WO 00/42992
`
`PCT/US99/31327
`
`Table 4: Mean values for parameters according to Example 1 in Table 1.
`
`Properties
`
`Weight (g/dosage film)
`
`Thickness (mil)
`
`5
`
`PH
`
`Density (g/cm2)
`
`% Water content
`
`Dry tack (g)
`
`Wet tack (g)
`
`10
`
`Tensile strength (psi)
`
`% Elongation
`
`Modulus (psi)
`
`Tear-propagation resistance (N)
`
`Disintegration time (sec)
`
`15
`
`Dissolving time (sec)
`
`Value
`
`±SD (n)
`
`0.028
`
`0.001 (4)
`
`2.1
`
`3.07
`
`0.12 (3)
`
`(1)
`
`1.0485
`
`0.009 (3)
`
`1.7
`
`0.674
`
`0.24 (2)
`
`0.110 (6)
`
`60.169
`
`11.680 (6)
`
`5242
`
`2.9
`
`266834
`
`0.02
`
`12
`
`41
`
`379 (5)
`
`0.4 (5)
`
`7910 (5)
`
`0.00 (4)
`
`1 (3)
`
`5 (3)
`
`Examples 4 - 8: Hydropropylmethvlcellulose based quick dissolving intraoral film
`containing therapeutic agents
`
`The films were prepared according to Examples 1 - 3. Therapeutic agents were
`
`20 (cid:9)
`
`added to the homogeneous mixture (coating solution) prior to forming the film.
`
`- 20 -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 422
`
`(cid:9)
`

`

`WO 00/42992
`
`Table 5:
`
`PCT/US99/31327
`
`Composition (coating
`
`Ex. 4
`
`Ex. 5
`
`Ex. 6
`
`Ex. 7
`
`Ex. 8
`
`solution)
`
`Nicotine
`
`5
`
`Hydromorphone
`
`Oxybutynin
`
`Estradiol
`
`Peppermint
`
`1.4
`
`2.92
`
`3.71
`
`1.0
`
`1.0
`
`1.0
`
`1.0
`
`1.49
`
`1.0
`
`Methocel E5(HPMC)
`
`21.06
`
`21.06
`
`21.06
`
`21.06
`
`21.06
`
`10
`
`Propylene glycol
`
`Aspartame
`
`Citric acid
`
`Cremphor EL40
`
`Benzoic acid
`
`15
`
`FD&C blue #1
`
`FD&C yellow #5
`
`Water
`
`1.0
`
`0.8
`
`0.7
`
`1.0
`
`1.0
`
`0.8
`
`0.7
`
`1.0
`
`1.01
`
`0.8
`
`0.7
`
`1.0
`
`1.0
`
`0.8
`
`0.7
`
`1.0
`
`1.0
`
`0.8
`
`0.7
`
`1.0
`
`0.013
`
`0.013
`
`0.013
`
`0.013
`
`0.013
`
`qs.
`
`qs.
`
`74.43
`
`73.03
`
`71.51
`
`70.72
`
`72.94
`
`20
`
`25
`
`- 21 -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 423
`
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`Table 6: Properties of the film formed according to the formulation in Table 5
`
`Properties
`
`Thickness (mil)
`
`Density (g/cm3)
`
`5
`
`Water content %
`
`Dry tack (g)
`
`Wet tack (g)
`
`Ex. 4
`
`Ex. 5
`
`Ex. 6
`
`Ex. 7
`
`Ex. 8
`
`3.0
`
`1.18
`
`1.8
`
`2.9
`
`1.19
`
`2.93
`
`2.9
`
`1.13
`
`2.42
`
`3.2
`
`1.20
`
`2.32
`
`2.7
`
`1.16
`
`2.31
`
`0.67
`
`0.608
`
`0.619
`
`1.215
`
`0.671
`
`49.08
`
`54.81
`
`84.34
`
`88.85
`
`39.91
`
`Tensile strength (psi)
`
`4393
`
`3373
`
`4138
`
`3549
`
`3688
`
`% Elongation (sec)
`
`8.3
`
`8.3
`
`7.6
`
`8.1
`
`7.5
`
`10
`
`Modulus (psi)
`
`45969
`
`48168
`
`42110
`
`41745
`
`53334
`
`Tear resistance (N)
`
`Disintegration (sec)
`
`Dissolving time (sec)
`
`0.03
`
`43.0
`
`73.7
`
`0.02
`
`34.3
`
`64.3
`
`0.01
`
`27.3
`
`58.0
`
`0.03
`
`36.0
`
`0.01
`
`55.7
`
`65.7
`
`111.3
`
`15
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 424
`
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`Table 7: Compostion of the Sildenafil film (%wet base)
`
`Composition
`
`Sildenafil citrate
`
`Xylitol
`
`5
`
`Methocel EIS
`
`Propylene Glycol
`
`Aspartame
`
`Benzoic acid
`
`peppermint oil
`
`10
`
`Sodium EDTA
`
`Polyoxamer L-44
`
`Water
`
`polypro 5000
`
`Percentage
`
`28.93
`
`3.21
`
`4.59
`
`3.67
`
`0.46
`
`0.0045
`
`0.46
`
`0.0045
`
`2.3
`
`55
`
`0.92
`
`15 (cid:9)
`
`Table 8: Properties of the film formed according to the formulation in Table 7
`
`20
`
`Properties
`
`Thickness
`
`Density (g/cm3)
`
`Dry tack (g)
`
`Wet tack (g)
`
`Tensile strength (psi)
`
`% Elongation
`
`Modulus (psi)
`
`Tear resistence (N)
`
`25
`
`Disintegration (sec)
`
`Dissolution (sec)
`
`Ex. 9
`
`3.2±0.1
`
`1.230
`
`1.21±0.19
`
`23 .79±3 .45
`
`421±49
`
`4.0±0.7
`
`31822±6137
`
`0.04±00
`
`8.3±1.5
`
`23.7±1.5
`
`Example 9: A comparison of properties of dosage units using different
`
`- 23 -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 425
`
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`hydroxvproovlmethyleellulose polymers
`
`The properties of a dosage unit according to the invention may be modified by
`
`varying individual components. For example, the dissolution of the film may be
`
`prolonged by using hydroxypropylmethylcellulose (HIPMC) with higher molecular
`
`5 (cid:9) weight as shown below in Table 9.
