111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20050233062Al
`
`(19) United States
`(12) Patent Application Publication
`Hossainy et al.
`
`(54) THERMAL TREATMENT OF AN
`IMPLANTABLE MEDICAL DEVICE
`
`(76)
`
`Inventors: Syed F.A. Hossainy, Fremont, CA
`(US); Yiwen Tang, San Jose, CA (US);
`Manish Gada, Santa Clara, CA (US)
`
`Correspondence Address:
`Paul J. Meyer, Jr.
`Squire, Sanders & Dempsey L.L.P.
`Suite 300
`1 Maritime Plaza
`San Francisco, CA 94111 (US)
`
`(21) Appl. No.:
`
`10/856,984
`
`(22) Filed:
`
`May 27, 2004
`
`Related U.S. Application Data
`
`(10) Pub. No.: US 2005/0233062 Al
`Oct. 20, 2005
`( 43) Pub. Date:
`
`application No. 09!750,595, filed on Dec. 28, 2000,
`now Pat. No. 6,790,228, which is a continuation-in-
`part of application No. 09/470,559, filed on Dec. 23,
`1999, now Pat. No. 6,713,119, which is a continua-
`tion-in-part of application No. 09/390,855, filed on
`Sep. 3, 1999, now Pat. No. 6,287,628, and which is a
`continuation-in-part of application No. 09/390,069,
`filed on Sep. 3, 1999, now Pat. No. 6,379,381.
`Said application No. 09!750,595 is a continuation-in-
`part of application No. 09/715,510, filed on Nov. 17,
`2000, now Pat. No. 6,749,626, which is a continua-
`tion-in-part of application No. 09/540,241, filed on
`Mar. 31, 2000, now abandoned.
`
`Publication Classification
`
`Int. Cl? ................................ BOSD 3/00; A61F 2/06
`(51)
`(52) U.S. Cl. ............................................................... 427/2.1
`
`(60) Continuation-in-part of application No. 10/603,794,
`filed on Jun. 25, 2003.
`Continuation-in-part of application No. 10/108,004,
`filed on Mar. 27, 2002.
`Continuation-in-part of application No. 10/304,360,
`filed on Nov. 25, 2002, which is a division of appli-
`cation No. 09/751,691, filed on Dec. 28, 2000, now
`Pat. No. 6,503,556.
`Continuation-in-part of application No. 10/751,043,
`filed on Jan. 2, 2004, which is a continuation of
`
`(57)
`
`ABSTRACT
`
`A method of manufacturing an implantable medical device,
`such as a drug eluting stent, is disclosed. The method
`includes subjecting an implantable medical device that
`includes a polymer to a thermal condition. The thermal
`condition can result in reduction of the rate of release of an
`active agent from the device subsequent to the implantation
`of the device and/or improve the mechanical properties of a
`polymeric coating on the device.
`
`28
`
`28
`
`26
`
`22
`
`"-20
`
`KASHIV1061
`IPR of Patent No. 9,492,393
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`Patent Application Publication Oct. 20, 2005 Sheet 1 of 19
`
`US 2005/0233062 A1
`
`24
`
`26
`
`26
`24
`
`268
`248
`26A
`24A
`
`FIG. 1A
`
`FIG. 1 B
`
`28
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`28
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`28
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`28
