Bibliographic data
`
`Title:
`
`Injectable pharmaccutical compositions having improved stability,
`anid methods. of producing the same.
`
`Pub/Pat no:
`
`HPO332826A1
`
`Pub/Issue Date:
`
`1989-09-20
`
`Inventor(s):
`Applicant(s):
`
`TASHMA, ZEV
`TEVA PHARMAJIL]
`
`Classification:
`
`ASTE9/O8ATL, AGIK90AT, AG1B31/21SAT, AGI K47/02AT
`
`Application number:
`
`EP19890101629 1989-01-31]
`
`Priority number:
`
`IL19880085312 1988-02-03,
`
`Abstract of EP0332826A1
`
`Improved pharmaceutical compositions having along term shelf life, which comprises certain
`pharmacologically active water-hydrolyzable derivatives of alpha -amino- and alpha - 5 hydroxy-
`carboxylic acids:and a. solventimedium containing an aqueous component, characterized in that at
`least.a major proportion by volume of the ordinary water normally used in formulating such
`compositions 1s replaced by deutertum oxide.
`
`

`

`Oo)
`
`Europaisches Patentamt
`
`European Patent Office
`Office européen des brevets
`
`@) Publication number:
`
`0 332 826
`Al
`
`@)
`
`_ EUROPEAN PATENT APPLICATION
`
`@) Application number: 89101629.7
`
`&) int. cl.4 AB1K 9/08 , A61K 47/00
`
`G) Priority: 03.02.88 IL 85312
`
`Date of publication of application:
`20.09.89 Bulletin 89/38
`
`@)
`
`Inventor: Tashma, Zev
`2 Shahal! Street
`Jerusalem 93701(IL)
`:
`
`@) Dateoffiling: 31.01.89
`
`
`@) Applicant: Teva Pharmaceutical Industries
`The title of the invention has been amended
`Limited
`(Guidelines for Examination in the EPO, A-lll,
`
`Har Hotzvim behind Sanhedria Ha'Murhevet
`7.3).
`Jerusalem(IL)
`
`
`
`
`Representative: Brown, John David et al
`FORRESTER & BOEHMERT
`
`Widenmayersirasse 4/|
`D-8000 Miinchen 22(DE)
`
`
`Designated Contracting States:
`AT BE CH DE ES FR GB GR IT LI LU NL SE
`
`Injectable pharmaceutical compositions having Improved stability, and methods of producing the
`same.
`
`@) Improved pharmaceutical compositions having a
`long term shelf life, which comprises certain phar-
`‘ macologically active water-hydrolyzabie derivatives
`of a-amino- and a- 5 hydroxy-carboxylic acids and a
`solvent medium containing an aqueous component,
`characterized in that at least a major proportion by
`volume of the ordinary water normally used in for-
`mulating
`such
`compositions
`is
`replaced
`by
`deuterium oxide.
`
`EP0332826Al
`
`Xerox Copy Centre
`
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`EP 0 332 826 Al
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`BACKGROUND OF THE INVENTION
`
`Injectable pharmaceutical compositions usually
`require the presence of water.
`In certain cases,
`however, water has a destabilizing influence on the
`pharmaceutically active ingredients of such com-
`positions, ¢.g.
`it may cause such ingredients to
`hydrolyze and in consequence lose their pharma-
`cological potency. In these cases, where the com-
`positions are to be used in clinics or hospitals, one
`solution of the problem is to store the active ingre-
`dients in a form in which injectable compositions
`can be readily formulated therefrom by addition of
`water, and to prepare such compositions only on
`demand. There exist, however, situations in which
`such a solution to the problem of destabilization in
`presence of water cannot be applied. For example,
`for reasons of public health,
`in order to combat or
`prevent a disease, it may be desirable to maintain
`a stock of the order of hundred of thousands, or
`even millions of units, of injectable pharmaceutical
`compositions. Similarly,
`in order to provide an anii-
`dote in case of chemical warfare it may be desir-
`able to be able to distribute very large numberof
`injectable compositions which are ready for use to
`ihe civilian population or to military personnel.
