wo 2005/074536
`
`PCTIUS2005/002674
`
`positively charged drug molecules away from the electrode and into the tissues. In one
`
`embodiment, iontophoresis is used to deliver proton pump inhibitors to infants for
`
`treating and/or preventing GI disorders. In one embodiment, the gastrointestinal
`
`disorder is GERD.
`
`5
`
`The invention provides for the proton pump inhibitors and, optionally, other
`
`active ingredients, to be administered nasally to a patient to treat the diseases and
`disorders described herein and those described, for example, in PCT Application No.
`
`PCT/US02/36857, the disclosure of which is incorporated by reference herein in its
`
`entirety. "Administered nasally" or "nasal administration" is intended to mean that at
`
`10
`
`least one proton pump inhibitor is combined with a suitable delivery system for
`
`absorption across the nasal mucosa of a patient, preferably a human.
`
`The proton pump inhibitors of the invention can be administered, for example,
`
`as nasal sprays, nasal drops, nasal suspensions, nasal gels, nasal ointments, nasal
`
`creams or nasal powders. The proton pump inhibitors can also be administered using
`
`15
`
`nasal tampons or nasal sponges. The proton pump inhibitors of the invention can be
`
`brought into a viscous basis via systems conventionally used, for example, natural
`
`gums, methylcellulose and derivatives, acrylic polymers (carbopol) and vinyl polymers
`
`(polyvinylpyrrolidone). In the compositions, many other excipients known in the art
`
`can be added such as water, preservatives, surfactants, solvents, adhesives,
`
`20
`
`antioxidants, buffers, bio-adhesives, viscosity enhancing agents and agents to adjust the
`
`pH and the osmolarity.
`
`The nasal delivery systems can take various forms including aqueous solutions,
`
`non-aqueous solutions and combinations thereof. Aqueous solutions include, for
`
`example, aqueous gels, aqueous suspensions, aqueous liposomal dispersions, aqueous
`
`25
`
`emulsions, aqueous microemulsions and combinations thereof. Non-aqueous solutions
`
`include, for example, non-aqueous gels, non-aqueous suspensions, non-aqueous
`
`liposomal dispersions, non-aqueous emulsions, non-aqueous microemulsions and
`
`combinations thereof.
`
`In other embodiments, the nasal delivery system can be a powder formulation.
`
`30
`
`Powder formulations include, for example, powder mixtures, powder microspheres,
`
`coated powder microspheres, liposomal dispersions and combinations thereof.
`
`Preferably, the powder formulation is powder microspheres. The powder microspheres
`
`18
`
`

`
`wo 2005/074536
`
`PCTIUS2005/002674
`
`are preferably formed from various polysaccharides and celluloses selected from starch,
`
`methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose,
`
`carbomer, alginate polyvinyl alcohol, acacia, chitosans, and mixtures of two or more
`
`thereof.
`
`5
`
`In certain embodiments, the particle size of the droplets of the aqueous and/or
`
`non-aqueous solution or of the powders delivered to the nasal mucosa can be, for
`
`example, about 0.1 micron to about 100 microns; from about 1 micron to about 70
`
`microns; from about 5 microns to about 50 microns; or from about 10 microns to about
`
`20 microns. The particle sizes can be obtained using suitable containers or metering
`
`10
`
`devices known in the art. Exemplary devices include mechanical pumps in which
`
`delivery is made by movement of a piston; compressed air mechanisms in which
`
`delivery is made by hand pumping air into the container; compressed gas (e.g.,
`
`nitrogen) techniques in which delivery is made by the controlled release of a
`
`compressed gas in the sealed container; liquefied propellant techniques in which a low
`
`15
`
`boiling liquid hydrocarbon (e.g., butane) is vaporized to exert a pressure and force the
`
`composition through the metered valve; and the like. Powders may be administered,
`
`for example, in such a manner that they are placed in a capsule that is then set in an
`
`inhalation or insufflation device. A needle is penetrated through the capsule to make
`
`pores at the top and the bottom of the capsule and air is sent to blow out the powder
`
`20
`
`pruticles. Powder formulation can also be administered in a jet-spray of an inert gas or
`
`suspended in liquid organic fluids.
