(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2009/0035251 A1
`
` Wortzman et al. (43) Pub. Date: Feb. 5, 2009
`
`
`US 20090035251A1
`
`(54) METHOD OF APPLYING AN INJECTABLE
`FILLER
`Inventors:
`
`(76)
`
`Mitchell S. Wortzman, Scottsdale,
`AZ (US); Rhoda Narins, Scarsdale,
`NY (US); Xiaoming Lin, Cave
`Creek, AZ (US)
`
`Corresmndence Addressz
`KNOBBE MARTENS OLSON & BEAR LLP
`2040 MAIN STREET, FOURTEENTH FLOOR
`IRVINE, CA 92614 (US)
`
`(21) Appl. No.:
`
`12/184,966
`
`(22)
`
`Filed:
`
`Aug. 1, 2008
`.
`.
`Related US Application Data
`(60) Provisional application No. 60/953,661, filed onAug.
`23 2007.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`A61K 31/755
`A61K 31/728
`A61K 35/36
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`(52) us. Cl. ......................... 424/7831; 514/54; 424/574
`
`(57)
`
`ABSTRACT
`
`Methods for applying injectable fillers are provided. In some
`embodiments, the methods can extend effectiveness of the
`injectable filler. In some embodiments, the methods can pro-
`vide for an elevated level of effectiveness of the injectable
`filler. In some embodiments, the methods can prolong the
`effectiveness of the injectable filler.
`
`Visit 2
`
`(2 weeks
`
`after Visit 1
`
`or 2 weeks
`after Visit
`T)
`
`Photo‘ and
`
`A55
`
`I
`
`No
`Touch»up
`required
`2 Weeks
`Afier Visit
`
`1
`
`‘
`
`,
`M
`(Day 0)
`Screening
`and
`mama”
`
`Touch—up
`required
`2 WEEKS
`After Visit
`1
`
`
`
`Visit T
`(2 Weeks
`after Visit
`1)
`Photo, ABS
`and touch-
`
`u
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Visit3
`(4.5 months
`after Initial
`treatment or
`touch—u p)
`Photo
`Re—treatment
`one side
`
`'
`
`Visit4
`(9
`Months
`after
`initial ’
`treatment
`or touch-
`up)
`Photo
`Re-
`treatment
`contralater
`al side
`
`*
`
`Visit 5
`(12
`Months
`after
`initial
`treatment
`or touch-
`up)
`Photo
`
`Visit 6
`115
`Months
`after +
`initial
`treatment
`or touch-
`up)
`Photo
`
`,7”
`
`_,
`
`Visit 8
`(24
`Months
`aner
`initial
`treatment
`1
`11.
`or one
`UP)
`Photo
`
`Visit 7
`(18
`Months
`after +
`initial
`treatment
`or touch-
`UP)
`Photo
`Re-
`treatment
`both sides
`
`‘>
`
`Visit 9
`‘27
`Months
`after
`initial
`treatment
`or touch-
`up)
`Photo
`
`Visit 10
`(30
`Months
`after
`initial
`treatment
`or touch-
`up)
`Photo
`
`Page1
`
`Teoxane S.A.
`
`
`Exhibit 1005
`
`Page 1
`
`

`

`Patent Application Publication
`
`Feb. 5, 2009 Sheet 1 0f 11
`
`US 2009/0035251 A1
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`Page 2
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`Patent Application Publication
`
`Feb. 5, 2009 Sheet 2 0f 11
`
`US 2009/0035251 A1
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`Page 3
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`

`

`Patent Application Publication
`
`Feb. 5, 2009 Sheet 3 0f 11
`
`US 2009/0035251 A1
`
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`Page 4
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`

`

`Patent Application Publication
`
`Feb. 5, 2009 Sheet 4 0f 11
`
`US 2009/0035251 A1
`
`FIGURE 4
`
`Evaluator Wrinkle Severity Rating Scale (WSRS)
`(Intent to Treat Population)
`
`+ Re-Treated 41/2 Months
`Re»Treated 9 Months
`
`(WSRS)
`
`
`MeanImprovementScore
`
`\fisit 2
`(2 Weeks)
`
`Visit 3
`(Month 4%)
`
`\fisit 4
`(Month 9)
`
`\fisit 5
`(Month 12)
`
`\fisit 6
`(Month 15)
`
`Visit 7
`(Month 18)
`
`1 The positive change from initial baseline visit (current visit WSRS — initial visit WSRS).
`
`Page 5
`
`Page 5
`
`