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`FIG. 1C
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`FIG. 10
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`
`KASHIV1061
`IPR of Patent No. 9,492,393
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`Patent Application Publication Oct. 20, 2005 Sheet 2 of 19
`
`US 2005/0233062 Al
`
`28
`
`26
`
`30
`22
`~--~~~~--~~~~24
`
`FIG. 1 E
`
`"--20
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`28
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`
`FIG. 1 F
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`28
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`22
`
`FIG. 1G
`
`30
`26
`
`30A
`
`26A
`
`FIG. 1 H
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`KASHIV1061
`IPR of Patent No. 9,492,393
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`Patent Application Publication Oct. 20, 2005 Sheet 3 of 19
`
`US 2005/0233062 Al
`
`40
`
`42
`
`~ ·u E
`co
`......
`C..Q)
`co
`.s::::.
`0(5
`...... "'C
`co c:
`a>w
`:c
`
`Tg
`
`,-so
`~~~~~~
`
`I
`
`I
`
`48
`
`r2
`
`FIG.-2
`
`Temperature
`FIG. 3
`
`KASHIV1061
`IPR of Patent No. 9,492,393
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`Patent Application Publication Oct. 20, 2005 Sheet 4 of 19
`
`US 2005/0233062 Al
`
`10
`
`9
`8
`logE
`(Pa) 7
`
`6
`
`5
`
`glassy
`
`··, ·········· .... ···-!-~~~~~-~~~~----. -- ......
`
`rubbery
`
`T g
`
`temperature
`
`FIG. 4
`
`," (dv)
`dr T = Tg
`,"'
`
`~
`E 0.845
`
`-
`-Q)
`E
`:::J
`0 >
`u -.:::
`·~ 0.840
`a. en
`
`0.835 L....-----L._.......______. _
`8
`12
`16
`20
`
`___.__...~------L..-""'""------1----L....--I
`
`36
`
`40
`
`44
`
`32
`
`28
`24
`temp(°C)
`FIG. 5
`
`KASHIV1061
`IPR of Patent No. 9,492,393
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`Patent Application Publication Oct. 20, 2005 Sheet 5 of 19
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`US 2005/0233062 Al
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`FIG. SA
`
`~72
`
`70A
`
`FIG. 68
`
`~72
`
`708
`
`10~----------------------------------~~
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`8
`
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`0
`~
`a: t-
`z w
`(.) z
`0
`·(.)
`
`--Before Ebeam
`--*"--After Ebeam
`
`4
`
`2
`
`0~----~----~------~----~----~----~
`10
`15
`20
`25
`0
`5
`30
`TIME (HOURS)
`FIG. 7
`
`KASHIV1061
`IPR of Patent No. 9,492,393
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`Patent Application Publication Oct. 20, 2005 Sheet 6 of 19
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`US 2005/0233062 Al
`
`-+- Actinomycin D
`-Mitomycin
`""*- Docetaxel
`
`c
`0
`-...::::;
`
`«S -Q)
`~ 0 -a_
`
`Q)
`(.)
`~ 0
`
`100
`
`75
`
`50
`
`25
`
`0 ~------+---~--~----~----~-;
`10-9M
`10-8M
`10-6M
`10-7M
`10~5M
`
`Concentration {M)
`
`FIG. 8.
`
`KASHIV1061
`IPR of Patent No. 9,492,393
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`