`
`In one embodiment, the invention provides a nasally administrable
`
`pharmaceutical composition comprising at least one proton pump inhibitor dispersed in
`
`a nasal delivery system that improves the solubility of the proton pump inhibitor. The
`
`25
`
`nasal delivery system that improves solubility can include one of the following or
`
`combinations thereof: (i) a glycol derivative (e.g., propylene glycol, polyethylene
`
`glycol, mixtures thereof); (ii) a sugar alcohol (e.g., mannitol, xylitol, mixtures thereof);
`
`(iii) glycerin; (iv) a glycol derivative (e.g., propylene glycol, polyethylene glycol or
`
`mixtures thereof) and glycerin; (v) ascorbic acid and water; (vi) sodium ascorbate and
`
`30 water; or (vii) sodium metabisulfite and water.
`
`In another embodiment, the invention provides a nasally administrable
`
`pharmaceutical composition comprising at least one proton pump inhibitor and a nasal
`
`19
`
`

`
`wo 2005/074536
`
`PCTIUS2005/002674
`
`delivery system, where the nasal delivery system comprises at least one buffer to
`
`maintain the pH of the proton pump inhibitor, at least one pharmaceutically acceptable
`
`thickening agent and at least one humectant. The nasal delivery system can optionally
`
`further comprise surfactants, preservatives, antioxidants, bio-adhesives, pH adjusting
`
`5
`
`agents, isotonicity agents, solubilizing agents, and/or other pharmaceutically acceptable
`
`excipients. The proton pump inhibitor can optionally be dispersed in a nasal delivery
`system that improves its solubility.
`
`In another embodiment, the invention provides a nasally administrable
`
`pharmaceutical composition, comprising at least one proton pump inhibitor and a nasal
`
`10
`
`delivery system, where the nasal delivery system comprises at least one solubilizing
`
`agent, at least one pharmaceutically acceptable thickening agent and at-least one
`
`humectant. The nasal delivery system can optionally further comprise buffers, pH
`
`adjusting agents, isotonicity agents, surfactants, preservatives, antioxidants, bio(cid:173)
`
`adhesives, mid/or other pharmaceutically acceptable excipients. The proton pump
`
`15
`
`inhibitor can optionally be dispersed in a nasal delivery system that improves its
`
`solubility.
`
`In another embodiment, the invention provides a nasally administrable
`
`pharmaceutical composition comprising at least one proton pump inhibitor and a nasal
`
`delivery system, where the nasal delivery system comprises at least one buffer to
`
`20 maintain the pH of the proton pump inhibitor, at least one pharmaceutically acceptable
`
`thickening agent, at least one humectant, and at least one surfactant. The nasal deli very
`
`system can optionally further comprise pH adjusting agents, isotonicity agents,
`
`solubilizing agents, preservatives, antioxidants, bio-adhesives, and/or other
`
`pharmaceutically acceptable excipients. The proton pump inhibitor can optionally be
`
`25
`
`dispersed in a nasal delivery system that improves its solubility.
`
`In yet another embodiment, the invention provides a nasally administrable
`
`pharmaceutical composition comprising at least one proton pump inhibitor and a nasal
`
`delivery system, where the nasal delivery system comprises at least one
`
`pharmaceutically acceptable thickening agent, at least one humectant, at least one
`
`30
`
`surfactant, and at least one solubilizing agent. The nasal delivery system can optionally
`
`further comprise buffers, pH adjusting agents, isotonicity agents, preservatives,
`
`antioxidants, bio-adhesives, and/or other pharmaceutically acceptable excipients. The
`
`20
`
`

`
`wo 2005/074536
`
`PCTIUS2005/002674
`
`proton pump inhibitor can optionally be dispersed in a nasal delivery system that
`
`improves its solubility.
