USOO8450475B2

(12) United States Patent (10) Patent No.: US 8.450,475 B2

Lebreton (45) Date of Patent: May 28, 2013
(54) HYALURONIC ACID-BASED GELS 5,571,503 A 11/1996 MauSner
INCLUDING LIDOCANE 5,614,587 A 3, 1997 Rhee et al.
5,616,568 A 4/1997 Pouyani et al.
5,616,611 A 4/1997 Yamamoto
(75) Inventor: Pierre F. Lebreton, Annecy (FR) 5,616,689 A 4/1997 Shenoy et al.
5,633,001 A 5/1997 Agerup
(73) Assignee: Allergan, Inc., Irvine, CA (US) 5,643,464 A 7/1997 Rhee et al.
5,676,964 A 10, 1997 della Valle
(*) Notice: Subject to any disclaimer, the term of this 5,823,671 A 10, 1998 Mitchell et al.
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5,843,907 A 12/1998 Sakai
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(22) Filed: Feb. 26, 2009 5,935,164 A 8, 1999 Iversen
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(65) Prior Publication Data 6,013,679 A 1/2000 Kuo et al.
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(58) Field of Classification Search FOREIGN PATENT DOCUMENTS
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nation of mannitol in human serum.” Clin Chem Lab Med. 41 Zheng et al. “In situ crosslinkable hyaluronan hydrogels for tissue
(8): 1049-1055 (2003). engineering.” Biomaterials 25(7-8): 1339-1348 (2004).
Intramed Mannitol 20% m/v Infusion, package insert, pp. 1-2 (2010), Millay et al.; “Vasoconstrictors in Facial Plastic Surgery': Archives
http://homme.intekom.com/pharm/intramed manit 120.html. of Otolaryngology—Head & Neck Surgery; vol. 117: pp. 160-163;
Kablik et al. “Comparative physical properties of hyaluronic acid Feb. 1991.
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Levy, Jaime et al., "Lidocaine hyperSensitivity after Subconjunctival porating Lidocaine'. Journal of Cosmetic Dermatology; vol. 7, pp.
injection'. Can J Ophthalmol2006:41:204-6. 298-303; 2008.
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Dermatol, vol. 139, Mar. 2003, pp. 343-346. Journal of Plastic, Reconstructive and Aesthetic Surgery, (2009),
Matsumoto, Alan H. et al., “Reducing the Discomfort of Lidocaine 62:11-18, XPO02668828.
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U.S. Patent May 28, 2013 US 8,450.475 B2

