(12) Umted States Patent
`(10) Patent No.:
`US 8,357,795 B2
`
`Lebreton
`(45) Date of Patent:
`*Jan. 22, 2013
`
`USOO8357795B2
`
`(54) HYALURONIC ACID-BASED GELS
`INCLUDING LIDOCAINE
`
`(75)
`
`.
`Inventor: Plerre F.Lebreton,Annecyle-V1eux
`(FR)
`
`(
`
`(73) Assignee: Allergan, Inc., Irvine, CA (US)
`~
`:1:
`~
`.
`~
`~
`~
`) Not1ce.
`Subjectto any d1scla1mer, the term ofth1s
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 612 days.
`.
`.
`.
`.
`.
`This patent 1s subject to a terrmnal d1s-
`Clalmer.
`
`(21) Appl.No.: 12/393,884
`~
`.
`QB Fmd
`
`$3
`
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`PumimemwnDfia
`
`US 2010/0028438A1
`
`Feb. 4, 2010
`_
`_
`Related U.S. Appllcatlon Data
`
`(60) Provisional application No. 61/085,956, filed onAug.
`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)
`
`(52)
`(58)
`
`(56)
`
`Int. Cl.
`
`C07H1/00
`(2006.01)
`
`US. Cl.
`....................
`536/124; 514/54; 424/488
`Field of Classification Search .................. 424/484;
`514/54; 536/124
`See application file for complete search history.
`
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`
`(Continued)
`
`Primary Examiner 7 Ali Soroush
`(74) Attorney, Agent, or Firm iLinda Fox;
`Donovan; Debra Condino
`
`Stephen
`
`(57)
`
`ABSTRACT
`
`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-
`based compositions including lidocaine have an enhanced
`stability and cohesivity, relative to conventional composi-
`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
`
`Page 1
`
`Teoxane S.A.
`
`Exhibit 1064
`
`Page 1
`
`

`

`US 8,357,795 B2
` Page2
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`

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`US 8,357,795 B2
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`Page 3
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`et
`al.,
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`(1997).
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`able synthetic extracellular matrices for tissue engineering.” J.
`Biomed. Mater. Res. A. 79(4): 902-912 (2006).
`Smith, Kevin C., et al., “Five Percent Lidocaine Cream Applied
`Simultaneously to Skin and Mucosa of the Lips Creates Excellent
`Anesthesia for Filler Injections”, Dermatol Surg 2005; 31:1635-
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`formance Liquid Chromatographic Analysis of Lidocaine Hydro-
`chloride and Lidocaine Hydrochloride with Epinephrine Injectable
`Solutions”, Journal ofPharmaceutical Sciences, vol. 70, No. 11, Nov.
`1981, pp. 1215-1218.
`Xia, Yun et al., “Comparison of Effects of Lidocaine Hydrochloride,
`Buffered Lidocaine, Diphenhydramine, and Normal Saline After
`Intradermal Injection”, Journal of Clinical Anesthesia 14:339-343,
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`* cited by examiner
`
`Page 4
`
`Page 4
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`

`

`U.S. Patent
`
`Jan. 22, 2013
`
`Sheet 1 of 5
`
`US 8,357,795 B2
`
`SAMPLE 1
`
`Viscosity
`
`Viscosity
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
`No Lido
`— —<>— —
`—A— Lido with pH control
`
`—0— Lido no pH control
`
`
`
`
`
`
`
`
`
`
`
`0.1
`
`Frequency (Hz)
`
`SAMPLE 2
`
`
`
`lVo Lido
`
`__<>__
`—A— Lido with pH control
`
`—0— Lido no pH control
`
`
`
`
`
`
`
`
`
`Frequency (Hz)
`
`FIG. 2
`
`Page 5
`
`Page 5
`
`

`

`US. Patent
`
`Jan. 22, 2013
`
`Sheet 2 of5
`
`US 8,357,795 B2
`
`SAMPLE 3
`
`
`
`
`
`No Lido
`——<>——
`—A— Lido with pH control
`
`—O— Lido no pH control
`
`
`
`
`
`
`
`0.1
`
`1
`
`Frequency (Hz)
`
`10
`
`F].G 3
`
`SAMPLE 4
`
`
`
`
`No Lido
`——<>——
`—A— Lido with pH control
`—0— Lido no pH control
`
`
`
`
`
`
`
`
`
`0.1
`
`1
`
`Frequency (Hz)
`
`Page 6
`
`10
`
`F].G 4
`
`120
`
`100
`
`30
`
`60
`
`40
`
`20
`
`0
`
`ba
`, g
`
`>
`
`16
`
`14
`12
`
`% 10
`E
`8
`>
`
`6 4 2 0
`
`Page 6
`
`

