WORLD INTELLECTUAL PROPERTY ORGANIZATION
`Intemauonal Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(51) International Patent Classification 5 :
`
`
`WO 96/30022
`(11) International Publication Number:
`A1
`(43) International Publication Date:
`3 October 1996 (O3.10.96)
`
`
`
`
`
`
`
`
`A6lK 31/557, 31/52, 9/00, 31/355 31/40, 31/38,
`31/195, 31/19 // (A6lK 31/557 3 :52 31355)
`S/1611-I 31/52 31:40 31355) $3.611: 31/52
`1:33 31:35§) (A6lI( 31/52, 1:19s,31:355)
`(A61f( 31/52, 31:19, 31:3s5)
`
`
`PT, SE).
`(21) International Application Number:
`PCT/US96/01976
`(81) Designated States: AU, CA, JP, MX, European patent (AT,
`BE, CH, DE, DK, ES, FR. GB, GR, IE, IT, LU, MC, NL,
`
`
`(22) International Filing Date:
`14 February 1996 (14.02.96)
`
`
`
`
`
`
`(30) Priority Data:
`08/412,435
`
`29 March 1995 (29.03.95)
`
`US
`
`
`
`
`(71) Applicant: ALCON LABORATORIES, INC. [US/US]; 6201
`South Freeway, Fort Worth, TX 76134-2099 (US).
`
`
` (72) Inventors: DESAI, Suketu; 7401 Kingswood Drive, Fort
`
`
`
`Worth, TX 76133 (US). BAWA, Rajan; 6365 Hulen Bend
`Court #505, Fort Worth, TX 76132 (US).
`
`
`
` (74) Agents: YEAGER, Sally, S. et al.; Alcon Laboratories, lnc.,
`Patent Dept., Q-148, 6201 South Freeway, Fort Worth, TX
`76134-2099 (US).
`
` Published
`With international search report.
`
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(54) Title: TOPICAL OPHTHALMIC FORMULATIONS COMPRISING AN ACIDIC DRUG, VITAMIN E TPGS, BENZALKONIUM
`CHLORIDE AND CAFFEINE
`
`
`
`
` 0.1% Diclofenac, O.O1°/.1 BAC, 1.5% TPGS
`
`
`> S. aureus PET screen
`
`
`
`LogReduction
`
`
`
`0.75
`
` 1.25 ’
`
`% Caffeine
`
`(57) Abstract
`
`
`Stable, comfortable, preserved, topical, ophthalmic compositions of acid drugs and their use for treating inflammation of the eye
`are disclosed. The compositions contain an acidic drug (e.g. a NSAID, preferably diclofenac, or a prostaglandin), Vitamin E. TPGS,
`Benzalkonium chloride or homologues thereof and caffeine.
`
` -
`
`|PR2015—01099 |PR2015—01097 |PR2015—01100 |PF{2015-01105
`
`Lupin EX1175
`
`1
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`P
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`age
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`Page 1
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AM
`AT
`AU
`33
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`EE
`ES
`Fl
`FR
`GA
`
`Annenia
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d‘Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Gennany
`Denmark
`Estonia
`Spain
`Finland
`France
`Gabon
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`1-9111
`Kenya
`Kyrgystan
`Democratic People’s Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Liberia
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Vier Nam
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`Page 2
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`W0 96/30022
`
`PCT/US96/01976
`
`TOPICAL OPHTHALMIC FORMULATIONS COMPRISING AN ACIDIC DRUG.
`VITAMIN E TPGS, BEN ZALKONIUM CHLORIDE AND CAFFEINE
`
` n
`
`This application is directed to stable and comfortable preserved ophthalmic
`
`formulations containing an acidic drug.
`
`
`
`Carboxyl containing compounds, including most non-steroidal antiinflam-matory
`
`drugs (NSAIDS), are difficult to formulate into stable, preserved, comfortable, ophthalmic
`
`compositions. Acidic drugs with carboxyl groups are inherently irritating to the eye.
`
`In
`
`addition, the drugs tend to form insoluble complexes with quaternary ammonium
`
`preservatives, such as benzalkonium chloride (BAC). Many NSAIDS have been
`
`formulated with other than desirable preservatives (e.g. sorbic acid, thimerosol) because
`
`the compounds complex with desired preservatives, such as, quaternary ammonium
`
`compounds, particularly BAC.
`
`In addition, it has proved difficult to fonnulate carboxyl
`
`containing compounds that are comfortable when applied topically to the eye.
