(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`Document FP6
`Appl. No.: 11/273,575
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) lntemational Publication Date
`
`12 May 2005 (12.05.2005)
`
`I|||||IIIIIIIHIlllllllllllllllllllllllll|||l||llllllllllIlllllllllllllllllllllllflllllllllIl||
`
`(10) International Publication Number
`
`WO 2005/041940 A1
`
`
`(51) International Patent Classification": A61K 9/20, 9/48
`
`(21) '“‘°’““"°““' APP"°“"°" ”mm“
`PCT/[N2003/000346
`
`(22) International Filing Date: 30 October 2003 (30.10.2003)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(71) Applicant (for all designated States except US): LUPIN
`LTD. [IN/1N]; 159, CST Road, Kalina, Santacruz (E), 400
`098 Mumbai (1N),
`
`(74) Agents: MAJUMDAR, S. et 211.; S, MAJUMDAR & CO.,
`5, Harish Mukherjee Road, 700 025 Kolkata (IN).
`
`(81) Designated States (national): AE, AG, AL, AM. AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, co, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE,
`GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR,
`KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK,
`
`MN, MW, MX, MZ, NI, NO, NZ, OM, PG, PH, PL, PT,
`RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR,
`
`Tr’ 12' UA’ UG' US’ UZ’ VC‘ VN' YU’ ZA’ ZM’ ZW'
`(84) Designated States (regional): ARl'PO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL. SZ, TZ, UG, ZM, ZW):
`Eurasian patent (AM. AZ, BY, KG, KZ, MD. RU. T1. TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HU, IE, IT, LU, MC, NL, PT, R0,
`
`9
`SE, SI, SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM,
`(72) Inventory and
`GA’ GN‘ GQ‘ GW‘ ML’ MR’ NE’ SN’ TD’ TG)'
`BHAMARE,
`(for US only):
`(75) Inventors/Applicants
`Published:
`Shailesh [IN/IN]; Lupin Ltd. (Research Park), 46A/47A,
`Nande Village, Taluka Mulshi, 411 042 Pune (IN). - with international search report
`BHUSHAN, Indu [IN/IN]; Lupin Ltd.
`(Research Park), _ with amended claims and statement
`46A/47A, Nandc Village, Taluka Mulshi, 411 042 Pune
`(IN). SEN, Himadri [IN/IN]; Lupin Ltd. (Research Park),
`46A/47A, Nande Village, Taluka Mulshi, 411 042 Pune
`(IN).
`
`For two-letter codes and other abbreviations, refer to the ”Guid-
`ance Notes on Codes andAbbreviatians" appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`
`
`(54) Title: STABLE FORMULATIONS OF ACE INHIBITORS AND METHODS FOR PREPARATION THEREOF
`
`(i
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`
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`041940A1||||||||||||||||||||l||l||l||||||||||l|ll||||||||l||||||||||||||ll||||||||ll|l|||||l|||||||||||
`
`E (57) Abstract: Stabilized pharmaceutical solid composition of ACE inhibitor comprising an ACE inhibitor and a selective dosage
`: formulation thereof comprising of meglumine. The ACE inhibitor selectively combined with a dosage form including essentially
`O the meglumine is surprisingly found to avoid the degradation of ACE inhibitor by such dosage forms especially the commonly used
`N pharmaceutical excepients.
`In particular, the presence of the meglumine in the dosage form for the active along with the active
`ACE inhibitor surprisingly avoid the degradation of the ACE inhibitor due to a) cyclization via internal nucleophilic attack to form
`a substituted diketopiperazines, b) hydrolysis of the side chain ester group, and c) oxidation to form products having often unwanted
`coloration.
`
`