`

`Patent Application Publication
`
`Feb. 5, 2009 Sheet 5 0f 11
`
`US 2009/0035251 A1
`
`FIGURE 5
`
`Mean Evaluator Wrinkle Severity Rating Scale (WSRS)
`(Intent to Treat Population)
`
`—I- Re—Treated 41/2 Months
`Re-Treated 9 Months
`
`MeanWSRS
`
`\fisit 2
`(2 Weeks)
`
`Visit 3
`(Month 41/2)
`
`\fisit 4
`(Month 9)
`
`Wait 5
`(Month 12)
`
`\fisit 6
`(Month 15)
`
`\fisit 7
`(Month 18)
`
`Page 6
`
`Page 6
`
`

`

`Patent Application Publication
`
`Feb. 5, 2009 Sheet 6 0f 11
`
`US 2009/0035251 A1
`
`FIGURE 6
`
`Mean Improvement Score1
`Evaluator Wrinkle Severity Rating Scale (WSRS)
`(Completersi)
`
`1.9
`
`Re-Treated 4% Months
`(AUG: 23.9, AUC/TVI= 11,4)
`Re»Treated 9 Months
`(AUG: 23.7, AUC/TVI= 11.4)
`
`_\_‘_.to'01k1
`
`_.
`
`A
`
`0.9
`
`
`
`MeanImprovementScore(WSRS)
`
`
`
`
`
`\fisit 2
`(2 Weeks)
`
`Wait 3
`(Month 4%)
`
`\fisit 4
`(Month 9)
`
`Wait 5
`(Month 12)
`
`\fisit 6
`(Month 15)
`
`Visit 7
`(Month 18)
`
`‘ The positive change from initial baseline visit (current visit WSRS - initial visit WSRS).
`2 Patients with blinded evaluator scores available at all visits and with no missing data for injection volume.
`
`Page 7
`
`Page 7
`
`

`

`Patent Application Publication
`
`Feb. 5, 2009 Sheet 7 0f 11
`
`US 2009/0035251 A1
`
`FIGURE 7
`
`Mean Improvement Score1
`Evaluator Wrinkle Severity Rating Scale (WSRS)
`(Intent to Treat Population)
`
`—I—-— Re-Treated 41/2 Months
`Re-Treated 9 Months
`
`(WSRS)
`
`
`MeanImprovementScore
`
`02
`
`3
`
`4%
`
`6
`
`71/2
`
`9
`
`10V:
`
`1372
`
`
`
`‘ The positive change from initial baseline visit (current visit WSRS - initial visit WSRS).
`2 Time at which initial rte—treatment was received.
`
`Time Since Re—treatment (months)
`
`Page 8
`
`Page 8
`
`

`

`Patent Application Publication
`
`Feb. 5, 2009 Sheet 8 0f 11
`
`US 2009/0035251 A1
`
`
`
`
`
`100.0
`
`80.0 -
`
`60.0
`
`40.0
`
`20.0
`
`
`
`%SubjectswithZ1GradeImprovement
`
`
`
`
`
`
`
`0.0 -
`
`Month 4.5
`
`Month 9
`
`Month 12
`
`Month 15
`
`Month 18
`
`
`
`
`
`a Blinded Evaluator
`l independent Photo Reviewer
`Cl Subject
`
`
`Follow-up Visit
`
`Error bar=Exact 95% confidence interval of the proportion
`
`FIG. 8: Proportion of subjects With at least one grade improvement
`from baseline — side re-treated at 4.5 months
`
`Page 9
`
`Page 9
`
`

`

`Patent Application Publication
`
`Feb. 5, 2009 Sheet 9 0f 11
`
`US 2009/0035251 A1
`
`
`
`
`
`100
`
`
`
`%Subjectswith21GradeImprovement
`
`
`
`8O 7“
`
`607‘
`
`
`40
`
`
`
`Month 4.5
`
`Month 9
`
`Month 12
`
`Month 15
`
`Month 18
`
`Follow-up Visit
`
`El Blinded Evaluator
`I independent P hoto Reviewer
`El Subject
`
`
`Error bar=Exact 95% confidence interval of the proportion
`
`FIG. 9: Proportion of subjects with at least one grade
`improvement from baseline — side re—treated at 9 months
`
`Page 10
`
`Page 10
`
`

