Us 10485896

US010485896B2
( 12 ) United States Patent ( 10 ) Patent No.: US 10,485,896 B2

Lebreton (45 ) Date of Patent: *Nov. 26 , 2019
(54 ) HYALURONIC ACID -BASED GELS (58 ) Field of Classification Search
INCLUDING LIDOCAINE CPC A61K 8/42; A61K 8/735 ; A61K 9/002;
(71) Applicant: Allergan Industrie SAS , Pringy (FR ) A61K 9/06 ; A61K 31/167; A61K 31/728 ;
A61L 27/52 , A61L 27/20 ; A61L 27/54 ;
A61L 2300/402 , A61L 2300/602; A61L
(72 ) Inventor: Pierre F. Lebreton , Annecy (FR ) 2400/06 ; A61Q 19/08
( 73 ) Assignee: ALLERGAN INDUSTRIE SAS, See application file for complete search history.
Pringy (FR )
( * ) Notice : Subject to any disclaimer, the term of this (56 ) References Cited
patent is extended or adjusted under 35 U.S. PATENT DOCUMENTS
U.S.C. 154 (b ) by 0 days.
This patent is subject to a terminal dis 2,128,827 A 8/1938 Killian
claimer .
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(60 ) Provisional application No. 61/085,956 , filed on Aug. (Continued )
4 , 2008 , provisional application No.61/087,934 , filed
on Aug. 11, 2008, provisional application No.
61/096,278 , filed on Sep. 11 , 2008 . Primary Examiner Ali Soroush
(51) Int. Cl. (74 ) Attorney, Agent, or Firm Nathan S. Smith ;
A6IL 27/52 (2006.01 ) Morgan , Lewis & Bockius LLP
A61K 8/42 ( 2006.01 )
A61K 8/73 ( 2006.01 )
A61L 27/20 (2006.01) (57 ) ABSTRACT
A61L 27/54 ( 2006.01)
A61Q 19/08 ( 2006.01) Disclosed herein are cohesive soft tissue fillers, for example ,
A61K 31/167 ( 2006.01 ) dermal and subdermal fillers ,based on hyaluronic acids and
A61K 31/728 (2006.01) pharmaceutically acceptable salts thereof. In one aspect,
A61K 9/00 ( 2006.01 ) hyaluronic acid -based compositions described herein
A61K 9/06 ( 2006.01) include a therapeutically effective amount of at least one
A61K 4736 (2006.01 ) anesthetic agent, for example , lidocaine . The present
(52 ) U.S. CI. hyaluronic acid - based compositions including lidocaine
CPC A61L 27/52 ( 2013.01); A61K 8/42 have an enhanced stability and cohesivity , relative to con
(2013.01); A61K 8/735 ( 2013.01 ); A61K ventional compositions including lidocaine , for example
9/0021 ( 2013.01 ); A61K 9/06 ( 2013.01); A61K when subjected to sterilization techniques or when stored for
31/167 (2013.01 ); A61K 31/728 ( 2013.01); long periods of time. Methods and processes of preparing
A61K 47/36 (2013.01); A61L 27/20 (2013.01); such hyaluronic acid -based compositions are also provided .