`
`In yet another embodiment, the invention provides a nasally administrable
`
`pharmaceutical composition comprising at least one proton pump inhibitor and a nasal
`
`5
`
`delivery system, where the nasal delivery system comprises at least one buffer to
`
`maintain the pH of the proton pump inhibitor, at least one pharmaceutically acceptable
`thickening agent, at least one humectant, at least one surfactant, and at least one
`
`solubilizing agent. The nasal delivery system can optionally further comprise buffers,
`
`pH adjusting agents, isotonicity agents, preservatives, antioxidants, bio-adhesives,
`
`10
`
`and/or other pharmaceutically acceptable excipients. The proton pump inhibitor can
`
`optionally be dispersed in a nasal delivery system that improves its solubility.
`
`The nasally administrable pharmaceutical compositions of the invention
`
`preferably provide a peak plasma concentration of the proton pump inhibitor in less
`
`than one hour, preferably within about 5 minutes to about 30 minutes, more preferably
`
`15 within about 5 minutes to about 20 minutes, after administration to the patient.
`
`The buffer has a pH that is selected to optimize the absorption of the proton
`
`pump inhibitor across the nasal mucosa. The particular pH of the buffer can vary
`
`depending upon the particular nasal delivery formulation as well as the specific proton
`
`pump inhibitor selected. Buffers that are suitable for use in the invention include
`
`20
`
`acetate (e.g., sodium acetate), citrate (e.g., sodium citrate dihydrate), phthalate, borate,
`
`prolamine, trolamine, carbonate, phosphate (e.g., monopotassium phosphate, disodium
`
`phosphate), and mixtures of two or more thereof.
`
`The pH of the compositions should be maintained from about 3.0 to about 10.0.
`
`Compositions having a pH of less than about 3.0 or greater than about 10.0 can increase
`
`25
`
`the risk of irritating the nasal mucosa of the patient. Further, it is preferable that the pH
`
`of the compositions be maintained from about 3.0 to about 9.0. With respect to the
`
`non-aqueous nasal formulations, suitable forms of buffering agents can be selected such
`
`that when the formulation is delivered into the nasal cavity of a mammal, selected pH
`
`ranges are achieved therein upon contact with, e.g., a nasal mucosa.
`
`30
`
`The solubilizing agent for use in the compositions of the invention can be any
`
`known in the art, such as carboxylic acids and salts thereof. Exemplary carboxylic acid
`
`salts include acetate, gluconate, ascorbate, citrate, fumurate, lactate, tartrate, malate,
`
`21
`
`

`
`wo 2005/074536
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`PCTIUS2005/002674
`
`maleate, succinate, or mixtures of two or more thereof.
`
`The viscosity of the compositions of the present invention can be maintained at
`
`a desired level using a pharmaceutically acceptable thickening agent. For example, the
`
`viscosity may be at least 1000 cps; from about 1000 to about 10,000 cps; from about
`
`5
`
`2000 cps to about 6500 cps; or frmn about 2500 cps to about 5000 cps. Thickening
`
`agents that can be used in accordance with the present invention include, for example,
`methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose,
`carbomer, polyvinyl alcohol, alginates, acacia, chitosans, and mixtures of two or m~re
`thereof. The concentration of the thickening agent will depend upon the agent selected
`
`10
`
`and the viscosity desired. Such agents can also be used in a powder formulation.
`
`The nasally administrable compositions can also include a humectant to reduce
`
`or prevent drying of the mucus membrane and to prevent irritation thereof. Suitable
`
`humectants that can be used include, for example, sorbitol, mineral oil, vegetable oil
`
`and glycerol; soothing agents; membrane conditioners; sweeteners; and mixtures of two
`
`15
`
`or more thereof. The concentration of the humectant will vary depending upon the
`
`agent selected. In one embodiment, the humectant can be present in the nasal delivery
`
`system in a concentration ranging from about 0.01% to about 20% by weight of the
`
`composition.
