I 1111111111111111 11111 111111111111111 IIIII IIIII IIIII IIIII lll111111111111111
`US008357795B2
`
`c12) United States Patent
`Lebreton
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,357,795 B2
`*Jan. 22, 2013
`
`(54) HYALURONIC ACID-BASED GELS
`INCLUDING LIDOCAINE
`
`(75)
`
`Inventor: Pierre F. Lebreton, Annecy le-Vieux
`(FR)
`
`(73) Assignee: Allergan, Inc., Irvine, CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 612 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 12/393,884
`
`(22) Filed:
`
`Feb.26,2009
`
`(65)
`
`Prior Publication Data
`
`US 2010/0028438 Al
`
`Feb. 4, 2010
`
`Related U.S. Application Data
`
`(60) Provisional application No. 61/085,956, filed on Aug.
`4, 2008, provisional application No. 61/087,934, filed
`on Aug. 11, 2008, provisional application No.
`61/096,278, filed on Sep. 11, 2008.
`
`(51)
`
`Int. Cl.
`(2006.01)
`C07H 1100
`(52) U.S. Cl. ........................... 536/124; 514/54; 424/488
`(58) Field of Classification Search .................. 424/484;
`514/54; 536/124
`See application file for complete search history.
`
`(56)
`
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`
`Primary Examiner - Ali Soroush
`(74) Attorney, Agent, or Firm -Linda Fox; Stephen
`Donovan; Debra Condino
`
`ABSTRACT
`(57)
`Disclosed herein are cohesive soft tissue fillers, for example,
`dermal and subdermal fillers, based on hyaluronic acids and
`pharmaceutically acceptable salts thereof. In one aspect,
`hyaluronic acid-based compositions described herein include
`a therapeutically effective amount of at least one anesthetic
`agent, for example, lidocaine. The present hyaluronic acid(cid:173)
`based compositions including lidocaine have an enhanced
`stability and cohesivity, relative to conventional composi(cid:173)
`tions including lidocaine, for example when subjected to
`sterilization techniques or when stored for long periods of
`time. Methods and processes of preparing such hyaluronic
`acid-based compositions are also provided.
`
`41 Claims, 5 Drawing Sheets
`
`Exhibit 1082
`Prollenium v. Allergan
`
`

`

`US 8,357,795 B2
`Page 2
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`

`US 8,357,795 B2
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`
`* cited by examiner
`
`

`

`U.S. Patent
`
`Jan.22,2013
`
`Sheet 1 of 5
`
`US 8,357,795 B2
`
`SAMPLE 1
`700 - - - . - - - - - - - - - - - - - - - - - - -~
`600 - - - - - - - - - - - -1 ---<>-- No Lido
`~ Lido with pH control
`500
`Lido no pH control
`--0---
`
`0 - - - - 1 - - - - - - - - - -~ - - - - - - - - -
`0.1
`10
`1
`Frequency (Hz)
`
`FIG. 1
`
`SAMPLE2
`300 ~ - - - - - - - - - - - - - - - -~
`
`200
`
`---<>-- No Lido
`~ Lido with pH control
`--o---
`Lido no pH control
`
`---------------
`
`0 - - ; - - - - - - - - - - - - - - r - - - - - - - - - -....
`0.1
`10
`1
`Frequency (Hz)
`
`FIG. 2
`
`

`

`U.S. Patent
`
`Jan.22,2013
`
`Sheet 2 of 5
`
`US 8,357,795 B2
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`,e-
`"!g
`G
`~
`
`0
`
`0.1
`
`~
`~
`G
`~
`
`16
`
`14
`
`12
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`SAMPLEJ
`
`---<)- -
`No Udo
`~ Lido with pH control
`Lido no pH control
`--0--
`
`---------------
`
`1
`Frequency (Hz)
`
`10
`FIG. 3
`
`SAMPLE4
`
`---<>-- No Lido
`~ Lido with pH control
`--o--
`Lido no pH control
`
`' ' '
`' '
`' '
`'
`'
`
`------------
`
`--
`
`0.1
`
`1
`Frequency (Hz)
`
`10
`FIG. 4
`
`