A61L 27/54 (2013.01); A61Q 19/08 (2013.01 );
A61L 2300/402 (2013.01 ); AGIL 2300/602
(2013.01); A61L 2400/06 (2013.01) 30 Claims, 5 Drawing Sheets
US 10,485,896 B2
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* cited by examiner
U.S. Patent Nov. 26 , 2019 Sheet 1 of 5 US 10,485,896 B2
500 Lido no pH control
Viscosity 300
200
FIG . 1
SAMPLE 2
250 No Lido
Lido with pH control
Lido no pH control
Visco ity
100 HAN
DODOC 2009 DOGS
Frequency (Hz)
FIG . 2
SAMPLE 3
No Lido
80
Viscosity
0
ti AN
perar
Frequency (Hz)
FIG . 3
12 AURA Lido with pH control
Viscoity 6
MW
Barat
Frequency (Hz)
FIG . 4
SAMPLE 5

Lido no pu control
Visco ity 60
20
Xoooo
0
1
Frequency (Hz)
FIG . 5
/
"
G
Mod
veel soportation
mitWin
WWW
wordoogipos
No Lido
Lido no pH control
1
Frequency (Hz)
FIG . 6
SAMPLE 6
No Lido
Lido 10 ph control
Visco ity 300

250
150
1
Frequency (Hz)
FIG . 7
SAMPLE 6
with ph control
0.35 ???? no pH control
G
/
"
0.2
1
Frequency (Hz )
FIG . 8
0.30 theoreucal result if lidocaine is

retained in the gel
Lidocaine
(
w
%
gel
the
in
)
/ With Att West Authe W HAW HAWA WA W HAWA WA A W
0.15 theoretical result if lidocaine

is freely released
0.10 KAN
ww
0.00
100
Time (hrs)
FIG . 9
US 10,485,896 B2
1 2
HYALURONIC ACID - BASED GELS reactions, the human derived collagen fillers still suffered
INCLUDING LIDOCAINE from the rapid degradation of the injected product.
The search for fillers that do notprovoke allergic reactions
CROSS REFERENCE TO RELATED and sustain a smoother, more youthful appearance has
APPLICATIONS 5 brought about the development of hyaluronic acid (HA )
based products . In December 2003, the first HA -based filler
This application is a continuation ofU.S. patent applica was approved by the FDA . This was rapidly followed by the
tion Ser. No. 15 /443,080 , filed on Feb. 27 , 2017 , which is a development of other HA -based fillers.
continuation ofU.S. patent application Ser. No. 14 /754,504, HA , also known as hyaluronan , is a naturally occurring,
filed on Jun. 29, 2015,which is a continuation ofU.S. patent 10 water soluble polysaccharide, specifically a glycosamino
application Ser. No. 14 /242,752 , filed on Apr. 1, 2014 ,which glycan , which is a major component of the extra-cellular
is a continuation ofU.S. patent application Ser. No. 13/419 , matrix and is widely distributed in animal tissues. HA has
07 filed Mar. 13 , now U.S. Pat. No. 8,822,676 , excellentbiocompatibility and does not cause allergic reac
which is a continuation of U.S. patent application Ser. No. tions when implanted into a patient. In addition , HA has the
12/393,884 , filed Feb. 26 , 2009 , now U.S. Pat. No. 8,357, 15 ability to bind to large amounts of water, making it an
795 , which claims the benefit of each of U.S. Provisional excellent volumizer of soft tissues .
Patent Application No. 61/085,956 , filed Aug. 4 , 2008, U.S. The development of HA -based fillers which exhibit ideal
Provisional Patent Application No. 61/087,934, filed Aug. in vivo properties as well as ideal surgical usability has
11, 2008, and U.S. Provisional Patent Application No. proven difficult . For example, HA -based fillers that exhibit
61/096,278, filed Sep. 11, 2008 , the entire disclosure of each 20 desirable stability properties in vivo, can be so highly
of these applications being incorporated herein by this viscous that injection through fine gauge needles is difficult .
reference . Conversely, HA -based fillers that are relatively easily
injected through fine gauge needles often have relatively
FIELD OF THE INVENTION inferior stability properties in vivo .
25 One method to overcome this problem is to use cross
The present invention generally relates to injectable soft linked HA -based fillers. Crosslinked HA is formed by react
tissue fillers and more specifically relates to hyaluronic ing free HA with a crosslinking agent under suitable reaction
acid - based dermal and subdermal fillers including an anes conditions. Methods of preparing HA based soft tissue fillers
thetic agent. including both crosslinked and free HA are well known .
