( 12 ) United States Patent
`Lundahl et al .
`
`( 10 ) Patent No . : US 10 , 357 , 567 B1
`( 45 ) Date of Patent :
`Jul . 23 , 2019
`
`US010357567B1
`
`( * ) Notice :
`
`( 52 )
`
`( 58 )
`
`( 54 ) METHODS FOR PHOTODYNAMIC
`THERAPY
`( 71 ) Applicant : DUSA Pharmaceuticals , Inc . ,
`Wilmington , MA ( US )
`( 72 ) Inventors : Scott Lundahl , Lexington , MA ( US ) ;
`Michael Guttadauro , Carlisle , MA
`( US )
`( 73 ) Assignee : DUSA Pharmaceuticals , Inc . ,
`Wilmington , MA ( US )
`Subject to any disclaimer , the term of this
`patent is extended or adjusted under 35
`U . S . C . 154 ( b ) by 0 days .
`( 21 ) Appl . No . : 15 / 869 , 164
`( 22 ) Filed :
`Jan . 12 , 2018
`( 51 ) Int . Ci .
`A61N 5 / 06
`A61K 41 / 00
`A61P 17 / 12
`A61K 9 / 00
`A61K 31 / 75
`U . S . CI .
`CPC . . . . . . . . A61K 41 / 0061 ( 2013 . 01 ) ; A61K 9 / 0014
`( 2013 . 01 ) ; A61K 31 / 75 ( 2013 . 01 ) ; A61N 5 / 062
`( 2013 . 01 ) ; A61P 17 / 12 ( 2018 . 01 ) ; A6IN
`2005 / 0652 ( 2013 . 01 ) ; A61N 2005 / 0659
`( 2013 . 01 ) ; A61N 2005 / 0663 ( 2013 . 01 )
`Field of Classification Search
`CPC . . . . . . . . A61N 5 / 06 ; A61N 5 / 0616 ; A61N 5 / 062 ;
`A61N 2005 / 0662 ; A61N 2005 / 0663 ;
`A61N 2005 / 067 ; A61K 41 / 0057 ; A61K
`41 / 0061 ; A61K 41 / 0071 ; A61K 41 / 0076 ;
`A61K 31 / 74 ; A61K 31 / 745 ; A61K 31 / 75 ;
`A61K 31 / 756
`. . . . . . . 607 / 88 , 89 , 96 , 100 ; 128 / 898
`USPC . . . . . . . . . . . . . . . . . . . . . . . . 607
`See application file for complete search history .
`
`( 2006 . 01 )
`( 2006 . 01 )
`( 2006 . 01 )
`( 2006 . 01 )
`( 2006 . 01 )
`
`( 56 )
`
`WO
`WO
`
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`FOREIGN PATENT DOCUMENTS
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`OTHER PUBLICATIONS
`George J . Schmeider Do et al . , A Multicenter , Randomized , Vehicle
`Controlled Phase 2 Study of Blue Light Photodynamic Therapy
`With Aminolevulinic Acid HCI 20 % Topical Solution for the
`Treatment of Actinic Keratoses on the Upper Extremities : The
`Effect of Occlusion During the Drug Incubation Period , Journal of
`Drugs in Dermatology , vol . 11 , Issue 12 , Dec . 2012 , 10 pages .
`( Continued )
`Primary Examiner — Ahmed M Farah
`( 74 ) Attorney , Agent , or Firm — Foley & Lardner LLP
`ABSTRACT
`( 57 )
`A method of enhancing penetration of a topical composition
`of 5 - aminolevulinic acid ( ALA ) into tissue for photody
`namic therapy includes topically applying ALA to a treat
`ment area to be treated with photodynamic therapy . The
`method further includes , after the ALA is applied to the
`treatment area , covering the treatment area with a low
`density polyethylene barrier . The treatment area is covered
`with the low density polyethylene barrier prior to light
`treatment to minimize transepidermal water loss from the
`treatment area .
`10 Claims , 12 Drawing Sheets
`
`res
`
`???????????????p
`
`S
`
`012
`
`