`

`U.S. Patent
`
`Jan.22,2013
`
`Sheet 3 of 5
`
`US 8,357,795 B2
`
`120
`
`100
`
`~ -~
`~
`
`Cj
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0.1
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`~ 0.4
`0.3
`
`~
`
`0.2
`
`0.1
`
`0
`
`0.1
`
`SAMPLES
`
`---0---
`No Lido
`~ Lido with pH control
`Lido no pH control
`--0--
`
`10
`FIG. 5
`
`1
`Frequency (Hz)
`
`SAMPLES
`
`---
`
`------
`
`---0---
`No Lido
`~ Lido with pH control
`--o--
`Lido no pH control
`
`1
`Frequency (Hz)
`
`10
`FIG. 6
`
`

`

`U.S. Patent
`
`Jan.22,2013
`
`Sheet 4 of 5
`
`US 8,357,795 B2
`
`500
`450
`400
`350
`=E' 300
`~
`-~ 250
`::s:
`200
`150
`100
`50
`0
`0.1
`
`0.5
`0.45
`0.4
`0.35
`
`~ 0.3
`G 0.25
`0.2
`0.15
`0.1
`0.05
`
`4~
`
`0
`
`0.1
`
`SAMPLE6
`
`---0- -
`No Lido
`---fr- Lido with pH control
`--o--
`Lido no pH control
`
`1
`Frequency (Hz)
`
`10
`FIG. 7
`
`SAMPLE6
`
`---0--
`No Lido
`---fr- with pH control
`no pH control
`--0--
`
`-
`
`-
`
`-
`
`-
`
`I
`1
`Frequency (Hz)
`
`--'"
`
`~ ~
`
`10
`FIG. 8
`
`

`

`U.S. Patent
`
`Jan.22,2013
`
`Sheet 5 of 5
`
`US 8,357,795 B2
`
`0.35
`
`0.30
`
`0.25
`
`0.20
`
`0.15
`
`~
`~ -.....:..
`~
`.s.;
`Qj
`t::>)
`QJ
`:S
`.s.;
`cu'
`.s.;
`~ 0.10
`
`theoretical result if lidocaine is
`retained in the gel
`
`I
`is freely released I
`
`theoretical result if lidocaine
`
`~ ·-~
`
`0.05
`
`0.00
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Time (hrs)
`
`FIG. 9
`
`

