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`Table 4: Mean values for parameters according to Example 1 in Table 1.
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`0.001 (4)
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`0.12 (3)
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`5 (3)
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`Weight (g/dosage film)
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`Thickness (mil)
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`Dissolving time (sec)
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`Examples 4 — 8: Hydropropylmethylcellulose based Quick dissolving intraoral film
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`The films were prepared according to Examples 1 - 3. Therapeutic agents were
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`added to the homogeneous mixture (coating solution) prior to forming the film.
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`Dr. Reddyvs _ EXI004
`SUBSTITUTE SHEET (RULE 26)
`Page 422
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`Table 5:
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`solution)
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`Composition (coating
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`w m----
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`m----
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`WO 00/42992
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`Table 6: Properties of the film fomned according to the formulation in Table 5
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`SUBSTITUTE SHEET (RULE 26)
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`PCT/US99/31327
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`Table 7: Compostion of the Sildenafil film (%wet base)
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`Table 8: PrOperties of the film formed according to the formulation in Table 7
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`20
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`Example 9: A comgarison of progenies of dosage units using different
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`SUBSTITUTE SHEET (RULE 26)
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`WO 00/42992
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`PCT/US99/31327
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`hydroxvpropylmethvlcellulose polvmers
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`The properties of a dosage unit according to the invention may be modified by
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`varying individual components. For example. the dissolution of the film may be
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`prolonged by using hydroxypropylmethylcellulose (HPMC) with higher molecular
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`weight as shown below in Table 9.
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`Table 9212 Properties of selected commercial hydroxypropylmethylcellulose polymers.
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`iscosity 2%
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`2—4
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`* Each value is the mean SiD, n=6
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`EEEEEH
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`225:832::oBEEEEEEEEEEoBtE9%:AoEmem9$6.883335WEEgo3:535H59359
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`33.3303553035
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`8qu5:533:65
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`AZV8:235.33‘
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`2%:59.2;265%
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`SUBSTITUTE SHEET (RULE 26)
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`WO 00/42992
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`Example 10: Enhancement of mucoadhesion
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`The enhancement of mucoadhesion was similarly applicable to films of varying
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`copolymer°
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`Example 1
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`Example 10a
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`Example 10b
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`100%
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`0 Starch graft copolymers were prepared by polymerization in water using 1:3 Amioca
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`corn starch: acrylic acid (supplied by NSCC) and are described in further detail in US
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`Patent 4,690,996 and Block and Graft Copolymerization, vol 1, R.J.Ceresa, ed. John
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`Wiley and Sons 1973 both references herein incorporated by reference.
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`-- Mucoadhesion was tested using a tensile instrument (e.g. Texture Analyzer) which
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`measures force of detachment of the invention product from a simulated mucosal tissue
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`material. The mucosal—like material is prepared from a mixture of 3.25% gellan gum and
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`1.6% mucin in water. The product to be tested was brought into contact with the
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`simulated mucosal surface for 5 seconds and detached. The force of detachment was
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`measured as the value of mucoadhesion in grams force (g or gf). Test conditions used are
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`as follows: speed of application=3mm/s, speed of detachment=2mm/s, force applied
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`before detachment=150g, contact time=55, contact surface =122.7mm2
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`-26-
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`SUBSTITUTE SHEET (RULE 26)
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`dosage unit are described in Table 8.
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`A two way crossover study was conducted comparing intraoral sildenafil.
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`from the dissolving film is about 25% higher than the bioavailability of the tablet.
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`Table 11: A com arison of harmacokinetic arameters of Sildanedil film and Viagra
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`Statistical
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`Viagra (V) film Ratio
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`AUC
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`0775
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`(infinity)
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`* Area under the curve
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`WO 00/42992
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`PCT/US99/31327
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`(a)
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`combining, in any order, in a vessel having a heating source and a
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`and xylitol, and at least one reagent selected from the group consisting of
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`preservative, a permeation enhancer, a stabilizer, and a buffering agent;
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`mixing the combined ingredients during and after the addition of
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`forming the mixture into a film.
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`10
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`62.
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`A method according to claim 61, wherein the ratio of sildenafil to xylitol
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`63.
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`A method according to claim 61, wherein the water solubility of
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`sildenafil is at least 20 mg/ml.
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`64.