`
`In other embodiments, the nasal delivery system can further comprise
`
`20
`
`surfactants which enhance the absorption of the proton pump inhibitor. Suitable
`
`surfactants include non-ionic, anionic and cationic surfactants. Exemplary surfactants
`
`include oleic acid, polyoxyethylene derivatives of fatty acids, partial esters of sorbitol
`
`anhydride, such as for example, Tweens (e.g., Tween 80, Tween 40, Tween 20), Spans
`
`(e.g., Span 40, Span 80, Span 20), polyoxyl40 stearate, polyoxy ethylene 50 stearate,
`
`25
`
`fusieates, bile salts, octoxynol, and mixtures of two or more thereof. Exemplary
`
`anionic surfactants include salts of long chain hydrocarbons (e.g., C6-3o or C I0-2o)
`having one or more of the following functional groups: carboxylates; sulfonates; and
`
`sulfates. Salts of long chain hydrocarbons having sulfate functional groups are
`
`preferred, such as sodium cetostearyl sulfate, sodium dodecyl sulfate and sodium
`
`30
`
`tetradecyl sulfate. One particularly preferred anionic surfactant is sodium lauryl sulfate
`
`(i.e., sodium dodecyl sulfate). The surfactants can be present in an amount from about
`
`0.001% to about 50% by weight, or from about 0.001% to about 20% by weight.
`
`22
`
`

`
`wo 2005/074536
`
`PCTIUS2005/002674
`
`The pharmaceutical compositions of the invention may further comprise an
`
`isotonicity agent, such as sodium chloride, dextrose, boric acid, sodium tartrate or other
`
`inorganic or organic solutes.
`
`The nasal pharmaceutical compositions of the invention can optionally be used
`
`5
`
`in combination with a pH adjusting agent. Exemplary pH adjusting agents include
`
`sulfuric acid, sodium hydroxide, hydrochloric acid, and the like.
`
`To extend shelf life, preservatives can be added to the nasally administrable
`
`compositions. Suitable preservatives that can be used include benzyl alcohol, parabens,
`
`thimerosal, chlorobutanol, benzalkonium chloride, or mixtures of two or more thereof.
`
`10
`
`Preferably benzalkonium chloride is used. Typically, the preservative will be present in
`
`a concentration of up to about 2% by weight. The exact concentration of the
`
`preservative, however, will vary depending upon the intended use and can be easily
`
`ascertained by one skilled in the art.
`
`Other ingredients which extend shelf life can be added such as for example,
`
`15
`
`antioxidants. Some examples of antioxidants include sodium metabisulfite, potassium
`
`metabisulfite, ascorbyl palmitate and the like. Typically, the antioxidant will be present
`
`in the compositions in a concentration of from about 0.001% up to about 5% by weight
`
`of the total composition.
`
`Other optional ingredients can also be incorporated into the nasal delivery
`
`20
`
`system provided that they do not interfere with the action of the proton pump inhibitor
`
`or significantly decrease the absorption of the proton pump inhibitor across the nasal
`
`mucosa.
`
`The nasal delivery systems can be made following the processes described in,
`
`for example, U.S. Patent Nos. 6,451,848, 6,436,950, and 5,874,450, and WO 00/00199,
`
`25
`
`the disclosures of which are incorporated by reference herein in their entirety.
`
`Each of the patents and publications cited herein are incorporated by reference
`
`herein in their entirety.
`
`It will be apparent to one skilled in the art that various modifications can be
`
`made to the invention without departing from the spirit or scope of the appended
`
`30
`
`claims.
`
`23
`
`

`
`wo 2005/074536
`
`PCTIUS2005/002674
`
`What is claimed is:
`
`Claims
`
`1.