`

`US 10 , 357 , 567 B1
`Page 2
`
`( 56 )
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`7 / 2016 Lundahl
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`2006 / 0287696 Al 12 / 2006 Wright et al .
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`424 / 489
`2011 / 0053965 A1 *
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`514 / 274
`2012 / 0129879 A1 *
`5 / 2012 Cantrell
`A61K 9 / 0075
`514 / 282
`
`2013 / 0274834 A1 * 10 / 2013 Barolet . . . . . . . . . . . . . . . . . . A61N 5 / 062 10 / 2013 Barolet . . . . . . . . . . . .
`607 / 88
`2014 / 0010761 A1 *
`1 / 2014 Parent . . . . . . . . . . . . . . . . . C07C 229 / 22
`424 / 9 . 6
`2014 / 0067024 Al
`3 / 2014 Jones et al .
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`2017 / 0216616 AL
`8 / 2017 Boyajian et al .
`2018 / 0311507 A1 * 11 / 2018 Barolet
`. . . A61N 5 / 0616
`OTHER PUBLICATIONS
`Z . Apalla et al . , Skin Cancer : Preventive Photodynamic Therapy in
`Patients with Face and Scalp Cancerization . A Randomized Placebo
`Controlled Study , British Journal of Dermatology , 2010 , 162 , pp .
`171 - 175 .
`David M . Pariser , et al . , Randomized Vehicle - Controlled Study of
`Short Drug Incubation Aminolevulinic Acid Photodynamic Therapy
`for Actinic Keratoses of the Face or Scalp , American Society for
`Dermatologic Surgery , Inc . , Mar . 2016 , vol . 42 ( 3 ) , pp . 296 - 304 .
`DUSA Pharmaceuticals , Inc . , Levulan PDT Versus Vehicle for
`Extremity Actinic Keratoses ( AK ) , U . S . National Library of Medi
`cine , ClinicalTrials . gov , First Posted Oct . 25 , 2011 , Last Update
`Posted Mar . 14 , 2013 , 80 pgs .
`DUSA Pharmaceuticals , Inc . , Maximal Use Systemic Exposure
`( MUSE ) Study of Levulan Kerastick , U . S . National Library of
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`Medicine , Clinical Trials . gov , First Posted Nov . 3 , 2014 , Last Update
`Posted Jan . 13 , 2017 , 68 pgs .
`DUSA Pharmaceuticals , Inc . , Maximal Use Systemic Exposure
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`Update Posted Sep . 18 , 2017 , 69 pgs .
`DUSA Pharmaceuticals , Inc . , Safety and Efficacy Study of
`Photodynamic Therapy With Levulan Kerastick Blue Light for
`Actinic Keratoses on the Upper Extremities , U . S . National Library
`of Medicine , ClinicalTrials . gov , First Posted May 14 , 2014 , Last
`Update Posted Sep . 16 , 2015 , 112 pgs .
`DUSA Pharmaceuticals , Inc . , Short - Incubation Levulan Photodynamic
`Therapy Versus Vehicle for Face / Scalp Actinic Keratosis ( AK ) , U . S .
`National Library of Medicine , ClinicalTrials . gov , First Posted Nov .
`22 , 2011 , Last Update Posted Oct . 28 , 2016 , 184 pgs .
`George J . Schmieder et al . , A Multicenter , Randomized , Vehicle
`Controlled Phase 2 Study of Blue Light Photodynamic Therapy
`With Aminolevulinic Acid HC1 20 % Topical Solution for the
`Treatment of Actinic Keratoses on the Upper Extremities : The
`Effect of Occlusion During the Drug Incubation Period , Journal of
`Drugs in Dermatology , vol . 11 , Issue 12 , Dec . 2012 , pp . 1483 - 1489 .
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`vol . 10 , Issue 10 , pp . 1124 - 1132 .
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`H . Matsumura et al . Effect of Occlusion on Human Skin , Contact
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`vol . 134 , pp . 949 - 954 .
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`ogy , 1989 , 21 , pp . 511 - 514 .
`Sulzberger et al . , Thin Pliable Plastic Films in Topical Dermatologic
`Therapy , Arch Dermatol , 1961 , 84 ( 6 ) , pp . 1027 - 1028 .
`Taub et al . , A Randomized , Blinded , Bilateral Intraindividual ,
`Vehicle - Controlled Trial of the Use of Photodynamic Therapy With
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`ogy , Sep . 2011 , vol . 10 , Issue 9 , pp . 1049 - 1056 .
`Partial International Search , Annex to Form PCT / ISA / 206 , Inter
`national Application No . PCT / US2018 / 027070 , dated Jul . 19 , 2018 ,
`10 pages .
`* cited by examiner
`
`

`

`U . S . Patent
`
`Jul . 23 , 2019
`
`Sheet 1 of 12
`
`US 10 , 357 , 567 B1
`
`10e
`
`100
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`FIG . 1B
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`
`FIG . 1A
`
`

`

`atent
`
`Jul . 23 , 2019
`
`Sheet 2 of 12
`
`US 10 , 357 , 567 B1
`
`CODOS OOOO
`YEDOODLE 1
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`

`

`U . S . Patent
`
`Jul . 23 , 2019
`
`Sheet 3 of 12
`
`US 10 , 357 , 567 B1
`
`Rain
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`nenninnen es
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`FIG . 3
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`

`

`U . S . Patent
`
`Jul . 23 , 2019
`
`Sheet 4 of 12
`
`US 10 , 357 , 567 B1
`
`200
`FIG . 4
`
`Occlusive Wrap
`Results based on RG - 1 Evaporimeter Readings
`
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`FIG . 5
`
`

`

`U . S . Patent
`
`Jul . 23 , 2019
`
`Sheet 5 of 12
`
`US 10 , 357 , 567 B1
`
`Occlusive Wrap
`Results based on RG - 1 Evaporimeter Readings
`
`
`
`Mean Degree of Occlusion
`
`UUED GEELE
`
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`
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`
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`
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`
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`
`2 Post 3 Hours
`FIG . 6
`Ocolusive Wrap
`Results based on RG - 1 Evaporimeter Readings
`
`baocodeCODOCELLSCE ELETTE
`
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`