`Patent Application Publication Oct. 20, 2005 Sheet 7 of 19
`
`US 2005/0233062 Al
`
`FIG. 9A
`
`FIG. 98
`
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`
`·t
`·~·.
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`
`FIG. 10A
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`...
`:. ~ ·.. . . .
`,·· ..
`..
`:. ·.··
`._
`!. .
`r<
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
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`

`Patent Application Publication Oct. 20, 2005 Sheet 8 of 19
`
`US 2005/0233062 Al
`
`\ I
`
`.. I • · , . ,
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`\ ..... .:._ ... •.
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`:~
`
`:.
`
`80
`
`FIG. 108
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
`

`

`Patent Application Publication Oct. 20, 2005 Sheet 9 of 19
`
`US 2005/0233062 Al
`
`• Stents From Example 37
`a Stents From Example 39
`• Stents From Example 40
`
`320.00
`280.00-
`
`C')
`
`~
`
`- 240.00-
`~ -"0 200.00-
`Q) en cu Q) 160.00-
`Q) a:
`C') 120.00-
`~ 0
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`40.00-
`0.00
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`16 20
`Time (hrs)
`FIG. 11
`
`+ Stents From Example 51
`• Stents From Example 52
`
`c;:;
`2..
`"0
`Q)
`en cu Q)
`Q) a:
`ci
`......
`0
`
`~
`
`90.00
`80.00
`70.00
`60.00
`50.00
`40.00
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`Time (hrs)
`FIG. 12
`
`• •
`
`•
`•
`
`I
`40
`
`I
`50
`
`60
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
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`

`Patent Application Publication Oct. 20, 2005 Sheet 10 of 19
`
`US 2005/0233062 A1
`
`5.928
`
`9.132
`
`11.378 12.997
`
`Q) u c
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`I
`
`I
`I
`1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 1
`
`Residence Time (Min.)
`
`FIG. 13
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
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`

`Patent Application Publication Oct. 20, 2005 Sheet 11 of 19
`
`US 2005/0233062 Al
`
`• Stents From Example 70 Without Sterilization
`• Stents From Example 71 Without Sterilization
`~ Stents From Example 70 With Sterilization
`181 Stents From Example 71 With Sterilization
`
`350
`
`- 300-
`
`0)
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`:::::1
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`CJ)
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`Time (hrs)
`
`I
`
`i
`
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`15
`
`I
`20
`
`25
`
`FIG. 14
`
`KASHIV1061
`IPR of Patent No. 9,492,393
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`