30 It has been proposed to incorporate certain therapeutic
BACKGROUND agents, for example , anesthetic agents such as lidocaine, into
injectable HA -based compositions. Unfortunately ,
It is generally accepted that as a person ages , the face HA -based injectable compositions which incorporate lido
begins to show effects of gravity, sun - exposure , and years of caine during the manufacturing process are prone to partial
facial muscle movement, such as smiling , frowning, chew- 35 or almost complete degradation prior to injection , particu
ing and squinting . The underlying tissues that keep the skin larly during high temperature sterilization steps and /or when
appearing youthful begin to break down , often resulting in placed in storage for any significant length of time.
laugh lines, smile lines, “ crow's feet” and facial creases It is an objective of the HA -based soft filler compositions
often referred to as the " effects of aging.” and methods of making and using them as described herein
In an effort to treat or correct the effects of aging, soft 40 to provide soft tissue fillers that do not cause allergic
tissue fillers have been developed to help fill in facial lines reactions in patients, are biocompatible and are stable and
and depressions and for restoring fat loss -related tissue usable in vivo and include one or more local anesthetic
volume loss. The soft tissue fillers thereby temporarily agents .
restore a smoother, more youthful appearance .
Ideally, soft tissue fillers are long-lasting, soft , smooth and 45 SUMMARY
natural appearing when implanted in the skin or beneath the
skin . Further , soft tissue fillers are easy to implant into a The present description relates to soft tissue fillers, for
patient using a fine gauge needle and require low extrusion example , dermal and subdermal fillers, based on hyaluronic
force for injection. Ideal fillers would also cause no adverse acid (HA ) and pharmaceutically acceptable salts ofHA , for
side effects , and would be injectable with minimal or no 50 example , sodium hyaluronate (NaHA ). HA -based composi
discomfort to the patient. tions described herein include a therapeutically effective
Collagen based soft tissue fillers were developed over 20 amount of at least one anesthetic agent. In one embodiment,
years ago , and for some time, bovine collagen -based fillers for example , the anesthetic agent is lidocaine . The present
were the only U.S. Food and Drug Administration (FDA ) HA -based compositions including at least one anesthetic
approved dermal fillers . Because these dermal fillers are 55 agent have an enhanced stability, relative to conventional
bovine based , one of the main disadvantages has been the HA -based compositions including, for example , lidocaine,
potential for allergic reaction in patients . It is believed that when subjected to sterilization techniques such as autoclav
approximately 3-5 % of human subjects show serious aller ing , and /or when stored for long periods at ambient tem
gic reactions to bovine collagen , thus requiring careful perature . Methods for preparing such HA -based composi
testing before using these fillers in any particular person . In 60 tions are also provided as well as products made by such
addition to allergic reactions, collagen based fillers degrade methods.
rapidly upon injection and require frequent treatments to Described herein are soft tissue filler compositions, the
sustain a smoother , more youthful appearance . compositions generally comprising: a hyaluronic acid com
In February 2003 , human -derived collagen filler compo ponent crosslinked with a crosslinking agent selected from
sitions received FDA approval. These collagens provide the 65 the group consisting of 1,4 -butanediol diglycidyl ether
advantage of a significantly reduced risk of allergic reac (BDDE ), 1,4 -bis ( 2,3 -epoxypropoxy)butane, 1,4 -bisglycidy
tions. However, despite the reduced incidence of allergic loxybutane , 1,2-bis (2,3 -epoxypropoxy )ethyl ene and 1-(2,3
US 10,485,896 B2
3 4
epoxypropyl) -2,3 -epoxycyclohexane, and 1,4-butanediol In another embodiment, the step of providing a HA
diglycidyl ether ; and at least one anesthetic agent combined component comprises providing dry free NaHA material and
with the crosslinked HA component. hydrating the dry free NaHA material in an alkaline solution
In yet another embodiment, the at least one anesthetic to obtain an alkaline , free NaHA gel. In yet another embodi
agent is lidocaine. In a further embodiment, the amount of 5 ment, the alkaline, free NaHA gel has a pH greater than
the anesthetic agent is present at a concentration between about 8.0 . In still another embodiment the pH is greater than
about 0.1 % and about 5.0 % by weight of the composition . about 10 .