`

`U . S . Patent
`
`Jul . 23 , 2019
`
`Sheet 6 of 12
`
`Sheet 6 of 12
`
`US 10 , 357 , 567 B1
`
`Occusive Wrap
`Resuits based on RG - 1 Evaporimeter Readings
`
`tttt
`
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`
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`
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`FIG . 8
`
`

`

`U . S . Patent
`
`Jul . 23 , 2019
`
`Sheet 7 of 12
`
`US 10 , 357 , 567 B1
`
`FIG . 9
`Water Loss Baseline
`B
`C
`A
`SN #
`3 . 2
`SN004 13 . 4 1
`SNOO2
`3 . 9
`5 . 2
`SN001
`4 . 7
`3 . 6
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`6 . 8
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`8 . 2
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`3 . 8
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`3 . 4
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`SN003
`3 . 8
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`6 . 6
`SN015
`3 . 1
`SN011
`3 .
`5 . 0
`SN014
`SN007
`4 . 0
`SN009
`4 . 1
`SN031
`4 . 6
`SN008
`SNO17
`SN035
`SN018
`SNO24
`SNO29
`4 . 2
`5 . 7
`2 . 2
`SN019
`5 . 8
`SN021
`6 . 0
`6 . 3
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`4 . 3
`5 . 5
`SN028
`3 . 8
`3 . 9
`2 . 4
`SN033
`4 . 4
`6 . 0
`SN030
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`SN023
`4 . 6
`8 . 8
`50
`5 . 02
`Mean 14 . 88
`SD
`1 . 78
`1 . 54
`
`+ + +
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`+ + + + + + + + +
`
`5 . 6 + + + + + +
`5 . 91
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`4 . 1
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`4 . 9
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`4 . 60
`1 . 67
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`3 . 1
`6 . 4
`6 . 3
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`4 . 0
`3 . 3
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`4 . 5
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`
`12
`13
`14
`15
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`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`
`

`

`U . S . Patent
`
`Jul . 23 , 2019
`
`Sheet 8 of 12
`
`US 10 , 357 , 567 B1
`
`?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????
`
`FIG . 10
`Water Loss Post 3 Hours
`Wear Time
`B
`C
`
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`1 . 2
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`
`1 . 8
`0 . 8
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`
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`0 . 76
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`
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`
`Control
`3 . 6
`4 . 7
`3 . 3
`5 . 7
`5 . 5
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`6 . 0
`3 . 0
`3 . 6
`2 . 8
`8 . 3
`5 . 4
`0 . 6
`2 . 9
`1 . 7
`4 . 3
`2 . 0
`6 . 1
`4 . 8
`3 . 9
`5 . 4
`2 . 0
`5 . 2
`5 . 6
`6 . 2
`4 . 0
`3 . 2
`3 . 1
`3 . 1
`6 . 8
`4 . 22
`1 . 69
`
`0 . 6
`1 . 9
`1 . 2
`0 . 9
`0 . 5
`0 . 8
`1 . 8
`
`3 . 3
`0 . 2
`1 . 3
`1 . 7
`0 . 6
`0 . 9
`0 . 9
`0 . 3
`
`1 . 5
`0 . 8
`0 . 7
`- 0 . 8
`1 . 5
`0 . 3
`0 . 1
`0 . 9
`1 . 0
`1 . 3
`0 . 4
`0 . 8
`0 . 3
`0 . 96
`0 . 73
`
`SN #
`SN004 1
`SN002
`SN001
`SN006
`SN010
`SN012
`SN020
`SN025
`SN013
`SN003
`SN026
`SN015
`SN011
`SN014
`SN007
`SN009
`SN031
`SN008
`SN017
`SN035
`SNO18
`SNO24
`SN029
`SN019
`SNO21
`SNO27
`SNO28
`SN033
`SN030
`SN023
`Mean 1
`SD
`
`??????????????????????????????????????????????????????
`
`10
`
`13
`
`15
`16
`
`20
`21
`122
`23
`24
`25
`26
`- 27
`28
`29
`30
`
`tttttttttttttt
`
`A
`2
`
`??????????????????
`
`+
`
`. 7
`3 . 0
`2 . 8
`2 . 4
`5 . 1
`2 . 9
`4 . 6
`0 . 6
`7 . 0
`1 . 9
`6 . 5
`0 . 9
`1 . 6
`3 . 7
`3 . 5
`2 . 4
`1 . 1
`3 . 5
`4 . 1
`1 . 9
`3 . 5
`2 . 6
`3 . 3
`2 . 8
`3 . 8
`0 . 9
`4 . 3
`0 . 9
`4 . 3
`5 . 5
`. 14
`1 . 61
`
`3
`
`