`

`Patent Application Publication
`
`Feb. 5, 2009 Sheet 10 0f 11
`
`US 2009/0035251 A1
`
`
`
`
`
`._\
`
`CDN
`
`
`
`
`
`
`
`
`
`
`
`
`,‘
`
`
`
`9o9#CDCO
`
`.0 N
`
`0
`
`
`
`
`
`
`
`MeanImprovementfromBaseline
`
`
`
`El Blinded Evaluator
`l Independent P hoto Reviewer
`D Subject
`
`
`Month 4.5
`
`Month 9
`
`Month 12
`
`Month 15
`
`Month 18
`
`Follow-up Visit
`
`FIG. 10: Mean improvement from baseline — side re—
`treated at 4.5 months
`
`Page11
`
`Page 11
`
`

`

`Patent Application Publication
`
`Feb. 5, 2009 Sheet 11 of 11
`
`US 2009/0035251 A1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_\._\_\—|
`
`Amnmoom
`
`oooA0300
`
`.0 N
`
`0
`
`
`
`
`
`Meanlmprovemen:fromBaseline
`
`
`
`Month 4.5
`
`Month 9
`
`Month 12
`
`Month 15
`
`Month 18
`
`a Blinded Evaluator
`l independent Photo Reviewer
`El Subject
`
`Follow-up Visit
`
`
`
`FIG. 11: Mean improvement from baseline — side re-
`treated at 9 months
`
`Page12
`
`Page 12
`
`