`
`A method for treating or preventing a gastrointestinal disorder induced
`
`or caused by a nonsteroidal anti-inflammatory drug comprising administering to a
`
`5
`
`patient in need thereof a therapeutically effective amount of at least one proton pump
`
`inhibitor and at least one nonsteroidal anti-inflammatory drug selected from the group
`consisting of diclofenac, celecoxib, rofecoxib, and valdecoxib.
`
`2.
`
`The method of claim 1, wherein the proton pump inhibitor is
`
`rabeprazole.
`
`10
`
`3.
`
`A method for treating cystic fibrosis in a patient in need thereof
`
`comprising administering a therapeutically effective amount of at least one proton
`
`pump inhibitor and at least one cystic fibrosis drug selected from the group consisting
`
`of albuterol, theophylline, ipratropium, guaifenesin, dnase, n-acetylcysteine,
`
`triamcinolone, flunisolide, fluticasone, beclomethasone, prednisone, methylprednisone,
`
`15
`
`ibuprofen, montelukast, cromolyn, ciprofloxacin, co-trimoxazole, tobramycin,
`
`cephalexin, colistin, dicloxacillin, azithromycin, vitamins, pancrelipase, docusate,
`
`casanthranol/docusate, omeprazole, ranitidine, loratadine, cetirizine, and fexofenadine.
`
`4.
`
`A method for treating or preventing radiation therapy induced emesis in
`
`a patient in need thereof comprising administering a therapeutically effective amount of
`
`20
`
`at least one proton pump inhibitor.
`
`5.
`
`A method for treating or preventing chronic ear infection in a patient in
`
`need thereof comprising administering a therapeutically effective amount of at least one
`
`proton pump inhibitor and, optionally, at least one antibiotic.
`
`6.
`
`The method of claim 5, wherein the antibiotic is selected from the group
`
`25
`
`comprising of amoxicillin, amoxicillin and clavulanate potassium, cefpodoxime
`
`proxetil, ceftriaxone, cefuroxime, and trimethoprirn!sulfamethoxazole.
`
`7.
`
`A method for treating or preventing bruxism in a patient in need thereof
`
`comprising administering a therapeutically effective amount of at least one proton
`
`pump inhibitor.
`
`30
`
`8.
`
`A method for treating or preventing gastroesophageal reflux in a patient
`
`comprising administering a therapeutically effective amount of at least one proton
`
`pump inhibitor prior to anesthesia.
`
`24
`
`

`
`wo 2005/074536
`
`PCT IUS2005/00267 4
`
`9.
`
`The method of claim 8, wherein the proton pump inhibitor is
`
`administered before surgery when the patient is anesthetized.
`
`10.
`
`The method of claim 8, wherein the proton pump inhibitor is
`
`administered during surgery when the patient is anesthetized.
`
`5
`
`11.
`
`The method of claim 8, wherein the proton pump inhibitor is
`
`administered after surgery when the patient is anesthetized.
`
`12.
`
`A method for treating or preventing motion sickness in a patient in need
`
`thereof comprising administering a therapeutically effective amount of at least one
`
`proton pump inhibitor and, optionally, at least one motion sickness drug~
`
`10
`
`13.
`
`The method of claim 12, wherein the motion sickness drug is selected
`
`from the group comprising of scopolamine, promethazine hydrochloride,
`
`dimenhydrinate, diphenhydramine, cyclizine, buclizine, and meclizine.
`
`14.
`
`A method for treating or preventing migraines in a patient in need
`
`thereof comprising administering a therapeutically effective amount of at least one
`
`15
`
`proton pump 1nhibitor and at least one migraine drug selected from the group consisting
`
`of diclofenac, celecoxib, rofecoxib, and valdecoxib.
`
`15.
`
`A method for treating or preventing tooth decay caused by emesis in a
`
`patient in need thereof comprising administering a therapeutically effective amount of
`
`at least one proton pump inhibitor.
`
`20
`
`16.
`
`A method for treating gastroesophageal reflux disease in an infant in
`
`need thereof comprising administering a therapeutically effective amount of at least one
`
`proton pump inhibitor to the infant by iontophoresis.
`
`17.