`Moreover, for reasons of convenience or econ-
`omy,
`it may be desirable to store these injectable
`pharmaceutical compositions for
`long terms. The
`expression “long term", when used herein in this
`context, means a period of at least one year. That
`is to say,
`it
`is contemplated that such injectable
`compasitions may be stored under ambient con-
`ditions with a tolerable degree of deterioration of
`their pharmacological effectiveness, for periods of
`at least one year, possibly even for several years.
`It has previously been proposed to replace
`some of the water in injectable compositions by
`propylene glycol. Thus, in U.S. 4,212,886 (Homan),
`the contents of which are to be regarded as incor-
`porated herein by reference, there is described and
`claimed a pharmaceutical composition comprising
`(as active ingredient) benactyzine hydrochloride
`dissolved in a solvent mixture of 30-50% propylene
`giycol and 70-50%waiter, by volume, subject to the
`qualifications that the amount of propylene glycol is
`sufficient
`to increase the stability of
`the active
`ingredient over that
`in water along and that the
`amount of water is sufficient to prevent dehydration
`of the active ingredient. Additionally, ethanol may
`be present in order to reduce the viscosity so as to
`render the composition more easily injectable; thus,
`the solvent mixture may comprise by volume, 50%
`propylene glycol. 40% water and 10%ethanol.
`However, Homan's compositions suffer from a
`number of disadvantages. Firstly,
`the degree of
`stabilization appears to be insufficient for practical
`
`the long term, pro-
`application. Secondly, over
`pylene glycol may give rise to undesirable deg-
`radation products per se and also to undesirable
`reaction products with the active ingredients, there-
`by detracting from the pharmaceutical purity of the
`compositions. Thirdly,
`the viscosity characteristics
`of aqueous solutions of propylene glycol are incon-
`venient, both from a handling and an administration
`paint of view.
`Siegel et al J. Pharm. Sci. 53: 978 (1964) and
`51: 1166 (1962) proposed to stabilize solutions of
`procaine, which may be suitable for ophtalmic use,
`by substituting the ordinary water in these solutions
`by deuterium oxide. Siegel's experiments relate to
`the stabilization of these solutions in the alkaline
`pH range at 40° C;
`in no case does such stabiliza-
`tion lead to a half-life greater than 115 hours. Thus,
`there is no suggestion that it could be practicable
`to use deuterium oxide for long term stabilization of
`pharmaceutical compositions of any kind.
`In accordance with the invention it has now
`been surprisingly discovered that
`the stability of
`certain aqueous pharmaceutical compositions in-
`tended for long term storage can be enhanced by
`replacing at least a major part of the ordinary water
`in such compositions by deuterium oxide.
`
`SUMMARY OF THE INVENTION
`
`is, therefore an object of the present inven-
`It
`tion to stabilize and thus prolong the long term
`shelf-life of certain injectable pharmaceutical com-
`positions by replacing the greater part of the or-
`dinary water normally used therein by deuterium
`oxide.
`
`the invention is to signifi-
`Another object of
`canily reduce the amount of ordinary water present
`in certain injectable pharmaceutical compositions,
`by replacing at
`least a major part
`thereof by
`deuterium oxide, whereby the deteriorative reaction
`with water of the active ingredient(s) in the long
`term will be significantly retarded.
`Other objects of the invention will become ap-
`parent from the following description.
`and
`Throughout
`the
`present
`specification
`claims, "%" in relation to ingredients of solvent
`media is intended to signify % by volume.
`in
`The present invention accordingly provides,
`one aspect, an injectable pharmaceutical composi-
`tion having a long term shelf life, which composi-
`tion comprises:
`at
`least one pharmacologically active ingredient
`which is susceptible to deterioration due to the
`presence of waiter, selected from the group consist-
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`EP 0 332 826 Al
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`ing of water-hydrolyzable derivatives of a-amino-
`and a-hydroxy- carboxylic acids, pharmaceutically
`acceptable acid addition salts and alkali metal, al-
`kaline earth metal and ammonium salts of such
`derivatives; and
`a solvent medium containing an aqueous compo-
`nent, said aqueous component comprising at least
`a major proportion by volume of deuterium oxide.
