Bibliographic data
`
`Title:
`
`Injectablc pharm accutical compositions having improved stability,
`and methodsofprodueing the same.
`‘
`
`Pub/Tat no:
`
`,EPO332826A1
`
`Pub/”Issue Date:
`
`1989-09—20
`
`Inventods):
`
`TASHMA, ZEV
`
`Applicanfls):
`
`TE'V‘A PHARMNDQ]
`
`Classification;
`
`A61K9/08A1; AolKQfOO'Al; AfilKBl/21 5A1; A61 K47/02Al
`
`Application number;
`
`EP19'8901 01 629 1989—01-31
`
`Priority number:
`
`IL19880085312 1983-02-03;
`
`Abstract of EP0332826A1
`
`Improved pharmaceutical compositions having along term shelf life, which comprises certain
`
`pharm recologically active Water—hydrolyza'ble derivatives of‘alpha —amino— and alpha — 5 hydroxy—
`
`ca‘rboxyli‘c acids and a solVent medium containing an aqueous COmponent, characterized in that at
`
`least 21 maj 0r proportion by volume of the ordinary water normally Used in formulating such
`
`compositions is replacedby deuterium oxide.
`
`

`

`0’
`
`Euro paisches Patentamt
`
`European Patent Office
`Office européen des brevets
`
`63 Publication number:
`
`0 332 826
`A1
`
`69
`
`7 EUROPEAN PATENT APPLICATION
`
`@ Application number: 89101629.?
`
`@ Int. Cl.4: A61K 9/08 , A61K 47/00
`
`€23 Date of filing: 31.01.89
`
`(Guidelines for Examination in the EPO. A-lll.
`7.3).
`
`6-) Priority: 03.02.88 IL 85312
`
`Date of publication of application:
`20.09.39 Bulletin 89/38
`
`Jerusalem(lL)
`
`(73 Inventor: Tashma. Zev
`2 Shahal Street
`Jerusalem 93701(IL)
`
`
`The title of the invention has been amended
`
`@ Applicant: Teva Pharmaceutical Industries
`Limited
`
`Har Hotzvim behind Sanhedria Ha'Murhevet
`
`
`
`
`
`
`
`Designated Contracting States:
`AT BE CH DE ES FR GB GRIT LI LU NL SE
`
`Representative: Brown, John David et al
`FORRESTER & BOEHMERT
`
`Widenmayerstrasse 4/l
`0-8000 Miinchen 22(DE)
`
`Iniectable pharmaceutical compositions havlng 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.
`
`EP0332826A1
`
`Xerox Copy Centre
`
`

`

`1
`
`EP 0 332 826 A1
`
`2
`
`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, e.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 anti-
`dote in case of chemical warfare it may be desir-
`able to be able to distribute very large number of
`injectable compositions which are ready for use to
`the civilian population or to military personnel.
`Moreover, for reasons of convenience or econ-
`
`it may be desirable to store these injectable
`omy,
`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
`compositions 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 US. 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
`glycol and 70-50% water, 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 thh the active ingredients. there-
`by detracting from the pharmaceutical purity of the
`compositions. Thirdiy,
`the viscosity characteristics
`of aqueous solutions of propylene glycol are incon-
`venient. both from a handling and an administration
`point 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
`
`in no case does such stabiliza-
`pH range at 40° C;
`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
`
`the stability of
`been surprisingly discovered that
`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-iife 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
`cantly 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 water. selected from the group consist-
`
`TO
`
`75
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`

`

`3
`
`EP 0 332 826 A1
`
`4
`
`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 a-amino and a-hydroxy- carboxylic
`acids, pharmaceuticaiiy acceptable acid addition
`salts and alkali metal, alkaline earth metal and
`ammonium salts of such derivatives;
`in a solvent
`
`medium containing an aqueous component. said
`aqueous component comprising at
`least a major
`proportion by volume of deuterium oxide.
`is
`The term "ordinary water", as used herein.
`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 replacement of 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-
`
`the ordinary water
`tion a major proportion of
`present in the aqueous component of the solvent
`medium is replaced by deuterium oxide. it will be
`
`70
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`evident that other percentages than those just men-
`tioned are viable. Thus. for example, 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 10 %
`deuterium oxide and from about 2 to about 0%
`
`ordinary water, and more particularly from about 99
`to 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-aqueous liquid.
`As is well known, deuterium oxide is itself both
`stable and effectively non-toxic (in the amounts
`presently contemplated for use herein, eg. up to
`about 10 ml)§lt is therefore an ideal solvent me-
`dium for the present purposes.
`Deuterium oxide is present in small amounts in
`ordinary water.
`including the water content of the
`human body; an average adult male contains about
`6 ml deuterium oxide.
`it
`is close in chemical and
`
`physical properties to ordinary water. in connection
`with its physiological 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 (1986)), considerable
`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, adapted, it 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;
`
`

`

`5
`
`EP 0 332 826 A1
`
`6
`
`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 possible-use 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-hydrolyzable 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, 8.9. the H01 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 com‘posi~
`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-
`ceutically 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, 9.9., 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. Sci. 71:321
`(1982), described a 3-component mixture contain-
`ing 2 ml 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-compo-
`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.
`7
`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, Le. comprising a single coma
`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 compartments 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 substance, 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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`