`

`U . S . Patent
`
`Jul . 23 , 2019
`
`Sheet 9 of 12
`
`US 10 , 357 , 567 B1
`
`FIG . 11
`Degree of Occlusion at Post 3 Hours Wear Time
`SN #
`A
`B
`C
`D
`E
`SN004 1
`21 . 4
`89 . 1
`84 . 4
`48 . 31 88 . 0
`SN002
`21 . 71 77 . 4
`43 . 11 73 . 9
`84 . 1
`SN001
`39 . 0
`97 . 4
`71 . 1
`35 . 6
`93 . 3
`SN006
`63 . 0
`78 . 1
`87 . 4
`37 . 0
`93 . 0
`91 . 3
`SNO10
`24 , 7
`69 . 6
`46 . 8
`96 . 8
`78 . 5
`80 . 5
`40 . 1
`SNO12
`24 . 7
`94 . 4
`SNO20
`41 . 9
`96 . 9
`73 . 6
`24 . 5
`92 . 7
`SN025
`79 . 8
`79 . 7
`68 . 2
`27 . 2
`89 . 5
`SN013
`- 40 . 41 47 . 7
`37 . 0
`- 92 . 5
`76 . 8
`SN003
`522 1 84 . 7
`93 . 6
`58 . 6
`77 . 6
`SNO26
`24 . 1
`- 37 . 8
`79 . 8
`32 . 31 97 . 9
`84 . 8
`81 . 2
`72 . 6
`SNO15
`74 , 0
`80 . 2
`SNO11
`22 . 5
`85 . 2
`51 . 5
`56 . 01 12 . 3
`55 . 7
`85 . 0
`SNO14
`39 . 31 98 . 3
`77 . 8
`SN007
`3 . 7
`- 51 . 5
`73 . 1
`20 . 0
`98 . 8
`SN009 1
`46 . 0
`94 . 5
`90 . 0
`- 32 . 0
`86 . 8
`SN031
`66 . 8
`91 . 9
`62 . 5
`- 1 . 2
`80 . 2
`91 . 8
`85 . 3
`SN008 -
`37 . 7
`85 . 7
`74 . 0
`45 . 0
`SN017
`49 . 3
`94 . 8
`86 . 1
`35 . 0
`SN035
`76 . 9
`98 . 2
`90 . 61 31 . 4
`98 . 8
`SN018
`19 . 7
`88 . 21 115 . 9
`43 . 9
`93 . 6
`SNO24
`42 . 8
`100 . 2
`73 . 9
`- 34 . 4
`96 . 5
`SN029
`18 . 71 101 . 6
`94 . 4
`32 . 6
`80 . 1
`SNO19 - 31 . 4
`96 . 4
`94 . 3
`37 . 7
`77 . 4
`SNO21
`34 . 5
`83 . 2
`77 . 5
`39 . 3
`97 . 9
`SN027
`78 . 8
`88 . 2
`82 . 7
`82 . 0
`SN028
`22 . 4
`93 . 9
`57 . 0
`15 . 71 88 . 3
`SN033
`60 . 8
`52 . 21 64 . 4
`67 . 6
`61 . 9
`SNO30
`29 . 6
`80 . 71 83 . 5
`18 . 6
`99 . 3
`92 . 9
`SNO23
`- 20 . 9
`91 . 1
`68 . 3
`90 . 8
`Mean
`34 . 10
`77 . 18
`77 , 50
`33 , 11
`84 . 51
`SD
`30 . 03
`35 . 45
`16 . 48
`36 . 20
`17 . 92
`
`MU
`
`|
`
`-
`
`LIL
`
`SSSSSSSSSS
`
`Control
`21 . 3
`4 . 9
`. - 6 . 7
`22 . 6
`12 . 8
`5 . 5
`24 . 4
`12 . 1
`6 . 1
`44 . 7
`
`- 82 . 6
`73 . 5
`60 . 0
`49 . 9
`8 . 3
`63 . 8
`2 . 9
`36 . 1
`53 . 6
`
`44 . 9
`13 . 7
`- 68 . 8
`- 7 . 9
`7 . 5
`- 34 . 6
`- 76 . 7
`40 . 1
`5 . 4
`10 . 85
`38 . 45
`
`2
`
`10
`
`12
`
`15
`
`17
`18
`
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`
`