`In another aspect,
`the invention provides a
`method of producing an injectable pharmaceutical
`composition having a long term shelf-life, which
`comprises dissolving at
`least one pharmacologi-
`cally active ingredient which is susceptible to dete-
`rioration due to the presence of water, selected
`from the group consisting of water-hydrolyzable
`derivatives of aamino and a-hydroxy- carboxylic
`acids, pharmaceutically acceptable acid addition
`salts and alkali metal, alkaline earth metal and
`ammonium salts of such derivatives;
`in a soivent
`medium containing an aqueous component, said
`aqueous component comprising at
`least a major
`proportion by volume of deuterium oxide.
`The term “ordinary water", as used herein, is
`intended to mean water suitable for preparing injec-
`table pharmaceutical formulations, but which in any-.
`event contains no more than the normally occurring
`amount of deuterium oxide. As previously men-
`tioned, "long term" (storage or shelf
`life)
`in the
`present context signifies a period of at least one
`year. Thus,
`in accordance with the present inven-
`tion,
`the injectable pharmaceutical compositions
`will have a storage or shelf-life of at least one year,
`and the initial storage or shelf-life, whatever it may
`be, is prolonged by the replacementof at least the
`major part by volume of the ordinary water present,
`by deuterium oxide.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`it has been
`Contrary to the prior art teaching,
`found in accordance with the present invention that
`there is no minimum amount of ordinary water
`required "sufficient
`to prevent dehydration of the
`active ingredient”. In accordance with the invention,
`99.9 or 100% of the ordinary water present in the
`injectable
`composition
`could be
`replaced by
`deuterium oxide, but for practical reasons there will
`usually be present a small residual amount of or-
`dinary water. Thus from a practical and economic
`point of view, the aqueous component of the sol-
`vent medium in the injectable pharmaceutical com-
`positions may contain, say, about 98% or 99%
`deuterium oxide, the balance being ordinary water.
`However, since in accordance with the inven-
`tion a major proportion of
`the ordinary water
`present in the aqueous component of the solvent
`medium is replaced by deuterium oxide, it will be
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`evident that other percentages than those just men-
`tioned are viable. Thus, for exampie, the aqueous
`component of the injectable composition according
`to the invention may comprise from about 75 to
`about 100%, preferably from about 90 to about
`100% deuterium oxide and from about 25 to about
`%, preferably from about 10 to about 0% ordinary
`water. Most preferably,
`the aqueous component
`comprises from about 95 to about 100% deuterium
`oxide and from about 5 to about 0% ordinary
`water. It is especially preferred that in the composi-
`tions according to the invention, the aqueous com-
`ponent comprises from about 98 to about 100%
`deuterium oxide and from about 2 to about 0%
`ordinary water, and more particularly from about 99
`fo about 99.75%deuterium oxide and from about 1
`to about 0.25%ordinary water.
`As will be appreciated by those skilled in the
`pharmaceutical art,
`the solvent medium may be
`wholly comprised of an aqueous component or,
`alternatively, the solvent medium may be a mixture
`of an aqueous component with a water-miscible
`non-aqueousliquid.
`As is well known, deuterium oxide is itself both
`stable and effectively non-toxic (in the amounts
`presently contemplated for use herein, e.g. up to
`about 10 mi). It
`is therefore an ideal solvent me-
`dium for the present purposes.
`Deuterium oxide is present in small amounis in
`ordinary water,
`including the water content of the
`human body; an average adult male contains about
`6 mi deuterium oxide.
`It
`is close in chemical and
`physical properties to ordinary water. [n connection
`with its physialogical properties,
`it
`is to be noted
`that deuterium oxide has been routinely used over
`a period of years for measuring total body water
`content. For this purpose, quantities up to about
`100 ml are used. In a published experiment (Taylor
`et al, Arch. Path., 81: 213 (1966)), consicerabie
`amounts of deuterium oxide were administered
`continuously to humans over a period of about 6 to
`7 weeks, with little or no notable ill effects.
`The deuterium oxide according to the invention
`should preferably pass the tests for ordinary water
`for injection as required by a recent edition of a
`recognized pharmacopoeia, adapied, if and as nec-
`essary, for the specific characteristics of deuterium
`oxide.
`The use of deuterium oxide in accordance with
`the present invention is believed to have the follow-
`ing advantages over
`the possible use of other
`solvents (except ordinary water) for the same pur-
`pose:
`
`is far less toxic than other known sol-
`it
`1.