`

`WO 2005/041940
`
`PCT/IN2003/000346
`
`STABLE FORMULATIONS OF ACE INHIBITORS AND
`METHODS FOR PREPARATION THEREOF.
`
`Field of invention:
`
`The present invention relates to stable formulations of ACE inhibitors and to a method
`
`for their preparation.
`
`Background of invention:
`
`ACE inhibitors, or inhibitors of angiotensin converting enzymes, are drugs useful in the
`
`treatment of cardiovascular disorders, especially hypertension.
`
`10
`
`15
`
`ACE inhibitors are generally very difficult to formulate into dosage forms, as most ACE
`
`inhibitors on contact with some of the commonly used pharmaceutical excipients
`
`undergo degradation at accelerated rates due to:
`
`i)
`
`cyclization
`
`via
`
`internal
`
`nucleophilic
`
`attack
`
`to
`
`form substituted
`
`diketopiperazines,
`
`hydrolysis of the side chain ester group, and
`
`oxidation to form products having ofien unwanted coloration.
`
`ii)
`
`iii)
`
`These drugs are therefore not sufficiently stable to enable long shelf life. It is thus
`
`generally difficult to select the excipients that enable dosage forms with adequate
`
`20
`
`stability.
`
`Certain stabilized compositions and formulations of ACE inhibitors have been
`
`suggested and utilized in the prior art.
`
`US. patent 5,562,921 discloses that stable tablet formulations containing enalapril
`
`maleate can be made comprising anhydrous lactose as filler and zinc stearate as
`
`lubricant.
`
`US. 4,830,853 discloses that ACE inhibitors can be stabilized against oxidation and
`
`30
`
`discoloration by including ascorbic acid or sodium ascorbate in the composition.
`
`

`

`r)
`
`10
`
`15
`
`25
`
`30
`
`WO 2005/041940
`
`PCT/IN2003/000346
`
`US. patent 4,743,450 discloses stable formulations of ACE inhibitors containing
`
`alkaline earth metal carbonate and saccharide as stabilizing agents.
`
`W0 03/ 059388 describes stable formulation of ACE inhibitors comprising only
`
`alkaline earth metal carbonate and alkaline earth metal hydrogen phosphate and no
`
`saccharide.
`
`US. patent 5,006,344 demonstrates that compositions containing fosinopril sodium are
`
`relatively unstable if they comprise magnesium stearate as lubricant, but stability can be
`
`improved by use of sodium stearyl fumarate or hygrogenated vegetable oil as lubricant. '
`
`Although each of the above patents represent an attempt to overcome the instability
`
`problems associated with ACE- inhibitor containing compositions, there still exists a
`
`dire need for ACE- inhibitor containing compositions exhibiting improved stability. To
`
`this end, the present invention is directed to pharmaceutical compositions of ACE-
`
`inhibitors exhibiting improved stability.
`
`Objects of the invention:
`
`The object of the present invention is to provide stabilized pharmaceutical compositions
`
`comprising ACE- inhibitors which would avoid the instability associated with ACE '
`
`inhibitors when in dosage forms discussed above.
`
`It is a further object of this invention to disclose stabilized pharmaceutical compositions
`
`comprising ramipril and meglumine.
`
`It is another object of the present invention to disclose a process for the preparation of
`
`stabilized pharmaceutical compositions comprising an ACE inhibitor.
`
`It is yet another object of the present invention to disclose a stable pharmaceutical
`
`composition comprising an ACE inhibitor and selective diluent which would not have
`
`problems of compatibility and/or stability usually found in such combination.
`
`