`

`U . S . Patent
`
`Jul . 23 , 2019
`
`Sheet 10 of 12
`
`US 10 , 357 , 567 B1
`
`FIG . 12
`
`Water Loss Baseline
`Code E
`Code W
`Code X
`SN #
`3 . 6
`5 . 6
`6 . 3
`SN007
`5 . 0
`4 . 3
`3 . 3
`SN012
`3 . 5
`1 . 4
`2 . 1
`SN001
`SN002
`2 . 0
`1 . 8
`2 . 1
`5 . 8
`4 . 1
`6 . 1
`SN008
`5 . 8
`3 . 6
`3 . 4
`SN011
`2 . 6
`2 . 1
`2 . 5
`SN006
`3 , 1
`4 . 8
`2 . 8
`SN003
`SN005
`4 . 7
`5 . 8
`SN010
`4 . 1
`4 . 7
`1 . 8
`1 . 2
`SN016
`2 . 8
`2 . 6
`SN038
`6 . 7
`3 . 5
`SN013
`1 . 2
`2 . 3
`SN031
`3 . 5
`3 . 3
`SN024
`SN023
`8 . 0
`7 . 5
`5 . 3
`5 . 1
`SN025
`SN014
`2 . 7
`4 . 0
`SN026
`2 . 7
`2 . 4
`2 . 8
`2 . 1
`SN015
`4 . 2
`5 . 3
`SN037
`4 . 6
`4 . 2
`SN021
`4 . 0
`SNO221
`5 . 2
`5 . 8
`SN033
`4 . 6
`4 . 6
`4 . 1
`SN018
`4 . 2
`3 . 8
`SN020
`4 . 1
`3 . 3
`SN034
`SN028
`5 . 1
`6 . 5
`5 . 6
`4 . 7
`SN027
`3 . 5
`5 . 3
`SN028
`4 . 04
`Mean 14 . 04
`1 . 76 |
`SD
`1 . 38 |
`
`4 . 6
`2 . 1
`2 . 7
`
`1
`
`YYYYYY
`
`12
`
`14
`
`16
`17
`
`* * * *
`
`*
`
`*
`
`*
`
`*
`
`* * *
`
`* *
`
`23
`24
`25
`26
`27
`
`28
`
`* * *
`
`* * *
`
`*
`
`*
`
`* *
`
`* *
`
`* *
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`* *
`
`*
`
`*
`
`* * *
`
`* * *
`
`*
`
`*
`
`*
`
`*
`
`* * *
`
`*
`
`3 . 5
`7 . 6
`5 . 0
`2 . 0
`2 . 4
`1 . 8
`4 . 8
`3 . 7
`3 . 0
`5 . 5
`4 . 2
`5 . 1
`3 . 6
`3 . 6
`6 . 1
`5 . 4
`4 . 04
`1 . 71 1
`
`RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR
`
`vivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivivi
`
`????????????????
`
`Code Y
`5 . 8
`4 . 0
`1 . 3
`1 . 3
`4 . 4
`2 . 6
`3 . 2
`3 . 8
`6 . 2
`3 . 8
`3 . 4
`3 . 4
`5 . 1
`2 . 4
`3 . 8
`5 . 8
`3 . 8
`5 . 4
`2 . 3
`
`-
`
`* YYYYYYY ??? ??
`
`Code Z
`6 . 0
`4 . 2
`2 . 5
`2 . 2
`
`Control
`5 . 6
`3 . 4
`1 . 1
`4 . 0
`6 . 3
`3 . 6
`2 . 01
`2 . 4
`6 . 2
`4 . 2
`3 . 0
`3 . 0
`4 . 6
`2 . 3
`4 . 0
`7 . 8
`6 . 5
`3 . 8
`3 . 1
`2 . 1
`5 . 4
`4 . 3
`4 . 0
`5 . 5
`4 . 4
`3 . 81
`4 . 3
`4 . 7
`3 . 4
`3 . 8
`4 . 81 4 . 7
`4 . 04
`4 . 11
`1 . 50
`1 . 49
`
`4 . 3
`1 . 2
`2 . 8
`6 . 4
`3 . 6
`1 . 7
`3 . 5
`4 . 1
`2 . 3
`2 . 6
`7 . 6
`6 . 1
`3 . 3
`3 , 4
`2 . 3
`5 . 1
`4 . 3
`3 . 3
`
`??????????
`
`5 . 2
`4 . 4
`4 . 8
`
`4 . 84
`
`4 . 13
`
`????????????????????????????????????
`
`5 . 8
`3 . 1
`2 . 3
`4 . 0
`3 . 6
`4 . 0
`3 . 6
`5 . 3
`3 . 3
`4 . 1
`3 . 76
`1 . 33 |
`
`3 . 79
`
`1 . 98
`
`