`

`US 2009/0035251 A1
`
`Feb. 5, 2009
`
`METHOD OF APPLYING AN INJECTABLE
`FILLER
`
`RELATED APPLICATIONS
`
`[0001] This application claims priority to US. Provisional
`Application Ser. No. 60/953,661, filed Aug. 2, 2007, hereby
`incorporated by reference in its entirety.
`
`FIELD OF THE INVENTION
`
`[0002] Methods and systems for using dermal fillers are
`disclosed.
`
`BACKGROUND OF THE INVENTION
`
`Description of the Related Art
`
`[0003] A variety of methods and substances exist for add-
`ing volume or firmness to a subject or subject’s face for
`cosmetic purposes. Despite the fact that such methods are
`being used with ever increasing frequency, the art has seen
`little in the way of developments in regard to certain aspects
`of these treatment methods.
`
`SUMMARY OF THE INVENTION
`
`In some aspects, the present disclosure provides a
`[0004]
`method for maintaining and/or prolonging injectable filler
`composition efiicacy. This can be especially relevant to
`increase the aesthetic benefit of implanted materials.
`[0005]
`In some aspects, the present disclosure provides a
`method of injecting an injectable filler such as hyaluronic
`acid (HA) so that it provides longer lasting, superior, or longer
`lasting and superior benefits. In some embodiments, these
`benefits can include improved volume and/or firmness to a
`subject’s skin.
`[0006]
`In some aspects, the invention comprises a method
`for providing an injectable filler composition to a subject for
`cosmetic purposes. The method can comprise performing an
`initial treatment session on a subject that comprises a first
`injection of a first injectable filler composition into the sub-
`ject at a target area, thereby providing an increase in volume
`and/or firmness to the target area. The method can further
`comprise performing a re-treatment session on the subject.
`The re-treatment session can comprise a second injection of a
`second injectable filler composition into the target area at a
`time subsequent to the initial treatment session. The second
`injection extends the increase in volume and/or firmness of
`the target area. The time subsequent to the initial treatment
`session is in the range of 1 month to less than 9 months, and
`at least one ofthe first or second inj ectable filler compositions
`comprises hyaluronic acid.
`[0007]
`In some aspects, the invention comprises a method
`for providing a target area of a subject with a continuing
`increase in firmness and/or volume following a re-treatment
`session of an injectable filler composition. The method can
`comprise identifying a subject that will benefit from a con-
`tinuing increase in a volume and/or firmness of a target area
`during a period following a re-treatment session and continu-
`ing for at least 13 months after the re-treatment session. The
`volume and/or firmness can increase throughout this period.
`The method can further comprise performing an initial treat-
`ment session on the subject. The initial treatment session can
`comprise a first injection ofa nonanimal stabilized hyaluronic
`acid and thereby provide an increase in volume and/or firm-
`ness to the target area. The method can further comprise
`
`performing a re-treatment session on the subject. The re-
`treatment session can comprise a second injection of the
`nonanimal stabilized hyaluronic acid into the target area at a
`time subsequent to the initial treatment session. The subject’s
`global aesthetic improvement scale can continue to improve
`for at least 10.5 months following the re-treatment session.
`The re-treatment session can occur 2 to 6 months after the
`
`initial treatment session. The subject can maintain at least a 1
`point improvement in a global aesthetic improvement scale
`score and/or a wrinkle severity rating score for 18 months
`after the initial treatment session. In some embodiments, the
`subject receives no additional injections of said nonanimal
`stabilized hyaluronic acid to the target area, except for the
`initial treatment session and the re-treatment session.
`
`In some aspects, the invention comprises a kit for
`[0008]
`providing a continuing increase in firmness and/or volume
`from an inj ectable filler composition. The kit can comprise a
`dermal filler, a syringe, a needle, and instructions to l) per-
`form an initial treatment session on a subject. The initial
`treatment session comprises a first injection of a first inject-
`able filler composition into the subject at a target area, which
`provides an increase in volume and/or firmness to the target
`area. The instructions further instruct one to 2) perform a
`re-treatment session on the subject. The re-treatment session
`comprises a second injection of a second injectable filler
`composition into the target area at a time subsequent to the
`initial treatment session. The second injection extends the
`increase in volume and/or firmness of the target area. The
`time subsequent to the initial treatment session is in the range
`of 1 month to less than 9 months. At least one of the first or
`
`second injectable filler compositions comprises hyaluronic
`acid.
`
`[0009] These and other embodiments are described in
`greater detail below.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a schematic depicting a protocol for a study
`[0010]
`involving comparison of a re-treatment session after 4.5
`months with re-treatment session after 9 months.
`
`FIG. 2 is a table outlining the schedule ofprocedures
`[0011]
`for a trial study involving comparison of a re-treatment ses-
`sion after 4.5 months with re-treatment session after 9
`months.
`
`FIG. 3 is a bar graph summarizing results from a
`[0012]
`trial study. The bar graph shows a comparison of the percent
`of responders that received a re-treatment session at 4.5
`months to the percent of responders that received a re-treat-
`ment session after 9 months.
`
`FIG. 4 is a line graph summarizing results from a
`[0013]
`trial study. The line graph shows a comparison of the
`improvement resulting from re-treatment at 4.5 months with
`re-treatment after 9 months at the indicated time points.
`[0014]
`FIG. 5 is a line graph summarizing results from a
`trial study. The line graph shows a comparison of wrinkle
`severity from re-treatment at 4.5 months with re-treatment
`after 9 months at the indicated time points.
`[0015]
`FIG. 6 is a line graph summarizing results from a
`trial study. The line graph shows a comparison of the
`improvement resulting from re-treatment at 4.5 months with
`re-treatment after 9 months at the indicated time points. The
`data used to prepare the curves represents the completers
`subset of the data.
`
`FIG. 7 is a line graph summarizing results from a
`[0016]
`trial study. The line graph shows a comparison of the
`
`Page 13
`
`Page 13
`
`