theoretical result if lidocaine is

retained in the gel

theoretical result if lidocaine

is freely released
/
0 20 40 60 80 100
Time (hrs)
 US 8,450.475 B2
1. 2
HYALURONCACID-BASED GELS can, which is a major component of the extra-cellular matrix
INCLUDING LIDOCANE and is widely distributed in animal tissues. HA has excellent
biocompatibility and does not cause allergic reactions when
CROSS REFERENCE TO RELATED implanted into a patient. In addition, HA has the ability to
APPLICATIONS bind to large amounts of water, making it an excellent Volu
mizer of soft tissues.
This application claims the benefit of U.S. provisional The development of HA-based fillers which exhibit ideal in
patent application No. 61/085,956, filed Aug. 4, 2008, U.S. Vivo properties as well as ideal Surgical usability has proven
provisional patent application No. 61/087,934 filed on Aug. difficult. For example, HA-based fillers that exhibit desirable
11, 2008, and U.S. provisional patent application No. 61/096, 10 stability properties in Vivo, can be so highly viscous that
278 filed Sep. 11, 2008, the entire disclosures all of which are injection through fine gauge needles is difficult. Conversely,
incorporated herein by reference. HA-based fillers that are relatively easily injected through
fine gauge needles often have relatively inferior stability
FIELD OF THE INVENTION properties in vivo.
15 One method to overcome this problem is to use crosslinked
The present invention generally relates to injectable soft HA-based fillers. Crosslinked HA is formed by reacting free
tissue fillers and more specifically relates to hyaluronic acid HA with a crosslinking agent under Suitable reaction condi
based dermal and Subdermal fillers including an anesthetic tions. Methods of preparing HA based soft tissue fillers
agent. including both crosslinked and free HA are well known.
It has been proposed to incorporate certain therapeutic
BACKGROUND agents, for example, anesthetic agents such as lidocaine, into
injectable HA-based compositions. Unfortunately, HA-based
It is generally accepted that as a person ages, the face injectable compositions which incorporate lidocaine during
begins to show effects of gravity, Sun-exposure, and years of the manufacturing process are prone to partial or almost com
facial muscle movement, such as Smiling, frowning, chewing 25 plete degradation prior to injection, particularly during high
and squinting. The underlying tissues that keep the skin temperature sterilization steps and/or when placed in storage
appearing youthful begin to break down, often resulting in for any significant length of time.
laughlines, smile lines, “crows feet and facial creases often It is an objective of the HA-based soft filler compositions
referred to as the “effects of aging.” and methods of making and using them as described hereinto
In an effort to treat or correct the effects of aging, soft tissue 30 provide soft tissue fillers that do not cause allergic reactions in
fillers have been developed to help fill in facial lines and patients, are biocompatible and are stable and usable in vivo
depressions and for restoring fat loss-related tissue volume and include one or more local anesthetic agents.
loss. The soft tissue fillers thereby temporarily restore a
Smoother, more youthful appearance. SUMMARY
Ideally, Soft tissue fillers are long-lasting, soft, Smooth and 35
natural appearing when implanted in the skin or beneath the The present description relates to soft tissue fillers, for
skin. Further, soft tissue fillers are easy to implant into a example, dermal and Subdermal fillers, based on hyaluronic
patient using a fine gauge needle and require low extrusion acid (HA) and pharmaceutically acceptable salts of HA, for
force for injection. Ideal fillers would also cause no adverse example, sodium hyaluronate (NaHA). HA-based composi
side effects, and would be injectable with minimal or no 40 tions described herein include a therapeutically effective
discomfort to the patient. amount of at least one anesthetic agent. In one embodiment,
Collagen based soft tissue fillers were developed over 20 for example, the anesthetic agent is lidocaine. The present
years ago, and for some time, bovine collagen-based fillers HA-based compositions including at least one anesthetic
were the only U.S. Food and Drug Administration (FDA)- agent have an enhanced stability, relative to conventional
approved dermal fillers. Because these dermal fillers are 45 HA-based compositions including, for example, lidocaine,
bovine based, one of the main disadvantages has been the when Subjected to sterilization techniques such as autoclav
potential for allergic reaction in patients. It is believed that ing, and/or when stored for long periods at ambient tempera
approximately 3-5% of human Subjects show serious allergic ture. Methods for preparing such HA-based compositions are
reactions to bovine collagen, thus requiring careful testing also provided as well as products made by Such methods.
before using these fillers in any particular person. In addition 50 Described herein are soft tissue filler compositions, said
to allergic reactions, collagen based fillers degrade rapidly compositions generally comprise: a hyaluronic acid (HA)
upon injection and require frequent treatments to Sustain a component crosslinked with a crosslinking agent selected
Smoother, more youthful appearance. from the group consisting of 1,4-butanediol diglycidyl ether
In February 2003, human-derived collagen filler composi (BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidy
tions received FDA approval. These collagens provide the 55 loxybutane, 1.2-bis(2,3-epoxypropoxy)ethylene and 1-(2,3-
advantage of a significantly reduced risk of allergic reactions. epoxypropyl)-2,3-epoxycyclohexane, and 1,4-butanediol
However, despite the reduced incidence of allergic reactions, diglycidyl ether, and at least one an anesthetic agent com
the human derived collagen fillers still suffered from the rapid bined with the crosslinked HA component.
degradation of the injected product. In yet another embodiment, the at least one anesthetic
The search for fillers that do not provoke allergic reactions 60 agent is lidocaine. In a further embodiment, the amount of the
and Sustain a Smoother, more youthful appearance has anesthetic agent is present at a concentration between about
brought about the development of hyaluronic acid (HA)- 0.1% and about 5.0% by weight of the composition. In still
based products. In December 2003, the first HA-based filler another embodiment, the anesthetic agent is present at a con
was approved by the FDA. This was rapidly followed by the centration between about 0.2% and about 1.0% by weight of
development of other HA-based fillers. 65 the composition. In one embodiment, the anesthetic agent is
HA, also known as hyaluronan, is a naturally occurring, lidocaine and is present at a concentration of about 0.3% by
water Soluble polysaccharide, specifically a glycosaminogly weight of the composition.
 US 8,450.475 B2
3 4
In still another embodiment, the soft tissue filler composi Some embodiments, the average size of Such particles is at
tion has an extrusion force of between about 10 N and about least about 200 um, and in other embodiments the average
13 N, for example, at a rate of about 12.5 mm/minute. In yet size of such particles is at least about 250 Lum.
another embodiment, the composition has a viscosity of Further described herein is a soft tissue filler composition
between about 5 Pas and about 450 Pas, for example, when 5 comprising: a hyaluronic acid (HA) component crosslinked
measured at about 5 Hz. with 1,4-butanediol diglycidyl ether (BDDE), said HA com
In one embodiment, the HA component is a gel, for ponent having a degree of crosslinking of less than about 5%,
example, a cohesive, hydrated gel. In one embodiment, the and an anesthetic component having a concentration between
HA component is a crosslinked HAgel having no greater than about 0.1% and about 5.0% by weight of the soft tissue filler