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`A method according to claim 63, wherein the water solubility of
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`A dosage unit, comprising: an effective dose of sildenafil citrate; the
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`sildenafil citrate being formed in a solid dispersion with a water soluble inert filler, the
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`solid dispersion being mixed with film forming reagents including a hydropolymer so as
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`to form a film, the film being capable of dissolving on a mucosal surface so as to release
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`25
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`105456
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`-36-
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`SUBSTITUTE SHEET (RULE 26)
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`WO 00/42992
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`1/6
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`UPPER UP 1
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`.N
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`u.‘~u'.g0 Q‘ s: '-._ ~s
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`(HNGNA 2
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`HARD PAUHE 3
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`SUBUNGUAL 6
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`CHEEK 4
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`LOWER UP 7
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`FIG.1
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`SUBSTITUTE SHEET (RULE 26)
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`._<~_o<~=z_025.585550
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`3mmoo=2:
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`No:
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`25mmoz_v_o<m
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`1:?84m0258
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`a3.3858mmuzxog
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`oz_>._omm_o550
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`EBMEE fl3:.5252.
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`SUBSTITUTE SHEET (RULE 26)
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`1:;55“V255
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`ZEdam—zoo205%?
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`Page 440
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`/Wxww
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`”’_._:::::___=_:=...
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`2n=Em3:8.5285;
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`m.o_.._
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`w.EmzmmmaMat.20
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`392052.5
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`2xenon.3.5mEm:
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`SUBSTITUTE SHEET (RULE 26)
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` (cid:9)
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`atn_<zm$23.28
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`cm3:~89502m
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`om2Emmoo“.3025
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`4/6
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`c—
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`vas525.5
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`m ¢N
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`m2:295.535IOI
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` #6:
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`us:285.8265IOI
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`SUBSTITUTE SHEET (RULE 26)
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`Page 442
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`Page 444
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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`(19) World Intellectual Property Organization
`International Bureau
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`(43) International Publication Date
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`27 September 2001 (27.09.2001)
`
` |||||||||||l|l||||l|||||l||||||l|ll||||||l||l|l|||||l||l||l|||||||l|||l||||l||||
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`(10) International Publication Number
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`WO 01/70194 A1
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`(74) Agents: FEDERMAN, Evan, J.; Warner-Lambert Com-
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`pany, 201 Tabor Road, Morris Plains, NJ 07950 et al. (US).
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`(81) Designated States (national): AE, AG, AL, AU, BA, BB,
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`BG, BR, BZ, CA, CN, CR, CU, CZ, DM, DZ, EE, GD9 GE7
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`HR, HU, ID, IL, IN, IS, JP, KP, KR, LC, LK, LR, LT, LV,
`MA, MG, MK, MN, MX. MZ, NO, NZ, PL, R0, SG, SI,
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`(84) Designated States (regional): ARIPO patent (GH, GM,
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`patent (AM. AZ, BY’KG, KngD‘ RUELTMLEurOpean
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`t AT, BE, CH,CY, DE, DK, ES, Fl, FR, GB, GR, IE,
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`MC’ NL’ PT, SE, TR), OAPI patent (BF, BJ’ CE
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`CG, CL CM’ GA, GN, GW’ ML, MR, NE, SN, TD, TG)_
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`Published:
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`with international search report
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`For two-letter codes and other abbreviations, refer to the "Guid—
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`ance Notes on Codes and Abbreviations ” appearing at the begin-
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`ning ofeach regular issue of the PCT Gazette.
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`(51) International Patent Classification7: A61K 9/00, 9/20
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`(21) International Application Number:
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`PCT/USO 1/021 92
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`(22) International Filing Date: 23 January 2001 (23.01.2001)
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`(25) Flhng Language:
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`(30) P“°“ty Data:
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`US
`23 March 2000 (23.03.2000)
`09/535,005
`WARNER-LAMBERT
`COMPANY
`(71) Applicant:
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`Egggusy 201 Tabor Road, Moms Plains, NJ 07950
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`(72) Inventors: BESS, William, S.; 31 Greenwish Road, Edi—
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`son, NJ 08820 (US). KULKARNI, Neema; 16 Wilkeshire
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`Boulevard, Randolph, NJ 07869 (US). AMBIKE, Suhas,
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`H.; 73 Charcoal Drive, West Hill, Ontan'o MlC 3T9 (CA).
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`RAMSAY, Michael, Paul; 45 Sayor Drive, Ajax, Ontario
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`194A1
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`(57) Abstract: Physiologically acceptable films, including edible films, are disclosed. The films include a water soluble film-form-
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`o ing polymer, such as pullulan, and a taste masked pharrnaceutically active agent, such as dextromethorphan. The taste masking agent
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`g is preferably a sulfonated polymer ion exchange resin comprising polystyrene cross—linked with divinylbenzene, such as AMBER-
`LITE. Methods for producing the films are also disclosed.
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`Page 445
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`G (54) Title: FAST DISSOLVING ORALLY CONSUMABLE FILMS CONTAINING AN ION EXCHANGE RESIN AS A TASTE
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`MASKING AGENT
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