`
`There are ophthalmic products containing acidic drugs. Commonly, these drugs are
`
`NSAIDS containing acarboxyl group. Examples of these products are suprofen
`
`(Profenal®, Alcon Laboratories, Inc. which is preserved with thimerosol); diclofenac
`
`sodium (Voltaren Ophthalmic”, Ciba Vision Ophthalmics which is preserved with sorbic
`
`acid); flurbiprofen sodium (Ocufen®, Allergan Medical Optics which is preserved with
`
`thimerosol); and ketorolac tromethamine (Acular®, Allergan, Inc. which is preserved with
`
`BAC and Octoxynol 40).
`
`U. S. Patent No. 5,110,493 discloses aqueous, ophthalmic, non-steroidal anti-
`
`inflarnmatory fonnulations which include a preservative system fonned of a quaternary
`
`ammonium compound and a nonionic surfactant which is an ethoxylated alkyl phenol,
`
`such as Octoxynol 10 or 40.
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`WO 96130022
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`PCTIUS96I0l976
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`W0 94/ 15597 discloses the use of lauralkonium chloride, a Cu homologue of
`
`BAC, which is compatible with acidic drug entities in ophthalmic formulations.
`
`U. S. Patent No. 4,960,799 discloses an ophthalmic formulation of a salt of ortho-
`
`(2,6-dichlorophenyl) aminophenylacetic acid, EDTA, a solubilizer, and a bacteriostat.
`
`EP 0,621,036-A1 discloses ophthalmic fonnulations of particular arginine amides
`
`and either cyclodextrin or caffeine. The application discloses that the use of cyclodextrin
`
`or caffeine improves the arginine amide solubility in water and that the caffeine can
`
`stabilize the compound in water.
`
`U. S. Patent No. 4,559,343 discloses ophthalmic formulations containing NSAIDS
`
`and a xanthine derivative to reduce ocular discomfort.
`
`The compositions of the present invention are stable, yet they contain an acidic
`
`drug and the desired preservative, BAC, or mixtures of at least two homologues of BAC.
`
`In addition, the compositions are comfortable upon topical instillation in the eye.
`
`S.mnnnry_Q£1h9_lny_enlinn
`
`The present invention is directed to stable, comfortable, and preserved topical
`
`ophthalmic formulations comprising an acidic drug, Vitamin E Tocopherol Polyethylene
`
`Glycol 1000 Succinate (TPGS) (Eastman Chemical Co., Kingsport, TN), BAC, or mixtures
`
`of at least two homologues of BAC, and caffeine. Types of acidic drugs can include
`
`NSAIDS, antibacterials, diagnostic agents, antiinfective agents, and prostaglandins.
`
`Methods for the compositions‘ use are also disclosed.
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`WO 96/30022
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`PCT/US96/01976
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`Em .. ND.
`
`F_igu[e_1 shows the effect of caffeine concentration on the preservative efficacy of
`
`BAC.
`
`
`
`The compositions of the present invention comprise an acidic drug, Vitamin E
`
`TPGS, BAC, or mixtures of BAC homologues, such as C12 and CM and caffeine. As used
`
`herein the term "acidic" means the drug contains a carboxyl moeity or a salt thereof and/or
`
`a sulfamide group or a salt thereof.
`
`Acidic drugs which can be formulated according to the present invention include
`
`NSAIDS, including, but not limited to, diclofenac, bromfenac, flurbiprofen, naproxen,
`
`ketorolac, suprofen, ibuprofen, and tolmetin, including their pharmaceutically acceptable
`
`salts, esters, and prodrugs; prostaglandins; antibacterial and antiinfective agents; and
`
`diagnostic agents. BAC is used to preserve the formulations. The Vitamin E TPGS is
`
`used to solubilize the acidic drug and reduce ocular discomfort in aqueous conditions.
`
`The caffeine is added to reduce ocular discomfort, but surprisingly, it was found that it
`
`acts synergistically with Vitamin E TPGS to reduce discomfort and it also potentiates the
`
`preservative eflicacy of BAC.
`
`In the formulations, the acidic drug is present at concentrations from 0.001 weight
`
`percent (wt. %) to 2.5 wt. %, preferably 0.01 to 1.0 wt. %. The Vitamin E TPGS
`
`concentration is 0.0001 to 30 wt. %, preferably 0.01 to 10 wt. %. BAC or its homologue
`
`mixtures are present at concentrations from 0.00001 to 0.02 wt. %, preferably .0001 to
`
`0.01 wt. %; and the caffeine concentration is from 0.001 to 5.0 wt. %, preferably 0.01 to
`
`1.0 wt. %.
`
`The compositions of the invention may also contain other components such as, but
`
`not limited to, those listed below:
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`WO 96/30022
`
`PCT/US96I0l976
`
`1.