`
`Table 9a: Properties of selected commercial hydroxypropylmethylcellulose polymers.
`
`Property (cid:9)
`
`Methocel Type (Dow Pharmaceuticals)
`
`10
`
`% Methoxyl
`
`% Hydroxypropyl
`
`Viscosity 2%
`
`(cps)
`
`E3
`
`E5
`
`K3
`
`EIS
`
`A15
`
`E50
`
`F50
`
`29
`
`8.5
`
`2-4
`
`29
`
`8.5
`
`4-6
`
`22
`
`8.1
`
`29
`
`8.5
`
`30
`
`0
`
`29
`
`8.5
`
`28
`
`5.0
`
`2-4
`
`12-18
`
`12-18
`
`40-60
`
`40-60
`
`* Each value is the mean S±D, n=6
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 426
`
`(cid:9)
`

`

`Z66Z17/00 OM
`
`LZETE/66SIVIDd
`
`Table 9b: Properties of films prepared according to Example 1, using different hydroxypropylmethylcellulose polymers
`
`Property
`
`E3
`
`E5
`
`K3
`
`E15
`
`A15
`
`E50
`
`F50
`
`Dry tack (g)
`
`0.61±0.08
`
`0.67±0.110
`
`0.82±0.12
`
`0.66±0.09
`
`0.52±0.09
`
`0.68±0.14
`
`0.52±0.12
`
`Wet tack (g)
`
`93.4±8.95
`
`60.169±11.6
`
`60.2±8.77
`
`65.4±17.8
`
`18.4±3.0
`
`79.1±17.1
`
`64.1±11.2
`
`Tensile strength (psi)
`
`1921±442
`
`5242±379
`
`2043±268
`
`4316±384
`
`3351±165
`
`3725±123
`
`3905±590
`
`% Elongation
`
`4.2±1.2
`
`2.9±0.4
`
`3.8±0.8
`
`16.9±4.3
`
`11.1±2.4
`
`11.4±2.4
`
`15.0±3.4
`
`Modulus (psi)
`
`44368±864 266834±79 41737±816 46889±416 35914±964 41651±282 43644±942
`
`Tear resistance (N)
`
`(1040.01±
`
`0.02±0
`
`0.05±0.01
`
`0.09±0.03
`
`0.12±0.02
`
`0.05±0.01
`
`0.08±0.01
`
`Disintegration (sec)
`
`17.0±4.4
`
`12±1
`
`15.3±1.5
`
`21.9±1.6
`
`161.0±15.9
`
`33.2±5.1
`
`24.1±1.3
`
`Dissolution (sec)
`
`35.7±2.1
`
`41±5
`
`31.0±1.0
`
`51.6±1.3
`
`>600
`
`71.6±3.3
`
`62.1±2.8
`
`(9z alaw) iaaHs alniiisans
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 427
`
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`Example 10: Enhancement of mucoadhesion
`
`The enhancement of mucoadhesion was similarly applicable to films of varying
`
`thickness. The following formulations were prepared:
`
`Table 10
`
`5
`
`Composition/Test
`
`Example 1
`
`Example 10a
`
`Example 10b
`
`results
`
`Composition of
`
`100%
`
`99.9%
`
`example 1
`
`Starch graft
`
`0
`
`10
`
`copolymer•
`
`Mean
`
`17.5
`
`Mucoadhesion
`
`Measurement (g)••
`
`Standard deviation
`
`7.8
`
`15
`
`Increase in
`
`base value
`
`0.1%
`
`26.6
`
`4.7
`
`52%
`
`95%
`
`5%
`
`32.3
`
`4.0
`
`84.6%
`
`mucoadhesion %
`• Starch graft copolymers were prepared by polymerization in water using 1:3 Amioca
`
`corn starch: acrylic acid (supplied by NSCC) and are described in further detail in US
`
`Patent 4,690,996 and Block and Graft Copolymerization, vol 1, R.J.Ceresa, ed. John
`
`20 (cid:9) Wiley and Sons 1973 both references herein incorporated by reference.