about 1% to about 10% free HA. For purposes of this disclo 10 composition, wherein the anesthetic is lidocaine.
sure, free HA includes truly uncrosslinked HA as well as In a specific embodiment of the invention, a method of
lightly crosslinked HA chains and fragments, all in soluble preparing a soft tissue filler composition is further described,
form in water. the method comprising the steps of providing dry free NaHA
In yet other embodiments, the HA component comprises material and hydrating the dry free NaHA material in an
greater than about 10%, for example, greater than about 15%, 15
alkaline solution to obtain an alkaline, free NaHA gel;
for example, up to or greater than about 20% free HA. crosslinking the free NaHA gel with BDDE to form a
In yet another embodiment, the HA component is a gel crosslinked alkaline HA composition with a degree of
comprising particles of crosslinked HA in a relatively fluidic crosslinking less than about 5% and a pH above about 7.2:
medium of free HA. In some embodiments, the HA compo adding a solution containing 0.3% lidocaine HCl to the HA
nent has an average particle size of greater than about 200um, component having the adjusted pH to obtain said HA-based
for example, greater than about 250 um. filler composition; homogenizing the HA-based filler com
Further described herein is a soft tissue filler composition position thereby forming a homogenized HA-based filler
comprising: a HA component crosslinked with 1,4-butane composition; and sterilizing the homogenized HA-based
diol diglycidyl ether (BDDE), said HA component having a filler composition thereby forming a sterilized HA-based
degree of crosslinking of less than about 5%, for example, 25 filler composition, wherein the soft tissue filler composition
about 2%, and an anesthetic component having a concentra has a particle size of greater than about 200 um, for example,
tion between about 0.1% and about 5.0% by weight of the soft a particle size of greater than about 250 Lum.
tissue filler composition, wherein the anesthetic is lidocaine.
Further described herein are methods of preparing soft BRIEF DESCRIPTION OF THE DRAWINGS
tissue filler compositions, the methods comprising the steps 30
of providing a HA component crosslinked with at least one FIG. 1 graphically illustrates the lidocaine concentration
crosslinking agent selected from the group consisting of 1,4- over time, in a gel tested in accordance with Example 4.
butanediol diglycidyl ether (BDDE), 1,4-bis(2,3-epoxypro
poxy)butane, 1,4-bisglycidyloxybutane, 1.2-bis(2,3-ep DEFINITIONS
oxypropoxy)ethylene and 1-(2,3-epoxypropyl)-2,3- 35
epoxycyclohexane, and 1,4-butanediol diglycidyl ether or Certain terms as used in the specification are intended to
combinations thereof, adjusting the pH of said HA compo refer to the following definitions, as detailed below. Where
nent to an adjusted pH above about 7.2; and adding a solution the definition of terms departs from the commonly used
containing at least one anesthetic agent to the HA component meaning of the term, applicant intends to utilize the defini
having the adjusted pH to obtain a HA-based filler composi 40 tions provided below, unless specifically indicated.
tion. Autoclave stable or stable to autoclaving as used herein
In another embodiment, the composition is sterilized, for describes a product or composition that is resistant to degra
example, by autoclaving, to formasterilized composition and dation Such that the productor composition maintains at least
wherein the sterilized composition is stable at ambient tem one, and preferably all, of the following aspects after effective
perature for at least about 6 months, for example, at least 9 45 autoclavesterilization: transparent appearance, pH, extrusion
months, at least about 12 months or more. force and/or rheological characteristics, hyaluronic acid
Instill another embodiment, the adjusted pH is above about (HA) concentration, sterility, osmolarity, and lidocaine con
7.5. In another embodiment, the method further comprises the centration.
step of homogenizing the HA component during or after the High molecular weight HA as used herein describes a HA
step of adding the Solution containing the at least one anes 50 material having a molecular weight of at least about 1.0
thetic agent. In a further embodiment, the step of homogeniz million Daltons (mw210 Da or 1 MDa) to about 4.0 MDa.
ing comprises Subjecting the composition to mixing with a For example, the high molecular weight HA in the present
controlled shear. compositions may have a molecular weight of about 2.0
In another embodiment, the step of providing a HA com MDa. In another example, the high molecular weight HA may
ponent comprises providing dry free NaHA material and 55 have a molecular weight of about 2.8 MDa.
hydrating the dry free NaHA material in an alkaline solution Low molecular weight HA as used herein describes a HA
to obtain an alkaline, free NaHA gel. In yet another embodi material having a molecular weight of less than about 1.0
ment, the alkaline, free NaHA gel has a pH greater than about MDa. Low molecular weight HA can have a molecular
8.0. In still another embodiment the pH is greater than about weight of between about 200,000 Da (0.2 MDa) to less than
10. 60 about 1.0 MDa, for example, between about 300,000 Da (0.3
In a further embodiment, the HA component comprises MDa) to about 750,000 Da. (0.75 MDa).
greater than about 20% free HA and the crosslinked portion of Degree of Crosslinking as used herein refers to the inter
the HA component has a degree of crosslinking of less than molecular junctions joining the individual HA polymer mol
about 6% or less than about 5%. ecules, or monomer chains, into a permanent structure, or as
In still a further embodiment, the soft tissue filler compo 65 disclosed herein the soft tissue filler composition. Moreover,
sition has a particulate nature in that it comprises particles of degree of crosslinking for purposes of the present disclosure
crosslinked HA dispersed in a fluid soluble HA medium. In is further defined as the percent weight ratio of the crosslink
 US 8,450.475 B2
5 6
ing agent to HA-monomeric units within the crosslinked por ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprocin,
tion of the HA based composition. It is measured by the fenalcomine, fomocaine, hexylcaine, hydroxytetracaine,
weight ratio of HA monomers to crosslinker (HA monomers: isobutyl p-aminobenzoate, leucinocaine mesylate, levoxa
crosslinker). drol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine,
Free HA as used herein refers to individual HA polymer methyl chloride, myrtecaine, naepaine, octocaine,
molecules that are not crosslinked to, or very lightly orthocaine, oxethazaine, parethoxycaine, phenacaine, phe
crosslinked to (very low degree of crosslinking) the highly nol, piperocaine, piridocaine, polidocanol, pramoxine,
crosslinked (higher degree of crosslinking) macromolecular prilocaine, procaine, propanocaine, proparacaine, propipoc
structure making up the Soft tissue filler composition. Free aine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine,
HA generally remains water soluble. Free HA can alterna 10
salicyl alcohol, tetracaine, tolycaine, trimecaine, Zolamine,
tively be defined as the “uncrosslinked,” or lightly crosslinked and salts thereof. In one embodiment, the at least one anes
component of the macromolecular structure making up the thetic agent is lidocaine, such as in the form of lidocaine HC1.
soft tissue filler composition disclosed herein. The compositions described herein may have a lidocaine
Cohesive as used herein is the ability of a HA-based com concentration of between about 0.1% and about 5% by weight
position to retain its shape and resist deformation. Cohesive 15
of the composition, for example, about 0.2% to about 1.0% by
ness is affected by, among other factors, the molecular weight weight of the composition. In one embodiment, the compo