`
`Buffers (e.g., phosphate, borate, citrate, acetate, carbonate, borate-polyol
`
`complexes, etc.);
`
`Tonicity agents (e.g. mannitol, sodium chloride, xylitol, etc.)
`
`Viscosity building agents, e.g., carboxylic polymers like Carbopol®
`
`(carbomers), Noveon® (polycarbophils), etc.; cellulose derivatives
`
`including alkyl and hydroxyalkyl cellulose like methylcellulose,
`
`hydroxypropyleellulose, carboxymethylcellulose, etc.; gums like locust
`
`beam, xanthan, agarose, karaya, guar, etc.; and other polymers including
`
`but not limited to polyvinyl alcohol, polyvinyl pyrollidone, polyethylene
`
`glycol, Pluror1ic® (Poloxamers),
`
`tragacanth, and hyaluronic acid.
`
`Phase-transition polymers for providing sustained and controlled delivery of
`
`enclosed medicaments to the eye (e.g., alginic acid, carrageenans (e.g.,
`
`Eucheuma), xanthan and locust bean gum mixtures, pectins, cellulose
`
`acetate phthalate, alkylhydroxyalkyl cellulose and derivatives thereof,
`
`hydroxyalkylated polyacrylic acids and derivatives thereof, poloxamers and
`
`their derivatives, etc. The phase-transition in these polymers can be
`
`mediated by changes in environmental factors such as ionic strength, pH,
`
`or temperature alone or in combination with other factors.
`
`Other excipients include but are not limited to: antioxidants (ascorbic acid,
`
`sodium metabisulfite, etc.), oomplexing agents (cyclodextrins and
`
`derivatives thereof), drug carriers or drug-laden ion exchange carriers, such
`
`as, Amberlite® and Duolite®, and some chelating agents.
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`WO 96/30022
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`PCT/US96/01976
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`The ophthalmic compositions can be administered topically to the eye as
`
`suspensions, emulsions, ointments, gels, or solutions. The compositions may be aqueous
`
`or nonaqueous, but are preferably aqueous. The compositions may have the drugs
`
`incorporated and/or encapsulated in microcapsules, nanocapsules, nanoparticles, or
`
`liposomes which are dispersed in an aqueous or nonaqueous medium.
`
`The preferred formulation of this invention comprises diclofenac sodium, as
`
`illustrated in Example 2.
`
`The following Examples are illustrative, but not limiting:
`
`Examples 1 and 2 are usefiil in treating ophthalmic inflammation. The
`
`formulations are administered 1-4 times daily according to the routine discretion of a
`
`skilled clinician.
`
`Examplel
`
`Ingredients
`
`'
`
`°
`
`/V
`
`NSAID
`HPMC
`Tromethamine
`Boric Acid
`Vit E TPGS
`Cafl°eine
`Mannitol
`Benzalkonium Chloride
`
`or its homologue mixtures
`Disodium EDTA
`HCl/NaOH
`Purified Water
`
`0.1 - 2.5
`0.05 - 1.0
`0.1 - 1.2
`0.01 - 1.0
`0.1 — 5.0
`0.01 - 2.0
`2.0 - 4.4
`
`0.005 - 0.01
`0.01 - 0.1
`q.s. to pH 7.4
`q.s. 100%
`
` :
`
`To a tared glass vessel containing purified water, fiist caffeine is added. The
`
`solution is stirred imtil the caffeine dissolves. Next, the rest of the ingredients are added
`
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`-5-
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`Page 7
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`Page 7
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`

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`W0 96I30022
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`PCT/US96I01976
`
`in the order given below and each ingredient is completely dissolved by stirring before the
`
`next one is added.
`
`NSAID
`
`Vitamin E TPGS
`
`Tromethamine
`
`Boric acid
`
`Disodium EDTA
`
`Benzalkonium chloride
`
`Mannitol
`
`HPMC
`
`The formulation is then brought to 95% of its final weight. The pH is adjusted to
`
`about 7-7.4 using NaOH or HCl. The final weight is adjusted to 100% with purified
`
`water. The formulation's tonicity is 300 mOsms.
`
`Emnlmel
`
`Ingredients
`
`C_Qn§entLa1is211_(°_/o_\>v/_W1
`
`Diclofenac Sodium
`HPMC
`Tromethamine
`Boric Acid
`Vit E TPGS
`Caffeine
`Mannitol
`Benzalkonium Chloride
`Disodium EDTA
`HCl/NaOH
`Purified Water
`
`0.1
`0.1
`1.2
`0.6
`2.0
`0.2
`4.2
`0.01
`0.1
`q.s. pH 7.4
`q.s. 100%
`
`Qonlzmnxlingjfimzqinmz
`
`A.