`

`WO 2005/041940
`
`PCT/IN2003/000346
`
`Summagy of the Invention
`
`Thus according to the basic aspect of the present invention there is provided stabilized
`
`pharmaceutical solid composition of ACE inhibitor comprising an ACE inhibitor and a
`
`selective dosage formulation thereof comprising of meglumine.
`
`Importantly, it is surprisingly found by way of the present invention that if the ACE
`
`inhibitor is selectively combined with dosage form including essentially the meglumine, .
`
`the degradation of ACE inhibitor by such dosage forms especially the commonly used
`
`pharmaceutical excepients can be avoided.
`
`In otherwords,
`
`the presence of the
`
`meglumine in the dosage form for the active along with the active ACE inhibitor
`
`surprisingly avoid the degradation of the ACE inhibitor due to
`
`i)
`
`cyclization
`
`via
`
`internal
`
`nucleophilic
`
`attack
`
`to
`
`form substituted
`
`diketopiperazines,
`
`hydrolysis of the side chain ester group, and
`
`oxidation to form products having ofien unwanted coloration.
`
`ii)
`
`iii)
`
`Accordingly, the composition of the invention involving the active ACE inhibitor and
`
`the dosage form including essentially the meglumine provide surprising stable and long
`
`, shelf life for the ACE inhibitor in selective dosage forms.
`
`Detailed description of the invention:
`
`It is thus possible by way of the above pharmaceutical formulation of present invention
`
`to provide an ACE-
`
`inhibitor
`
`in dosage form including other pharmaceutically
`
`acceptable excipients in the presence of meglumine.
`
`The ACE- inhibitor in accordance with present invention may be selected from the
`
`group of enalapril, delapril, lisinopril, moxipril, perindopril, ramipril, trandolapril and
`
`pharmaceutically acceptable salts thereof. The amount of ACE—inhibitor
`
`in the
`
`formulation is selected as per its approved dosage strength.
`
`10
`
`15
`
`25
`
`30
`
`

`

`WO 2005/041940
`
`PCT/IN2003/000346
`
`Meglumine is used as a stabilizer. It is an organic base used as pH adjusting agent and
`
`solubilizing agent.
`
`It is mostly used for parenteral preparations. The ratio of ACE-
`
`inhibitor to meglumine is from about 1: 0.01 to about 1: 2.0 and more preferably from
`
`about 1: 0.03 to about 121.2.
`
`The formulations in accordance with the present invention can due to the selective
`
`stability provided by meglumine include other pharmaceutically acceptable excipients
`
`selected from amongst diluents and lubricants.
`
`There are many diluents that can be used in pharmaceutical formulations, including for
`
`example starch cellulose, calcium sulphate, calcium carbonate, dicalcium phosphate,
`
`lactose, dextrose,
`
`sucrose, dextrates, mannitol, maltodextrin, methylcellulose, and
`
`polyethylene glycol.
`
`However, ACE-inhibitors are incompatible with many of these commonly used
`
`pharmaceutical diluents and it is essential to choose a diluent which is compatible with
`
`the ACE inhibitors and provide formulations with adequate stability.
`
`According to another aspect of the present invention it has been surprisingly found that
`
`better stability 'of ACE—inhibitors is achieved by using selectively low substituted
`
`hydroxypropyl cellulose as a diluent in the dosage formulation.
`
`The ratio of ACE-
`
`inhibitor to low substituted hydroxypropyl cellulose used in
`
`accordance with the present invention is from about 1:10 to about 1:100.
`
`It was surprisingly found that the combination of meglumine and low substituted
`
`hydroxypropyl cellulose or the combination of meglumine with previously known
`
`diluents such as pregelatinized starch results in enhanced stability of ACE-inhibitor
`
`containing compositions.
`
`Incorporation of meglumine along with low substituted
`
`hydroxypropyl cellulose or pregelatinized starch produces the stability superior to that
`
`of low substituted hydroxypropyl cellulose or pregelatinized starch when used alone.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO 2005/041940
`
`PCT/IN2003/000346
`
`The lubricant used in accordance with the present invention is selected from amongst
`
`stearates such as magnesium stearate, zinc stearate or calcium stearate. Preferably the
`
`lubricant is magnesium stearate. It is present in an amount from about 0.2 mg to about 2
`
`mg per tablet or capsule and is more preferably from about 0.5 mg to about 1.5 mg per
`
`tablet or capsule.
`
`Examples
`
`The objects of the invention and its advantages are explained in greater detail in relation
`
`to non-limiting exemplary illustrations of the ACE inhibitor based dosage forms
`
`including meglumine of the invention discussed above.
`
`To ascertain the selective stable dosage form for the ACE inhibitors
`
`following
`
`exemplary preparations with Ramipril as the ACE inhibitor were obtained as per
`
`Examples 1 to 5:
`
`10
`
`15'
`
`
`
`
`
`_—=---nn
`
`
`til—m--=--- 2000 2-000
`
`
`
`
`
`
`
`
`
`Low substituted Hydroxypropyl
`Cellulose
`
`Me_lurnine
`
`
`
`--
`
`For each of five examples,
`
`the ingredients in the proportions shown were mixed
`
`together. The produced mixture was then filled into glass vials and closed with rubber
`
`20
`
`stopper and aluminium seals.
`
`The vials were stored at 60°C for 15 days and then tested by High Performance liquid
`
`Chromatography method (I-[PLC) to determine assay and degradation products.
`
`25
`
`