ratio of the initial free HA, the degree of crosslinking, the
amount of residual free HA following crosslinking, and HA sition has a lidocaine concentration of about 0.3% by weight
based composition pH. A cohesive HA-based composition (w/w %) of the composition. The concentration of lidocaine
resists phase separation when tested according to the method in the compositions described herein can be therapeutically
disclosed in Example 1 herein. effective meaning the concentration is adequate to provide a
therapeutic benefit without inflicting harm to the patient.
DETAILED DESCRIPTION In one aspect of the invention, a method is provided for
preparing a HA-based composition including an effective
The present disclosure generally relates to soft tissue fill 25 amount of lidocaine wherein the method comprises providing
ers, for example, dermal and Subdermal fillers, based on a precursor composition further comprising a cohesive
hyaluronic acids (HA) and pharmaceutically acceptable salts crosslinked HA-based gel, adding a solution containing
of HA, for example, sodium hyaluronate (NaHA). In one lidocaine, for example in the form of lidocaine HCl, thereto
aspect, HA-based compositions described herein include a and homogenizing the mixture to obtain a cohesive, at least
therapeutically effective amount of at least one anesthetic 30
partially crosslinked, HA-based composition including
agent, for example, lidocaine. The present HA-based compo lidocaine that is stable to autoclaving. The cohesive,
sitions including at least one anesthetic agent have an crosslinked HA-based gel includes no greater than about 1%
enhanced stability, relative to conventional HA-based com to about 10% of free or lightly crosslinked HA material by
positions including, for example, lidocaine, when Subjected
to high temperatures and pressures, for example, those expe 35 volume (w/v '%).
rienced during heat and/or pressure sterilization techniques, Without wishing to be bound by any particular theory of
for example, autoclaving, and/or for example, when stored at operability, it is believed that the high cohesivity of the pre
ambient temperature for an extended period of time. cursor composition in Some embodiments of the invention
The stable compositions maintain at least one of, or all of acts to Substantially or entirely prevent or impede any break
the following aspects after effective autoclave sterilization 40 down or degradation of the crosslinked HA in the composi
and/or prolonged storage: transparent appearance, pH for use tion with the addition of lidocaine.
in a patient, extrusion force and/or rheological characteris It is believed that Such degradation may primarily occur
tics, HA concentration, sterility, osmolarity, and lidocaine because many, perhaps most crosslinked HA based gels are
concentration. Methods or processes of preparing such HA conventionally manufactured in a manner that produces gels
based compositions are also provided as well as products 45 which are not sufficiently cohesive to prevent Such degrada
made by Such methods or processes. tion when lidocaine is added. It has now been discovered that
As used herein, hyaluronic acid (HA) can refer to any of its the addition of lidocaine to sufficiently cohesive crosslinked
hyaluronate salts, and includes, but is not limited to, sodium HA-based compositions does not cause Substantial or signifi
hyaluronate (NaHA), potassium hyaluronate, magnesium cant degradation of the compositions, and the compositions
hyaluronate, calcium hyaluronate, and combinations thereof. 50 maintain their integrity in terms of rheology, Viscosity,
Generally, the concentration of HA in the compositions appearance and other characteristics even when stored for a
described herein is preferably at least 10 mg/mL and up to lengthy period of time, for example, for a period of time of at
about 40 mg/mL. For example, the concentration of HA in least 6 months to a year or more, and even after being Sub
Some of the compositions is in a range between about 20 jected to sterilization procedures, for example, autoclaving.
mg/mL and about 30 mg/mL. Further, for example, in some 55 It is a Surprising discovery that formulations of crosslinked
embodiments, the compositions have a HA concentration of HA-based compositions including lidocaine can be manufac
about 22 mg/mL, about 24 mg/mL, about 26 mg/mL, or about tured in a manner in accordance with the invention to produce
28 mg/mL. sterilization-stable, injectable HA/lidocaine compositions.
In addition, the concentration of one or more anesthetics is Further described herein is a method for preparing stable
in an amount effective to mitigate pain experienced upon 60 HA-based compositions containing an effective amount of
injection of the composition. The at least one local anesthetic lidocaine by preparing a cohesive, crosslinked HA-based pre
can be selected from the group of ambucaine, amolanone, cursor composition, adding lidocaine chlorhydrate to the pre
amylocaine, benoximate, benzocaine, betoxycaine, biphe cursor composition to form a HA/lidocaine gel mixture, and
namine, bupivacaine, butacaine, butamben, butanilicaine, homogenizing the mixture, to obtain a crosslinked HA-based
butethamine, butoxycaine, carticaine, chloroprocaine, coca 65 composition that is stable to autoclaving.
ethylene, cocaine, cyclomethycaine, dibucaine, dimethiso In certain embodiments, the precursor composition is a gel
quin, dimethocaine, diperodon, dicyclomine, ecgonidine, which includes less than about 1% of soluble-liquid form or
 US 8,450.475 B2
7 8
free HA. In other embodiments, the precursor composition pounds per square inch (PSI) to about 20 PSI during auto
comprises no greater than about 1% to about 10% of free HA claving for a period of at least about 1 minute to about 15
by volume. minutes.
The precursor composition may comprise a first compo The present products and compositions also remain stable
nent including relatively highly crosslinked HA particles in a when stored for long periods of time at room temperature.
Substantially solid phase, and a second component compris Preferably, the present compositions remain stable for a
ing free or relatively less crosslinked HA in a substantially period of at least about two months, or at least about six
fluidic phase in which the relatively highly crosslinked par months, or at least about 9 months, or at least about 12
ticles are dispersed. The composition can include about 10% months, or at least about 36 months, attemperatures of at least
to about 20% or greater of free HA by volume. 10 about 25°C. In a specific embodiment, the compositions are
In some embodiments, the free HA makes up less than 20% stable at a temperature up to about 45° C. for a period of at
by weight of the composition. For example, the free HA least two months.
makes up less that 10% by weight of the HA component. In a The manufacturing process includes, in one embodiment,
further example, the second portion makes up between about the initial step of providing raw HA material in the form of dry
1% and about 10% by weight of the HA component. 15 HA fibers or powder. The raw HA material may be HA, its
For example, the precursor composition may comprise a salts and/or mixtures thereof. In a preferred embodiment, the
cohesive, HA-based gel. HA material comprises fibers or powder of NaHA, and even
In other embodiments, the free HA makes up greater than more preferably, bacterial-sourced NaHA. In some aspects of
about 20% by weight of the HA component. the present description, the HA material may be animal
In some embodiments, the present compositions have a derived. The HA material may be a combination of raw mate
particulate nature and comprise particles of relatively highly rials including HA and at least one other polysaccharide, for
crosslinked HA dispersed in a medium of relatively less example, glycosaminoglycan (GAG).
crosslinked HA. In some embodiments, the average size of In some embodiments, the HA material in the composi