`
`•• Mucoadhesion was tested using a tensile instrument (e.g. Texture Analyzer) which
`
`measures force of detachment of the invention product from a simulated mucosal tissue
`
`material. The mucosal-like material is prepared from a mixture of 3.25% gellan gum and
`
`1.6% mucin in water. The product to be tested was brought into contact with the
`
`25 (cid:9)
`
`simulated mucosal surface for 5 seconds and detached. The force of detachment was
`
`measured as the value of mucoadhesion in grams force (g or gf). Test conditions used are
`
`as follows: speed of application=3mm/s, speed of detachment=2mm/s, force applied
`
`before detachment=150g, contact time=5s, contact surface =122.7mm2
`
`- "-)6 -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 428
`
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`Example 11: Preparation of film using dry extrusion techniques
`
`77.8g Polyethylene Oxide (PolyoxOWSR N-10) was mixed using mechanical
`
`force and additional ingredients were added during the mixing as follows: 5.5g Estradiol,
`
`3.7g Peppermint, 3.7g Propylene Glycol, 3.0g Aspartame, 2.6g Citric Acid. 3.7g
`
`5 (cid:9) Cremphor EL 40 and 0.05g Benzoic acid.. The temperature was maintained at about
`
`70°C.
`
`The blend was allowed to mix at 70°C until uniform. It was then forced through
`
`an extrusion die to form a film 5 mils in thickness. The film was then cut into dosage
`
`forms ready for packaging.
`
`10
`
`Example 12: Human clinical acute irritation study
`
`An initial clinical irritation study of placebo samples formulated according to
`
`Example 1 was conducted. Six HPMC-based films were applied by each of 12 subjects
`
`within one hour. The site of application and the oral mucosae were evaluated for any
`
`15 (cid:9)
`
`acute irritation prior to each application, immediately after each application, one hour
`
`and 24 hours after last application. The following indications: erythema, edema, bullae,
`
`maceration and discharge were scored on a scale of 0-4. There was no measurable
`
`irritation for any of the sites examined and for any of the indications during each
`
`application, or one hour and 24 hours after the last application.
`
`20 (cid:9)
`
`Each subject was asked to assess the mouth feel, product taste, sensation and
`
`dissolution time for each application. All twelve subjects did not experience any sensation
`
`for any application. All subjects described films gave them very smooth mouth feel and
`
`indicated the taste of freshness the film delivered into the oral cavity for each application.
`
`All subjects felt the dissolution time of the film was very short (<2 min).
`
`25 (cid:9)
`
`The majority of the subjects stated a preference for the film compared with
`
`tablets or capsules. All of the subjects indicated that they preferred the film to solutions
`
`or syrups.
`
`Example 13: Human pharmacokinetics study showing increased bioavailabilitv of a
`active (cid:9)
`agent delivered by an dosage unit in the form of a film
`
`30 (cid:9)
`
`A dissolving film suitable for administration via the oral mucosa and containing the
`
`active agent, sildenafil citrate, formulated according to Table 7. The properties of the
`
`_ (cid:9)
`
`_
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 429
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`dosage unit are described in Table 8.
`
`A two way crossover study was conducted comparing intraoral sildenafil,
`
`applied sublingually, with a commercial tablet (Viagra®) at the same dosage. The
`
`average plasma levels and the pharmacokinetics analysis are displayed in Figure 6 and
`
`5 (cid:9)
`
`Table 11. Figure 6 and Table 11 show that the bioavailability of the equivalent dosage
`
`from the dissolving film is about 25% higher than the bioavailability of the tablet.
`
`Table 11: A comparison of pharmacokinetic parameters of Sildanedil film and Viagra
`
`film
`
`10
`
`Parameters
`
`Sildanefil (S) film Viagra (V) film Ratio
`
`AUC*(0-t)
`
`365.5
`
`AUC
`
`(infinity)
`
`Cmax
`
`15
`
`Tmax
`
`Ke
`
`378
`
`109.9
`
`1
`
`0.354
`
`1.99
`T
`* Area under the curve
`
`293.1
`
`310.4
`
`106.8
`
`1
`
`0.285
`
`2.56
`
`S/V
`
`1.247
`
`1.218
`
`1.029
`
`1
`
`1.245
`
`0.775
`
`Statistical
`power
`
`0.86
`
`0.88
`
`0.15
`
`0.08
`
`0.32
`
`0.23
`
`20
`
`25
`
`_ 78 _
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 430
`
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`What is claimed:
`
`1.