`
`E
`
`.
`
`‘Coin.
`
`.EIE3S
`
`I 1.
`
`Deionized water (70% of final weight of TPGS stock solution) was taken in a
`
`large beaker and brought to boiling with heat. The required quantity of Vitamin E TPGS
`
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`WO 96/30022
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`PCT/US96/01976
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`was added in small proportions under stirring. Final weight was adjusted to 100% with
`
`additional d.i. water after all of Vitamin E TPGS had gone in solution.
`
`
`
`containing deionized water which was 70% of final weight of HPMC stock solution. Final
`
`weight was adjusted to 100% with additional d.i. water afier all of the added HPMC had
`
`dissolved completely.
`
`
`
`0.2 g of cafi"eine was weighed in a tared vessel containing a stir bar and d.i.
`
`water which is 40% of final weight. Then 0.1 g of diclofenac, 20 g of 10% Vitamin E
`
`TPGS stock solution, 1.2 g of tromethamine, 0.6 g of boric acid, 0.1 g of disodium EDTA,
`
`0.01 g of BAC, 4.2 g of mannitol and 5 g of 2% HPMC stock solution were added
`
`sequentially. Weight was adjusted to 95% of final weight with d.i. water. Next, pH was
`
`measured and if necessary, it was adjusted to 7.4 with 0.1N NaOH or 0.1N HCI. Finally
`weight was adjusted to 100 g with additional d.i. water.
`
`10
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`

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`WO 96/30022
`
`PCT/US9610 1976
`
`Examples of other NSAII) and pmstaglandin formulations
`
`Formulation
`
`% weight by volume
`
`Ingredient
`
`A
`
`B
`
`C
`
`1)
`
`E
`
`F
`
`
`
`Caffeine
`
`0.2
`
`0.2
`
`Flurbiprofen
`Sodium
`
`Bromfenac
`
`0.03
`
`-
`
`0.2
`
`-
`
`0.2
`
`0.2
`
`-
`
`-
`
`-
`
`
`
`
`
`Prostaglandin
`(PG1-=4)
`
`Prostaglandin
`(PGFZU)
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`0.1
`
`-
`
`-
`
`0. 1
`
`10% Vitamin E
`TPGS Stock Soln.
`
`20.0
`
`20.0
`
`15.0
`
`20.0
`
`25.0
`
`25.0
`
`
`
`
`tromethamine
`
`boric acid
`
`Disodium EDTA
`
`Benzalkonium
`
`Chloride (BAC)
`
`
`
`
`
`Page 10
`
`
`
`C12 and C14
`
`-
`
`-
`
`0.01
`
`-
`
`-
`
`0.01
`
`homologues of
`BAC (80:20)
`
`Mannitol
`
`2% HPMC Stock
`
`Soln.
`
`
`
`
`
`0.1N NaOH or
`
`0.1N HC1 to
`
`adjust pH
`
`Suprofen
`
`Suprofen
`
`-
`
`-
`
`-
`
`0-25
`
`-
`
`-
`
`
`
`
`
`
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`WO 96/30022
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`PCT/US96/01976
`
` :
`
`Formulations A-F are prepared by adding caffeine to a tared glass vessel containing
`
`deionized water. The solution is stirred until caffeine is dissolved. Next, the remaining
`
`ingredients are added sequentially as listed and after the previous ingredient has
`
`completely dissolved. The solution is then brought to 95% of final weight with water and
`
`the pH is adjusted to 7.4. The final weight is then made 100% with water.
`
`Ev_tmple_4
`
`A simplified preservative efficacy screen based on the United States Phamracopeia
`
`(USP) XXII, 1990 Antimicrobial Preservative Effectiveness standards was performed
`
`against Staphylococcus aureus for the compositions shown in the following table. The
`
`screen entailed challenging the formulations with the gram-positive bacteria, S. aureus, and
`
`sampling at 7 and 14 days. The initial preservative efficacy test for the formulations had
`
`indicated that the formulations had poor preservation only against S. aureus, whereas the
`
`fonnulations exhibited appropriate preservative efficacy according to USP against the other
`
`organisms such as gram—negative (Pseudomonas aeruginosa) and fungi (Aspergillus niger)
`
`at 7 and 14 days.