In still another embodiment, the anesthetic agent is present In a further embodiment, the HA component comprises
at a concentration between about 0.2 % and about 1.0 % by greater than about 20 % free HA and the crosslinked portion
weightagent
thetic of theis lidocaine
compositionand. Inis present
one embodiment , the anes-of 10 of the HA component has a degree of crosslinking of less
at a concentration than about 6 % or less than about 5 % .
about 0.3 % by weight of the composition. In still a further embodiment, the soft tissue filler com
In still another embodiment, the soft tissue filler compo position has a particulate nature in that it comprises particles
sition has an extrusion force of between about 10 N and
about 13 N , for example , at a rate of about 12.5 mm /minute. 15 of crosslinked HA dispersed in a fluid soluble HA medium .
In yet another embodiment, the composition has a viscosity In some embodiments , the average size of such particles is
ofbetween about 5 Pa* s and about 450 Pa* s, for example , at least about 200 um , and in other embodiments the average
when measured at about 5 Hz. size of such particles is at least about 250 um .
In one embodiment, the HA component is a gel, for Further described herein is a soft tissue filler composition
example, a cohesive, hydrated gel. one embodiment, the 20 comprising: a hyaluronic acid (HA ) component crosslinked
HA component is a crosslinked HA gel having no greater with 1,4 -butanediol diglycidyl ether (BDDE ), said HA com
than about 1 % to about 10 % free HA . For purposes of this ponent having a degree of crosslinking of less than about
disclosure, free HA includes truly free HA as well as lightly 5 % , and an anesthetic component having concentration
crosslinked HA chains and fragments, all in soluble form in between about 0.1 % and about 5.0 % by weight of the soft
water. 25 tissue filler composition , wherein the anesthetic is lidocaine.
In yet other embodiments, the HA component comprises In a specific embodiment of the invention , a method of
greater than about 10 % , for example , greater than about preparing a soft tissue filler composition is further described ,
15 % , for example , up to or greater than about 20 % free HA. the method comprising the steps of providing dry free
In yet another embodiment, the HA component is a gel NaHA material and hydrating the dry free NaHA material in
comprising particles of crosslinked HA in a relatively fluidic 30 an alkaline solution to obtain an alkaline, free NaHA gel;
medium of free HA. In some embodiments, the HA com crosslinking the free NaHA gel with BDDE to form a
ponent has an average particle size of greater than about 200 crosslinked alkaline HA composition with a degree ofcross
um , for example , greater than about 250 um . linking less than about 5 % and a pH above about 7.2 ; adding
Further described herein is a soft tissue filler composition a solution containing lidocaine HCl to the HA component
comprising: a HA component crosslinked with 1,4 -butane- 35 having the adjusted pH to obtain said HA -based filler
diol diglycidyl ether (BDDE), said HA component having a composition ; homogenizing the HA -based filler composi
degree of crosslinking of less than about 5 % , for example , tion thereby forming a homogenized HA -based filler com
about 2 % , and an anesthetic component having a concen position , and sterilizing the homogenized HA- based filler
tration between about 0.1 % and about 5.0 % by weight of the composition thereby forming a sterilized HA -based filler
soft tissue filler composition , wherein the anesthetic is 40 composition,wherein the soft tissue filler composition has a
lidocaine. particle size of greater than about 200 um , for example , a
Further described herein are methods of preparing soft particle size of greater than about 250 um .