`

`US 2009/0035251 A1
`
`Feb. 5, 2009
`
`improvement resulting from re-treatment at 4.5 months with
`re-treatment after 9 months at the indicated time points. The
`zero time in the graph represents the time immediately fol-
`lowing the re-treatment time.
`[0017]
`FIG. 8 is a graph depicting the percent of subjects
`with at least one grade of improvement from baseline by Visit
`for the 4.5 month re-treatment.
`
`FIG. 9 is a graph depicting the percent of subjects
`[0018]
`with at least one grade of improvement from baseline by visit
`for the 9 month re-treatment.
`
`FIG. 10 is a graph depicting the mean improvement
`[0019]
`from baseline by visit for the WSRS results for the re-treat-
`ment at 4.5 months.
`
`FIG. 11 is a graph depicting the mean improvement
`[0020]
`from baseline by visit for the WSRS results for the re-treat-
`ment at 9 months.
`
`[0021] While the subject matter of this application can now
`be described in detail with reference to the figures, it is done
`so in connection with the illustrative embodiments. It is
`
`intended that changes and modifications can be made to the
`described embodiments without departing from the true
`scope and spirit of the subject invention as defined in part by
`the appended claims.
`
`DETAILED DESCRIPTION OF THE PREFERRED
`EMBODIMENT
`
`It has now been realized that the standard method of
`[0022]
`adding volume or firmness to a subject by administering a
`dermal filler (for example, via a single treatment session),
`while adequate for some purposes, has various shortcomings.
`The present disclosure provides various methods for admin-
`istering dermal fillers, and particularly hyaluronic acid based
`dermal fillers, to subjects. It has now been discovered that a
`specific manner of repeated administration of such dermal
`fillers (a “re-treatment”) can result in numerous surprisingly
`superior results. At a first level, the repeated administration
`techniques described herein can not only extend the effective-
`ness of the inj ectable filler, but actually provide for effective-
`ness that lasts longer than what would be expected from two
`independent applications of an injectable filler. Simply put, in
`some embodiments there is a synergistic result when the
`described method is employed that provides for results that
`last for a length oftime that is surprisingly long. Furthermore,
`in some embodiments, the degree or extent of the improve-
`ment itself, at various time points following the re-treatment,
`is also improved over what would ordinarily be expected from
`two unrelated administrations of a dermal filler; thus, not only
`is the duration ofthe benefit extended, but the degree or extent
`of the benefit itself is also improved. In addition, in some
`embodiments, the timing of the re-treatment session can
`allow one to maintain more ofthe benefits from the inj ectable
`filler throughout a continuous period, without losing some of
`the benefits of the initial treatment session. Furthermore, in
`some embodiments,
`the actual amount of dermal
`filler
`required to obtain the above surprising and superior results, is
`surprisingly less than the amount required for two traditional
`treatment sessions. In some embodiments, not only does the
`method provide a synergistically long lasting and unexpect-
`edly high level of volume and/or firmness throughout the
`longer period of time, but such results are achieved with
`substantially less dermal filler than would be expected for two
`separate administrations. As described herein, not all of the
`embodiments will exhibit all of these superior and unex-
`
`pected results; however, many of the embodiments can
`exhibit more than one of the above noted surprising and
`superior results.
`the methods described
`[0023]
`In some embodiments,
`herein involve applying an inj ectable filler to correct areas or
`locations that appear to lack volume or are “under volume,”
`and, at a subsequent time (as a separate treatment session),
`re-treating the area with the inj ectable filler composition. As
`noted below, this retreatment session will occur within a
`specific time period and/orbefore the subject might otherwise
`believe that they would benefit from an additional adminis-
`tration of the injectable filler composition (absent the infor-
`mation provided in the present disclosure). In some embodi-
`ments, the re-treatment session is provided within or less than
`9 months from the initial treatment session. In addition, in
`order for the re-treatment session to provide some of the
`benefits described herein, at least one of the sessions will
`involve an injectable filler composition that can induce or
`stimulate collagen production (such as a hyaluronic acid-
`containing composition). In some embodiments, further sur-
`prising and unexpected results can be obtained if the re-
`treatment session is provided less than 6 months from the
`initial treatment date. In some embodiments, re-treatment can
`slow the rate of resorbtion of the injectable filler after re-
`treatment. In some embodiments, re-treatment can slow the
`rate of resorbtion of the injectable filler after re-treatment by
`maintaining tissue expansile tension. Thus, in some embodi-
`ments, the re-treatment procedure can provide results lasting
`for at least 13.5 months if not longer. In some embodiments,
`little or no loss of volume is observed after about 18 months
`after initial treatment.
`
`In some embodiments, re-treatment can be per-
`[0024]
`formed, for example, prior to the occurrence of an unfavor-
`able change in wrinkle severity in the treated area. One advan-
`tage of such an embodiment is that a substantial increase to a
`subject’s baseline wrinkle severity can be avoided throughout
`a longer duration of time. Thus, in some embodiments, it has
`been appreciated that the timing of the re-treatment schedule
`can be such that one can reduce decreases or losses in a first
`
`treatment’s effectiveness, while still providing for a second
`treatment (the “re-treatment”) in a sufficient period oftime to
`allow for the enhanced duration of effectiveness of the treat-
`ment.
`
`It has also been appreciated that many traditional
`[0025]
`techniques do not take full advantage of the characteristics of
`volumetric fillers. Thus, some of the disclosed embodiments
`are useful in allowing one to improve the results of treatment
`with inj ectable fillers. In some embodiments, re-treatment
`provides continued improvement of volume and/or firmness.
`In some embodiments, the improvement is continuous over a
`period oftime up to about, for example, 13 or 14 months after
`re-treatment. In some embodiments, the improvement is due
`at least in part to the stimulation of collagenesis. For example,
`re-treatment can increase collagen production by fibroblasts.
`These, and additional aspects, are discussed in greater detail
`below. However, these aspects are not to be interpreted as
`limiting upon the claims, unless explicitly recited in the
`claims themselves.
`
`[0026] The present description first describes various terms
`used in describing various aspects described herein. A general
`description of various embodiments of the administration
`methods is then provided and is followed by a more detailed
`description of specific aspects of the methods and variations.
`
`Page 14
`
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`