`

`WO 2005/041940
`
`PCT/IN2003/000346
`
`The results are summarized in the Table I below:
`
`
`
`As can be seen from the Table 1 above, vials containing meglumine (Ex 2 and 5)
`
`5
`
`exhibited enhanced stability as shown by reduced formation of degradation products
`
`(0.75-1.59 %) compared with the vials which did not contain meglumine (Exl ,3 and 4).
`
`The extent of degradation observed in samples containing meglumine either with
`
`pregelatinized starch or low substituted hydroxypropyl cellulose was substantially lower
`
`10
`
`than the samples without meglumine.
`
`Surprisingly,
`
`low substituted hydroxypropyl cellulose showed higher degree of
`
`compatibility unlike observed and reported incompatibility with other celluloses.
`
`15
`
`It is thus possible by way of the above selective dosage formulation of ACE inhibitors
`
`to provide stabilized pharmaceutical compositions comprising ACE- inhibitors which
`
`would avoid the instability associated with ACE inhibitors when in dosage forms
`
`‘discussed above. Importantly,
`
`the stable pharmaceutical composition comprising an
`
`ACE inhibitor and selective diluent would avoid problems of compatibility and/or
`
`20
`
`stability usually found in such combination.
`
`

`

`WO 2005/041940
`
`PCT/IN2003/000346
`
`CLAIMS
`
`1. A stabilized pharmaceutical solid composition of ACE inhibitor comprising an ACE
`
`inhibitor and a selective dosage formulation thereof comprising of meglumine.
`
`2. A composition of claim 1, where in the ACE inhibitor is selected from the group of
`
`enalapril,
`
`delapril,
`
`lisinopril, moxipril, perindopril,
`
`ramipril,
`
`trandolapril
`
`and
`
`pharmaceutically acceptable salts thereof.
`
`3. A composition of claim 2, wherein the ACE—inhibitor is ramipril.
`
`4. A composition of claim 3, wherein the amount of ramipril in the composition is from
`
`about 1.25 mg to about 10 mg.
`
`5. A composition of anyone of claims 1
`
`to 4 , wherein the ratio of ACE-inhibitor to
`
`meglumine is from about 120.01 to about 122.0.
`
`6. A composition of claim 5 , wherein the ratio of ACE-inhibitor to meglumine is
`preferably from about 1:0.03 to about 1:12.
`
`7. A composition of anyone of claims 1 to 6 wherein the dosage formulation further
`contains a diluent.
`
`10
`
`15
`
`20
`
`is selected from amongst
`8. A composition of claim 7, wherein the diluent
`substituted hydroxypropyl cellulose or pregelatinized starch.
`
`low
`
`9. A composition of anyone of claims 1 to 7, wherein the. ratio of ACE-inhibitor to
`diluent is from about 1:10 to about 1:100.
`
`30
`
`10. A composition of anyone of claims 1 to 10 wherein the dosage formulation further
`contains lubricant.
`
`