`
`A method for treating or preventing exercise-induced gastroesophageal
`
`reflux disease in a patient in need thereof comprising administering a therapeutically
`
`25
`
`effective amount of at least one proton pump inhibitor.
`
`25
`
`

`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`Intemational Bureau
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`( 43) International Publication Date
`18 August 2005 (18.08.2005)
`
`PCT
`
`(10) International Publication Number
`WO 2005/074536 A3
`
`(51) International Patent Classification7 :
`311435
`
`A61K 31/415,
`
`(21) International Application Number:
`PCT IUS2005/00267 4
`
`(22) International Filing Date: 31 January 2005 (31.01.2005)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/539,981
`
`30 January 2004 (30.01.2004) US
`
`(71) Applicant (jor all designated States except US): EISAI
`CO., LTD. [JP/JP]; Koishikawa4-6-10, Bunkyo-ku, Tokyo
`112-8088 (JP).
`
`(72) Inventor; and
`(75) Inventor/Applicant (jor US only): IENI, John [US/US];
`253 Ridgewood Avenue, Glen Ridge, NJ 07028 (US).
`
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`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, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ,
`TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA,
`ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO,
`SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`(74) Agents: GRIEFF, Edward, D. et al.; Wilmer Cutler
`Pickering Hale and Dorr LLP, 1455 Pennsylvania Avenue,
`N.W., Washington, DC 20004 (US).
`
`(88) Date of publication of the international search report:
`29 December 2005
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`iiiiiiiiiiiiiii
`
`----iiiiiiiiiiiiiii
`iiiiiiiiiiiiiii ---iiiiiiiiiiiiiii ---
`iiiiiiiiiiiiiii ----iiiiiiiiiiiiiii
`iiiiiiiiiiiiiii ----
`
`\0
`~ an
`~ r-
`0
`~ --------------------------------------------------------------------------------------------------
`~ (54) Title: COMPOSITIONS AND METHODS USING PROTON PUMP INHIBITORS
`0
`M
`0 ear infections, bruxism, motion, sickness, tooth decay due to emesis and other disorders by administering to a patient a therapeutically
`
`(57) Abstract: The invention provides methods for treating and preventing cystic fibrosis, radiation therapy-induced emesis, chronic
`
`:;;;...,. effective amount of at least one proton pump inhibitor. In other embodiments, the proton pump inhibitor can be administered with
`~ one or more cystic fibrosis drugs, motion sickness drugs, antibiotics, NSAIDs, and migraine drugs.
`
`

`
`INTERNATIONAL SEARCH REPORT
`
`International application No.
`
`PCT/US05/02674
`
`A
`
`CLASSIFICATION OF SUBJECT MATTER
`: A61K 31/415, 435
`IPC(7)
`514/277, 396
`USCL
`According to International Patent Classification OPC) or to both national classification and IPC
`B.
`FIElDS SEARCHED
`
`Minimum documentation searched (classification system followed by classification symbols)
`u.s. : 514/277, 396
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
`
`c.
`OOCUM:ENTS CONSIDERED TO BE RELEVANT
`Category*
`Citation of document, with indication, where appropriate, of the relevant passages
`X
`US 6,649,629 B2 (BANDARAGE et al.) 18 November 2003 (18.11.2003), abstract, column
`3, lines 43-65, column 57, lines 16-25, lines 53-65, column 58, lines 28-43).
`US 6,544,556 B 1 (CHEN et al.) 08 April 2003 (08.04.2003), abstract, column 5, lines 58-
`65, column 7, lines 9-11, column 3)
`-
`
`X
`
`Relevant to claim No.
`1-17
`
`1-17
`
`0 Further documents are listed in the continuation ofBox C. D
`.
`..,...