`
`A dosage unit, comprising: a water-soluble hydrocolloid, mucosal
`
`surface-
`
`coat-forming film, such film including an effective dose of an active agent.
`
`2.
`
`A dosage unit according to claim 1, wherein the film has a dry tack value
`
`10 (cid:9)
`
`of less than 3.5g.
`
`3.
`
`A dosage unit according to claim 1, wherein the film has a dry tack value
`
`of less than 2.0g.
`
`15 (cid:9)
`
`4. (cid:9)
`
`A dosage unit according to claim 1, wherein the film has a water content
`
`of 0.1%-10%.
`
`5. (cid:9)
`
`A dosage unit according to claim 4, wherein the film has a water content
`
`of less than 5%.
`
`20
`
`6.
`
`A dosage unit according to claim 1, wherein the film has a wet tack value
`
`of greater than 35g.
`
`7.
`
`A dosage unit according to claim 2, wherein the film has a wet tack value
`
`25 (cid:9)
`
`of greater than 35g.
`
`8.
`
`A dosage unit according to claim 1, where the hydrocolloid has a gelation
`
`temperature that is greater than 70°C for a 2% polymer solution.
`
`30 (cid:9)
`
`9. (cid:9)
`
`A dosage unit according to claim 1, wherein the hydrocolloid has a
`
`hydration rate in 24 hours of 5-20% at 75% humidity at room temperature.
`
`_ ',9 _
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 431
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`10.
`
`A dosage unit according to claim 1, wherein the hydrocolloid is present at
`
`a concentration in the range of 5%-99%.
`
`11.
`
`A dosage unit according to claim 1, wherein the hydrocolloid is a polymer
`
`5 (cid:9)
`
`selected from the group consisting of a natural, semi-natural and synthetic biopolymer.
`
`12.
`
`A dosage unit according to claim 11, wherein the hydrocolloid is selected
`
`from the group consisting of a polysaccharide and a polypeptide.
`
`10 (cid:9)
`
`13. (cid:9)
`
`A dosage unit according to claim 11, wherein the hydrocolloid is a
`
`hydroxypropylmethylcellulose polymer.
`
`14.
`
`A dosage unit according to claim 11, wherein the hydroxypropylmethyl-
`
`cellulose polymer has a molecular weight of less than 200,000.
`
`15
`
`15. A dosage unit according to claim 1, wherein the film further includes one
`
`or more of an emulsifier, a plasticizer, a taste modifying agent, a water soluble inert
`
`filler, a preservative, a coloring agent and a stabilizer.
`
`20 (cid:9)
`
`16. (cid:9)
`
`A dosage unit according to claim 15, wherein the emulsifier has a
`
`concentration in the range of 0.1 — 10 %w.
`
`17.
`
`A dosage unit according to claim 15, wherein the taste modifying agent
`
`consists of one or more of a sweetening agent, a flavoring agent and a taste masking
`
`25 agent.
`
`18.
`
`A dosage unit according to claim 1.5, wherein the film contains the water
`
`soluble inert filler has a concentration in the range of 0.5 to 50%.
`
`30 (cid:9)
`
`19. (cid:9)
`
`A dosage unit according to claim 15, wherein the preservative has a
`
`concentration in the range of 0.01 to 10%.
`
`- 30 -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 432
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 00/42992 (cid:9)
`
`PCT/US99/31327
`
`20.
`
`A dosage unit according to claim I wherein the active agent is present at a
`
`concentration in the range of 0.01 to 75%.
`
`21.
`
`A dosage unit according to claim 1, wherein the active agent is selected
`
`5 (cid:9)
`
`from the group consisting of a therapeutic agent, a dietary supplement and a hygiene aid.
`
`22.
`
`A dosage unit according to claim 21, wherein the therapeutic agent is
`
`sildenafil citrate.
`
`10 (cid:9)
`
`23. (cid:9)
`
`A dosage unit according to claim 21, wherein the therapeutic agent is
`
`selected from the group consisting of nicotine, hydromorphone, oxybutynine and
`
`estradiol.
`
`24.
`
`A dosage unit according to claim 1, wherein the film has a dry film
`
`15 (cid:9)
`
`thickness in the range of 1-20 mil.
`
`25.
`
`A dosage unit according to claim 24, wherein the film has a dry film
`
`thickness less than 10 mils.
`
`20 (cid:9)
`
`26. (cid:9)
`
`A dosage unit according to claim 1, wherein the film has a tensile strength
`
`greater than 1500psi.
`
`27. (cid:9)
`
`A dosage unit according to claim 1, wherein the film has a % elongation
`
`less than 20%.
`
`25
`
`28.
`
`A dosage unit according to claim 1, wherein the film disintegrates in a
`
`range from 1-300 seconds.
`
`29.
`
`A dosage unit according to claim 1, wherein the film has a modulus in a
`
`30 (cid:9)
`
`range from 35,000-300,000 psi.