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`wo 96I30022
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`PCT/US96/01976
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`A
`
`0.0
`
`0.1
`
`0.2
`
`0.1
`
`C
`
`0.75
`
`0.1
`
`1.25
`
`0.1
`
`Formulation
`
`Ingredient
`
`Caffeine
`
`Diclofenac Sodium
`
`Vitamin E TPGS
`
`Tromethamine
`
`Boric acid
`
`Disodium EDTA
`
`BAC
`
`Mannitol
`
`HPMC
`
`
`
`
`
`
`NaOH or HCl, qs to
`adjust pH to
`
`
`
`Purified Water, qs to
`
`According to the USP preservative eflicacy standards for S. aureus, a formulation
`
`has to exhibit a minimum of 3.0 log reduction on day 14 and no increase in count between
`
`14 to 28 days. Figure 1 shows the results for the S. aureus screen for the fonnulations in
`
`the above table. The formulations had similar compositions except for the varying
`
`concentrations of caffeine fi'om 0.0% to 1.25%. As shown in Figure 1, the higher the
`
`caffeine concentration in the formulation the higher was the S. aureus log reduction value.
`
`The figure also shows that the required 3.0 log reduction is achieved by 7 days at higher
`
`caffeine concentration rather than on 14 days.
`
`The formulation of Example 2 above showed the S. aureus log reduction values of
`
`3.1 and 5.1 on days 7 and 14, respectively, when the S. aureus screen was performed.
`
`Thus, surprisingly caffeine was found to potentiate the preservative efficacy of
`
`BAC in the formulations of the invention.
`
`Page 12
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`WO 96/30022
`
`1r¥e_Qaim:
`
`PCT/US96I0l976
`
`1.
`
`A topical ophthalmic composition comprising an acidic drug, Vitamin E TPGS,
`
`BAC or mixtures of at least two homologues of BAC, and caffeine.
`
`2.
`
`The composition of Claim 1 having the following concentrations; 0.001 to 2.5 wt.
`
`% acidic drug; 0.0001 to 30 wt. % Vitamin E TPGS; 0.00001 to 0.02 wt. % BAC; and
`
`0.001 to 5.0 wt. % caffeine.
`
`3.
`
`The composition of Claim 2 wherein the acidic drug is selected from the group
`
`consisting of a NSAID and a prostaglandin.
`
`4.
`
`5.
`
`The composition of Claim 3 wherein the acid drug is a NSAID.
`
`The composition of Claim 4 wherein the NSAID is selected fiom the group
`
`consisting of diclofenac, bromfenac, flurbiprofen, naproxen, ketorolac, suprofen, ibuprofen,
`
`and tolmetin and their salts, esters, and prodrugs.
`
`6.
`
`7.
`
`The composition of Claim 5 wherein the NSAID is diclofenac.
`
`A topical ophthalmic composition comprising 0.01 to 2.5 wt. % NSAID, 0.0001 to
`
`30 wt. % Vitamin E TPGS, 0.00001 to 0.02 wt. % BAC or mixtures of at least two
`
`homologues of BAC, and 0.001 to 5.0 wt. % caffeine.
`
`8.
`
`The composition of Claim 7 wherein the NSAID is selected from the group
`
`consisting of diclofenac, bromfenac, flurbiprofen, naproxen, ketorolac, suprofen,
`
`ibuprofen, and tolmetin and their salts, esters, and prodrugs.
`
`9.
`
`The composition of Claim 8 wherein the NSAID is diclofenac.
`
`10.
`
`A method for treating inflammation of the eye, which comprises, applying the
`
`composition of Claim 7 to the inflammed eye.
`
`-11-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Page 13
`
`Page 13
`
`

`
`WO 96/30022
`
`PCT/U S96/01976
`
`11.
`
`The method of Claim 10 wherein the NSAID is diclofenac.
`
`12.
`
`A method for treating an eye with an acidic drug, which comprises, applying the
`
`composition of Claim 1 to the eye.
`
`Page 14
`
`Page 14
`
`

`
`WO 96/30022
`
`PCT/U S96/0 1976
`
`1/1
`
`_.2:9".
`
`
`
`men:33.o<m$8.:.u.2_£o_..._n$3
`
`
`
`
`
`cwflom._.m_mmzmgam.mA
`
`x>>NEx>>_,
`
`to
`
`ID V C‘? N 1- O
`
`uonanpaa 601
`
`SUBSTITUTE SHEET (RULE 26)
`
`3..3...N5c
`
`
`
`2__2.._.8..\..