`

`U . S . Patent
`
`Jul . 23 , 2019
`
`Sheet 11 of 12
`
`US 10 , 357 , 567 B1
`
`FIG . 13
`
`#
`1
`2
`
`12
`
`L
`
`20
`21
`
`1 . 1 . 1 . 1 . 1 . 1 . 1 . 1 . 1 . 1 . 1 . 1 . 1 . 1 . 1 . 1 .
`
`23
`24
`
`28
`30
`
`AARRRRRRRRRR
`
`. .
`
`.
`
`. .
`
`. .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. .
`
`SN #
`SN007
`SN012
`SN001
`SN002
`SN008
`SN011
`SN006
`SN003
`SN005
`SN010
`SN016
`SN038
`SN013
`SN031
`SN024
`SN023
`SN025
`SN014
`SN026
`SN015
`SN037
`SNO21
`SN022
`SN033
`SN018
`SN020
`SN034
`SN028
`SN027
`SN028
`Mean
`SD
`
`1 . - . - . - . - . - . - . - . - . - . - . - . - . - . - . - .
`
`- . - . - .
`
`?????
`
`1 . 1
`1 . 2
`
`0 . 6
`1 . 1
`0 . 4
`0 . 1
`- 0 . 2
`2 . 5 L
`0 . 2
`0 . 1
`- 0 . 6
`0 . 0
`- 0 . 41
`0 . 4
`- 0 . 7
`- 0 . 2
`0 . 8
`0 . 72
`0 . 8
`0 . 0
`1 . 0
`1 . 21
`0 . 2
`0 . 0
`0 . 4
`0 . 4
`0 . 3
`0 . 39 10 . 41
`0 . 63
`0 . 49
`
`0 . 5
`0 . 6
`- 0 . 6
`0 . 4
`- 0 . 3
`0 . 5
`- 0 . 1
`0 . 2
`0 . 6
`- 0 . 2
`0 . 4
`0 . 6
`0 . 3
`- 0 . 3
`
`. - . - . - . - . - . - . - . - . - . - . - .
`
`1 . 0
`0 . 8
`0 . 8
`0 . 8
`1 . 2
`0 . 4
`0 . 3
`
`- .
`
`g
`
`.
`
`1 . 1 . 1 . 1 . 1 .
`
`. .
`
`?????????
`
`YRRRRRRRRRRRRRRR
`
`2 . 2
`1 . 3
`1 . 0
`1 . 2
`1 . 6
`1 . 4
`2 . 0
`2 . 5
`1 . 0
`2 . 2
`3 . 7
`1 . 2
`2 . 8
`5 . 2
`5 . 2
`1 . 7
`1 . 4
`1 . 4
`3 . 0
`3 . 0
`1 . 8
`3 . 8
`1 . 1
`3 . 5
`3 . 6
`3 . 0
`4 . 7
`2 . 8
`2 . 43
`1 . 25
`
`Water Loss
`Post 3 Hours Wear Time
`Code E Code W
`Code X
`Code Y
`0 . 3
`0 . 2
`2 . 6
`0 . 7
`0 . 5
`- 0 . 2
`0 . 3
`
`Code Z
`2 . 2
`0 . 7
`2 . 3
`0 . 5
`3 . 6
`1 . 2
`
`HAAR
`
`Control
`4 . 4
`4 . 1
`1 . 1
`4 . 6
`5 . 1
`4 . 1
`2 . 0
`4 . 1
`3 . 8
`3 . 4
`2 . 3
`2 . 8
`4 . 0
`2 . 1
`1 . 1
`4 . 5
`2 . 6
`3 . 1
`4 . 8
`1 . 8
`2 . 4
`2 . 4
`4 . 0
`3 . 8
`7 . 8
`4 . 7
`8 . 2
`2 . 6
`4 . 1
`2 . 0
`2 . 5
`1 . 7
`3 . 1
`2 . 6
`7 . 1
`1 . 8
`5 . 1
`2 . 5
`3 . 8
`4 . 3
`5 . 4
`2 . 8
`4 . 6
`1 . 2
`3 . 8
`2 . 6
`4 . 7
`4 . 5
`5 . 6
`1 . 6
`4 . 8
`2 . 0
`4 . 6
`2 . 42
`4 . 36
`1 . 091 . 67
`
`1 . 2
`0 . 8
`0 . 1
`0 . 7
`1 . 2
`
`- 0 . 2
`0 . 3
`1 . 3
`
`- 0 . 1
`0 . 2
`- 0 . 2
`0 . 2
`
`0 . 2
`0 . 6
`
`0 . 1
`0 . 8
`0 . 7
`0 . 2
`0 . 5
`0 . 6
`
`????????
`
`1 . 0
`
`0 . 37
`0 . 45
`
`