`
`Special categories of cited docummts:
`
`~A" document defmingthe general state of tho art which is not considered to be of
`particular relevance
`
`earlier application or patent published on or after the international ftling date
`
`doCWlliOill which may throw doubts on priority clairr(s) or which is cited to
`establish the publication date of another citation or other special reason (as
`specified)
`
`doC"U~T~ent referring to an oral disclosure~ use, exhibition or other means
`
`"X'
`
`"Y"
`
`"E"
`
`"L"
`
`"0"
`
`"P"
`
`See patent fumily annex.
`lator document published aft or tho international flling elate or priority
`date and not in conflict with tho application but cited to understand the
`principle or theory underlying the invention
`
`. document of particular relevance; the claiired invention cannot be
`considered novel or cannot be considered to involve an inventive step
`when the document is taken alone
`
`document of particular relevance; the claimed invention cannot be
`conaidered to involve an inventiw step when the document is combined
`with one or IIDre other such documents, such combination being
`obvious to a person skilled in the art
`
`document publmhed prior to the international filing date but later than the
`priority date claimed
`
`"&"
`
`docurrent m:rd>er of the same patent family
`
`Date of the actual completion of the international searcl-
`
`22 September 2005 (22.09.2005)
`Name and mailing address of the IS A/US
`Mail Stop PCT, Attn: JSAIUS
`Connnissioner for Patents
`P.O. Box 1450
`Alexandria, Vitginia 22313-1450
`Facsimile No. (703) 305-3230
`Form PCT/ISN210 (second sheet) (April2005)
`
`Date~: tifftlovn?n~t::al search report
`r... ~ IJJ.IJL. .Lt ... A. f;
`
`~~zed officer
`'
`(
`;
`ivasan Padrnanabhan
`
`Telephone No. 703-308-1235
`
`

`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`Intemational Bureau
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`( 43) International Publication Date
`18 August 2005 (18.08.2005)
`
`PCT
`
`(10) International Publication Number
`WO 2005/074930 Al
`
`(51) International Patent Classification7 : A61K 31/4439,
`31100, A61P 1/04
`
`(21) International Application Number:
`PCT/EP2005/050335
`
`(22) International Filing Date: 27 January 2005 (27 .0 1.2005)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`zw.
`
`(84) Designated States (unless othe1wise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO,
`SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
`
`(30) Priority Data:
`04001755.0
`
`(71) Applicant (jor all designated States except US): ALTANA
`PHARMA AG [DE/DE]; Byk-Gulden-Str. 2, 78467 Kon(cid:173)
`stanz (DE).
`
`(72) Inventors;and
`(75) Inventors/Applicants (for US only): HUBER, Rein(cid:173)
`hard [DE/DE]; Oehmdwiesenweg 10, 78476 Allensbach
`(DE). KOHL, Bernhard [DE/DE]; Zum Bruehl 9,
`78465 Konstanz (DE). KROMER, Wolfgang [DE/DE];
`Hinterhauserstr. 5, 78464 Konstanz (DE). SIMON, Wolf(cid:173)
`gang-Alexander [DE/DE]; Schubertstrasse 17, 78464
`Konstanz (DE).
`
`(74) Agents: WOLF, Ulrich et al.; c/o ALTANA Pharma AG,
`Byk-Gulden-Str. 2, 78467 Konstanz (DE).
`
`28 January 2004 (28.01.2004) EP Declarations under Rule 4.17:
`as to applicant's entitlement to apply for and be granted
`a patent (Rule 4.17(ii))for the following designations AE,
`AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ,
`CA, CH, CN, CO, CR, CU, CZ. DE, DK, DM, DZ, EC, EE,
`EG, ES, Fl, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS,
`JP; KE, KG, KP; KR, KZ, LC, LK, LR, LS, LT, LV, LV, MA,
`MD, MG, MK, MN, MW, MX, MZ. NA, Nl, NO, NZ, OM,
`PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY,
`TJ, TM, TN, TR, TT, IZ, VA, UG, UZ, VC, VN, YU, Z4,
`ZM, ZW, ARIPO patent (BW, GH, GM, KE, LS, MW, MZ,
`NA, SD, SL, SZ, IZ, UG, ZM, ZW). Eurasian patent (AM,
`AZ, BY, KG, KZ, MD, RU, TJ. TM), European patent (AT,
`BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl, FR. GB, GR.