`vents, except for ordinary water;
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`EP 0 332 826 Al
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`2. no new decomposition products due to
`drug-solvent
`interactions are to be expected, be-
`sides those which are known from ordinary water
`(or analogues of such known products);
`3. no contamination due to dehydration, re-
`sinification, oxidation or other chemical changes of
`the solvent per se, is to be expected, as compared
`with the possibleuse of non-aqueous solvents; and
`4. unlike most other non-aqueous solvents,
`deuterium oxide can be brought
`to a high and
`uniform standard of chemical and microbiologtical
`purity, by adapting the pharmacopoeia standards
`and tests for ordinary water for injection.
`
`the
`the compositions of
`is preferred that
`It
`present
`invention have a pH within the range of
`about 1.5 to about 5.5. The manner of adjustment
`of pH vaiues is of course well known to those
`skilled in the art.
`
`The compositions of the present invention may
`contain additionally at least one further pharmaco-
`logically active ingredient, besides the at least one
`carboxylic acid derivative susceptible to hydrolysis
`as defined herein.
`least one active
`the at
`As previously noted,
`ingredient is a water-hydrelyzable derivative of an
`a-amino- or a-hydroxy-carboxylic acid (including
`salts thereof). Such derivatives include, particularly,
`esters and amides, including N-substituted amides.
`The carboxylic acid derivative is also characterized
`by the fact that it contains an a-amino or a-hydroxy
`group. A presently preferred sub-group comprises
`the a-hydroxy- carboxylic acid derivatives. An ex-
`emplary member of this sub-group is benactyzine
`and its pharmaceutically acceptable acid addition
`salts, e.g. the HC1 salt.
`In the case of benactyzine
`and its pharmaceutically acceptable acid addition
`salts, the pH of the composition of the invention is
`preferably within the range of about 2.0 to about
`4.0, more preferably within the range of about 2.7.
`to about 2.8.
`As already indicated generally, such composi-
`tions which contain benactyzine (or its salts) may
`contain additionally at least one further pharmaco-
`logically active ingredient; the latter may, for exam-
`ple, be selected from cholinolytic drugs, pharma-
`csuiically accepted oximes and pharmaceutically
`acceptable salts thereof.
`It
`is preferably selected
`from atropine, pharmaceutically acceptable salts
`thereof and trimedoxime (which is also known as
`"TMB-4"). Atropine may be used as the sulfate
`salt,
`for example. Trimedoxime is a diquaternary
`salt in which the anion may be, e.g., bromide.
`The medical treatment of an acute exposure to
`certain organophosphorus
`insecticides or nerve
`gases. which are anticholinesterase agents, de-
`mands immediate administration of cholinolytics, to
`control
`the excessive cholinergic stimulation. For
`
`this purpose, it is well known to use atropine, and a
`combination of atropine with benactyzine. Addition
`of oximes to cholinolytic drugs has the effect of
`reactivating and restoring the cholinesterase activ-
`ity. Zvirblis and Ellin,
`in J. Pharm. Sct. 71:321
`(1982), described a 3-component mixture contain-
`ing 2 mi of injection solution: 40 mg of trimedoxime
`bromide,
`1 mg of atropine sulfate and 4.1 mg of
`benactyzine hydrochloride.
`It will be evident
`to
`those skilled in the art
`that the proportions and
`quantities of the ingredients in such a three-campo-
`nent mixture can be varied. Other
`related drug
`mixtures are described in Schenk et al., Arch.
`Toxicol., 36:71 (1976). The contents of both the
`Zvirblis and Ellin article and the Schenk et al.
`article are to be regarded as incorporated herein
`by reference.
`The susceptibility of benactyzine to hydrolysis
`(which under optimal conditions of pH 2.7-2.8 may
`amount to about 20% per year at 25°C and about
`2% per year at 5°C according to Zvirblis and
`Ellin}, detracts from its usefulness as a component
`of a large scale antidote to organophosphorus poi-
`soning, because the evident necessity for refrigera-
`tion requires considerable expense and logistics to
`store the quantity of units required. In accordance
`with
`the
`present
`invention, making
`use
`of
`deuterium oxide, the storage characteristics of be-
`nactyzine, whether kept alone or
`in combination
`with other ingredients, are considerably enhanced.
`_
`The invention moreover extends to an auto-
`matic injector characterized by the presence there-
`in of an injectable composition according to the
`invention. Normally, the automatic injector will be a
`single stage injector, i.e. comprising a single com-
`partment containing the
`injectable composition.