such particles of crosslinked HA is at least about 200 um or at tions nearly entirely comprises or consists of high molecular
least about 250 um. Such particulate compositions are gen 25 weight HA. That is, nearly 100% of the HA material in the
erally less cohesive than otherwise similar compositions present compositions may be high molecular weight HA as
which have no discernable particles, or have particles having defined above. In other embodiments, the HA material in the
an average size of less than 200 um. compositions comprises a combination of relatively high
For example, in some embodiments, the precursor compo molecular weight HA and relatively low molecular weight
sition may be manufactured by pressing a mass of relatively 30 HA, as defined above.
highly crosslinked HA-based gel through a sieve or a mesh to The HA material of the compositions may comprise
create relatively highly crosslinked HA particles of generally between about 5% to about 95% high molecular weight HA
uniform size and shape. These particles are then mixed with a with the balance of the HA material including low molecular
carrier material, for example, an amount of free HA to pro weight HA. In a typical embodiment of the invention, the ratio
duce a gel. 35 of high molecular weight to low molecular weight HA is at
Further, a method of preparing a HA-based composition least about, and preferably greater than 2 (w/w22) with the
including an effective amount of lidocaine is provided high molecular weight HA having a molecular weight of
wherein the method comprises providing a precursor compo above 1.0 MDa.
sition including a Substantially pH neutral, at least partially It will be appreciated by those of ordinary skill in the art
crosslinked HA-based gel and adjusting the pH of the gel to a 40 that the selection of high and low molecular weight HA
pH of greater than about 7.2, for example, about 7.5 to about material and their relative percentages or ratios is dependent
8.0. The method further comprises the step of combining a upon the desired characteristics, for example, extrusion force,
Solution containing lidocaine, for example in the form of elastic modulus, viscous modulus and phase angle expressed
lidocaine HCl, with the slightly alkaline gel after the pH has as the ratio of viscous modulus to elastic modulus, cohesivity,
been so adjusted and obtaining a HA-based composition 45 etc. of the final HA-based product. For additional information
including lidocaine that is stable to autoclaving. that may be helpful in understanding this and other aspects of
Another method of preparing a stable HA-based composi the present disclosure, see Lebreton, U.S. Patent Application
tion containing an effective amount of lidocaine, as described Publication No. 2006/0194758, the entire disclosure of which
elsewhere herein, generally comprises the steps of providing is incorporated herein by this reference.
purified NaHA material, for example, in the form of fibers: 50 The HA-based gels can be prepared according to the
hydrating the material; and crosslinking the hydrated material present description by first cleaning and purifying dry or raw
with a suitable crosslinking agent to form a crosslinked HA HA material having a desired high/low molecular weight
based gel. The method further comprises the steps of neutral ratio. These steps generally involve hydrating the dry HA
izing and Swelling the gel, and adding to the gel a solution fibers or powder in the desired high/low molecular weight
containing lidocaine, preferably an acidic salt of lidocaine 55 ratio, for example, using pure water, and filtering the material
chlorhydrate, to form a HA/lidocaine gel. Further still, the to remove large foreign matters and/or other impurities. The
method further comprises homogenizing the HA/lidocaine filtered, hydrated material is then dried and purified. The high
gel and packaging the homogenized HA/lidocaine gel, for and low molecular weight HA may be cleaned and purified
example, in Syringes for dispensing. The Syringes are then separately, or may be mixed together, for example, in the
sterilized by autoclaving at an effective temperature and pres 60 desired ratio, just prior to crosslinking.
Sure. In accordance with the present description, the pack In one aspect of the present disclosure, pure, dry NaHA
aged and sterilized cohesive NaHA/lidocaine gels exhibit fibers are hydrated in an alkaline solution to produce an free
enhanced stability relative to HA-based compositions includ NaHA alkaline gel. Any suitable alkaline solution may be
ing lidocaine which are made using conventional methods. used to hydrate the NaHA in this step, for example, but not
The present products and compositions are considered to 65 limited to aqueous solutions containing sodium hydroxide
besterile when exposed to temperatures of at least about 120° (NaOH), potassium hydroxide (KOH), sodium bicarbonate
C. to about 130° C. and/or pressures of at least about 12 (NaHCO), lithium hydroxide (LiOH), and the like. In
 US 8,450.475 B2
10
another embodiment, the Suitable alkaline Solution is aqueous material, to stabilize the pH of the material and to remove any
solutions containing NaOH. The resulting alkaline gel will un-reacted crosslinking agent. Additional water or a slightly
have a pH above 7.5. The pH of the resulting alkaline gel can alkaline aqueous solution can be added to bring the concen
have a pH greater than 9, or a pH greater than 10, or a pH tration of the NaHA in the composition to a desired concen
greater than 12, or a pH greater than 13. tration.
The next step in the manufacturing process involves the The pH of the purified, substantially pH neutral,
step of crosslinking the hydrated, alkaline NaHA gel with a crosslinked HAgels are preferably adjusted to cause the gel to
Suitable crosslinking agent. The crosslinking agent may be become slightly alkaline such that the gels have a pH of
any agent known to be suitable for crosslinking polysaccha greater than about 7.2, for example, about 7.5 to about 8.0.
rides and their derivatives via their hydroxyl groups. Suitable 10 This step may be accomplished by any Suitable means, for
crosslinking agents include but are not limited to, 1,4-butane example, by adding a suitable amount of dilute NaOH, KOH,
diol diglycidyl ether (or 1,4-bis(2,3-epoxypropoxy)butane or NaHCO or LiOH, to the gels or any other alkaline molecule,
1,4-bisglycidyloxybutane, all of which are commonly known Solution and/or buffering composition know by one skilled in
as BDDE), 1,2-bis(2,3-epoxypropoxy)ethylene and 1-(2,3- the art.
epoxypropyl)-2,3-epoxycyclohexane. The use of more than 15 An effective amount of lidocaine, such as lidocaine HCl, is
one crosslinking agent or a different crosslinking agent is not then added to the purified cohesive NaHA gels. For example,
excluded from the scope of the present disclosure. In one in some embodiments, the lidocaine HCl is provided in a
aspect of the present disclosure, the HAgels described herein powder form which is solubilized using water for injection
are crosslinked using BDDE. (WFI). The gels are kept neutral with a buffer or by adjust
The step of crosslinking may be carried out using any ment with diluted NaOH in order that the final HA/lidocaine
means known to those of ordinary skill in the art. Those composition will have a desired, substantially neutral pH.
skilled in the art appreciate how to optimize conditions of Preferably, the final HA-based filler compositions including
crosslinking according to the nature of the HA, and how to lidocaine will have a lidocaine concentration of between at
carry out crosslinking to an optimized degree. least about 0.1% and about 5%, for example, about 2% by
Degree of crosslinking for purposes of the present disclo 25 weight of the composition, or in another example about 0.3%.
Sure is defined as the percent weight ratio of the crosslinking After the addition of the lidocaine HCl, or alternatively,