`US 2009/0035251 A1
`
`Feb. 5, 2009
`
`An additional section regarding additional embodiments is
`then provided. Finally, examples of using the various meth-
`ods are disclosed.
`
`DEFINITIONS AND VARIOUS EMBODIMENTS
`
`[0027] The terms “injectable filler composition” and
`“injectable filler” are used in their ordinary sense as under-
`stood by those skilled in the art and thus include a composi-
`tion that can be administered through injection into or
`beneath the skin ofa subject. The injectable filler composition
`should not be unduly problematic for the subject receiving the
`composition. As can be appreciated by one of skill in the art,
`there are a large number of compositions that can be used as
`a filler for various embodiments disclosed herein. In some
`embodiments, the fillers are dermal fillers. In some embodi-
`ments, the filler is selected from RESTYLANE® and PER-
`LANE® dermal fillers. Examples of fillers include those dis-
`closed in US. Pat. Nos. 5,633,001, 5,007,940, 5,827,937,
`5,128,326, 5,399,351, and 5,143,724, as well as PCT Pub.
`No. WO 87/07898, all of which are herein incorporated by
`reference in their entireties. In some embodiments, the com-
`position is a cross-linked biocompatible polysaccharide gel
`composition.
`In some embodiments,
`the composition is
`formed by forming an aqueous solution of a water soluble,
`cross-linkable polysaccharide; initiating a cross-linking of
`said polysaccharide in the presence of a polyfunctional cross-
`linking agent; sterically hindering the cross-linking reaction
`from being terminating before gelation occurs, an activated
`polysaccharide thereby being obtained; and reintroducing
`sterically unhindered conditions for said activated polysac-
`charide so as to continue the cross-linking thereof up to a
`viscoelastic gel.
`[0028]
`In some embodiments, the injectable filler is char-
`acterized by its source. In some embodiments, the source can
`be biologic and/or synthetic. Biologic inj ectable fillers can be
`those that are derived from a living organism. Synthetic
`injectable fillers can further be divided into two groups, a)
`man-made fillers for which there is no biologic counterpart
`and b) man-made substances for which there is a counterpart
`biologic. In some embodiments, the injectable filler can be
`characterized by the body’s ability to clear a product without
`external intervention (e.g., these can be biodegradable or
`nonbiodegradable).
`[0029] Examples of biologic, biodegradable fillers are
`those that include materials derived from organism, human,
`and/or animal tissues and/or products. Examples of such fill-
`ers include the following: hyaluronic acid, (such as the fol-
`lowing: avian HA, bovine HA, and non-animal stabilized HA
`(“NASHA”, e.g., RESTYLANE® (injectable filler)), col-
`lagen (such as collagen I, collagen II, collagen III, cross-
`linked and/or noncross-linked, bovine, porcine, human, and
`autologous collagen). Additional examples of collagen based
`fillers include ZYPLAST® (collagen derived from bovine
`tissue), ZYDERM® I (collagen derived from bovine tissue),
`ZYDERM® II, (collagen derived from bovine tissue), EVO-
`LENCETM (porcine derived collagen), and FIBRELTM (por-
`cine derived collagen). As can be appreciated by one of skill
`in the art, in some embodiments, the injectable filler is self-
`replicating, and can include living cells (such as collagen-
`producing cells or fibroblasts). Thus, in some embodiments
`there are inj ectable fillers that are biological and are relatively
`long lasting or relatively “permanent.”
`[0030]
`Synthetic, biodegradable, injectable fillers include
`RADIANCETM and RADIESSETM (microspheres of at least
`
`calcium and phosphate ions) inj ectable fillers, polyacids and