tissue filler compositions, the methods comprising the steps
of: providing a HA component crosslinked with at least one BRIEF DESCRIPTION OF THE DRAWINGS
crosslinking agent selected from the group consisting of 45
1,4 -butanediol diglycidyl ether (BDDE ), 1,4 -bis(2,3 -epoxy FIG . 1 graphically illustrates the viscosity of Sample 1
propoxy)butane , 1,4 -bisglycidyloxybutane, 1,2 -bis( 2,3 - ep prepared without lidocaine , with lidocaine and pH adjust
oxypropoxy Jethylene and 1-(2,3 - epoxypropyl)-2,3 -epoxy ment during formation and with lidocaine but without pH
cyclohexane, and 1,4 -butanediol diglycidyl ether or adjustment during formation versus the shear frequency.
combinations thereof; adjusting the pH of said HA compo- 50 FIG . 2 graphically illustrates the viscosity of Sample 2
nent to an adjusted pH above about 7.2 ; and adding a prepared without lidocaine, with lidocaine and pH adjust
solution containing at least one anesthetic agent to the HA ment during formation and with lidocaine but without pH
component having the adjusted pH to obtain a HA -based adjustment during formation versus the shear frequency.
filler composition. FIG . 3 graphically illustrates the viscosity of Samp
In another embodiment, the composition is sterilized , for 55 prepared without lidocaine , with lidocaine and pH adjust
example , by autoclaving, to form a sterilized composition ment during formation and with lidocaine but without pH
and wherein the sterilized composition is stable at ambient adjustment during formation versus the shear frequency.
temperature for at least about months, for example, at least FIG . 4 graphically illustrates the viscosity of Sample 4
9 months , at least about 12 months, for example , at least prepared without lidocaine, with lidocaine and pH adjust
about 36 months, or more . 60 ment during formation and with lidocaine but without pH
In still another embodiment, the adjusted pH is above adjustment during formation versus the shear frequency .
about 7.5. In another embodiment, the method further com FIG . 5 graphically illustrates the viscosity of Sample 5
prises the step of homogenizing the HA component during prepared without lidocaine, with lidocaine and pH adjust
or after the step of adding the solution containing the at least ment during formation and with lidocaine but without pH
one anesthetic agent. In a further embodiment, the step of 65 adjustment during formation versus the shear frequency .
homogenizing comprises subjecting the composition to mix FIG . 6 graphically illustrates the relative viscosity / elas
ing with a controlled shear. ticity characteristics of Sample 5 prepared without lidocaine ,
US 10,485,896 B2
5 6
with lidocaine and pH adjustmentduring formation and with HA generally remains water soluble . Free HA can alterna
lidocaine but without pH adjustment during formation ver tively be defined as the “ uncrosslinked ,” or lightly cross
sus the shear frequency . linked component of the macromolecular structure making
FIG . 7 graphically illustrates the viscosity of Sample 6 up the soft tissue filler composition disclosed herein .
prepared without lidocaine , with lidocaine and pH adjust- 5 Cohesive as used herein is the ability of a HA -based
ment during formation and with lidocaine but without pH composition to retain its shape and resist deformation .
adjustment during formation versus the shear frequency. Cohesiveness is affected by, among other factors, the
FIG . 8 graphically illustrates the relative viscosity / elas molecular weight ratio of the initial free HA , the degree of
ticity characteristics ofSample 6 prepared without lidocaine, crosslinking, the amount of residual free HA following
with lidocaine and pH adjustmentduring formation and with 10 crosslinking, and HA-based composition pH . Moreover, a
lidocaine but without pH adjustment during formation ver cohesive HA -based composition resists phase separation
sus the shear frequency. when tested according to the method disclosed at Example
FIG . 9 graphically illustrates the lidocaine concentration 1 herein .