`Patent Application Publication Oct. 20, 2005 Sheet 12 of 19
`
`US 2005/0233062 Al
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`FIG. 15
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`KASHIV1061
`IPR of Patent No. 9,492,393
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`

`Patent Application Publication Oct. 20, 2005 Sheet 13 of 19
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`US 2005/0233062 A1
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`FIG. 17
`
`FIG. 18
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`KASHIV1061
`IPR of Patent No. 9,492,393
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`

`Patent Application Publication Oct. 20, 2005 Sheet 14 of 19
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`US 2005/0233062 A1
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`FIG. 19
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
`

`

`.... 0 =
`0' -....
`.... 0 =
`~ 't:l -....
`~ ..... ~ = .....
`
`""""
`N >
`~ c 0'1
`~ c N
`N c c
`
`~
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`Cj
`
`~=
`N
`!"""
`0 (')
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`"""" Ul
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`'JJ. =-~
`N c c Ul
`
`~ .....
`
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`
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`
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`
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`
`FIG. 20
`
`18 min
`oc
`
`16
`
`14
`
`12
`
`1 0
`
`140
`
`120
`
`100
`
`80
`
`I
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`
`8
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`
`Delta cp ASTM,IEC 0.524 Jgl\.1 Kl\.1
`Midpoint ASTM,IEC 45.84 °C
`49.65 oc
`Extrapol. Peak
`45.66 oc
`Midpoint
`43.69 oc
`Onset
`Glass Transition
`
`Delta cp ASTM,IEC 0.545 Jg"-1 Kl\.1
`Midpoint ASTM,IEC 48.71 °C
`51.58 oc
`Extrapol. Peak
`47.64 °C
`Midpoint
`48.19 °C
`Onset
`Glass Transition
`
`Second run
`
`mW
`0.5
`
`First run
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
`

`

`.... 0 =
`0' -....
`.... 0 =
`~ 't:l -....
`~ ..... ~ = .....
`
`~ .....
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`~ .....
`'JJ. =-~
`N c c Ul
`
`Delta cp A~TM,IEC. 0.358 Jgl\.1 Kl\.1
`Midpoint ASTM,IEC 49.07 °C
`53.59 oc
`Extrapol. Peak
`48.00 °C
`Midpoint
`48.28 oc
`Onset
`Glass Transition
`
`Delta cp ASTM,IEC 0.323 Jgl\.1 K/\;1
`Midpoint ASTM,IEC 51.80 oc
`Extrapol. Peak
`54.59 °C
`50.56 oc
`Midpoint
`Onset
`51.51 °C
`ass
`Gl
`Stent B
`
`T
`rans1t1on
`. .
`
`\
`
`Delta cp ASTM,IEC 0.365 Jgl\.1 Kl\.1
`Midpoint ASTM,IEC 50.07 °C
`53.92 oc
`Extrapol. Peak
`49.02 oc
`Midpoint
`49.35 oc
`Onset
`Glass Transition
`
`\stentA
`
`mW
`0.5
`
`""""
`N >
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`
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`I I I A>
`60.0 BC
`
`16.0
`18.0
`I I I
`I I I
`30.0
`50.0
`Delta cp ASTM,IEC 0.237 Jgl\.1 Kl\.1
`Midpoint ASTM,IEC 51.61 oc
`54.4 7 oc
`Extrapol. Peak
`49.74 oc
`Midpoint
`51.36 oc
`Onset
`Glass Transition
`
`17.0
`I I I
`40.0
`
`I
`
`I
`
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`
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`
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`
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`
`FIG. 21
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`
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`
`/1
`
`\stentC
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
`

`

`.... 0 =
`0' -....
`.... 0 =
`~ 't:l -....
`~ ..... ~ = .....
`
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`
`min
`oc
`
`56
`140
`
`54
`120
`83.78 oc
`Peak
`72.37 oc
`Onset
`normalized -3.36 Jg/\.1
`Crystallinity 63.41 %
`
`52
`100
`
`FIG. 22
`48
`50
`60
`80
`
`Delta cp ASTM,IEC 0.346 Jg""1K""1
`Midpoint ASTM,IEC 46.64 °C
`46.87 oc
`Midpoint
`44.1 0 oc
`Onset
`Glass Transition
`
`46
`40
`
`44
`20
`
`42
`0
`
`40
`-20
`
`82.61 oc
`Delta cp ASTM,IEC 0.289 Jg/\.1 K/\.1 Peak
`72.07 oc
`Midpoint ASTM,IEC 47.47 °C
`Onset
`Midpoint
`47.71 °C
`normalized -4.29 Jg""1
`45.36 oc
`Crystallinity 80.91 %
`Onset
`Glass Transition
`
`Delta cp ASTM,IEC 0.361 Jg""1 K""1
`Midpoint ASTM,IEC 45.59 °C
`45.00 °C
`Midpoint
`43.42 °C
`Onset
`Glass Transition
`
`Stent B)
`
`mW
`1
`
`--------
`
`'-Stent A
`\
`
`Delta cp ASTM,IEC 0.503 Jg""1 K""1
`Midpoint ASTM,IEC 45.52 °C
`45.64 oc
`Midpoint
`42.00 °C
`Onset
`
`~ Glass Transition
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
`