agent to HA-monomeric units within the crosslinked portion during the addition of the lidocaine HCl, the HA/lidocaine
of the HA based composition. It is measured by the weight gels, or compositions, are homogenized to create highly
ratio of HA monomers to crosslinker (HA monomers: homogenous cohesive HA/lidocaine gels having a desired
crosslinker). 30 consistency and Stability. Preferably, the homogenization
The degree of crosslinking in the HA component of the step comprises mixing, stirring, or beating the gels with a
present compositions is at least about 2% and is up to about controlled shearing force obtaining substantially homog
20%. enous mixtures.
In some embodiments, the degree of crosslinking is The HA/lidocaine compositions described herein display a
between about 4% to about 12%. In some embodiments, the 35 Viscosity which is dependent on the composition's properties
degree of crosslinking is less than about 6%, for example, is and the presence of at least one anesthetic agent. The Viscosity
less than about 5%. of the HA/lidocaine composition can be from about 50 Pas
In other embodiments, the degree of crosslinking is greater to about 450 Pas. In other embodiments, the viscosity can be
than 5%, for example, is about 6% to about 8%. from about 50 Pas to about 300 Pas, from about 100 Pas to
In some embodiments, the HA component is capable of 40 about 400 Pas, or about 250 Pas to about 400 Pas, or about
absorbing at least about one time its weight in water. When 50 Pas to about 250 Pa S.
neutralized and Swollen, the crosslinked HA component and After homogenization, the HA/lidocaine compositions are
water absorbed by the crosslinked HA component is in a introduced into Syringes and sterilized. Syringes useful
weight ratio of about 1:1. The resulting hydrated HA-based according to the present description include any syringe
gels have a characteristic of being highly cohesive. 45 known in the art capable of delivering viscous dermal filler
The HA-based gels in accordance with some embodiments compositions. The Syringes generally have an internal Vol
of the invention may have sufficient cohesivity such that the ume of about 0.4 mL to about 3 mL, more preferably between
gels will not undergo Substantial phase separation after cen about 0.5 mL and about 1.5 mL or between about 0.8 mL and
trifugation of the gel at 2000 rd/min for 5 minutes. In another about 2.5 mL. This internal volume is associated with an
embodiment, the gels have the characteristic of being capable 50 internal diameter of the Syringe which plays a key role in the
of absorbing at least one time their weight of water and have extrusion force needed to inject high viscosity dermal filler
sufficient cohesivity such that when swollen with water at a compositions. The internal diameters are generally about 4
gel/water weight ratio of about 1:1, the gels maintain their mm to about 9 mm, more preferably from about 4.5 mm to
integrity, for example, when Subjected to centrifugation. about 6.5 mm or from about 4.5 mm to about 8.8 mm. Further,
The hydrated crosslinked, HA gels may be swollen to 55 the extrusion force needed to deliver the HA/lidocaine com
obtain the desired cohesivity. This step can be accomplished positions from the Syringe is dependent on the needle gauge.
by neutralizing the crosslinked, hydrated HAgel, for example The gauges of needles used generally include gauges between
by adding an aqueous solution containing of an acid, such as about 18G and about 40G, more preferably about 25G to
HC1. The gels are then swelled in a phosphate buffered saline about 33G or from about 16G to about 25G. A person of
(PBS) solution for a sufficient time and at a low temperature. 60 ordinary skill in the art can determine the correct Syringe
In one embodiment, the resulting Swollengels are highly dimensions and needle gauge required to arrive at a particular
cohesive with no visible distinct particles, for example, no extrusion force requirement.
visibly distinct particles when viewed with the naked eye. In The extrusion forces displayed by the HA/lidocaine com
a preferred embodiment, the gels have no visibly distinct positions described herein using the needle dimensions
particles under a magnification of less than 35X. 65 described above are at an injection speeds that are comfort
The gels are now purified by conventional means such as, able to a patient. Comfortable to a patient is used to define a
dialysis or alcohol precipitation, to recover the crosslinked rate of injection that does not injure or cause excess pain to a
 US 8,450.475 B2
11 12
patient upon injection to the soft tissue. One skilled in the art mixed for about 1 hour to obtain a homogenous mixture.
will appreciate that comfortable as used herein includes not Then, the homogenized mixture is centrifuged for 5 min at
only patient comfort, but also comfort and ability of the 2000 tr/minto remove the air bubbles and to allow the decan
physician or medical technician injecting the HA/lidocaine tation of any particles. The Syringe is then held in a vertical
compositions. Although certain extrusion forces may be position and one drop of eosin colorant is deposited at the
achievable with the HA/lidocaine compositions of the present Surface of the gel by means of a syringe and an 18G needle.
description, one skilled in the art understands that high extru After 10 min, the dye has slowly diffused through the gel.
sion forces can lead to lack of control during injection and that After dilution of the gel, homogenization and decantation,
Such lack of control may result in additional pain to the a relatively low cohesivity gel shows a phase separation (an
patient. Extrusion forces of the present HA/lidocaine compo 10 upper diluted less viscous phase without particles and a lower
sitions can be from about 8 N to about 15 N, or more prefer one composed of decanted particles that are visible with the
ably from about 10N to about 13 N, or about 11 N to about 12 naked eye or under microscope). Under the same conditions,
N. a highly cohesive gel shows Substantially no phase separa
Sterilization, as used herein comprises any method known tion, and the dye is prevented from diffusing into the cohesive
in the art to effectively kill or eliminate transmissible agents, 15 formulation. A relatively less cohesive gel, on the other hand,
preferably without Substantially altering of degrading the shows a clear phase separation.
HA/lidocaine compositions.
One preferable method of sterilization of the filled syringes Example 2
is by autoclave. Autoclaving can be accomplished by apply
ing a mixture of heat, pressure and moisture to a sample in Synthesis of a Soft Tissue Filler with Lidocaine
need of sterilization. Many different sterilization tempera
tures, pressures and cycle times can be used for this step. For NaHA fibers or powder are hydrated in an alkaline solu
example, the filled Syringes may be sterilized at a temperature tion, for example, an aqueous solution containing NaOH. The
of at least about 120° C. to about 130° C. or greater. Moisture mixture is mixed at ambient temperature, about 23° C., to
may or may not be utilized. The pressure applied is in some 25 form a substantially homogenous, alkaline HA gel.
embodiments depending on the temperature used in the ster A crosslinking agent, BDDE, is diluted in an aqueous
ilization process. The sterilization cycle may be at least about solution and added to the alkaline HA gel. The mixture is
1 minute to about 20 minutes or more. homogenized for several minutes.
Another method of sterilization incorporates the use of a Alternatively, BDDE can be added directly to the HA fibers
gaseous species which is known to kill or eliminate transmis 30 (dry state) at the beginning of the process, prior to the hydra
sible agents. Preferably, ethylene oxide is used as the steril tion. The crosslinking reaction will then start relatively
ization gas and is known in the art to be useful in sterilizing slowly at ambient temperature, ensuring even better homo