`

`US. Patent
`
`Jan. 22, 2013
`
`Sheet 3 of5
`
`US 8,357,795 B2
`
`SAMPLE 5
`
`
`
`\
`
`
`
`—<>— No Lido
`—A— Llo'o with pH control
`
`—O— Lido no pH control
`
`
`
`
`
`
`
`0-1
`
`1
`
`Frequency (Hz)
`
`SAMPLE 5
`
`10
`
`FIG 5
`
`120
`
`100
`
`80
`
`50
`
`40
`
`20
`
`0
`
`ba g
`
`>
`
`
`
`
`
`
`
`
`
`;\
`Q)
`
`
`
`
`
`
`
`lVo Lido
`——<>— —
`—A— Lido with pH control
`
`—0— Lido no pH control
`
`0.1
`
`1
`
`Frequency (Hz)
`
`Page 7
`
`10
`
`FIG 6
`
`Page 7
`
`

`

`US. Patent
`
`Jan. 22, 2013
`
`Sheet 4 of5
`
`US 8,357,795 B2
`
`SAMPLE 6
`
`No Lido
`—A— Lido with pH control
`
` — —<>— —
`
`—0— Lido no pH control
`
`
`
`
`
`
`
`
`
`
`
`
`Frequency (Hz)
`
`F].G 7
`
`SAMPLE 6
`
`
`
`
`
`
`
`
`
`
`
`
`
`Frequency (Hz)
`
`Page 8
`
`F].G 8
`
`Page 8
`
`

`

`US. Patent
`
`Jan. 22, 2013
`
`Sheet 5 of5
`
`US 8,357,795 B2
`
`theoretical result if lidocaine is
`retained in the gel
`
`inthegelin%(w/w)
`[Lidocaine]
`
`theoretical result if lidocaine
`is freely released
`
`/
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Time (hrs)
`
`FIG. 9
`
`Page 9
`
`Page 9
`
`

`

`US 8,357,795 B2
`
`2
`
`1
`HYALURONIC ACID-BASED GELS
`INCLUDING LIDOCAINE
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims the benefit of US. provisional
`patent application No. 61/085,956, filed Aug. 4, 2008, US.
`provisional patent application No. 61/087,934 filed on Aug.
`11,2008, and US. provisional patent application No. 61/096,
`278 filed Sep. 1 1, 2008, the entire disclosures all ofwhich 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-
`based dermal and subdermal fillers including an anesthetic
`agent.
`
`BACKGROUND
`
`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
`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
`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 US. Food and Drug Administration (FDA)-
`approved dermal fillers. Because these dermal fillers are
`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
`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-
`tions received FDA approval. These collagens provide the
`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
`and sustain a smoother, more youthful appearance has
`brought about the development of hyaluronic acid (HA)-
`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-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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
`bind to large amounts of water, making it an excellent volu-
`mizer of soft tissues.
`
`The development ofHA-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
`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-
`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-
`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 ofmaking and using them as described herein to
`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.
`
`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-
`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-
`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-
`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-
`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 anesthetic agent combined
`with the crosslinked HA component.
`In yet another embodiment, the at least one anesthetic
`agent is lidocaine. In a further embodiment, the amount ofthe
`anesthetic agent is present at a concentration between about
`0.1% and about 5.0% by weight of the composition. In still
`another embodiment, the anesthetic agent is present at a con-
`centration between about 0.2% and about 1.0% by weight of
`the composition. In one embodiment, the anesthetic agent is
`lidocaine and is present at a concentration of about 0.3% by
`weight of the composition.
`
`Page 10
`
`Page 10
`
`

`

`US 8,357,795 B2
`
`3
`In still another embodiment, the soft tissue filler composi-
`tion has an extrusion force of between about 10 N and about
`
`13 N, for example, at a rate of about 12.5 mm/minute. In yet
`another embodiment, the composition has a Viscosity of
`between about 5 Pa*s and about 450 Pa*s, for example, when
`measured at about 5 Hz.
`
`the HA component is a gel, for
`In one embodiment,
`example, a cohesive, hydrated gel. In one embodiment, the
`HA component is a crosslinked HA gel having no greater than
`about 1% to about 10% free HA. For purposes of this disclo-
`sure, free HA includes truly free HA as well as lightly
`crosslinked HA chains and fragments, all in soluble form in
`water.
`
`In yet other embodiments, the HA component comprises
`greater than about 10%, for example, greater than about] 5%,
`for example, up to or greater than about 20% free HA.
`In yet another embodiment, the HA component is a gel
`comprising particles of crosslinked HA in a relatively fluidic
`medium of free HA. In some embodiments, the HA compo-
`nent has an average particle size ofgreater than about 200 pm,
`for example, greater than about 250 um.
`Further described herein is a soft tissue filler composition
`comprising: a HA component crosslinked with 1,4-butane-
`diol diglycidyl ether (BDDE), said HA component having a
`degree of crosslinking of less than about 5%, for example,
`about 2%, and an anesthetic component having a concen