`polyethers described in US. Pat. No. 7,192,984 (e.g., car-
`boxymethyl cellulose (CMC) and polyethylene oxide), and
`LARESSE® (polymer, polyacid, and/or polyether, similar
`but not identical to HA type materials).
`injectable fillers
`[0031]
`Synthetic, non-biodegradable,
`include injectable fillers that are not readily broken down in
`the body. Synthetic, non-biodegradable, injectable fillers can
`include injectable fillers that include a biologic component
`(and vice versa). In some embodiments, at least a portion of
`product cannot be significantly broken down by various body
`processes. Additional examples of synthetic non-biodegrad-
`able fillers include the following: ARTEFILTM (polymethyl-
`methacrylate (PMMA) microspheres suspended in bovine
`collagen), ARTECOLTM (polymethylmethacrylate (PMMA)
`microspheres suspended in bovine collagen), polymethyl-
`methacrylate (Plexiglas) in bovine collagen carrier, dena-
`tured, silicone, and various polymers, polyacids, and poly-
`ethers.
`In some embodiments,
`the carrier has
`rapid
`biodegradation. Of course, as can be appreciated by one of
`skill in the art, in some embodiments, any one, combination,
`or ingredient of the above fillers can be combined with the
`other fillers (or alternative fillers) in various embodiments
`and for particular results.
`[0032] As can be appreciated by one of skill in the art,
`injectable fillers need not be categorized by both their source
`and their ability to stay or be cleared from the body. That is,
`some fillers can simply be biological, synthetic, biodegrad-
`able, or nonbiodegradable. Additionally, as can be appreci-
`ated by one of skill in the art, some injectable fillers can
`include parts or aspects of various combinations of the above
`or following substances.
`[0033] Examples of injectable fillers include a substance
`selected from the following: collagen, fat, human or animal
`derived collagen, bovine collagen, type I collagen, type II
`collagen, type III collagen, 3.5% bovine dermal collagen
`cross-linked by glutaraldehyde to form a latticework, natural
`human collagen, autologous collagen, polymethylmethacry-
`late microspheres (optionally suspended in bovine collagen),
`suspension of collagen fibers prepared from the subject’s
`tissue, human tissue collagen matrix derived from cadaveric
`dermis, the polyacids and polyethers described in US. Pat.
`No. 7,192,984 (e.g., carboxymethyl cellulose (CMC) and
`polyethylene oxide), acellular human cadaveric dermis that
`has been freeze-dried, micronized acellular human cadaveric
`dermis that has been freeze-dried, cultured autologous fibro-
`blasts, hyaluronic acid, non-animal-stabilized hyaluronic
`acid derivative, microspheres of calcium hydroxyl appetite
`suspended in an aqueous gel carrier, dextran beads suspended
`in hylan gel of nonanimal origin (e.g., 40- to 60-um in diam-
`eter), solubilized elastin peptides with bovine collagen, sili-
`cone, solubilized elastin peptides with bovine collagen, poly-
`L-lactic acid, Gore-Tex (PTFE), glycosylated collagen,
`PMMA, bone-forming calcium apatite, cultured human cells,
`expanded polytetrafluoroethylene (e-PTFE), SOFTFORM®
`of ePTFE, and some combination thereof. Further examples
`of injectable fillers include the following: AQUAMID®
`(comprising water and cross-linked polymers), ARTEFIL®
`(polymethylmethacrylate (PMMA) microspheres suspended
`in bovine collagen), LARESSE® Dermal Filler (synthetic,
`biocompatible polymers, non-HA gel comprising absorbable
`medical polymers), ARTECOLL® (polymethylmethacrylate
`(PMMA) microspheres
`suspended in bovine collagen),
`BELOTERO®, BIO-ALCAMIDTM (synthetic
`reticulate
`
`Page 15
`
`Page 15
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`