`
`30.
`
`A dosage unit according to claim 1, wherein the film has a dissolving
`
`- 31 -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 433
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`time in a range from 10-600 seconds.
`
`31.
`
`A dosage unit according to claim 1, wherein the film has a tensile strength
`
`greater than 1,500 psi, a % elongation less than 20%, a disintegration time in a range
`
`5 (cid:9)
`
`from 1-300 seconds and a dissolution time in a range from 10-600 seconds.
`
`32.
`
`A dosage unit according to claim 1, wherein the film has an effective
`
`wettability profile in the absence of a mixture of two nonionic surfactants.
`
`10 (cid:9)
`
`33. (cid:9)
`
`A dosage unit according to claim 1, wherein the active agent is
`
`encapsulated within a polymer, wherein the polymer is chemically or physically distinct
`
`from the hydrocolloid, the encapsulated agent being dispersed within the film.
`
`34.
`
`A dosage unit according to claim 1, wherein the dosage unit comprises
`
`15 (cid:9) more than one active agent.
`
`35.
`
`A dosage unit according to claim 1, wherein the dosage unit further
`
`comprises a mucosal adhesion enhancer, the mucosal adhesion enhancer being located in
`
`the film.
`
`20
`
`36.
`
`A dosage unit according to claim 35, wherein the mucosal adhesion
`
`enhancer
`
`is a starch graft copolymer.
`
`25 (cid:9)
`
`37. (cid:9)
`
`A dosage unit according to claim 35, wherein the mucosal adhesion
`
`enhancer
`
`is present at 0%-50% by weight.
`
`38. (cid:9)
`
`A method of making a dosage unit suitable for mucosa] administration,
`
`30 comprising:
`
`- .3? -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 434
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`(a)
`
`dissolving a hydrocolloid in a solvent so as to form a substantially
`
`homogeneous preparation;
`
`(b)
`
`adding to the hydrocolloid preparation. an active agent and at least
`
`one reagent selected from the group consisting of an emulsifier, a
`
`5
`
`plasticizer, a taste modifier, a water soluble inert filler, a coloring agent, a
`
`preservative, a permeation enhancer, a stabilizer and a buffering agent to
`
`form a coatable or extrudable mixture; and
`
`c) (cid:9)
`
`forming a mucosal surface-coat forming film from the mixture for
`
`packaging as a dosage unit.
`
`10
`
`39. (cid:9)
`
`A method according to claim 38, wherein step (b) further comprises
`
`coating the mixture onto a backing film.
`
`40. (cid:9)
`
`A method of making a dosage unit suitable for mucosal administration,
`
`15 comprising:
`
`(a)
`
`combining, in any order, in a vessel having a heating source and a
`
`mechanical mixing device, a hydrocolloid, an active agent, and at least
`
`one reagent selected from the group consisting of an emulsifier, a
`
`plasticizer, a taste modifier, a water soluble inert filler, a coloring agent, a
`
`20 (cid:9)
`
`preservative, a permeation enhancer, a stabilizer, and a buffering agent;
`
`(b)
`
`mixing the combined ingredients during and after the addition of
`
`the ingredients to the vessel and applying an effective amount of heat for
`
`melting a substantial portion of the mixture; and
`
`(c)
`
`forming the mixture into a film.
`
`25
`
`41. (cid:9)
`
`A method according to claim 40, wherein step (b) further comprises
`
`coating or extruding the mixture onto a backing film.
`
`42. (cid:9)
`
`A method according to claim 40, wherein step (c) further comprises
`
`30 (cid:9)
`
`removing the flexible film from the backing film and die cutting the film to form the
`
`dissolving dosage unit.
`
`- 33 -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 435
`
`(cid:9)
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`43.
`
`A method for administering an active agent to a subject. comprising:
`
`(a) (cid:9)
`
`obtaining a water-soluble hydrocolloid, mucosal surface coat-
`
`forming- film, such film including an effective dose of an active agent:
`
`and
`
`(b) (cid:9)
`
`placing the film on a mucosal surface in the subject so as to
`
`release the active agent.
`
`44.
`
`A method according to claim 43, wherein the film has a dry tack value of
`
`less than 3.5g.
`
`45.
`
`A method according to claim 43, wherein the film has a water content of
`
`0.1%40%.
`
`5
`
`10
`
`46.
`
`A method according to claim 43, wherein the hydrocolloid has a
`
`15 (cid:9)
`
`hydration rate in 24 hours of 5-20% at 75% humidity at room temperature.
`
`47.
`
`A method according to claim 43, wherein the hydrocolloid is present at a
`
`concentration in the range of 5-99%.
`
`20
`
`48.
`
`A method according to claim 43, wherein the hydrocolloid is a
`
`hydroxypropylmethylcellulose polymer.
`
`49.
`
`A method according to claim 48, wherein the
`
`25 (cid:9)
`
`hydroxypropylmethylcellulose polymer has a molecular weight of less than 200,000.
`
`50.