`

`""""
`N >
`~ c 0'1
`~ c N
`N c c
`
`~
`
`'Jl
`Cj
`
`.... 0 =
`0' -....
`.... 0 =
`~ 't:l -....
`~ ..... ~ = .....
`
`~ .....
`
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`
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`~
`
`19 min
`I 'l>
`I
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`60
`oc
`
`I
`
`FIG. 23
`
`I
`
`I
`
`I
`
`I
`
`18
`I
`50
`
`I ·1
`
`I
`
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`
`17
`I
`40
`
`I
`
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`
`I
`
`I
`
`16
`I
`30
`
`I
`
`I
`
`I
`
`I
`
`15
`I
`20
`
`I
`
`I
`
`I
`
`I
`
`14
`I
`10
`
`I
`
`I
`
`I
`
`I
`
`13
`I
`0
`
`I
`
`I
`
`I
`
`12
`I
`I
`I
`-10
`
`I
`
`I
`
`11
`I
`I
`I
`-20
`
`I
`
`I
`
`<1
`
`DeltacpASTM,IEC 0.327Jg~KA.1
`Midpoint ASTM,IEC 44.78 °C
`45.09 oc
`Midpoint
`41.94 oc
`Onset
`Glass Transition
`
`Delta cp ASTM,IEC 0.197 Jg ~ K 1\.1
`. Midpoint ASTM,IEC 44.54 oc
`44.77 oc
`Midpoint
`42.39 oc
`Onset
`Glass Transition
`
`\
`StentE)
`
`mW
`0.5
`
`(Stent D
`
`First run
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
`

`

`'"""'
`N >
`~ c 0'1
`~ c N
`N c c
`
`~
`
`'JJ.
`Cj
`
`FIG. 24
`
`min
`)'
`oc
`
`I
`
`56
`I
`140
`
`I
`
`54
`I
`120
`
`I
`
`52
`I
`100
`
`I
`
`50
`I
`80
`
`I
`
`48
`I
`60
`
`I
`
`46
`I
`40
`
`I
`
`44
`I
`20
`
`I
`
`42
`I
`0
`
`I
`
`40
`<"I
`-20
`
`.... 0 =
`0' -....
`.... 0 =
`~ 't:l -....
`~ ..... ~ = .....
`
`~=
`N
`!"""
`0 (')
`
`'"""'
`'0
`0 ......,
`'"""'
`'0
`~ .....
`'JJ. =-~
`N c c Ul
`
`~ .....
`
`(')
`
`~
`
`~ .....
`
`(')
`
`""C
`
`\
`Stent E
`~
`
`Peak
`67.82 ~c
`59.59 oc
`Onset
`normalized -0.39 Jg J\.1
`Crystallinity 7.38 %
`
`-
`
`t
`
`Delta cp ASTM,IEC 0.317 Jg "-1 K"-1
`Midpoint ASTM,IEC 35.88 °C
`36.30 oc
`Midpoint
`31.98 oc
`Onset
`Glass Transition
`
`67.49 oc
`Peak
`63.00 oc
`Onset
`normalized -0.59 JgJ\.1
`Crystallinity 11.2.1 %
`
`Delta cp ASTtyi,IEC 0.290 Jg"-1 K"-1
`Midpoint ASTM,IEC 36.91 °C
`Midpoint
`37.04 °C
`33.89 oc
`Onset
`Glass Transition
`
`mW
`0.5
`
`Stent D)
`
`Drug's Tm
`
`Polymer's Tg
`
`Second run
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
`