in the gel from Sample 5 in Example 4 made by the
procedure of Test 2 versus time. 15 DETAILED DESCRIPTION
DEFINITIONS The present disclosure generally relates to soft tissue
fillers , for example, dermal and subdermal fillers, based on
Certain terms as used in the specification are intended to hyaluronic acids (HA) and pharmaceutically acceptable salts
refer to the following definitions, as detailed below . Where 20 of HA , for example, sodium hyaluronate (NaHA ). In one
the definition of terms departs from the commonly used aspect, HA - based compositions described herein include a
meaning of the term , applicant intends to utilize the defini therapeutically effective amount of at least one anesthetic
tions provided below , unless specifically indicated . agent, for example , lidocaine. The present HA -based com
Autoclave stable or stable to autoclaving as used herein positions including at least one anesthetic agent have an
describes a product or composition that is resistant to 25 enhanced stability , relative to conventional HA -based com
degradation such that the product or composition maintains positions including, for example , lidocaine, when subjected
at least one , and preferably all , of the following aspects after to high temperatures and pressures , for example , those
effective autoclave sterilization: transparent appearance , pH , experienced during heat and /or pressure sterilization tech
extrusion force and/or rheological characteristics , niques, for example , autoclaving , and/ or for example , when
hyaluronic acid (HA ) concentration , sterility, osmolarity, 30
stored at ambient temperature for an extended period of
and lidocaine concentration . time.
Centrifugation as used herein refers to the process of The stable compositionsmaintain at least one of, or all of,
using centrifugal forces to evenly distribute substances of the following aspects after effective autoclave sterilization
greater and lesser density . Centrifugation is commonly usedand /or prolonged storage: transparent appearance , pH for
to separate a liquid phase from a solid or gel phase . 35 use in a patient, extrusion force and /or rheological charac
Substantial phase separations resulting from centrifugation teristics, HA concentration, sterility , osmolarity , and lido
would be at least those visible by the naked eye , for caine concentration .Methods or processes of preparing such
example, a liquid phase and a solid phase distinctly sepa HA -based compositions are also provided as well as prod
rated when viewed with the naked eye. ucts made by such methods or processes .
High molecular weightHA as used herein describes a HA 40 As used herein , hyaluronic acid (HA ) can refer to any of
material having a molecular weight of at least about 1.0 its hyaluronate salts , and includes, but is not limited to ,
million Daltons (mw210 Da or 1 MDa) to about 4.0 MDa. sodium hyaluronate (NaHA ), potassium hyaluronate, mag
For example , the high molecular weight HA in the present nesium hyaluronate , calcium hyaluronate, and combinations
compositions may have a molecular weight of about 2.0 thereof.
MDa. In another example , the high molecular weight HA 45 Generally , the concentration of HA in the compositions
may have a molecular weight of about 2.8 MDa. described herein is preferably at least 10 mg/mL and up to
Low molecular weight HA as used herein describes a HA about 40 mg/mL . For example, the concentration of HA in
material having a molecular weight of less than about 1.0 some of the compositions is in a range between about 20
MDa. Low molecular weight HA can have a molecular mg/mL and about 30 mg/mL. Further, for example, in some
weight of between about 200,000 Da (0.2 MDa) to less than 50 embodiments , the compositions have a HA concentration of
about 1.0 MDa, for example , between about 300,000 Da (0.3 about 22 mg/mL , about 24 mg/mL , about 26 mg/mL , or
MDa ) to about 750,000 Da. (0.75 MDa). about 28 mg/mL .