`

`WO 2005/041940
`
`PCT/IN2003/000346
`
`11. A composition of claim 11, wherein the lubricant is a stearate, which is selected
`
`from the group consisting of magnesium stearate, zinc stearate and calcium stearate.
`
`12. A composition of claim 12,wherein the lubricant is magnesium stearate.
`
`13. A composition of anyone of claims 1 to 13, wherein the amount of lubricant in the
`
`composition is from about 0.2 mg to about 2 mg.
`
`14. A composition of claim 14, wherein the amount of lubricant in the composition is
`
`10
`
`preferably from about 0.5 mg to about 1.5 mg.
`
`15. A stabilized pharmaceutical ACE inhibitor composition comprising ramipril and a
`
`dosage formulation comprising of meglumine along with atleast one of 10W substituted
`
`hydroxypropyl cellulose and pregelatinized starch and magnesium stearate.
`
`15
`
`16. A composition of anyone of claims 1 to 16 in any dosage form preferably is filled
`
`into a capsule or compressed to a tablet.
`
`17. The process for the preparation of a stable formulation of ACE-inhibitor comprising
`
`20
`
`mixing of the ACE inhibitor with a selective dosage formulation comprising of
`meglumine and a diluent followed by compressing the mixture to a tablet or filling it
`
`into a capsule.
`
`18. The process as claimed in claim 18 wherein the diluent
`
`is selected from amongst
`
`25
`
`low substituted hydroxypropyl cellulose and pregelatinized starch.
`
`19. A stabilized pharmaceutical solid composition of ACE inhibitor and its process for
`
`manufacture substantially as described and exemplified herein.
`
`30
`
`

`

`WO 2005/041940
`
`9
`
`PCT/IN2003/000346
`
`AMENDED CLAIMS
`[received by the International Bureau on lSt November 2004 (01.11.04);
`original claims 1—19 replaced by amended claims 1-23 (2pages).]
`
`+statement
`
`1. A stabilized pharmaceutical solid composition comprising of an ACE inhibitor and
`
`meglumine.
`
`5
`
`-2. A stabilized composition of claim 1, where in the ACE inhibitor is selected from
`
`the group of enalapril, delapril, lisinopril, moxipril, perindopril, ramipril, trandolapril
`
`and pharmaceutically acceptable salts thereof.
`
`10
`
`3. A stabilized composition of claim 2, wherein the ACE-inhibitor is ramipril.
`
`4. A stabilized composition of claim 3, wherein the amount of ramipril
`
`in the
`
`composition is from about 1 mg to about 10 mg.
`
`15
`
`5. A stabilized composition of claim 1, wherein the ratio of ACE-inhibitor to
`
`meglumine is from about 120.01 to about 1:20.
`
`20
`
`25
`
`6. A stabilized composition of claim 5, wherein the ratio of ACE-inhibitor to
`
`meglumine is preferably from about 110.03 to about 1:12.
`
`7. A stabilized composition of claim 1, which further comprises of a diluent.
`
`8. A stabilized composition of claim 7, wherein the diluent is selected from amongst
`
`low substituted hydroxypropyl cellulose and pregelatinized starch.
`
`9. A stabilized composition of claim 7, wherein the ratio of ACE-inhibitor to diluent is
`
`from about 1:10 to about 1:100.
`
`10. A stabilized composition of claim 1 wherein the dosage formulation further
`
`30
`
`comprises of lubricant.
`
`11. A stabilized composition of claim 10, wherein the lubricant is a stearate, which is
`
`selectedfrom the group consisting of magnesium stearate, zinc stearate and
`
`calcium stearate.
`
`35
`
`12. A stabilized composition of claim 10,wherein the lubricant is magnesium stearate.
`
`AMENDED SHEET (ARTICLE 19)
`
`