`

`U . S . Patent
`
`Jul . 23 , 2019
`
`Sheet 12 of 12
`
`US 10 , 357 , 567 B1
`
`FIG . 14
`
`… .
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`We
`
`… . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`8
`
`UUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUU
`
`.
`
`. . . .
`
`. .
`
`. . . . . .
`
`. . . . . .
`
`. . .
`
`. . . . . . . .
`
`. . . . . . . .
`
`. . .
`
`wan
`
`12
`13
`
`20
`
`22
`23
`24
`25
`26
`27
`28
`28
`30
`
`tutttttttttttttttttttt
`
`????????????????????????????????
`
`?????????
`
`LLLLLLLLLLLLLLLLLLLLL
`
`Degree of Occlusion at Post 3 Hours Wear Time
`SN #
`T Code E
`Code W
`Code X
`Code Y
`Code Z
`SN007
`81 . 3
`86 . 2
`58 . 2
`88 . 7
`62 . 5
`SN012
`80 . 3
`102 . 7
`
`66 . 4
`8 7 . 6
`82 . 7
`SN001
`104 . 5
`20 . 3
`- 7 . 5
`
`12 . 4
`. 8
`SN002
`85 . 7
`35 . 8
`38 . 8
`40 . 3
`78 . 7
`SN008
`88 . 0
`81 . 3
`74 . 31 87 . 8
`37 . 3
`SN011
`81 . 4
`68 . 1
`64 . 7
`73 . 0
`72 . 6
`63 . 3
`- 18 . 5
`SN006
`77 . 8
`23 . 2
`81 . 6
`SN003
`65 . 3
`87 . 1
`50 . 8
`74 . 3
`- 41 . 4
`SN005
`81 . 5
`107 . 7
`64 . 8
`102 . 8
`64 . 8
`SNO101 87 . 7
`81 . 2
`46 . 3
`82 . 6
`22 . 3
`SN016
`110 . 8
`115 . 3
`22 . 8
`110 . 0
`33 , 6
`SN0381
`4 . 8
`82 . 8
`22 . 5
`103 . 8
`26 . 3
`24 . 5
`SN013
`84 . 7
`101 . 2
`45 . 0
`102 . 8
`SN0311 84 .
`8
`88 . 8
`82 . 1
`18 . 4
`0 . 8
`13 , 1
`SNO24
`116 . 7 |
`82 . 7
`104 . 1
`10 . 3
`SN023
`88 . 5
`103 . 1
`42 . 2
`86 . 3
`48 . 5
`OKTOOBER
`18
`- 3 . 0
`87 . 1
`22 . 8
`SN025
`106 . 8
`SN014
`81 . 0
`71 . 2
`38 . 0
`87 . 0
`20 . 0
`SN026 1
`128 . 0
`88 . 4
`46 . 4
`41 . 2
`72 . 8
`SNO15
`107 . 5
`115 . 3
`51 . 8
`106 . 8
`28 . 4
`SN037
`84 . 3
`108 . 3
`28 . 8
`88 . 0
`48 . 8
`SN0211 83 . 2
`73 . 3
`33 . 8
`76 . 1
`55 . 8
`SN022
`77 . 2
`73 . 1
`66 . 3
`67 . 8
`25 . 5
`84 . 0
`3 . 0
`SN0331 88 . 5
`85 . 5
`18 . 1
`SNO181 75 . 2
`78 . 7
`76 . 5
`86 . 5
`45 , 3
`72 . 7
`SN020
`67 . 6
`77 . 3
`17 . 6
`85 . 5
`SN0341 82 . 6
`87 . 7
`12 . 3
`101 . 8
`46 . 8
`SN028
`88 . 8
`80 . 5
`54 . 4
`78 . 1
`58 . 4
`SN027
`82 . 3
`84 . 1
`15 . 5
`70 . 8
`58 . 4
`SN028
`85 . 1
`83 . 4
`18 . 7
`86 . 5
`35 . 78
`Mean 89 . 87 86 . 22 36 . 80 | 86 . 11
`SD 21 . 07 20 . 06 23 . 45 20 . 97 28 . 59
`
`-
`
`Control
`22 . 0
`- 21 . 3
`2 . 8
`- 14 . 4
`18 . 8
`- 13 . 0
`2 . 2
`- 63 . 6
`45 . 1
`4 . 7
`31 . 0
`- 52 . 8
`- 4 . 5
`- 3 . 3
`- 0 . 6
`- 1 . 8
`~ 42 . 4
`- 6 . 7
`18 . 1
`- 50 . 5
`- 32 . 8
`- 18 . 3
`3 . 8
`2 . 0
`- 3 . 5
`- 0 . 3
`- 8 . 8
`- 18 . 7
`- 43 . 8
`-
`1 . 2
`- 8 . 39
`24 . 95
`
`1
`
`