`
`Page 15
`
`Page 15
`
`

`
`
`
`
`
`INTERNATIONAL SEARCH REPORT
`
`Int
`
`ional Application No
`
`
`
`PCT/US 96/01976
`
`
`
`
`
`LASSIFICATION OF SUBJECT MATTER
`
`6
`
`A61K31/40
`A61K31/355
`A61K9/00
`A61K31/52
`A61K31/557
`//(A61K31/557,31:52,
`A61K31/19
`A61K31/195
`A61K31/38
`31:355),(A61K31/52,31:40,31:355),(A61K31/52,31:38,31:355),
`According to lntemational Patent Clanficauon (IPC) or to both national clasification and IPC
`B. FIELDS SEARCHED
`
`Minimum documentation seardied (dasificauon system followed by dasificatiorn symbols)
`IPC 6
`A61K
`
`Documentation searched other than minimI.im documentation to the extent that such documents are included in the fields searched
`
`
`
`
`
`
`
`
` Electromc data base consulted during the international search (name of data base and, where practical. search terms used)
`
`see the whole document
`
`
`
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation of document. with indication, where appropriate, of the relevant pasages
`
`Relevant to claim No.
`
`W0,A,95 30420 (ALCON LAB INC) 16 November
`1995
`
`
`
`US,A,5 110 493 (CHERNG-CHYI ROGER F
`AL) 5 May 1992
`cited in the application
`see the whole document
`
`ET
`
`
`
`
`
`
`
`
`
`
`w0,A,94 15597 (ALLERGAN INC) 21 July 1994
`cited in the application
`see the whole document
`
`EP,A,0 163 924 (ROSHDY ISMAIL) 11 December
`1985
`see the whole docunent
`
`
`
`
`
` ../--
`
`
`
`Further documents are listed in the continuation of box C.
`
` - sped“ canon“ 0‘ cud dommems :
`
`‘T’
`
`Patent family members are listed in annex.
`later documait published alter the international tiling date
`or prionty date and not in conflict with the application but
`med ,0 mdemmd me P“-Mme or may mdmym‘ me
`mwnuon
`-x- docmnmt of Pun-cum. Mama; ,3,‘ dmmd m,,mu~°n
`cannot be oonadered novel or cannot 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 sud’: docu-
`iiienis. such combination being obvious to a person skilled
`in the art.
`‘
`'a.' document member of the same patent family
`Date of mailing of the inteijiauonal search report
`
`
`
`
`
`
`
`
`
`
`
`.
`
`
`
`
`
`
`
`
`
`.
`.
`.
`A document defining the general state ofthe art which is not
`considered to be of particular relevance
`‘E’ earlier docummt but published on or alter the international
`mm‘ ‘m‘
`‘L’ document which may throw douhtson priority da.ini(s) or
`"?h“'f" “ “W1 ‘° ““b“’h ‘M P“h"““°.“ "“‘ °f ‘"°'h“
`°"“°“ °" °‘h°‘ ’P““' "“°“ (3 ‘9°“fi°d)
`'0' document refernng to an oral disclosure. me, exliibition or
`other means
`
`‘P’ document published prior to the international filing date but
`later than the priority date claimed
`
` Date of the actual completion of the international search
`
`
`
`
`Name andinailin; addrss of die [SA
`
`
`European Patent Office, P.B. 58l3 Patentlaan 2
`
`Ni. - 2280 HV Rijswijk
`Tel. (+3l-70) 340-2040, TX. 31 651 epo n1.
` Stierman, B
`Fax: (+ 3|-70) 340-3016
`
`27 August 1996
`
`06.09.96
`
`Authorized officer
`
`Form PCT/ISAIZIII (sound sheet) (July I992)
`
`page 1 of 3
`
`Page16
`
`Page 16
`
`

`
`
`
`
`
`
`According to International Patent Classificauon (IPC) or to both nauonal claslftcauon and [PC
`B. FIELDS SEARCHED
`
`Mimmum documentation searched (elaslficauon system followed by clamfieauon symbols)
`
`Documentauon searched other than mlnrmum documentation to the extent that such documents are included In the fields searched
`
`Electrome data base consulted dunng the mternauonal search (name of data base and. where pracucal, search terrm used)
`
`
`
`
`
`
`Citation ofdocument. wlth nndlcauan, where appropriate, olthe relevantpasages
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`
`
`Y
`
`
`
`US,A,4 559 343 (HAN WESLEY N
`December 1985
`cited in the application
`see the whole document
`see example 1
`
`ET AL) 17
`
`STP PHARMA SCIENCES,
`vol. 3, no. 3, 1993,
`pages 266-270, XP002011711
`I. POPOVICI ET AL.:
`“Formulation et
`essais in vivo de collyres huileux
`d'indométacine“
`
`
`
`
`
`see the whole document
`
`../--
`
`
`
`
`
`
`
`
`
`
`
`E Patmt family manha-3 are listed in anne
`
`x.