`

`WO 2005/041940
`
`10
`
`PCT/IN2003/000346
`
`13.A stabilized composition of claim 10, wherein the amount of lubricant in the
`
`composition is from about 0.2 mg to about 2 mg. .
`
`14.A stabilized composition of claim 10, wherein the amount of lubricant in the
`
`composition is from about 0.5 mg to about 1.5 mg.
`
`15. A stabilized pharmaceutical ACE inhibitor composition comprising ramipril and
`
`meglumine along with atleast one of low substituted hydroxypropyl cellulose,
`
`pregelatinized starch and magnesium stearate.
`
`16. A stabilized composition of claim 1 in any dosage form.
`
`17.A stabilized composition of claim 16 wherein the composition is filled into a
`
`capsule.
`
`18.A stabilized composition of claim 16 wherein the composition is made into a
`tablet.
`
`19.A process of preparation of a stable formulation of ACE-inhibitor comprising
`
`mixing of the ACE inhibitor with meglumine and optionally atleast one of
`
`a
`
`diluent and a lubricant followed by compressing the mixture to a tablet or filling
`
`the mixture into a capsule.
`
`20. The process as claimed in Claim 19 wherein the diluent is selected from amongst
`
`low substituted hydroxypropyl cellulose and pregelatinized starch.
`
`21. The process as claimed in Claim 19 wherein the lubricant,
`
`is selected from the
`
`group consisting of magnesium stearate, zinc stearate and calcium stearate.
`
`22. The process as claimed in Claim 21 wherein the lubricant is magnesium stearate.
`
`23. A stabilized pharmaceutical solid composition of ACE inhibitor and its process for
`
`manufacture substantially as described and exemplified herein.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`AMENDED SHEET (ARTICLE 19)
`
`

`

`WO 2005/041940
`
`11
`
`PCT/IN2003/000346
`
`STATEMENT UNDER ARTICLE 19(1) RULE 46.4
`
`WO 03/063825 cited in the International Search Report relates to a pharmaceutical
`composition directed to alleviate the problems of
`extended release profile
`of
`therapeutically active composition with limited solubility in aqueous or biological fluids.
`Further the cited art is directed to achieving the delivery of the therapeutically active
`ingredient from the composition such that it is not affected by the intrinsic solubility of the
`active and the released property of the solubility modifying agent. The said composition
`comprises a tablet core of
`the therapeutically active
`ingredient, solubility modifier,
`osmagents and other conventional excipients. The therapeutic active ingredient of the
`invention is weakly acidic in nature and is having a limited solubility in the aqueous
`environment. The tablet core is coated with a rate controlling semi-permeable and
`permeable membrane forming polymers. The solubility modifiers are in immediate
`contact with the active ingredient and are capable of improving the solubility of the agent
`by elevating the microenviromental pH above the pKa of the therapeutically active
`ingredient and thus improve its release profile from the pharmaceutical composition. Due
`to this, the release of the therapeutically active ingredient from the composition will be
`independent of its intrinsic water solubility and the environment of use.
`
`There are many solubility modifiers mentioned in the cited art which are alkalinizing
`agents and /or buffers and Meglumine hasbeen mentioned as one of the solubility
`modifiers. Among various therapeutically active ingredients cardiovascular agents are
`mentioned as one of the therapeutically active ingredients in which ACE inhibitors are
`covered under the category of cardiovascular drugs. Amongst the ACE inhibitors, only
`captopril is mentioned. The ratio of the therapeutically active ingredient to alkalinizing
`agent is in the range of 0.1: 9.9 to 7.3.
`
`On the other hand the present invention relates to a composition comprising ACE
`inhibitor and Meglumine.
`It is directed to achieving stabilization of ACE inhibitor in a
`composition for increased shelf life by incorporation of meglumine. The inventors have
`found that the degradation of the ACE inhibitors on contact with some pharmaceutical
`excipients can be prevented by use of meglumine. The incorporation of meglumine
`avoids the degradation of the ACE inhibitor due to cyclization via the internal nucleophilic
`attack to form substituted diketopiperazines, hydrolysis of the side chain ester group and
`oxidation to form products having often unwanted
`coloration. Accordingly such
`composition comprising ACE inhibitors and meglumine are stable and have long shelf
`life.
`
`solubility
`the
`of
`one
`indicates meglumine as
`03/063825
`Though W0
`modifiers/alkalinizing agent and captopn‘l as one of the cardiovascular agent but not ACE
`inhibitor specifically,
`it does not teach or suggest a composition essentially comprising
`ACE inhibitor and meglumine such that meglumine would avoid the degradation of the
`ACE as above. Moreover the ratio in which the active and alkanizing agent are combined
`is different from that in which the ACE inhibitor and meglumine is present in the
`composition of the present invention.
`
`The claims are amended to further clarify the scope of protection and the same may be
`taken as amendment under Article 19.
`
`