`However, in cases where an active ingredient which
`is beneficially stabilized in the long term is to be
`used together with one or more other active ingre-
`dients which are sufficiently stable (without sub-
`stitution of deuterium oxide for ordinary water),
`then it will be apparent that economy in the con- -
`sumption of deuterium oxide may be achieved by
`use of a multistage automatic injector comprising
`one compartment containing the relatively less sta-
`ble active ingredient dissolved in deuterium oxide,
`and one or more other comparimenis containing
`the relatively more stable active ingredients dis-
`solved in ordinary water.
`The invention will be illustrated by the following
`non-limitative
`examples,
`in
`which
`99.75%
`deuterium oxide was used initially. Owing to the
`hygroscopic nature of this subsianee, and to the
`presence of small amounts of ordinary water in the
`composition ingredients and in the apparatus,
`the
`solvent medium in the composition end-products
`contained about 99% deuterium oxide, the balance
`being ordinary water. The deuterium oxide should
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`pass the tests for Water for Injection of U.S.P. voi.
`XXI, adapted as appropriate for deuterium oxide.
`
`EXAMPLEI
`
`Benactyzine hydrochloride (80 mg) is dissolved
`in 18 mi of deuterium oxide, the pH is adjusted by
`known methods (see e.g. A.K. Covington, Analytical
`Chemistry, 40: 700 (1968)) to 2.7 with strong acid,
`and the volume is brought. to 20 ml with more
`deuterium oxide. The resulting solution is sterilized
`by passing through a pharmaceutically acceptable
`and antimicrobial filtering device, and then divided
`into 1 ml portions. The resultant composition is
`suitable for use in a single stage automatic injector,
`where benactyzine is the only active ingredient to
`be administered, or in a multistage automatic injec-
`tor together with relatively more stable active ingre-
`dients (such as atropine and trimedoxime) dis-
`solved in ordinary water in one or more further
`separate compartment(s).
`
`EXAMPLEII
`
`Benactyzine hydrochloride (40 mg), atropine
`sulfate (10 mg) and trimedoxime bromide (400 mg)
`are dissolved in 18 ml of deuterium oxide. The pH
`is adjusted by known methods to 2.7 with strong
`acid, and the volume is brought to 20 ml with more
`deuterium oxide. The resulting solution is sterilized
`by passing through a pharmaceutically acceptable
`and antirnicrobial filtering device, and then divided
`into 2 mi portions. The resultant composition is
`suitable for use in a single stage automatic injector.
`It was found that the shelflife at room tempera-
`ture of the compositions of Examples | and Il was
`considerably enhanced as compared to similar
`compositions prepared with ordinary water only.
`Since it will be apparent to those skilled in the
`art that many modifications and variations could be
`made in the particular description of the invention
`hereinabove,
`the invention is not to be construed
`as limited thereby, but rather the invention will be
`defined only by the claims which follow.
`The features disclosed in the foregoing de-
`scription, in the claims and/or in the accompanying
`drawings may, both, separately and in any com-
`bination thereof, be material for realising the inven-
`tion in diverse forms thereof.
`
`Claims
`
`1. An injectable pharmaceutical composition
`having a long term shelf life, which composition
`comprises:
`at
`least one pharmacologically active ingredient
`which is susceptible to deterioration due to the
`presence of water, selected from the group consist-
`ing of water-hydrolyzable derivatives of o-amino-
`and a-hydroxy- carboxylic acids, pharmaceutically
`acceptable acid addition salts and alkali metal, al-
`kaline earth metal and ammonium salts of such
`derivatives; and
`a solvent medium containing an aqueous compo-
`nent, said aqueous component comprising at least
`a major proportion by volume of deuterium oxide.
`2. A composition according to claim 1, wherein
`said aqueous component comprises from about 75
`to about 100% by volume of deuterium oxide and
`from about 25 to about 0% by volume of ordinary
`water.
`3. A composition according to claim 2, wherein
`said aqueous component comprises from about 90
`to about 100% by volume of deuterium oxide and
`from about 10 to about 0% by volume of ordinary
`waier.
`4. A composition according to claim 3, whérein
`said aqueous component comprises from about 95
`fo about 100% by volume of deuterium oxide and
`from about 5 to about 0% by volume of ordinary
`water.
