelf life, these bags can optionally be provided with a further outer packaging.
  • the solutions according to the invention show a high storage stability, which is not limited by the number of particles. The effort as described in documents EP 0 287 926 and DE-A-197 30 23 to make the solutions durable can be dispensed with.
  • Example 1 was essentially repeated. However, the solution obtained was not filled into a glass bottle but into a polyolefin-based bag, which is also suitable for medical purposes.
  • the solution thus obtained was filtered like Example 1, filled into a glass bottle for medical purposes and then sterilized at 121 ° C.
  • the sterile solution thus obtained was stored at room temperature for 2 months and regularly checked visually. After two months there was a visually detectable crystal formation. The attempt was then stopped.
  • the solution thus obtained was filtered like Example 1, filled into a glass bottle for medical purposes and then sterilized at 121 ° C.
  • the sterile solution thus obtained was stored at room temperature for 2 months and regularly checked visually. There were no visually detectable crystal formations.
  • the glass bottles were optically perfect.

Abstract

L'invention concerne des solutions stables au stockage, pour perfusion d'acide 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pipérazinyl)-quinoline-3-carboxylique (ciprofloxacine), qui s'obtiennent par mélange de 0,015 à 0,5 g de principe actif pour 100 ml de solution aqueuse avec de l'acide sulfurique ou de l'hydrogénosulfate de sodium dans des proportions inférieures ou égales à 0,96 mole par mole de principe actif, suffisamment élevées pour provoquer la dissolution du principe actif et pour stabiliser la solution. L'invention concerne également des procédés servant à produire ces solutions pour perfusion de ciprofloxacine ainsi que l'utilisation de ces dernières. Ces solutions pour perfusion permettent de réduire la teneur en acide, présentent, pour une même teneur en acide, une meilleure stabilité au stockage que les autres solutions connus et permettent la tolérance d'une proportion plus importante de composants secondaires dans le principe actif que les solutions pour perfusion de ciprofloxacine utilisées jusqu'à présent.
EP01983507A 2000-09-29 2001-09-27 Solution pour perfusion de ciprofloxacine stable au stockage et a teneur reduite en acide Withdrawn EP1320368A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10048510A DE10048510A1 (de) 2000-09-29 2000-09-29 Lagerstabile Infusionslösung des Ciprofloxacins mit verringertem Säuregehalt
DE10048510 2000-09-29
PCT/EP2001/011189 WO2002026233A1 (fr) 2000-09-29 2001-09-27 Solution pour perfusion de ciprofloxacine stable au stockage et a teneur reduite en acide

Publications (1)

Publication Number Publication Date
EP1320368A1 true EP1320368A1 (fr) 2003-06-25

Family

ID=7658237

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01983507A Withdrawn EP1320368A1 (fr) 2000-09-29 2001-09-27 Solution pour perfusion de ciprofloxacine stable au stockage et a teneur reduite en acide

Country Status (17)

Country Link
US (1) US20040082593A1 (fr)
EP (1) EP1320368A1 (fr)
JP (1) JP2004509921A (fr)
KR (1) KR20030068541A (fr)
CN (1) CN1466457A (fr)
AU (1) AU2002214993A1 (fr)
BR (1) BR0114293A (fr)
CA (1) CA2420556A1 (fr)
DE (1) DE10048510A1 (fr)
HU (1) HUP0302256A2 (fr)
IL (1) IL154509A0 (fr)
MX (1) MXPA03002770A (fr)
NO (1) NO20031411D0 (fr)
PL (1) PL360597A1 (fr)
SK (1) SK3322003A3 (fr)
WO (1) WO2002026233A1 (fr)
ZA (1) ZA200301459B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2011274472B2 (en) 2010-07-09 2017-03-30 Janssen Vaccines & Prevention B.V. Anti-human respiratory syncytial virus (RSV) antibodies and methods of use
CA2910121A1 (fr) 2013-04-25 2014-10-30 Kyorin Pharmaceutical Co., Ltd. Composition pharmaceutique contenant un acide carboxylique 1,4-dihydroquinoleine, un excipient cellulosique et un agent de relargage
US9603804B2 (en) 2013-04-25 2017-03-28 Kyorin Pharmaceutical Co., Ltd. Solid pharmaceutical composition
EP3210607A4 (fr) 2014-10-23 2018-06-06 Kyorin Pharmaceutical Co., Ltd. Composition pharmaceutique solide
WO2016195021A1 (fr) 2015-06-02 2016-12-08 杏林製薬株式会社 Formulation liquide aqueuse
JP6675396B2 (ja) 2015-06-02 2020-04-01 杏林製薬株式会社 水性液剤
WO2016195014A1 (fr) 2015-06-02 2016-12-08 杏林製薬株式会社 Médicament aqueux
CN114767627A (zh) * 2022-05-17 2022-07-22 广州南鑫药业有限公司 一种乳酸环丙沙星氯化钠注射液的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3537761A1 (de) * 1985-10-24 1987-04-30 Bayer Ag Infusionsloesungen der 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7- (1-piperazinyl)-chinolin-3-carbonsaeure
WO1990001933A1 (fr) * 1988-08-26 1990-03-08 Alcon Laboratories, Inc. Combinaison d'un antibiotique de quinolone et de steroides pour utilisation ophtalmique locale
DE10018783A1 (de) * 2000-04-15 2001-10-25 Fresenius Kabi De Gmbh Lagerstabile Infusionslösung des Ciprofloxacins mit verringertem Säuregehalt
DE10018781A1 (de) * 2000-04-15 2001-10-25 Fresenius Kabi De Gmbh Infusionslösungen des Ciprofloxacins mit verbesserter Lagerfähigkeit

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0226233A1 *

Also Published As

Publication number Publication date
MXPA03002770A (es) 2004-12-13
IL154509A0 (en) 2003-09-17
WO2002026233B1 (fr) 2002-07-04
JP2004509921A (ja) 2004-04-02
HUP0302256A2 (hu) 2003-11-28
CA2420556A1 (fr) 2003-02-25
BR0114293A (pt) 2003-07-29
NO20031411D0 (no) 2003-03-27
CN1466457A (zh) 2004-01-07
SK3322003A3 (en) 2003-07-01
PL360597A1 (en) 2004-09-20
ZA200301459B (en) 2003-08-27
KR20030068541A (ko) 2003-08-21
US20040082593A1 (en) 2004-04-29
DE10048510A1 (de) 2002-05-16
AU2002214993A1 (en) 2002-04-08
WO2002026233A1 (fr) 2002-04-04

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