medical devices and products. geneity and efficacy of the crosslinking. See, for example,
A further method of sterilization incorporates the use of an Piron et al., U.S. Pat. No. 6,921,819 which is incorporated
irradiation source which is known in theart to kill or eliminate 35 herein by reference in its entirety as if it were part of the
transmissible agents. A beam of irradiation is targeted at the present specification.
Syringe containing the HA/lidocaine Solution, and the wave The resulting crosslinked HAgel mixture is then heated at
length of energy kills or eliminates the unwanted transmis about 50° C. for about 2.5 hours. The material is now a highly
sible agents. Preferable energy useful include, but is not lim crosslinked HA/BDDE gel (aspect=solid gel). This
ited to ultraviolet (UV) light, gamma irradiation, visible light, 40 crosslinked gel is then neutralized with a suitable acidic solu
microwaves, or any other wavelength or band of wavelengths tion. The neutralized HAgel is then swollen in a phosphate
which kills or eliminates the unwanted transmissible agents, buffer at a cold temperature, for example a temperature of
preferably without Substantially altering of degrading the about 5° C., to obtain a highly cohesive HA gel. In this
HA/lidocaine composition. specific example, the phosphate buffered saline Solution con
Further described are methods of manufacturing HA-based 45 tains water-for-injection (WFI), disodium hydrogen phos
compositions generally comprising the steps of providing a phate, and Sodium dihydrogen phosphate. When neutralized
crosslinked HA-based gel without an anesthetic, (hereinafter, and Swollen, the crosslinked HA component and water
Sometimes, a precursor gel) adjusting the pH of the precursor absorbed by the crosslinked HA component is in a weight
gel to obtain a gel having a pH of between about 7.2 and 8.0, ratio of about 1:1.
and adding a suitable amount of lidocaine, or otheranesthetic 50 The cohesive swollen HA gel is then mechanical stirred
agent, to the pH-adjusted gel to obtain a HA-based composi and filled into dialysis membranes and dialyzed against a
tion that includes an anesthetic agent. In one embodiment, the phosphate buffer. The HA gel is filled into dialysis mem
precursor gel is a highly cohesive gel comprising no greater branes and dialyzed against a phosphate buffer for up to
than about 10% free HA by volume. In another embodiment, several days with regular changes of the bath, in order to
the precursor gel is a relatively less cohesive gel comprising at 55 remove the un-reacted crosslinker, to stabilize the pH close to
least 10% to about 20% free HA by volume. neutrality (pH=7.2) and to ensure proper osmolarity of the
HA gel. The osmolarity of the resulting cohesive HA gel is
Example 1 between about 200 mOsmol and about 400 mOsmol, most
preferably about 300 mOsmol.
Method for Testing for Cohesivity of Gel 60 After dialysis, the resulting cohesive HAgel has a Substan
tially neutral pH, preferably about 7.2, and no visibly distinct
The following tests may be performed in order to evidence particles in a fluidic media when viewed at a magnification of
cohesivity of a HA-based gel composition for purposes of the less than about 35x.
present disclosure. Lidocaine chlorhydrate (lidocaine HCl) in powder form is
First, 0.2 g or 0.4 g of a gel composition to be tested is 65 first solubilized in WFI and filtered through a 0.2 um filter.
placed in a glass Syringe. Next, 0.2 g or more of phosphate Dilute NaOH solution is added to the cohesive HA gel in
buffer is added to the syringe and the mixture is thoroughly order to reach a slightly basic pH (for example, a pH of
 US 8,450.475 B2
13 14
between about 7.5 and about 8). The lidocaine HCl solution is Table 2 provides a Summary of stability testing results on
then added to the slightly basic gel to reach a final desired the composition manufactured as described herein.
concentration, for example, a concentration of about 0.3%
(w/w). The resulting pH of the HA/lidocaine mixture is then TABLE 2
about 7 and the HA concentration is about 24 mg/mL. 5
Mechanical mixing is performed in order to obtain a proper HAlidocaine
homogeneity in a standard reactor equipped with an appro Composition
priate blender mechanism. Test 3 month results 6 month results 9 month results
If desired, a suitable amount of free HA gel may be added
to the HA/lidocaine gel mixture with the advantage of 10 Aspect Transparent Conforms Conforms Conforms
increasing the kinetics of lidocaine delivery. For example, pH and homogeneous
7.2 7.2 7.2
free HA fibers are swollen in a phosphate buffer solution, in Extrusion Force (N) 11.9 11.1 11.9
order to obtain a homogeneous viscoelastic gel. This free HA NaHA Concentration 23.8 23.1 24.2
gel is then added to the crosslinked HA/lidocaine gel (for (mg/g)
example, at about 5%, w/w). The resulting gel is then filled 15 Sterility Conforms Conforms Conforms
into Ready-to-Fill sterile syringes and autoclaved at sufficient Osmolarity (mCSm/kg) 349 329 342
Lidocaine Content (%)
temperatures and pressures for Sterilization for at least about 2,6-dimethylaniline O.29 O.29 O.29
Conforms Conforms Conforms
1 minutes. content
After autoclaving, the final HA/lidocaine product is pack
aged and distributed to physicians. The product manufactured 20
in accordance with this method exhibits one or more charac- It was discovered that at 9 months time (from manufacture
teristics of stability as defined elsewhere herein. For example, date), the composition continues to meet the product specifi
the autoclaved HA/lidocaine product has a viscosity, cohe- cations
sivity, and extrusion force that are acceptable. No degradation
of the HA/lidocaine gel product is found during testing of the 25
product after the product has spent several months in storage. Example 4
Example 3
Kinetic Release
Properties of Soft Tissue Fillers 30
The following example illustrates the kinetic of release of
Properties of HA/lidocaine compositions manufactured in lidocaine from cohesive HA gels according to the present
accordance with methods described herein are shown in the description. The aim of the Example is to show that the
Table 1 below. Extrusion force for example was measured lidocaine contained in HA gels according to the present
using an INSTRONR Advanced Materials Testing System 35 skin.
Model 5564 (Instron, Norwood, Mass.) running BLUE-
description is freely released from the gels when placed in the
HILL(R) software version 2.11 (Instron, Norwood, Mass.). Dialysis was performed for different periods of time (about
TABLE 1. 10g of gel were placed in a small dialysis bag and then put in
HAlidocaine 30g of water). After each dialysis was stopped at a given time,
Composition the gel was homogenized with a spatula and the amount of
lidocaine was determined by UV method. The final concen
Appearance ignogeneous transparent gel tration of the dialysis bath met the theoretical concentration
Ension force (N) 10.8N of lidocaine which indicates the free release of lidocaine from
NaHA Content 23.7 mgg -6
45 the gel.
E.
Smolarity Sterile
321 (SAL s 10)
mosml/kg Table 3 illustrates lidocaine concentration in % (w/w),
Lidocaine Content (%) O.29% correction of the value and determination of the '% of released
2,6-dimethylaniline content Conforms lidocaine. Additionally, FIG. 1 graphically illustrates the
results tabulated in Table 3 below. Within FIG. 1 is indicated
In order to ensure that product specifications were main- the theoretical equilibrium concentration of lidocaine that
tained throughout the shelf life of the composition, multiple would exist if the lidocaine were retained in the gel or if it
studies were performed. In addition, 2.6 dimethylaniline con- were to be freely released. As is graphically illustrated
tent was measured in order to confirm the absence of therein, the data Suggest that the lidocaine is freely released
lidocaine degradation. from the gel.
TABLE 3