`5. A composition according to claim 4, wherein
`said aqueous component comprises from about 98
`to about 100% by volume of deuterium oxide and
`from about 2 to about 0% by volume of ordinary
`water.
`6. A composition according to claim 5, wherein
`said aqueous component comprises from about 99
`to about99.75% by volume of deuterium oxide and
`from about 1 to about 0.25% by volume of ordinary
`water.
`7. A composition according to claim 5, wherein
`said aqueous component consists of substantially
`100% by volume of deuterium oxide.
`8. A composition according to any one of
`claims 1
`to 7, having a pH within the range of
`about 1.5 to about 5.5.
`.
`9. A composition according to any one of
`claims 1
`to 8, wherein said solvent medium com-
`prises a mixture of an aqueous component with a
`water-miscible solvent.
`10. A composition according to any one of
`claims 1
`to 9, wherein said at jeast one pharmaco-
`logically active ingredient
`is an esier of an a
`hydroxy-carboxylic acid.
`11. A composition according to claim 10,
`wherein said at
`least one active ingredient com-
`prises at
`least one member selected from ithe
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`EP 0 332 826 Al
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`group consisting of benactyzine and its pharma-
`ceutically acceptable acid addition salts, and the
`pH of the composition is within the range of about
`2.0 to about 4.0.
`12. A composition according to claim 11, hav-
`ing a pH within the range of about 2.7. to about 2.8.
`13. A composition according to any one of
`claims 1
`to 12, which contains additionally at least
`one further pharmacologically active ingredient.
`14. A composition according to claim 13,
`wherein said at least one further pharmacologically
`active ingredient
`is selected from the group con-
`sisting of cholinolytic drugs, pharmaceutically ac-
`ceptable oximes and pharmaceutically acceptable
`salts therecf.
`15. A composition according to claim 14,
`wherein said at least one further pharmacologicaily
`active ingredient is selected from the group con-
`sisting of atropine, pharmaceutically acceptable
`salts thereof and trimedoxime.
`16. A single stage automatic injector charac-
`terised by the presence therein of a composition
`according to any of claims 1 to 15.
`17. A multistage automatic injector characteris-
`ed by the presence therein of a composition ac-
`cording to any of claims 1 to 15.
`18. A method of producing an injectable phar-
`maceutical composition having a long term shelf-
`life, which comprises dissolving at least one phar-
`macologically active ingredient which is susceptible
`to deterioration due to the presence of water, se-
`lected
`from the
`group
`consisting
`of water-
`hydrolyzable derivatives of a-amino and a-hydroxy-
`carboxylic acids, pharmaceutically acceptable acid
`addition salts and alkali metal, alkaline earth metal
`and ammonium salts of such derivatives; in a sol-
`vent medium containing an aqueous component,
`said aguecus component comprising at
`feast a
`major proportion by volume of deuterium oxide.
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`9) European Patent
`
`Office
`
`EUROPEAN SEARCH REPORT
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Application Number
`
`EP
`
`89 10 1629
`
`Category
`
`Relevant
`to claim
`
`CLASSIFICATION OF THE
`APPLICATION Gat. Cl. 4)
`A61K 9/08
`A 61K 47/00
`
`of relevant passages
`JOURNAL OF PHARMACEUTICAL SCIENCES,
`vol. 71, no. 3, March 1982, pages
`321-325, American Pharmaceutical
`Association, Washington, DC, US; P.
`ZVIRBLIS et al.: "Kinetics and
`stability of a multicomponent
`organophosphate antidote formulation in
`glass and plastic"
`* Whole document *
`
`D,A Citation of document with indication, where appropriate,
`
`JOURNAL OF PHARMACEUTICAL SCIENCES,
`vol. 53, no. 8, August 1964, pages
`978-979, American Pharmaceutical
`Association, Washington, DC, US; F.P.
`SIEGEL et al.: "Stability of procaine
`in deuterium oxide"
`* Whole document *
`
`(G. HOMAN)
`US-A-4 212 886
`* Whole document *
`.