`
`A method according to claim 43, wherein the hydrocolloid mixture
`
`further includes one or more of an emulsifier, a plasticizer, a taste modifying agent, a
`
`water soluble inert filler, a preservative, a coloring agent and a stabilizer.
`
`30
`
`51.
`
`A method according to claim 43, wherein the active agent is present at a
`
`concentration in the ranee of 0.01 to 75%.
`
`- 34 -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 436
`
`(cid:9)
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`52.
`
`A method according to claim 43, wherein the active agent is selected
`
`from the group consisting of a therapeutic agent, a dietary supplement and a hygiene aid.
`
`53.
`
`A method according to claim 52, wherein the therapeutic agent is
`
`5 (cid:9)
`
`sildenafil citrate.
`
`54.
`
`A method according to claim 52, wherein the therapeutic agent is
`
`selected from the group consisting of nicotine, hydromorphone, oxybutynine and
`
`estradiol.
`
`10
`
`55.
`
`A method according to claim 43, having a dry film thickness in the range
`
`of 1-20 mil.
`
`56.
`
`A dosage unit, comprising: a water soluble hydrocolloid and an effective
`
`15 (cid:9)
`
`dose of sildenafil citrate in a mucosal-surface contacting film.
`
`57.
`
`A dosage unit according to claim 56, wherein the sildenafil citrate forms
`
`a solid dispersion with xylitol.
`
`20 (cid:9)
`
`58. (cid:9)
`
`A method of treating erectile dysfunction; comprising:
`
`(a)
`
`obtaining a film including a solid dispersion of an effective dose
`
`of sildenafil and xylitol in a water soluble hydrocolloid; and
`
`(b)
`
`applying the film to an oral mucosal surface.
`
`25 (cid:9)
`
`59. (cid:9)
`
`A method according to claim 58, wherein the film substantially
`
`completely dissolves at the oral mucosal surface in 10-600 seconds.
`
`60.A method according to claim 59, wherein the film substantially completely
`
`dissolves within 200 seconds.
`
`30
`
`61. (cid:9)
`
`A method of making a dosage unit for mucosal administration, suitable
`
`for treating erectile dysfunction , comprising:
`
`- 35 -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 437
`
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`(a)
`
`combining, in any order, in a vessel having a heating source and a
`
`mechanical mixing device, a hydrocolloid, a solid dispersion of sildenafil
`
`and xylitol, and at least one reagent selected from the group consisting of
`
`an emulsifier, a plasticizer, a taste modifier, a coloring agent, a
`
`5
`
`preservative, a permeation enhancer, a stabilizer, and a buffering agent;
`
`(b)
`
`mixing the combined ingredients during and after the addition of
`
`the ingredients to the vessel and applying an effective amount of heat for
`
`melting a substantial portion of the mixture; and
`
`(c)
`
`forming the mixture into a film.
`
`10
`
`is 9/1.
`
`62.
`
`A method according to claim 61, whereli the ratio of sildenafil to xylitol
`
`63.
`
`A method according to claim 61, wherein the water solubility of
`
`15 (cid:9)
`
`sildenafil is at least 20 mg/ml.
`
`64.
`
`A method according to claim 63, wherein the water solubility of
`
`sildenafil is about 50 mg/ml.
`
`20 (cid:9)
`
`65. (cid:9)
`
`A dosage unit, comprising: an effective dose of sildenafil citrate; the
`
`sildenafil citrate being formed in a solid dispersion with a water soluble inert filler, the
`
`solid dispersion being mixed with film forming reagents including a hydropolymer so as
`
`to form a film, the film being capable of dissolving on a mucosal surface so as to release
`
`the sildenafil citrate.