`

`US 2005/0233062 Al
`
`1
`
`Oct. 20, 2005
`
`THERMAL TREATMENT OF AN IMPLANTABLE
`MEDICAL DEVICE
`
`CROSS REFERENCE
`[0001] This application is a continuation-in-part of U.S.
`application Ser. No. 10/603,794, which was filed on Jun. 25,
`2003. This application is also a continuation-in-part of U.S.
`application Ser. No. 10/108,004, which was filed on Mar. 27,
`2002. Furthermore, this application is a continuation-in-part
`of U.S. application Ser. No. 10/304,360 filed on Nov. 25,
`2002, which is a divisional application of U.S. Pat. No.
`6,503,556 filed on Dec. 28, 2000. Additionally, this appli-
`cation is a continuation-in-part of U.S. application Ser. No.
`10/751,043 filed on Jan. 2, 2004, which is a continuation of
`U.S. application Ser. No. 09!750,595 filed on Dec. 28, 2000.
`U.S. application Ser. No. 09!750,595 is a continuation-in-
`part of U.S. patent application Ser. No. 09/470,559 filed on
`Dec. 23, 1999, which is a continuation-in-part of U.S. Pat.
`No. 6,287,628 filed on Sep. 3, 1999, and U.S. Pat. No.
`6,379,381 filed on Sep. 3, 1999. U.S. application Ser. No.
`09!750,595 is also a continuation-in-part of U.S. patent
`application Ser. No. 09/715,510 filed on Nov. 17, 2000,
`which is a continuation-in-part of U.S. patent application
`Ser. No. 09/540,241 filed on Mar. 31, 2000 (now aban-
`doned).
`
`BACKGROUND OF THE INVENTION
`[0002] 1. Field of the Invention
`implantable medical
`invention relates to
`[0003] The
`devices, one example of which is a stent. More particularly,
`the invention relates to a method of thermally treating an
`implantable medical device that includes a polymer, for
`example, a polymeric coating on the device.
`[0004] 2. Description of the Background
`[0005] Percutaneous transluminal coronary angioplasty
`(PTCA) is a procedure for treating heart disease. A catheter
`assembly having a balloon portion is introduced percutane-
`ously into the cardiovascular system of a patient via the
`brachial or femoral artery. The catheter assembly is
`advanced through the coronary vasculature until the balloon
`portion is positioned across the occlusive lesion. Once in
`position across the lesion, the balloon is inflated to a
`predetermined size to remodel the vessel wall. The balloon
`is then deflated to a smaller profile to allow the catheter to
`be withdrawn from the patient's vasculature.
`[0006] A problem associated with the above procedure
`includes formation of intimal flaps or torn arterial linings,
`which can collapse and occlude the conduit after the balloon
`is deflated. Vasospasms and recoil of the vessel wall also
`threaten vessel closure. Moreover, thrombosis and restenosis
`of the artery may develop over several months after the
`procedure, which may necessitate another angioplasty pro-
`cedure or a surgical by-pass operation. To reduce the partial
`or total occlusion of the artery by the collapse of arterial
`lining and to reduce the chance of the development of
`thrombosis and restenosis, a stent is implanted in the lumen
`to maintain the vascular patency.
`[0007] Stents act as scaffoldings, functioning to physically
`hold open and, if desired, to expand the wall of the pas-
`sageway. Typically, stents are capable of being compressed
`so that they can be inserted through small lumens via
`
`catheters and then expanded to a larger diameter once they
`are at the desired location. Mechanical intervention via
`stents has reduced the rate of restenosis as compared to
`balloon angioplasty. Yet, restenosis is still a significant
`clinical problem with rates ranging from 20-40%. When
`restenosis does occur in the stented segment, its treatment
`can be challenging, as clinical options are more limited as
`compared to lesions that were treated solely with a balloon.
`[0008] Stents are used not only for mechanical interven-
`tion but also as vehicles for providing biological therapy.
`Biological therapy can be achieved by medicating the stents.
`Medicated stents provide for the local administration of a
`therapeutic substance at the diseased site. In order to provide
`an efficacious concentration to the treated site, systemic
`administration of such medication often produces adverse or
`even toxic side effects for the patient. Local delivery is a
`preferred method of treatment in that smaller total levels of
`medication are administered in comparison to systemic
`dosages, but are concentrated at a specific site. Local deliv-
`ery thus produces fewer side effects and achieves more
`favorable results.
`[0009] One proposed method of medicating stents
`involves the use of a polymeric carrier coated onto the
`surface of the stent. A composition including a solvent, a
`polymer dissolved in the solvent, and an active agent dis-
`persed in the blend is applied to the stent by immersing the
`stent in the composition or by spraying the composition onto
`the stent. The solvent is allowed to evaporate, leaving on the
`stent strut surfaces a coating of the polymer and the active
`agent impregnated in the polymer.
`[0010] A stent coating can be exposed to significant stress,
`for example, radial expansion as the stent is deployed. A
`potential shortcoming of the foregoing method of medicat-
`ing stents is that the mechanical integrity of a polymeric
`drug coating can fail in the biological lumen, for example as
`a result of stress. In some instances, the polymeric coating
`may have poor adhesion to the surface of the stent. In other
`instances, if the polymeric coating contains multiple layers
`of materials, the different layers may not attach well to each
`other and lack sufficient cohesiveness. Poor cohesion can
`result if there is inadequate interfacial compatibility between
`the surface of the stent and the polymer in the coating.
`[0011] Failure of the mechanical integrity of the polymeric
`coating while the stent is localized in a patient can lead to a
`serious risk of embolization because a piece of the poly-
`meric coating can tear or break off from the stent. Polymeric
`stent coatings having a high drug loading are especially
`vulnerable to fracture during and after deployment.
`It is desirable to provide a polymeric coating that
`[0012]
`has improved adhesion to the surface of the stent. It also is
`desirable to improve the cohesion of multiple layers of
`polymeric material on a stent. Moreover, it is desirable to be
`able to increase the quantity of the therapeutic substance
`carried by the polymeric coating without perturbing the
`mechanical properties of the coating or significantly increas-
`ing the thickness of the coating.
`[0013] Another potential shortcoming of the foregoing
`method of medicating stents is that the release rate of the
`active agent may be too high to provide an efficacious
`treatment. This shortcoming may be especially pronounced
`with certain active agents. For instance, it has been found
`
`KASHIV1061
`IPR of Patent No. 9,492,393
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`