Degree of Crosslinking as used herein refers to the In addition , the concentration of one or more anesthetics
intermolecular junctions joining the individual HA polymer is in an amount effective to mitigate pain experienced upon
molecules, or monomer chains, into a permanent structure , 55 injection of the composition . The at least one local anes
or as disclosed herein the soft tissue filler composition . thetic can be selected from the group of ambucaine, amo
Moreover , degree of crosslinking for purposes of the present lanone, amylocaine, benoxinate , benzocaine , betoxycaine ,
disclosure is further defined as the percent weight ratio of the biphetamine , bupivacaine , butacaine , butamben , butanilic
crosslinking agent to HA -monomeric units within the cross aine, butethamine, butoxycaine, carticaine, chloroprocaine ,
linked portion of the HA based composition . It is measured 60 cocaethylene, cocaine, cyclomethycaine, dibucaine, dime
by the weight ratio of HA monomers to crosslinker (HA thisoquin , dimethocaine, diperodon , dicyclomine, ecgoni
monomers:crosslinker ). dine, ecgonine , ethyl chloride , etidocaine , beta - eucaine ,
Free HA as used herein refers to individual HA polymer euprocin , fenalcomine, fomocaine, hexylcaine, hydroxytet
molecules that are not crosslinked to , or very lightly cross racaine , isobutyl p -aminobenzoate , leucinocaine mesylate ,
linked to (very low degree of crosslinking) the highly 65 levoxadrol, lidocaine , mepivacaine, meprylcaine, metabu
crosslinked (higher degree of crosslinking ) macromolecular toxycaine, methyl chloride , myrtecaine , naepaine, octo
structure making up the soft tissue filler composition . Free caine , orthocaine , oxethazaine , parethoxycaine , phenacaine ,
US 10,485,896 B2
7 8
phenol, piperocaine, piridocaine, polidocanol, pramoxine, mixture, and homogenizing the mixture , to obtain a cross
prilocaine, procaine, propanocaine , proparacaine, propi linked HA -based composition that is stable to autoclaving .
pocaine, propoxycaine , pseudococaine, pyrrocaine, ropiva In certain embodiments, the precursor composition is a
caine, salicyl alcohol, tetracaine, tolycaine , trimecaine , cohesive, hydrated HA -based gel. Such a " cohesive” gelwill
zolamine, and salts thereof. In one embodiment, the at least 5 generally include no greater than between about 1 % to about
one anesthetic agent is lidocaine, such as in the form of 10 % soluble - liquid form or free HA by volume. Such
lidocaine HCl. The compositions described herein may have cohesive gels are considered by some in the industry to be
a lidocaine concentration ofbetween about 0.1 % and about monophasic , or substantially single-phase compositions, in
5 % by weight of the composition , for example, about 0.2 % that less than about 1 % to about 10 % of the composition
to about 1.0 % by weight of the composition . In one embodi- 10 comprises free HA .
ment, the composition has a lidocaine concentration of about In yet other embodiments, the precursor composition is a
0.3 % of the composition . The concentration of lidocaine in relatively non -cohesive , hydrated HA -based gel. Such a
the compositions described herein can be therapeutically “ non -cohesive” gel generally includes greater than 10 % , for
effective meaning the concentration is adequate to provide a example , greater than about 15 % , for example , greater than
therapeutic benefit without inflicting harm to the patient. 15 20 % or more of free HA .
In one aspect of the invention , a method is provided for In some embodiments, the precursor composition may
preparing a HA -based composition including an effective comprise a first component made up of relatively highly
amount of lidocaine wherein the method comprises provid crosslinked HA in a substantially solid phase, and a second
ing a precursor composition comprising a cohesive cross component comprising free or relatively less crosslinked HA
linked HA -based gel, adding a solution containing lidocaine, 20 in a substantially fluidic phase in which the relatively highly
for example in the form of lidocaine HCl, thereto and crosslinked HA is dispersed .
homogenizing the mixture to obtain a cohesive , at least In some embodiments, the present compositions have a
partially crosslinked , HA -based composition including lido somewhat particulate nature and comprise particles of rela
caine that is stable to autoclaving. The cohesive , crosslinked tively highly crosslinked HA dispersed in a medium of free
HA -based gel includes no greater than about 1 % to about 25 HA . In some embodiments , the average size of such par
10 % of free HA material by volume, for example , no greater ticles of crosslinked HA is at least about 200 um or at least
than about 5 % free HA material. about 250 um . Such particulate compositions are generally
In some embodiments of the present invention , the HA less cohesive than otherwise similar compositions which
component of the present compositions, hereinafter some have no discernable particles , or have particles having an
times, “ precursor composition ” is a hydrated , cohesive gel. 30 average size of less than 200 um .