`
`25
`
`105456
`
`- 36 -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 438
`
`(cid:9)
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`1/6
`
`UPPER LIP 1
`
`GINGIVA 2
`
`HARD PALATE 3
`
`LINGUAL 5
`
`CHEEK 4
`SUBLINGUAL 6
`
`LOWER LIP 7
`
`FIG.1
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 439
`
`(cid:9)
`

`

`Z66ZP/00 OM
`
`L.Z£ I £/6 6S IIJIDcl
`
`MIXING AND DEGASSING TANK 8
`
`DIE CUTTING 13
`
`o- -p
`
`DRYING OVEN WITH
`AERATION CONTROLLER 11
`QUICK DISSOLVING
`INTRAORAL FILM 12
`
`u u LI
`
`QUICK DISSOLVING INTRAORAL
`UNIT DOSE 14
`
`COATING SLOT WITH
`THICKNESS CONTROLLER 9
`
`POLYESTER BACKING BELT 10
`
`FIG.2
`
`(9z arum) iaatis ainiusuris
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 440
`
`

`

`SINGLE DOSE FILM 20
`
`SINGLE DOSE FILM 20
`
`( oZ0
`
`0 0 0 0
`0 0 0
`0 0 0 0
`0 0 0
`0 0 0 0
`0 0 0
`
`O 0 0 0 0 0
`O 0 0 0 0
`O 0 0 0 0 0
`O 0 0 0 0
`O 0 0 0 0 0
`O 0 0 0 0
`O 0 0 0 0 0
`O 0 0 0 0
`O 0 0 0 0 0
`1
`
`CONTAINER SNAP 17a
`LID CLOSURE 17b
`
`\Th
`
`MULTIPLE FILM 17
`
`0
`
`VD
`
`
`
`
`
`O o: 00 0 o 's 0 0 0 o 0
`
`O 0 0 0 0 0 0
`o 0 o o o o
`o 0 o o o
`O 0 0 0 0 0 0
`O 000000
`O 0 0 0 0 0 0
`O 000000
`o o o o o o 0\
`O 0 0 0 0 0 0
`O 0 0 0 0 0 0
`o o o o o 0 o
`• o
`o
`o o o
`o o o
`O 0 0 0 0 0 0
`O 0 0 0 0 0 0
`o o o o o o
`O 0 0 0 0 0 0
`O 0 0 0 0 0
`o o o
`...1111111111111111111111 ~
`
`HEAT SEALED POUCH 15
`
`BUSTER CARD 16 (cid:9)
`
`CONTAINER BODY 17c
`
`ROLL TYPE DISPENSER 18
`
`L.Z£ I £/6 6SIVID d
`
`PERFORATED FILM STRIP 19
`
`FIG.3
`
`(9z alf111) iamis 1iflIIISElf1S
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 441
`
`(cid:9)
`

`

`Z66ZP/00 OM
`
`LZE 1£/66S1111.Dd
`
`DISINTEGRATION TIME
`-0-- DISSOLUTION TIME
`
`4 (cid:9)
`6
`THICKNESS (mil)
`FIG.4
`
`10
`
`1200 (cid:9)
`
`
`
`1080-
`
`960-
`
`840-
`
`720-
`
`w 600-
`M
`
`480-
`
`360-
`
`240-
`
`120-
`
`0
`
`(9z 31f111) iaaHs ainnistias
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 442
`
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`5/6
`
`-00
`
`-
`
`LL_
`
`0 (cid:9)
`C:) (cid:9)
`'--- (cid:9)
`
`i (cid:9)
`1 (cid:9)
`1 (cid:9)
`0 (cid:9)
`C:0
`00 (cid:9)
`ca (cid:9)
`
`Vim' (cid:9)Vim'
`(%) 3SV3138 30V1N3383d
`
`I
`
`N CNI
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 443
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`6/6
`
`U7
`CO
`= cp (cid:9)
`•
`co = C.D
`w (cid:9)
`11...
`M
`
`C) (cid:9)
`C:) (cid:9)
`
`I (cid:9)
`I
`3 (cid:9)
`C) (cid:9)
`C)
`co
`co (cid:9)
`Co
`get' (cid:9)
`CV
`(qUV6U) NOIJAIN3ON00 VIISYld
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 444
`
`(cid:9)
`

`

`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`(43) International Publication Date
`27 September 2001 (27.09.2001)
`
`PCT
`
`(10) International Publication Number
`WO 01/70194 Al
`
`(51) International Patent Classification': A61K 9/00, 9/20
`
`(21) International Application Number: PCT/US01/02192
`
`(74) Agents: FEDERMAN, Evan, J.; Warner-Lambert Com-
`pany, 201 Tabor Road, Morris Plains, NJ 07950 et al. (US).
`
`(22) International Filing Date: 23 January 2001 (23.01.2001)
`(25) Filing Language: (cid:9)
`(26) Publication Language: (cid:9)
`
`English
`
`English
`
`(30) Priority Data:
`09/535,005
`
`23 March 2000 (23.03.2000) US
`
`WARNER-LAMBERT COMPANY
`(71) Applicant: (cid:9)
`[US/US]; 201 Tabor Road, Morris Plains, NJ 07950
`(US).
`
`(72) Inventors: BESS, William, S.; 31 Greenwish Road, Edi-
`son, NJ 08820 (US). KULKARNI, Neema; 16 Wilkeshire
`Boulevard, Randolph, NJ 07869 (US). AMBIKE, Suhas,
`H.; 73 Charcoal Drive, West Hill, Ontario M1C 3T9 (CA).
`RAMSAY, Michael, Paul; 45 Sayor Drive, Ajax, Ontario
`LiT 3K4 (CA).
`
`(81) Designated States (national): AE, AG, AL, AU, BA, BB,
`BG, BR, BZ, CA, CN, CR, CU, CZ, DM, DZ, EE, GD, GE,
`HR, HU, ID, IL, IN, IS, JP, KP, KR, LC, LK, LR, LT, LV,
`MA, MG, MK, MN, MX, MZ, NO, NZ, PL, RO, SG, SI,
`SK, SL, TR, TT, UA, UZ, VN, YU, ZA.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`— (cid:9) with international search report
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations" appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`11M1
`
`41'
`
`O (54) Title: FAST DISSOLVING ORALLY CONSUMABLE FILMS CONTAINING AN ION EXCHANGE RESIN AS A TASTE
`MASKING AGENT
`
`Tq
`
`(57) Abstract: Physiologically acceptable films, including edible films, are disclosed. The films include a water soluble film-form-
`
`C ing polymer, such as pullulan, and a taste masked pharmaceutically active agent, such as dextromethorphan. The taste masking agent
`
`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.