`
`
`
`M Furtha documents are hand in the continuation of box C.
`’
`'al
`d
`:
`'1" later document pziished alterngle |nteux"rl::em:;lPlfiling dag:
`SP“: “awn” of flu documnu
`date
`not In co
`ICI vn
`Icauon ut
`.
`.
`.
`of Fmmy
`V
`V
`~
`‘A’ document definm; the general Itate ofthe art Much Is not
`
`gadnyonmknund me pnnaplc or meow mdeflym‘ me
`oonddered to be of parucular relevance
`-x- documm of pmjcum. "lama; mg dmmd mwmon
`‘E’ earlier douunent but published on or alter the mta-nauonal
`
`cannot be oonsldered novel or cannot be consdered to
`film; date
`Involve an invenuve step when the document Is taken alone
`‘L’ document which may throw doubts on priority claI'm(s) or
`
`‘Y’ document of parucular relevance‘, the claimed invention
`"""‘-" " “"4 '° “'*°“"' “* P“b“°“°." 9*" °' "‘°‘*'°"
`
`cannot be conndered to involve an Inventive step when the
`°""°" °' °""“' ‘P"“' "“°" (“ §’°°‘fi‘d)
`
`document IS eombmed with one or more other such docu-
`'0' document referring to an oral disclosure, me, exlubiuorl or
`ments. such oomhmauon hem; obvious to a person slnlled
`otha means
`
`"' '3“ *"-
`A
`'9' document published prior to the internauonal film; date but
`
`‘Jr.’ document manber of the same patent famrly
`later than the puonty date claimed
` Date of mallmg of the mternauonal search report
`Date of the actual completion of the lnternanonal search
`
`Authonzed officer
`
`page 2 of 3
`
`Page 17
`
`
`
`
`Nameandmathn;addrcsofthe[SA
`European Patent Office. !’.B. 5818 Patentlaan 2
`NL - 2280 HV Rusvlijk
`Tel. (+3!-70) 340-2040, Tx. ill 65] epo nl,
`Fax: (+ 3|-70) 340-3016
`
`
`
`
`Form PCT/ISA/2lII (wanna meet) (July I992)
`
`Page 17
`
`

`
`
`
`
`
`
`
`INTERNATIONAL SEARCH REPORT
`
`C.(ConunuaIion) DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation of document, Wllh indication, where appropnatc, of the relevant pnsages
`
`
`
`Int:
`
`om] Application No
`
`u T
`
`0 .
`
`. 1 0
`
`.
`
`
`
`Relevant to claim No.
`
`1
`
`-12
`
`1-12
`
`1-12
`
`DATABASE wPI
`week 9333
`
`Derwent Publications Ltd., London, GB;
`AN 93-262882
`XP002011713
`
`& R0,A,105 131 (INST MEDICINA FARM IASI)
`25 July 1992
`see abstract
`
`,
`
`
`
`INT. TECHNOL. PHARM./ 6TH,
`CONGR.
`vol. 4, 1992,
`pages 254-262, XP00201l712
`M.w. ADAMS:
`"d-Alpha tocopheryl
`polyethylene glycol 1000 succinate
`(Eastman Vitamin E TPGS) as an emulsifier
`and bioenhancer for drugs and lipophilic
`compounds"
`see the whole document
`
`w0,A,93 03720 (TREVITHICK JOHN R) 4 March
`1993
`see the whole document
`
`Form PCT/ISAIJHI (mnunuuuon of umml sheet) (July I992)
`
`* 1'
`
`page 3 of 3
`
`P39e13
`
`Page 18
`
`

`
`INTERNATIONAL SEARCH REPORT
`
`international appiicauon No.
`
`
`
`PCT/IJS96/OI976
`
`Box I Observations where certain claims were found unsca-chable {Continuation 0|‘ item I of first sheet)
`
`This international search report has not been established zr. rcs;;.'. ;.' :;:'.:.:r. c‘.:.;.'.‘.s ;.‘.-..:c: .-\rt:cle ‘.7(2)(a) for the following reasons:
`
`10"l2
`Claims Nos;
`because they relate to subject matter not required to be reached by this .-\utr.ority. namely:
`REMARK: Although claims 10-12 are directed to a method of treatment of the
`human/animal body,
`the search has been carried out and based on the alleged
`effects of the compound/composition.
`
`1.
`
`2.
`
`3.