`US 2005/0233062 Al
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`2
`
`Oct. 20, 2005
`
`that the release rate of 40-0-(2-hydroxy)ethyl-rapamycin
`from a standard polymeric coating is greater than 50% in
`about 24 hours. Thus, there is a need for a coating that
`reduces the release rate of active agents in order to provide
`a more efficacious release rate profile.
`[0014] Yet another shortcoming is that there can be sig-
`nificant manufacturing inconsistencies. For instance, there
`can be release rate variability among different stents. It is
`believed that when some polymers dry on a stent surface to
`form a coating, different polymer morphologies can develop
`for different stent coatings, even if the coating process
`parameters are consistent. The differences in polymer mor-
`phology may cause the release rate of the active agent from
`the polymeric coatings to vary significantly. As a conse-
`quence of the inconsistent release rate profiles among stents,
`there can be clinical complications. Additionally, when
`stents are stored, the release rate from the stent coating can
`change during the storage time, known as "release rate
`drift." Thus, there is a need for a method that reduces the
`variability of the release rate of active agents among stents
`and over time.
`[0015] The present invention provides a method and coat-
`ing to meet the foregoing as well as other needs.
`
`SUMMARY
`
`[0016] According to one aspect of the present invention, a
`method of coating an implantable medical device is dis-
`closed, the method including applying a composition to an
`implantable medical device, the composition including a
`polymer component and a solvent; and heating the polymer
`component to a temperature equal to or greater than the glass
`transition temperature of the polymer component. In one
`embodiment, the temperature is (a) equal to the glass tran-
`sition temperature of the polymer component plus the melt-
`ing temperature of the polymer component, divided by 2; (b)
`equal to 0.9 times the melting temperature of the polymer
`component, wherein the melting temperature of the polymer
`component is expressed in Kelvin; (c) less than the melting
`temperature of the polymer component; (d) greater than the
`melting temperature of the polymer component; or (e) equal
`to or greater than the crystallization temperature of the
`polymer component. In another embodiment, the polymer
`component is heated at a temperature equal to or greater than
`the glass transition temperature until a dry coating is formed
`on the device and optionally for a period of time thereafter,
`the dry coating comprising (a) less than about 10% residual
`solvent or water (w/w); (b) less than about 2% residual
`solvent or water (w/w); (c) less than about 1% residual
`solvent or water (w/w); or (d) 0% residual solvent or water
`(w/w). In one embodiment, the composition is free of any
`active agents, while in another embodiment, the composition
`further includes an active agent.
`[0017] According to another aspect, a method of manu-
`facturing an implantable medical device is disclosed, the
`method including applying a semicrystalline polymer to an
`implantable medical device; and exposing the polymer to a
`temperature equal to or greater than the crystallization
`temperature of the polymer for a duration of time. In one
`embodiment, the polymer includes poly(lactic acid). In
`another embodiment, the polymer includes a block copoly-
`mer or a graft copolymer, wherein a moiety of the block
`copolymer or the graft copolymer is poly(lactic acid).
`
`In another aspect, a method of manufacturing a
`[0018]
`stent having a body made at least in part from a polymer
`component is disclosed, the method comprising exposing
`the polymer component to a temperature equal to or greater
`than the glass transition temperature of the polymer com-
`ponent. In one embodiment, the stent is a biodegradable
`stent.
`[0019] According to a further aspect, a method of manu-
`facturing an implantable medical device is disclosed, the
`method including forming a first region including a first
`polymer on the device; forming a second region of a second
`polymer on the device, the second region including an active
`agent, the first region being over or under the second region;
`and heating (i) the first polymer to a temperature equal to or
`above the glass transition temperature of the first polymer, or
`(ii) the second polymer to a temperature equal to or above
`the glass transition temperature of the second polymer. In
`one embodiment, the first polymer has a glass transition
`temperature greater than the second polymer. In another
`embodiment, the second polymer has a glass transition
`temperature greater than the first polymer.
`In yet another aspect, a method of manufacturing a
`[0020]
`stent coating is disclosed, the method including applying a
`composition to a stent, the composition including a polymer
`and a solvent; allowing some, most or all of the solvent to
`evaporate to form a coating; and exposing the coating to a
`temperature sufficient to increase the crystallinity of the
`polymer in at least a portion of the coating.
`In a further aspect of the present invention, a
`[0021]
`method of manufacturing an implantable medical device is
`disclosed, the device including a polymer and a drug, where
`the method comprises treating the device to a temperature
`greater than ambient temperature for a duration of time,
`wherein the temperature and the duration of exposure are
`sufficient to decrease the release rate of the drug from the
`device after the device has been implanted into a biological
`lumen. In one embodiment, the device is made in whole or
`in part from the polymer. In another embodiment, the
`polymer is biodegradable. In yet another embodiment, the
`standard deviation of the mean release rate of the drug in a
`24 hour period is lower than the standard deviation of the
`mean release rate for a group of devices which have not been
`exposed to the temperature.
`In yet another aspect, a method of manufacturing a
`[0022]
`coating for an implantable medical device is disclosed, the
`method including exposing a polymeric coating on the
`device to a temperature greater than ambient temperature for
`a duration of time, wherein the temperature and the duration
`of exposure is sufficient to increase the adhesion of the
`polymeric coating to the device. In one embodiment, the
`polymeric coating is free from any active agents. In another
`embodiment, the polymeric coating includes an amorphous
`polymer. In yet another embodiment, the polymeric coating
`includes a bioabsorable polymer.
`In a further aspect of the present invention, a
`[0023]
`method-of forming a coating for an implantable medical
`device is disclosed, the method including (a) applying a first
`composition including a first polymer and a solvent on the
`device; (b) heating the first polymer to a temperature equal
`to or greater than about the glass transition temperature of
`the first polymer; (c) applying a second composition includ-
`ing a second polymer and a solvent over the first polymer;
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
`