MMA4031- MMA4031 - MMA4031- MMA4031- MMA4031 - MMA4O29

MMA3056 EC6 EC2 EC3 EC4 EC5 EC7

Dialysis time Ohr 1 hr 30 min Shr 7hr 23 hr 48 hr 72 hr

(h)
lidocaine O.29 O.20 O16 O.15 O.08 O.O7 O.O7
 US 8,450.475 B2
15 16
FIG. 1 shows the concentration profile of lidocaine over Certain embodiments of this invention are described
time reaches an equilibrium that corresponds to free release herein, including the best mode known to the inventors for
of lidocaine. The formulation of the composition in FIG. 1 is carrying out the invention. Of course, variations on these
a cohesive crosslinked HA gel. The composition has a HA described embodiments will become apparent to those of
concentration of about 24 mg/mL, about 6% crosslinking, a 5 ordinary skill in the art upon reading the foregoing descrip
G' of about 170 and a high molecular weight to low molecular tion. The inventor expects skilled artisans to employ Such
weight HA ratio from about 95% to 5% to about 100% high variations as appropriate, and the inventors intend for the
molecular weight HA. This invitro study shows that lidocaine invention to be practiced otherwise than specifically
is freely released from the gel and not retained in the gel once 10 described herein. Accordingly, this invention includes all
modifications and equivalents of the Subject matter recited in
implanted.
Although the invention has been described and illustrated the claims appended hereto as permitted by applicable law.
Moreover, any combination of the above-described elements
with a certain degree of particularity, it is understood that the in all possible variations thereof is encompassed by the inven
present disclosure has been made only by way of example, tion unless otherwise
and that numerous changes in the combination and arrange 15 contradicted by context.indicated herein or otherwise clearly
ment of parts can be resorted to by those skilled in the art Furthermore, numerous references have been made to pat
without departing from the scope of the invention, as herein ents and printed publications throughout this specification.
after claimed. Each of the above-cited references and printed publications
Unless otherwise indicated, all numbers expressing quan are individually incorporated herein by reference in their
tities of ingredients, properties such as molecular weight, 20 entirety.
reaction conditions, and so forth used in the specification and Specific embodiments disclosed herein may be further lim
claims are to be understood as being modified in all instances ited in the claims using consisting of or and consisting essen
by the term “about.” Accordingly, unless indicated to the tially of language. When used in the claims, whether as filed
contrary, the numerical parameters set forth in the specifica or added per amendment, the transition term "consisting of
tion and attached claims are approximations that may vary 25 excludes any element, step, or ingredient not specified in the
depending upon the desired properties sought to be obtained claims. The transition term “consisting essentially of limits
by the present invention. At the very least, and not as an the scope of a claim to the specified materials or steps and
attempt to limit the application of the doctrine of equivalents those that do not materially affect the basic and novel char
to the Scope of the claims, each numerical parameter should at acteristic(s). Embodiments of the invention so claimed are
least be construed in light of the number of reported signifi- 30 inherently or expressly described and enabled herein.
cant digits and by applying ordinary rounding techniques. In closing, it is to be understood that the embodiments of
Notwithstanding that the numerical ranges and parameters the invention disclosed herein are illustrative of the principles
setting forth the broad scope of the invention are approxima of the present invention. Other modifications that may be
tions, the numerical values set forth in the specific examples employed are within the scope of the invention. Thus, by way
are reported as precisely as possible. Any numerical value, 35 of example, but not of limitation, alternative configurations of
however, inherently contains certain errors necessarily result the present invention may be utilized in accordance with the
ing from the standard deviation found in their respective teachings herein. Accordingly, the present invention is not
testing measurements. limited to that precisely as shown and described.
The terms “a,” “an,” “the' and similar referents used in the I claim:
context of describing the invention (especially in the context 40 1. A stable, sterile soft tissue filler comprising:
of the following claims) are to be construed to cover both the a hyaluronic acid (HA) component comprising HA
singular and the plural, unless otherwise indicated herein or crosslinked with 1,4-butanediol diglycidyl ether
clearly contradicted by context. Recitation of ranges of values (BDDE), and uncrosslinked HA, wherein the HA com
herein is merely intended to serve as a shorthand method of ponent comprises greater than about 10% uncrosslinked
referring individually to each separate value falling within the 45 HA by volume; and
range. Unless otherwise indicated herein, each individual lidocaine combined with said crosslinked HA component.
value is incorporated into the specification as if it were indi 2. The soft tissue filler of claim 1 wherein the HA compo
vidually recited herein. All methods described herein can be nent comprises at least about 15% uncrosslinked HA by vol
performed in any suitable order unless otherwise indicated le.
herein or otherwise clearly contradicted by context. The use 50 3. The soft tissue filler of claim 1 wherein the HA compo
of any and all examples, or exemplary language (e.g., “Such nent comprises at least about 20% uncrosslinked HA by vol
as') provided herein is intended merely to better illuminate le.
the invention and does not pose a limitation on the scope of 4. The soft tissue filler of claim 1 wherein the HA compo
the invention otherwise claimed. No language in the specifi nent comprises a first portion of crosslinked HA and a second
cation should be construed as indicating any non-claimed 55 portion of uncrosslinked HA.
element essential to the practice of the invention. 5. The soft tissue filler of claim 4 wherein the first portion
Groupings of alternative elements or embodiments of the has degree of crosslinking of less than about 6%.
invention disclosed herein are not to be construed as limita 6. The soft tissue filler of claim 4 wherein the HA compo
tions. Each group member may be referred to and claimed nent has a degree of crosslinking of less than about 5%.
individually or in any combination with other members of the 60 7. The soft tissue filler of claim 4 wherein the HA compo
group or other elements found herein. It is anticipated that one nent has a degree of crosslinking of about 2%.
or more members of a group may be included in, or deleted 8. The soft tissue filler of claim 1 wherein the lidocaine is
from, a group for reasons of convenience and/or patentability. at a concentration of between about 0.1% and about 5% by
When any Such inclusion or deletion occurs, the specification weight of said soft tissue filler.
is deemed to contain the group as modified thus fulfilling the 65 9. The soft tissue filler of claim 1 wherein the HA compo
written description of all Markush groups used in the nent comprises particles of crosslinked HA in a relatively
appended claims. fluidic medium of uncrosslinked HA.
 US 8,450.475 B2
17 18
10. A method of preparing a stable, sterile soft tissue filler, 23. The composition of claim 19 wherein the high molecu
the method comprising the steps of: lar weight HA component has a molecular weight of at least
providing a hyaluronic acid (HA) component crosslinked about 1.0 MDa and the low molecular weight HA has a
withHA1,4-butanediol urth
diglycidyl ether (BDDE), wherein
HA 5
molecular weight of lessofthan
24. The composition
p
about
claim 10 MDa.the low molecu
23 wherein
that a COICCIa1O
postOla
f t1eaSa)0l.
er restt of
o of the we1gnto
lar weight HA component has a molecular weight of between
about 0.2 MDa and less than 1.0 MDa.
the HA component; 25. The composition of claim 23 wherein the low molecu
adjusting the pH of said HA component to an adjusted pH lar weight HA component has a molecular weight of between
above about 7.2; and 10 about 0.3 MDa and less than 0.75 MDa.
adding a solution containing lidocaine to said HA compo- 26. The composition of claim 19 wherein the HA material
nent having said adjusted pH to obtain a HA-based soft comprises about 90% by weight of the low molecular weight
tissue filler that is stable after being subjected to heat HA component and about 10% by weight of the high molecu
sterilization. lar weight HA component.
11. The method of claim 10 wherein said adjusted pH is 15 27. A stable, sterile soft tissue filler composition compris
above about 7.5. 1ng:
12. The method of claim 10 wherein said step of providing
a HA component comprises the steps of providing dry
aR E. th EPE 9.
2% to about 20%: g a degr
uncrosslinked NaHA material and hydrating said dry To R a E. b 0. lume; and
uncrosslinked NaHA material in an alkaline solution to at least 10% ree y Volume; an
obtain an alkaline, uncrosslinked NaHA gel about 0.1% to about 5% lidocaine by weight of the com
13. The method of claim 12 wherein said alkaline, position. -
uncrosslinked NaHA gel has a pH greater than about 8.0. 28. TheO composition of claim 27, wherein the free HA is
14. The method of claim 12 wherein said alkaline, about 20% or less of the HA by Volume. -
uncrosslinked NaHA gel has a pH greater than about 10. 25 29. The composition of claim 27, wherein the free HA is
15. The method of claim 10 wherein the HA component about 10% to about 20% of the composition by volume.
comprises greater than about 10% uncrosslinked HA. 30. The composition of claim 27, wherein the composition
16. The method of claim 10 wherein the HA component is prepared by adding free HA to crosslinked HA.
comprises at least about 20% uncrosslinked HA. 31. A heat-sterilized, stable dermal filler comprising:
17. The method of claim 10 wherein the HA component a hyaluronic acid (HA) comprising both crosslinked HA
has a degree of crosslinking of less than about 5%. and uncrosslinked HA, the crosslinked HA being
18. A stable, sterile soft tissue filler comprising: crosslinked with 1,4-butanediol diglycidyl ether
a hyaluronic acid (HA) component crosslinked with 1,4- (BDDE) and having a degree of crosslinking of less than
- - -- - bout 5%; and
butanediol diglycidyl ether (BDDE), said HA compo- abol s -
nent having a degree of crosslinking of less than about is lity at AAcentration of about 0.3% by weight of
5% and uncrosslinked HA in an amount of at least about said dermal Iller.
10% by volume of the HA component; and the dermal filler having a pH of about 7.
lidocaine having a concentration of about 0.3% by weight 32. fe detail: of claim 31 sing a HA concentra
of said soft tissue filler; tion of between about 20 mg/mL to about 30 mg/mL.
wherein the soft tissue filler has been heat sterilized. 40 3. s depositss s the ENESSS
19. A stable, sterile soft tissue filler composition compris- t Out Oyo to about 2U% of the uncroSS1nke y
ing:
a hyaluronic acid (HA) material crosslinked with 1,4-bu- its. sts sts filler comprising: ing HA
tanediol diglycidyl ether (BDDE), said HA material
including a high molecular weight HA componentanda as
a CrOSS1nked
systW1ts' SES." E"
,4-butanedio
glyc1dyl ether
-
low molecular weight - a
HA component and having (BDDE),
. . . . and uncrosslinked HA;s and -
degree of crosslinking of less than about 5%; lidocaine at a concentration of about 0.3% by weight of the
free HA at a concentration of at least about 10% by volume soft tissue filler combined with said crosslinked HA
t;
of the soft tissue filler composition; and component -- - --
lidocaine having a concentration between about 0.1% and so wherein the soft tissue filler is stable after heat sterilization
about 5.0% by weight of the soft tissue filler composi- byen about 120 degrees C. and about 130 degrees
20.tion.
The composition of claim 19 wherein the high molecu- her the
wherein the son issue filler
soft tissue fillerhhas a pH offabout
about 7.7
lar weight HA component has a molecular weight of between 35. The soft tissue filler of claim 34 having a HA concen
about 1.0 MDa and about 4.0 MDa. 55
tration of between about 20 mg/mL to about 30 mg/mL.
21. The composition of claim 19 wherein the high molecu- 36. The soft tissue filler of claim 34 wherein the HA com
lar weight HA component has a molecular weight of about 2.0 prises at least about 10% to about 20% of the uncrosslinked
MDa - HA by volume.
22. The composition of claim 19 wherein the high molecu- 37. The soft tissue filler of claim34 wherein the crosslinked
lar weight HA component has a molecular weight of about 2.8 HA has a degree of crosslinking of less than about 5%.
MDa. :: *k, *k : :
 UNITED STATES PATENT AND TRADEMARK OFFICE
CERTIFICATE OF CORRECTION
PATENT NO. : 8.450,475 B2 Page 1 of 1
APPLICATIONNO. : 12/393768
DATED : May 28, 2013
INVENTOR(S) : Pierre F. Lebreton

It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

On the title page, first column, Item 73), delete “Allergan, Inc., Irvine, CA (US) and insert
-- Allergan Industrie, SAS (FR)--, therefor.

Signed and Sealed this

Twenty-ninth Day of October, 2013

Teresa Stanek Rea

Deputy Director of the United States Patent and Trademark Office