`

`US 8,357,795 B2
`
`1
`HYALURONIC ACID-BASED GELS
`INCLUDING LIDOCAINE
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims the benefit of U.S. provisional
`patent application No. 61/085,956, filed Aug. 4, 2008, U.S.
`provisional patent application No. 61/087,934 filed on Aug.
`11, 2008, and U.S. provisional patent application No. 61/096,
`278 filed Sep. 11, 2008, the entire disclosures all of which are
`incorporated herein by reference.
`
`FIELD OF THE INVENTION
`
`The present invention generally relates to injectable soft
`tissue fillers and more specifically relates to hyaluronic acid(cid:173)
`based dermal and subdermal fillers including an anesthetic
`agent.
`
`BACKGROUND
`
`2
`can, which is a major component of the extra-cellular matrix
`and is widely distributed in animal tissues. HA has excellent
`biocompatibility and does not cause allergic reactions when
`implanted into a patient. In addition, HA has the ability to
`5 bind to large amounts of water, making it an excellent volu(cid:173)
`mizer of soft tissues.
`The development of HA-based fillers which exhibit ideal in
`vivo properties as well as ideal surgical usability has proven
`difficult. For example, HA-based fillers that exhibit desirable
`10 stability properties in vivo, can be so highly viscous that
`injection through fine gauge needles is difficult. Conversely,
`HA-based fillers that are relatively easily injected through
`fine gauge needles often have relatively inferior stability
`properties in vivo.
`One method to overcome this problem is to use crosslinked
`HA-based fillers. Crosslinked HA is formed by reacting free
`HA with a crosslinking agent under suitable reaction condi(cid:173)
`tions. Methods of preparing HA based soft tissue fillers
`including both crosslinked and free HA are well known.
`It has been proposed to incorporate certain therapeutic
`agents, for example, anesthetic agents such as lidocaine, into
`injectable HA-based compositions. Unfortunately, HA-based
`injectable compositions which incorporate lidocaine during
`the manufacturing process are prone to partial or almost com-
`25 plete degradation prior to injection, particularly during high
`temperature sterilization steps and/or when placed in storage
`for any significant length of time.
`It is an objective of the HA-based soft filler compositions
`and methods of making and using them as described herein to
`30 provide soft tissue fillers that do not cause allergic reactions in
`patients, are biocompatible and are stable and usable in vivo
`and include one or more local anesthetic agents.
`
`15
`
`20
`
`It is generally accepted that as a person ages, the face
`begins to show effects of gravity, sun-exposure, and years of
`facial muscle movement, such as smiling, frowning, chewing
`and squinting. The underlying tissues that keep the skin
`appearing youthful begin to break down, often resulting in
`laugh lines, smile lines, "crow's feet" and facial creases often
`referred to as the "effects of aging."
`In an effort to treat or correct the effects of aging, soft tissue
`fillers have been developed to help fill in facial lines and
`depressions and for restoring fat loss-related tissue volume
`loss. The soft tissue fillers thereby temporarily restore a
`smoother, more youthful appearance.
`Ideally, soft tissue fillers are long-lasting, soft, smooth and 35
`natural appearing when implanted in the skin or beneath the
`skin. Further, soft tissue fillers are easy to implant into a
`patient using a fine gauge needle and require low extrusion
`force for injection. Ideal fillers would also cause no adverse
`side effects, and would be injectable with minimal or no 40
`discomfort to the patient.
`Collagen based soft tissue fillers were developed over 20
`years ago, and for some time, bovine collagen-based fillers
`were the only U.S. Food and Drug Administration (FDA)(cid:173)
`approved dermal fillers. Because these dermal fillers are 45
`bovine based, one of the main disadvantages has been the
`potential for allergic reaction in patients. It is believed that
`approximately 3-5% of human subjects show serious allergic
`reactions to bovine collagen, thus requiring careful testing
`before using these fillers in any particular person. In addition 50
`to allergic reactions, collagen based fillers degrade rapidly
`upon injection and require frequent treatments to sustain a
`smoother, more youthful appearance.
`In February 2003, human-derived collagen filler composi(cid:173)
`tions received FDA approval. These collagens provide the 55
`advantage of a significantly reduced risk of allergic reactions.
`However, despite the reduced incidence of allergic reactions,
`the human derived collagen fillers still suffered from the rapid
`degradation of the injected product.
`The search for fillers that do not provoke allergic reactions 60
`and sustain a smoother, more youthful appearance has
`brought about the development of hyaluronic acid (HA)(cid:173)
`based products. In December 2003, the first HA-based filler
`was approved by the FDA. This was rapidly followed by the
`development of other HA-based fillers.
`HA, also known as hyaluronan, is a naturally occurring,
`water soluble polysaccharide, specifically a glycosaminogly-
`
`SUMMARY
`
`The present description relates to soft tissue fillers, for
`example, dermal and subdermal fillers, based on hyaluronic
`acid (HA) and pharmaceutically acceptable salts of HA, for
`example, sodium hyaluronate (NaHA). HA-based composi(cid:173)
`tions described herein include a therapeutically effective
`amount of at least one anesthetic agent. In one embodiment,
`for example, the anesthetic agent is lidocaine. The present
`HA-based compositions including at least one anesthetic
`agent have an enhanced stability, relative to conventional
`HA-based compositions including, for example, lidocaine,
`when subjected to sterilization techniques such as autoclav-
`ing, and/or when stored for long periods at ambient tempera(cid:173)
`ture. Methods for preparing such HA-based compositions are
`also provided as well as products made by such methods.
`Described herein are soft tissue filler compositions, the
`compositions generally comprising: a hyaluronic acid com(cid:173)
`ponent crosslinked with a crosslinking agent selected from
`the group consisting of 1,4-butanediol diglycidyl ether
`(BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidy(cid:173)
`loxybutane, 1,2-bis(2,3-epoxypropoxy)ethylene and 1-(2,3-
`epoxypropyl)-2,3-epoxycyclohexane, and 1,4-butanediol
`diglycidyl ether; and at least one