`

`US 2005/0233062 Al
`
`3
`
`Oct. 20, 2005
`
`and (d) heating the second polymer to a temperature equal
`to or greater than about the glass transition temperature of
`the second polymer. In one embodiment, the heating of the
`first polymer is conducted after removal of some, most or all
`of the solvent in the first composition. In another embodi-
`ment, the heating of the second polymer is conducted after
`removal of some, most or all of the solvent in the second
`composition. In yet another embodiment, the first or the
`second composition, but not both, additionally include an
`active agent.
`
`BRIEF DESCRIPTION OF THE FIGURES
`[0024] FIGS. lA-lH illustrate coatings deposited on an
`implantable medical substrate in accordance with various
`embodiments of the present invention;
`[0025] FIG. 2 is an illustration of a system for thermally
`treating stents;
`[0026] FIG. 3 is a graph of the relationship of heat
`capacity versus temperature for a polymer;
`[0027] FIG. 4 is graph of the relationship of elasticity
`versus temperature for a polymer;
`[0028] FIG. 5 is a graph of the relationship of specific
`volume versus temperature for a polymer;
`[0029] FIG. 6A illustrates a fluid on a solid substrate
`having a contact angle <1> 1 ;
`[0030] FIG. 6B illustrates a fluid on a solid substrate
`having a contact angle <1>2 ;
`[0031] FIG. 7 graphically illustrates elution profiles for
`stents with a coating of ethylene vinyl alcohol copolymer
`impregnated with vinblastine made according to Example 4;
`[0032] FIG. 8 graphically illustrates in vitro experimental
`data, in accordance with Example 15, showing affects of
`actinomycin D, mitomycin, and docetaxel on smooth muscle
`cell proliferation;
`[0033] FIG. 9A is a picture of a histology slide of a
`coronary vessel from the control group in accordance with
`Example 16;
`[0034] FIG. 9B is a picture of a histology slide of a
`coronary vessel from the actinomycin D group in accor-
`dance with Example 16;
`[0035] FIG. lOA is a picture of a histology slide of a
`coronary vessel from the control group in accordance with
`Example 26;
`[0036] FIG. lOB is a picture of a histology slide of a
`coronary vessel from the actinomycin D group in accor-
`dance with Example 26;
`[0037] FIG. 11 is a graph showing the release rate of an
`active agent from stent coatings as referred to in Example
`42;
`[0038] FIG. 12 is a graph showing the release rate of an
`active agent from stent coatings as referred to in Example
`53;
`[0039] FIG. 13 is a chromatograph as referred to in
`Examples 68 and 69;
`
`[0040] FIG. 14 is a graph showing the release rate of an
`active agent from stent coatings as referred to in Example
`72;
`[0041] FIGS. 15-19 are photographs as referred to in
`Example 103; and
`[0042] FIGS. 20-24 are graphs as referred to in Example
`109.
`
`DETAILED DESCRIPTION
`
`[0043] Herein is disclosed a method of manufacturing an
`implantable medical device, such as a stent, by using a
`thermal treatment process. The implantable medical device
`manufactured in accordance with embodiments of the
`present invention may be any suitable medical substrate that
`can be implanted in a human or veterinary patient. In the
`interests of brevity, methods of manufacturing a drug deliv-
`ery or drug eluting stent are described herein. However, one
`of ordinary skill in the art will understand that other medical
`substrates can be manufactured using the methods of the
`present invention. For example, the thermal treatment pro-
`cess can be directed to an implantable medical device having
`a body that includes a polymer, and optionally a drug. In one
`embodiment, the polymer is biodegradable, bioabsorabable
`or bioerodable. The embodiments directed to a coating are
`equally applicable to a device, such as a stent, made from a
`polymer or a combination of polymers.
`
`Coating
`
`[0044] The thermal treatment process described herein
`includes exposing (i.e., heating) a polymer contained in a
`coating. In one aspect of the present invention, the polymer
`is exposed to a temperature sufficient to increase the adhe-
`sion of a coating to an implantable medical device. In
`another aspect, the polymer is exposed to a temperature
`sufficient to decrease the release rate of an active agent from
`a drug coating on an implantable medical device. "Polymer,
`""poly," and "polymeric" are inclusive of homopolymers,
`copolymers, terpolymers etc., including random, alternating,
`block, cross-linked, blends and graft variations thereof. The
`active agent can be any substance capable of exerting a
`therapeutic or prophylactic effect.
`[0045] Some of the embodiments of polymeric coatings
`are illustrated by FIGS. lA-lH. The Figures have not been
`drawn to scale, and the thickness of the various layers have
`been over or under emphasized for illustrative purposes.
`[0046] Referring to FIG. lA, a body of a medical sub-
`strate 20, such as a stent, is illustrated having a surface 22.
`A primer layer 24 is deposited on surface 22. The polymer
`in primer layer 24 is free of any active agents, although
`incidental active agent migration into primer layer 24 can
`occur. Primer layer 24 can include a poly(lactic acid).
`[0047] Referring to FIG. lB, a reservoir layer 26 having
`a polymer and an active agent 28 (e.g., 40-0-(2-hydroxy-
`)ethyl-rapamycin, known by the trade name of everolimus,
`available from Novartis as Certican™) dispersed in the
`polymer is deposited on surface 22. Reservoir layer 26 can
`release the active agent when medical substrate 20 is
`inserted into a biological lumen.
`[0048] Referring to FIG. lC, reservoir layer 26 is depos-
`ited on primer layer 24. Primer layer 24 serves as an
`
`KASHIV1061
`IPR of Patent No. 9,492,393
`
`

`

`US 2005/0233062 Al
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`4
`
`Oct. 20, 2005
`
`intermediary layer for increasing the adhesion between
`reservoir layer 26 and surface 22. Increasing the amount of
`active agent 28 admixed within the polymer can diminish
`the adhesiveness of reservoir layer 26 to surface 22. Accord-
`ingly, using an active agent-free polymer as an intermediary
`primer layer 24 allows for a higher active agent content for
`reservoir layer 26.
`[0049] The coating of the present invention can also have
`multiple primer and reservoir layers, the layers alternating
`between the two types of