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 445
`
`(cid:9)
`

`

`WO 01/70194 (cid:9)
`FAST DISSOLVING ORALLY CONSUMABLE FILMS CONTAINING
`AN ION EXCHANGE RESIN AS A TASTE MASKING AGENT
`
`PCT/US01/02192
`
`5 (cid:9)
`
`to (cid:9)
`
`SPECIFICATION
`
`FIELD OF THE INVENTION
`
`This invention relates to fast dissolving orally consumable films
`
`containing an agent to mask the taste of a pharmaceutically active agent
`
`therein, and more specifically to such films containing an ion exchange resin as
`
`the taste masking agent.
`
`BACKGROUND OF THE INVENTION
`
`It has been known to administer pharmaceutically active agents in an
`
`edible film vehicle.
`
`For example, WO 99/17753 discloses rapidly dissolving films for
`
`delivery of drugs to be adsorbed in the digestive tract.
`
`15 (cid:9)
`
`WO 98/26780 discloses a flat, foil, paper or wafer type presentation for
`
`the application and release of active substances in the buccal cavity. The
`
`specific active ingredient disclosed in WO 98/26780 is buprenorphine.
`
`WO 98/20862 discloses a film for use in the oral cavity that can contain
`
`a cosmetic or pharmaceutical active substance.
`
`20 (cid:9)
`
`WO 98/26763 discloses a flat, foil, paper or wafer like presentation for
`
`release of active substances into the buccal cavity. The particular active
`
`disclosed is apomorphine.
`
`U.S. Patent Application No. 09/395,104 also discloses the delivery of
`
`pharmaceutical agents in a edible film vehicle.
`
`25 (cid:9)
`
`U.S. Patent No. 5,411,945 to Ozaki et al. discloses a pullulan binder and
`
`products produced therewith, including edible films (Example B-2). The
`
`products can include a variety of ingredients in addition to pullulan, such as
`
`other polysaccharides, antibacterial agents, flavor-imparting agents and
`
`pharmaceutically active substances (column 4, lines 5-15).
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 446
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 01/70194 (cid:9)
`
`PCT/US01/02192
`
`U.S. Patent No. 3,784,390 Hijiya et al. discloses pullulan films and their
`
`use in coating and packing materials for foods, pharmaceuticals and other
`
`oxygen sensitive materials. All of the examples in this patent teach mixing
`
`pullulan in hot water.
`
`5 (cid:9)
`
`It has also been known to combine ion exchange resins with
`
`pharmaceutically active agents to provide sustained release formulations.
`
`For example, U.S. Patent No. 6,001,392 to Wen et al. discloses a
`
`controlled-release syrup suspension for oral administration containing
`
`dextromethorphan adsorbed to a polystyrene sulfonate ion exchange resin.
`
`10 (cid:9)
`
`Pharmaceutical films are not disclosed.
`
`U.S. Patent No. 5,980,882 to Eichman discloses a method for improving
`
`the stability of a pharmaceutical composition that contains a drug-resin
`
`complex, comprising adding a chelating agent in an amount effective to reduce
`
`the rate of degradation of the drug in the drug-resin complex. Although
`
`15 (cid:9)
`
`Eichman teaches that complexing a drug with an ion exchange resin can mask
`
`the taste of the drug. Pharmaceutical films are not disclosed.
`
`The inventors are not aware of any suggestion in the published art that
`
`ion exchange resins can act as taste masking agents in a fast dissolving orally
`
`consumable film. Accordingly, an object of this invention is to provide fast
`
`20 (cid:9)
`
`dissolving orally consumable films containing an ion exchange resin to mask
`
`the taste of a pharmaceutically active agent therein.
`
`All references cited herein are incorporated herein by reference in their
`
`entireties.
`
`SUMMARY OF THE INVENTION
`
`25 (cid:9)
`
`The invention provides a consumable film adapted to adhere to and
`
`dissolve in a mouth of a consumer, wherein the film comprises at least one
`
`water soluble polymer, at least one pharmaceutically active agent and at least
`
`one taste masking agent.
`
`2
`
`Par Pharm., Inc., et al.
`Exhibit 1004
`Page 447
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 01/70194 (cid:9)
`
`PCT/US01/02192
`
`Also provided is a method for preparing the consumable film of the
`
`invention, comprising:
`
`dissolving water-soluble ingredients in water to provide an
`
`aqueous solution;
`
`5 (cid:9)
`
`mixing at least one water soluble film former a