`

`WTERNANONALSEARCHREPORT
`
`BJECT MATTER
`A. CLASSIFICATION OF
`IPC 7
`A61K9 20
`A61K9/48
`
`int-lanai Application No
`
`Pct/1N 03/00346
`
`According to international Patent Classification (iPC) orto both national classification and [PC
`B. FIELDS SEARCHED
`Minimum documentation searched (classification system iollowed by classification symbols)
`IPC 7
`A61K
`
`Documentation searched other than minimUm documentation to the extent that such documents are lnclUded in the fields searched
`
`Electronic data base consulted during the international search (name of data base and. where practical. search terms used)
`
`EPO-Internai, NPI Data, PAJ, CHEM ABS Data
`
` Relevant to claim No.
`
`C._OCUMENTSCONSIDERED TO BE RELEVANT
`
`Cetegory'
`Citation oi document. with indication, where appropriate. of the relevant passages
`
`NO 03/063825 A (COUNCIL OF SCIENTIFIC AND
`INDUSTRIAL RESEARCH)
`7 August 2003 (2003- 08—07)
`claims 1, 4, 10, 11
`page 11,
`line 7 — line 8
`
`1, 5-7,
`16,17,19
`
`E] Further domments are listed in the continuation or box 0.
`" Specie! categories of died documents :
`
`'A' document defining the general state of the art which is not
`considered to be at particular relevance
`'E' earlier document but published on or after the lntematlonai
`filing date
`'L' document which may throw doubts on priority dalmis) or
`which is cited to establish the publication date of another
`citation or other special reason (as specified)
`'0' document referring to an oral disclosure. use. exhibition or
`other means
`'P' document published prior to the lntematlonai tiling date but
`iaterthan the priority date claimed
`Date of the actual completion otthe International search
`
`29 June 2004
`
`Name and mailing address of the iSA
`European Patent Office, RB. 5818 Palenilean 2
`NL- 2280 HV Fiiiswijk
`Tel. (+a1-70)340-2040. Tx. 31 651 epo ni
`Fax: (+31—70)340—3016
`
`Form PCTIISN210 (ascend shoal) (Jammy 2004)
`
`n Patent family members are listed In annex.
`'1" later document published after the lntematlonai filing date
`or priority date and not in conflict with the application but
`cited to understand the principle or theory underlying the
`invention
`'X' document of particular relevance; the claimed invention
`mnoi be considered novel orcannoi be considered to
`involve an inventive step when the document is taken alone
`'Y' document of particular relevance: the claimed invention
`cannot be considered to involve an Inventive step when the
`document is combined with one or more other such docu-
`n
`e a .
`Imegts. :uch oonbination being obvious to a person skilled
`'&' document member of the same patent family
`Date or mailing otthe lntematlonai search report
`
`09/07/2004
`Authorized officer
`
`Venture Amat, A
`
`

`

`INTERNAHONALSEARCHREPORT
`mtormatlon on patent famlly members
`
`
`
`
`Patent family
`member(s)
`
`Patent document
`cited In search report
`
`WO 03063825
`
`A
`
`
`
`
`Publication
`date
`
`07-08-2003
`
`NO
`US
`
`lute-lonal Application No
`
`PCT/IN 03/00346
`
`Publication
`date
`
`
`
`
`03063825 A1
`2003175349 A1
`
`
`07-08-2003
`18-09—2003
`
`
`
`
`
`Form PCT/ISA/Zw (p'atam larnly annex) (January 2004)
`
`