`US 2009/0035251 A1
`
`Feb. 5, 2009
`
`(poly-alkyl-imide), CAPTIQUETM (non-animal
`polymer
`hyaluronic acid), COSMODERMTM (human collagen skin
`filler), COMOPLASTTM, CYMETRA®, autologen, DER-
`MALOGEN®, FASCIANTM (fascia), fascia, fat, HylaformTM
`(avian hyaluronic acid), JUVEDERM® (biosynthesized,
`non-animal hyaluronic acid), RADIESSETM (microspheres
`of at least calcium and phosphate ions), SCULPTRA® (poly-
`L-lactic acid (PLLA)), collagen, hyaluronic acid, RESTY—
`LANE®, PERLANE®, ZYDERM®, ZYPLAST® (collagen
`derived from bovine tissue), DERMALIVE®, (hyaluronic
`acid and acrylic hydrogel particles), DERMADEEP® (hyalu-
`ronic acid and acrylic hydrogel particles), HYDRAFILL®,
`ISOLAGEN® (cultured autologous human fibroblasts),
`LARESSE® (carboxymethylcellulose (CMC) and polyeth-
`ylene oxide (PEO) filler), PURAGENTM (filler comprising
`double cross-linked hyaluron molecules), REVIDERM®
`INTRA (filler comprising flexible dextran micro-beads sus-
`pended in super-coiled, stabilized hyaluronic acid), SCULP-
`TRATM (Formerly NEW-FILLTM, filler from poly-L-lactic
`acid), Teosyal, SURGIDERM® (hyaluronic acid filler
`involving 3D hyaluronic acid matrix technology), OUT-
`LINE®, ANIKA®, Cosmetic tissue augmentation (CTA,
`from Anika), and combinations thereof.
`[0034] As can be appreciated by one of skill in the art, any
`of the above fillers or components thereof can include other
`materials, for example, anesthetic materials, including, with-
`out limitation, lidocaine, prilocalne, tetracaine, etc.
`[0035]
`“Volumetric filler” is a type of injectable filler com-
`position. Volumetric fillers can be dermal fillers. In some
`embodiments, the volumetric filler is capable of crosslinking
`and/or is cross-linked. Cross-linked compositions allow the
`filler to have predictably no or minimal volume or substance
`loss on injection. In some embodiments they also provide
`predictable expansion or “swelling” with re-hydration on
`injection: swelling to no more than 10% volume increase; not
`“shrinking” or losing volume as some fillers that lose water
`uncross-linked HA volumes; and/or have sufficient tensile
`compression resistance. In some embodiments, the volumet-
`ric filler involves microbead technology (e.g., as disclosed in
`US. Pat. Nos. 5,633,001 and 5,007,040, herein incorporated
`by reference in their entireties). In some embodiments, this
`allows compression resistance. In some embodiments this
`allows for the composition to have the ability to resist dis-
`placement. Other fillers, described as “slurries,” can be used
`but can be prone to displacement (e.g., disclosed in US. Pat.
`Nos. 5,143,724, 5,633,001, herein incorporated by reference
`in their entireties). In some embodiments, the filler has the
`biocompatibility and “feel” of tissue rather than bony
`implants or sedimentary products that can feel hard. How-
`ever, bony implant or sedimentary fillers can also be used in
`some embodiments.
`
`“Dermal filler” is a type of injectable filler compo-
`[0036]
`sition. Dermal filler denotes that the filler is compatible for
`use in or under the skin. Dermal fillers can be volumetric
`
`fillers. In some embodiments, the dermal filler composition
`comprises, consists, or consists essentially of a hyaluronic
`acid or hyaluronic acid derivative. The term “hyaluronic acid”
`includes salts and bases th