`-——
`JOURNAL OF PHARMACY AND PHARMACOLOGY,
`vol. 8, 1956, pages 907-914,
`Pharmaceutical Society of Great
`Britain, London, GB; J.P. JEFFERIES et
`al.: "The determination of benactyzine"
`* Page 911, last paragraph - page 912,
`paragraph 1 *
`
`CHEMICAL ABSTRACTS, vol. 58, no. 12,
`10th June 1963, column 12385c,d,
`Columbus, Ohio, US; $.G. KUZNETSOV et
`al.: "Comparative study of rates of
`hydrolysis of cholinolytically active
`aminoalkyl esters and thio esters", &
`ZH. OBSHCH. KHIM. 32, 2026-9(1962)
`* Abstract *
`—
`
`-/-
`
`TECHNICAL FIELDS
`
`A 61 kK
`
`The present search report has been drawn up for all claims
`
`CATEGORY OF CITED DOCUMENTS
`
`: theory or principle underlying the invention
`: earlier patent document, but published on, or
`after the filing date
`: particularly relevant if taken alone
`: document cited in the application
`: particularly relevant if combined with another
`: document cited for other reasans
`document of the same category
`:technological hackground=§»_—annettentetnncccnenasmnsanenaccnscnssncnsen sesnnsanessencesssesseeassesansescosanmeceassoassacarase
`3 hon-written disclosure
`3 member of the same patent family, corresponding
`: intermediate document
`
`document
`
`
`EPOFORM150303.82(P0401)
`
`

`

`0) omePatent
`)
`ice
`
`EUROPEAN SEARCH REPORT
`
`Page
`
`2
`
`ApplicationNumber
`
`EP
`
`89 10 1629
`
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`Citation of document with indication, where appropriate,
`
`of relevant passages
`
`
`
`
`
`vol. 68, no. 7, July 1979, pages
`
`856-859, American Pharmaceutical
`Association, Washington, DC, US; L.A.
`HULL et al.: "3-Quinuclidinyl benzilate
`hydrolysis in dilute aqueous solution"
`* Page 856,
`left-hand column; page 858,
`right-hand column - page 859,
`left-hand
`column *
`
`Relevant
`to claim
`
`CLASSIFICATION OF THE
`APPLICATION(lat. Cl. 4)
`
`
`
`
`
`
`
`
`
`CHEMICAL REVIEWS, vol. 55, 1955, pages
`713-743, American Chemical Society,
`Easton, PA, US; K.B. WIBERG: "The
`deuterium isotope effect!
`* Page 718, paragraph 4 - page 723;
`page 724, paragraph 3 *
`
`
`
`
`Catezo
`Bory
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`JOURNALOFPHARMACEUTICALSCIENCES, -
`
`JOURNAL OF THE AMERICAN PHARMACEUTICAL
`
`
`
`ASSOCIATION, vol. 46, no. 9, September
`
`
`1957, pages 531-535, American
`
`
`Pharmaceutical Association, Washington,
`
`
`DC, US; A.A. KONDRITZER et al.:
`
`
`"Stability of atropine in aqueous
`
`
`solution"
`
`* Whole document *
`
`
`
`
`
`
`
`
` Place of search
`
` EPOFORM150303.82(P0401)
`
`
`
`
`
`|EMCEEESS)|
`
`SEARCHED(at. Cl.4)
`
`JOURNAL OF PHARMACEUTICAL SCIENCES,
`vol. 55, no. 11, November 1966, pages
`1263-1267, American Pharmaceutical
`Association, Washington, DC, US; R.I.
`ELLIN et al.: "Kinetics of
`deterioration of trimethylene
`bis-(4-formylpyridinium bromide)
`
`dioxime in dilute aqueous solutions"
`* Whole document *
`
`THE HAGUE
`
`Date of completion of the search
`14-07-1989
`
`Examiner
`MUELLNERS W.
`
`
`
`CATEGORY OF CITED DOCUMENTS
`
`T : theory or principle underlying the invention
`E: earlier patent document, but published on, or
`after the filing date
`: particularly relevant if taken alone
`D : document cited in the application
`: particularly relevant if combined with another
`L: documentcited for other reasons
`document of the same category
`:technological background=§»-_—Casta ncnnenronaesante rornnronncccncone secvanserenssaeesarasaerenscreeesanesasseanasaarenaosaneaces
`: non-written disclosure
`& : memberof the same patent family, corresponding
`document
`: intermediate document
`
`
`Opdd
`
`