`
`1-12
`ClairnsNos.:
`.L‘.:~.; .;;. r.:.t cc.-npiy with t;-.: prescribed requirements to such
`because they relate to parts of the inter.-.:.:ione. .>.;:;:'.'i.;:.;....-.
`an extent that no meaningful international search can bi: c::r:e<i out, specifically:
`Reason: Compounds are not sufficiently defined as “acidic drug”, “homologue
`s of BAC”,
`"NSAID", “a prostaglandin", ”prodrugs” etc. The search had to be
`limited to the substances explicitly mentioned ir the claims and in the ex
`amples and to the general
`inven-ive cznceot.
`Claims l\'os.:
`_
`because they are dependent claims and are not tira.tt..
`
`..-.
`
`.-...::: 'i,'.‘.
`
`.r .
`
`i.~.;.n-1 and Lhlrd sentences of Rule 6.4(a).
`
`Box ll Observations where unity of invention is iaciting iLonunuation oi‘ item 2 ol first sheet)
`
`This International Searching Authority i'-Ju.-.d multiple -n- €'1Il|"."S
`
`- '2-..s '..'lLZ."l='.‘(')'i2l
`
`.-.-i_rl.i:.=.'.~i~..
`
`:=.s fellows‘
`
`1. D As all required additional sea.rc':i fees wei: unit}. -..ic .~
`searchable claims.
`
`L..ulI\I\ll'.,
`
`.iiA) .ii.i..i'.at;-iii.—.i :C'n'..'C.'1 h.‘;urL covers all
`
`2.
`
`As all searchable claims could :e sea-.'c::-. wit.:: -. ::',:
`of any additional fee.
`
`1
`
`‘
`
`tzjvng ':..'l
`
`.ii.‘c‘iticn2.i {cc
`
`this Aiit.‘iori'.y did not lf‘.‘v'lLE payment
`
`= ::
`3. D As only some of the required additional tears": I" ::
`covers only those claims for wnicr. fees were ;....:. sp:;::;; 3..
`
`'.:;i'. :;
`;
`:..-.:i .~.
`.::
`
`.:.: ;.;_ . -.. 1. tnzs ‘.n'.L‘.'!'l3.llOn3l search report
`..
`
`i
`
`
`4. D No required additional search fees were '_‘rr.el:»' _:a:.‘ "
`restricted to the invention first mentioned in the c!:.:r:.::
`
`'
`"
`
`F as;
`
`.51: inter.-.auo.-izl search report is
`
`Remark on Protest
`
`‘Q *.-
`
`'. ..“T i
`
`-.1 :'.‘.’-.:‘t
`
`‘. fees were accompanied by the applicant’: protest
`
`.3
`
`V: 7- ::;s'. .=.::cnrn:~.-.'iit'd '9-.3 -.2.)/-nent oi‘ additional search fees.
`
`Form PCTIISAF210 (continuation of firs‘. sneet fl‘.
`
`i’.'i.i_ ’ '.
`
`BAE)()RflayuAh—-—-4
`
`Page 19
`
`Page 19
`
`

`
`INTERNATIONAL SEARCH REPORT
`lnformauon on patent [umly mernbas
`
`
`lmr
`loml Appliution No
`
`
`
`
`Patent document
`cited in search report
`
`Publication
`date
`
`Patent farnily
`member(s)
`
`
`
`PCT/US 96/01976
`
`Publication
`date
`
`
`
`
`
`N0-A-9530420
`16-11-95
`AU-B-
`2476295
`29-11-95
`
`0708646
`
`
`US-A-5110493
`05-05-92
`AU-B-
`2204288
`16-03-89
`CA-A-
`1328614
`19-04-94
`
`
`DE-A-
`3870111
`21-05-92
`EP-A-
`0306984
`15-03-89
`FI-B-
`94924
`15-08-95
`
`
`IE-B-
`60717
`10-08-94
`JP-A-
`1104023
`21-04-89
`
`
`JP-B-
`6096542
`30-11-94
`KR-B-
`9513754
`15-11-95
`
`KR-B-
`9513745
`15-11-95
`N0-B-
`175404
`04-07-94
`5414011
`09-05-95
`
`
`
`
`
`EP-A-0163924
`
`11-12-85
`
`DE-A-
`
`
`
`3416209
`3584909
`
`21-11-85
`30-01-92
`
`EP-A-
`JP-C-
`
`1217144
`0105635
`1846167
`59073520
`
`
`27-01-87
`18-04-84
`25-05-94
`25-04-84
`
`
`
`
`
`
`Form PCT/ISA/210 (paunl family Inncx) (July I992)
`
`Page20
`
`Page 20