`

`7
`
`EP 0 332 826 A1
`
`8
`
`pass the tests for Water for Injection of U.S.P. vot.
`XXI, adapted as appropriate for deuterium oxide.
`
`EXAMPLE I
`
`Benactyzine hydrochloride (80 mg) is dissolved
`in 18 ml of deuterium oxide, the pH is adjusted by
`known methods (see eg. A.K. Covington, Analytical
`Chemistry, 40: 700 (1968)) to 2.7 with strong acid,
`and the volume is broughtto 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).
`
`EXAMPLE ll
`
`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 antimicrobial filtering device, and then divided
`into 2 ml portions. The resultant composition is
`suitable for use in a single stage automatic injector.
`it was found that the shelf life at room tempera-
`ture of the compositions of Examples I and II 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 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.
`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
`water.
`
`4. A composition according to claim 3, wherein
`said aqueous component comprises from about 95
`to 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 least one pharmaco-
`logically active ingredient
`is an ester 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 the
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`

`

`9
`
`EP 0 332 826 A1
`
`10
`
`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 ab0ut 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 thereof.
`
`15. A composition according to claim 14,
`wherein said at least one further pharmacologically
`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 aqueous component comprising at
`least a
`major proportion by volume of deuterium oxide.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4o
`
`45
`
`50
`
`55
`
`

`

`a)
`
`European Patent
`Office
`
`ElflR()PEAdNESEAJlCIIIIEPCNRT
`
`Applimtion Number
`
`EP
`
`89 10 1629
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation of document with indication, where appropriate,
`of relevant pasagec
`
`Relevant
`to claim
`
`CLASSIFICATION OF THE
`APPLICATION (Int Cl. 4)
`
`D,A 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 *
`
`9/08
`A 61 K
`A 61 K 47/00
`
`
`
`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. HUMAN)
`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; S.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
`SEARCHED (Int. CIA)
`
`A 61 K
`
`Place of search
`
`Date of completion of the search
`
`THE HAGUE
`
`14-07- 1989
`
`MUELLNERS W.
`
`............................................................................
`
`
`EPOFORM150303.32(P0401)
`
`CATEGORY OF CITED DOCUMENTS
`
`: particularly relevant if taken alone
`: particularly relevant if combined with another
`document of the same category
`:technologiml background
`: non-written disclosure
`: intermediate document
`
`:theory or principle underlying the invention
`:arlier patent document, but published on, or
`after the filing date
`D. document cited in the applimtion
`L : document cited for other masons
`
`& : member of the same patent family, corresponding
`document
`
`

`

`
`
`
`
`
`
`
`
`
`
`vol. 68, no. 7, Juiy 1979, pages
`856-859, American Pharmaceutical
`Association, Washington, DC, US; L.A.
`HULL et a1.: "3-Quinuclidiny1 benziiate
`hydrolysis in dilute aqueous solution"
`* Page 856,
`left-hand column; page 858,
`right-hand column - page 859,
`left-hand
`cqumn *
`
`CHEMICAL REVIEWS, vol. 55, 1955, pages
`713-743, American Chemicai Society,
`Easton, PA, US; K.B. WIBERG: "The
`deuterium isotope effect"
`* Page 718, paragraph 4 - page 723;
`page 724, paragraph 3 *
`
`
`
`
`
`
`
`
`
`
`
`
`
`0 ) gigopean Patent
`)
`ice
`
`EUROPEAN SEARCH REPORT
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Cate 0
`g ry
`
`Citation of document with indication, where appropriate,
`of relevant passages
`
`Relevant
`to claim
`
`Page
`
`2
`
`ApplicationNumber
`
`EP
`
`89 10 1629
`
`CLASSIFICATION OF THE
`APPLICATION (Int. Cl. 4)
`
`
`
`
`
`
`JOURNALOFPHARMACEUTICALSCIENCES, I
`
`
` Place of search
`
`
`T : theory or principle underlying the invention
`E : earlier patent document, but published on, or
`after the filing date
`X : particularly relevant if taken alone
`D : document cited in the application
`Y : particularly relevant if combined with another
`L : document cited for other reasons
`document of the same mtegory
`
`
`A : technological background
`......................................................................................................
`0 : non-written disclosure
`8: : member of the same patent family, corresponding
`
`P : intermediate document
`document
`
`
`
`
`
`
`
`
`JOURNAL OF THE AMERICAN PHARMACEUTICAL
`
`
`ASSOCIATION, v01. 46, no. 9, September
`
`
`1957, pages 531-535, American
`
`
`Pharmaceuticai Association, Washington,
`
`
`DC, US; A.A. KONDRITZER et ai.:
`
`
`"Stabiiity of atropine in aqueous
`
`
`solution"
`* Whole document *
`
`
`JOURNAL OF PHARMACEUTICAL SCIENCES,
`vol. 55, no. 11, November 1966, pages
`1263-1267, American Pharmaceuticai
`Association, Washington, DC, US; R.I.
`ELLIN et a1.: "Kinetics of
`deterioration of trimethylene
`bis-(4-formylpyridinium bromide)
`
`dioxime in diiute aqueous soiutions"
`
`* Whole document *
`
`llifiiiiiiifiiiiillll'
`
`SEARCHED (Int. CL4)
`
`
`
`
`
`
`
`THE HAGUE
`
`CATEGORY OF CITED DOCUMENTS
`
`7
`
`Date of completion of the search
`14-07-1989
`
`Examiner
`MUELLNERS W.
`
`2
`g
`§
`..
`2
`g
`a.
`FE!
`2
`
`