`

`US 10 , 357 , 567 B1
`
`METHODS FOR PHOTODYNAMIC
`THERAPY
`
`Illuminator For Photodynamic Therapy And Diagnosis , "
`published on Apr . 20 , 2017 as WO 2017 / 066270 , ( 5 ) U . S .
`patent application Ser . No . 15 / 292 , 731 to Boyajian et al . ,
`entitled “ Adjustable Illuminator For Photodynamic Therapy
`FIELD
`5 And Diagnosis , ” published on Apr . 20 , 2017 as U . S . Pub .
`No . 2017 / 0106205 , and ( 6 ) U . S . patent application Ser . No .
`The present disclosure relates generally to methods for
`photodynamic therapy .
`15 / 487 , 991 to Boyajian et al . , entitled “ Adjustable Illumi
`nators And Methods For Photodynamic Therapy And Diag
`BACKGROUND
`nosis , ” published on Aug . 3 , 2017 as U . S . Pub . No . 2017 /
`10 0216616 . The entire contents of the foregoing patents and / or
`patent applications ( 1 ) - ( 6 ) are incorporated herein by refer
`Photodynamic therapy ( PDT ) , photodynamic diagnosis
`ence for background information and the compositions ,
`( PD ) , or photochemotherapy is generally used to treat and / or
`devices , processes and techniques relating to photodynamic
`diagnose several types of ailments in or near the skin or
`therapy and diagnosis disclosed therein .
`other tissues , such as those in a body cavity . For example ,
`photodynamic therapy or photodynamic diagnosis may be 15
`used for treatment or diagnosis of actinic keratosis of the
`SUMMARY
`upper extremities ( e . g . , the dorsal surface of the hand or
`Through research and experimentation in photodynamic
`forearms ) , scalp or facial areas of a patient . In addition , such
`therapeutic techniques , the inventors have found that cov
`techniques may be used for treatment and diagnosis of other
`indications ( e . g . , acne , warts , psoriasis , photo - damaged skin , 20 ering a treatment area with polyethylene ( such as low
`cancer ) and other areas of the patient ( e . g . , the legs or
`density polyethylene ( LDPE ) ) for a period of time prior to
`portions of the arms other than the forearms ) .
`light treatment is particularly effective to minimize transepi
`During one form of photodynamic therapy , a patient is
`dermal water loss from the treatment area . Surprisingly , it
`first administered a photoactivatable agent or a precursor of
`was found that a polymeric barrier having a degree of
`a photoactivatable agent that accumulates in the tissue to be 25 occlusion more than 65 %
`( such as LDPE ) was superior to
`treated . The area in which the photoactivatable agent is
`other materials such as polyurethane and polyvinylidene
`administered is then exposed to visible light , which causes
`chloride ( PVDC ) . The low density polyethylene can be
`chemical and / or biological changes in the agent . These
`applied to a wide variety of treatment areas , such as the
`changes allow the agent to then selectively locate , destroy ,
`arms , legs , chest , back , portions of the head , and the like ,
`or alter the target tissue while , at the same time , causing at 30 and can be used with drugs other than ALA .
`most only mild and reversible damage to other tissues in the
`According to one aspect of the disclosure , a method of
`treatment area . One example of a precursor of a photoacti -
`enhancing penetration of a topical composition of 5 - amin
`vatable agent is 5 - aminolevulinic acid ( “ ALA ” ) , which is
`olevulinic acid ( ALA ) into tissue for photodynamic therapy
`commonly used in photodynamic therapy of actinic kerato
`is disclosed . The method includes topically applying ALA to
`sis . As they are used here , the terms ALA or 5 - aminolevu - 35 a treatment area to be treated with photodynamic therapy .
`linic acid refer to ALA itself , precursors thereof , esters
`The method further includes , after the ALA is applied to the
`thereof and pharmaceutically acceptable salts of the same .
`treatment area , covering the treatment area with a polymeric
`Photosensitization following application of a topical com -
`barrier have a degree of occlusion of 65 % or more .
`position ( e . g . , a topical solution or emulsion ) containing
`According to another aspect of the disclosure , a method of
`ALA occurs through the metabolic conversion of aminole - 40 enhancing penetration of a topical composition of 5 - amin
`vulinic acid to protoporphyrin IX
`( PpIX ) , as discussed in
`olevulinic acid ( ALA ) into tissue for photodynamic therapy
`more detail below . PpIX is a photosensitizer which accu -
`is disclosed . The method includes topically applying ALA to
`mulates in the skin .
`a treatment area to be treated with photodynamic therapy .
`For photodynamic therapy to be effective , it is desirable
`The method further includes , after the ALA is applied to the
`to have a power output that can be controlled for intensity 45 treatment area , covering the treatment area with a low
`and duration , among other factors . Illuminators are typically
`density polyethylene barrier . The treatment area is covered
`used to provide the proper uniformity of light for treatment
`with the low density polyethylene barrier prior to light
`purposes . These devices generally include a light source
`treatment to minimize transepidermal water loss from the
`( e . g . , a fluorescent tube or LED ) , coupling elements that
`treatment area .
`direct , filter or otherwise conduct emitted light so that it 50
`According to still another aspect of the disclosure , a
`arrives at its intended target in a usable form , and a control
`method of photodynamic treatment of the stratum corneum
`system that starts and stops the production of light when
`is disclosed . The method includes applying 5 - aminolevu
`linic acid ( ALA ) to a lesion on the stratum corneum and
`necessary .
`Photodynamic therapy may be carried out using certain
`reducing evaporation from a portion of the stratum corneum
`compositions , such as ALA , in connection with illuminators 55 including an area where the lesion is present . The method
`as described above . Such compositions and / or devices are
`further includes heating the area where the lesion is present
`disclosed , for example , in ( 1 ) U . S . Pat . No . 5 , 954 , 703 to
`before or during illumination of the area where the lesion is
`Golub , entitled “ Method and apparatus for applying 5 - ami
`present .
`nolevulinic acid , ” issued on Sep . 21 , 1999 , ( 2 ) U . S . Pat . No .
`According to a further aspect of the disclosure , a method
`6 , 223 , 071 to Lundahl et al . , entitled “ Illuminator for pho - 60 of using 5 - aminolevulinic acid ( ALA ) and a low density
`todynamic therapy and diagnosis which produces substan -
`polyethylene barrier is disclosed . The method includes con
`tially uniform intensity visible light , ” issued on Apr . 24 ,
`tacting a treatment site with a composition comprising the
`2001 , ( 3 ) U . S . patent application Ser . No . 15 / 371 , 363 to
`ALA so as to wet the treatment site , and , following wetting
`Boyajian et al . , entitled “ Method And Apparatus For Apply
`of the treatment site , covering the wetted treatment site with
`ing A Topical Solution , ” published on Jun . 8 , 2017 as U . S . 65 the low density polyethylene barrier .
`Pub . No . 2017 / 0157379 , ( 4 ) International Application No .
`According to an additional aspect of the disclosure , a
`PCT / US2016 / 056572 to Boyajian et al . , entitled “ Adjustable
`method of enhancing penetration of a topical composition of
`
`

`

`US 10 , 357 , 567 B1
`
`The following terms are used throughout and are as
`5 - aminolevulinic acid ( ALA ) HCl into tissue for photody
`defined below .
`namic therapy is disclosed . The method includes topically
`As used herein and in the appended claims , singular
`applying the composition to a treatment area to be treated
`articles such as “ a ” and “ an ” and “ the ” and similar