`HU, IE, IS, IT, LT, LV, MC, NL, PL, PT, RO, SE, Sf, SK,
`TR). OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GQ.
`GW, ML, MR, NE. SN, TD, TG)
`ofinventorship (Rule 4.17(iv))for US only
`
`--
`----
`iiiiiiiiiiiiiii ----iiiiiiiiiiiiiii
`iiiiiiiiiiiiiii ----
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, 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,
`
`Published:
`with international search report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`0
`~
`0'\
`~ r-
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`0 --l£1
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`o
`M
`(54) Title: PHARMACEUTICAL COMBINATIONS OF (S) -PANTOPRAZOLE WITH NSAID OR CORTICOSTEROIDS
`~ (57) Abstract: The present invention relates to new combinations and new use of (S)-pantoprazole and/or its salts in the prevention
`
`~ or treatment of medicament caused gastrointestinal diseases.
`
`

`
`wo 2005/074930
`
`PCT /EP2005/050335
`
`PHARMACEUTICAL COMBINATIONS OF
`
`(S}-PANTOPRAZOLE WITH NSAID OR CORTICOSTEROIDS
`
`1
`
`Field of application of the invention
`
`The invention relates to the new use of (S)-pantoprazole and its salts in the prevention or treatment of
`medicament caused gastrointestinal diseases andfor medicament associated gastrointestinal disorders
`and to new use of (S)-pantoprazole and its salts in combination therapy, and to new combinations
`comprising (S)-pantoprazole and its salts.
`
`Known technical background
`
`In U. S. Patent 6,544,556 pharmaceutical formulations containing a non-steroidal anti-inflammatory
`drug (NSAID) and a proton pump inhibitor are disclosed. - In European Patent Application 1 352 660
`oral pharmaceutical dosage forms comprising a proton pump inhibitor and an NSAJD are described
`and claimed. - U. S. Patent Application 20031069255 is directed to drug dosage forms that release an
`agent that raises the pH of a patient's gastrointestinal tract, for example a proton pump inhibitor, fol(cid:173)
`lowed by an NSAID. - International Patent Application WO 03/075884 provides effervescent composi(cid:173)
`tion comprising a bisphosphonate, an acidic compound, an alkaline effervescing component, and op(cid:173)
`tionally an anti-ulcer agent, such as a proton pump inhibitor, and methods of treating osteoporosis in a
`mammal using the effervescent compositions. - In U. S. Patent 5,888,535, according to the abstract of .
`said patent "methods and compositions are disclosed utilizing optically pure (-)-pantoprazole for the
`treatment of ulcers in humans while substantially reducing the concomitant liability of adverse effects
`associated with the racemic mixture of pantoprazole." -In U.S. Patent 6,410,569 the dihydrate of the
`magnesium salt of pantoprazole is disclosed.
`
`~p
`
`~0
`
`Description of the invention
`
`It has now b~en found that (S)-pantoprazole and its salts, which are described in grea~er detail below,
`have, as a first aspect (aspect 1) of the present invention, advantageous gastro-protective action
`against certain medicaments (such as, for example, those medicaments mentioned below in the de(cid:173)
`scription of this invention, especially antiinflammatoriies and anti rheumatics, andfor, in particular,
`those medicaments which cause erosive changes and/or lesions in the gastrointestinal system) andfor
`are well useful and effective in prevention or treatment of gastrointestinal disorders associated with
`certain medicaments indicated below and/or are particularly useful and effective in prevention or
`treatment of gastrointestinal diseases caused by certain medicaments selected from the group consist(cid:173)
`ing of NSAIDs (non-steroidal antiinflammatory drugs), COX-2 (cyclooxygenase 2) inhibitors, NO(cid:173)
`NSAIDs (nitric oxide r