A cohesive gel, relative to a non -cohesive gel, is better able For example , in some embodiments , the precursor com
retain its shape and resist deformation , for example, after position may be manufactured by pressing a mass of rela
being subjected to shear or other stresses. It has been tively highly crosslinked HA -based gel through a sieve or a
discovered by the present inventor that such cohesive gels mesh to create relatively highly crosslinked HA particles of
are less likely to substantially degrade or become unstable 35 generally uniform size and shape . These particles are then
over time or when subjected to external stimuli such as mixed with a carriermaterial, for example , an amount of free
sterilization , relative to non -cohesive gels . HA to produce a gel.
Without intending to be bound by any particular theory of In other embodiments , a method of preparing a HA -based
operability , it is believed that the cohesivity of the precursor composition including an effective amount of lidocaine is
composition in some embodiments of the invention acts to 40 provided wherein the method comprises providing a precur
substantially or entirely prevent or impede any breakdown sor composition including a substantially pH neutral, at least
or degradation of the crosslinked HA in the composition partially crosslinked HA -based gel and adjusting the pH of
with the addition of lidocaine . the gel to a pH of greater than about 7.2, for example, about
It is believed that such degradation may primarily occur 7.5 to about 8.0 . The method further comprises the step of
because many, perhaps most crosslinked HA based gels are 45 combining a solution containing lidocaine , for example in
conventionally manufactured in a manner that produces gels the form of lidocaine HCl, with the slightly alkaline gel after
which are not sufficiently cohesive to prevent such degra the pH has been so adjusted and obtaining a HA -based
dation when lidocaine is added . It has now been discovered composition including lidocaine that is stable to autoclaving.
that the addition of lidocaine to sufficiently cohesive cross Another method of preparing a stable HA -based compo
linked HA -based compositions does not cause substantial or 50 sition containing an effective amount of lidocaine , as
significant degradation of the compositions, and the com described elsewhere herein , generally comprises the steps
positions maintain their integrity in terms of rheology, of: providing purified NaHA material, for example , in the
viscosity , appearance and other characteristics even when form of fibers; hydrating the material; and crosslinking the
stored for a lengthy period of time, for example, for a period hydrated material with a suitable crosslinking agent to form
of time of at least about 6 months, about 9 months, about 12 55 a crosslinked HA -based gel. The method further comprises
months, or about 36 months or greater, for example , at the steps of neutralizing and swelling the gel, and adding to
ambient temperatures, and even after being subjected to the gel a solution containing lidocaine, preferably an acidic
sterilization procedures, for example , autoclaving . salt of lidocaine chlorhydrate , to form a HA / lidocaine gel.
It is a surprising discovery that formulations of cross Further still, the method further comprises homogenizing
linked HA -based compositions including lidocaine can be 60 the HA/ lidocaine gel and packaging the homogenized HA /li
manufactured in a manner to produce sterilization -stable , docaine gel , for example, in syringes for dispensing . The
injectable HA / lidocaine compositions. syringes are then sterilized by autoclaving at an effective
Further described herein is a method for preparing stable temperature and pressure . In accordance with the present
HA -based compositions containing an effective amount of description , the packaged and sterilized cohesive NaHA /
lidocaine by preparing a precursor composition , for 65 lidocaine gels exhibit enhanced stability relative to HA
example , a cohesive , crosslinked HA -based gel, adding based compositions including lidocaine which are made
lidocaine chlorhydrate to the gel to form a HA / lidocaine gel using conventional methods.
US 10,485,896 B2
9 10
The present products and compositions are considered to limited to aqueous solutions containing sodium hydroxide
be sterile when exposed to temperatures of at least about (NaOH ), potassium hydroxide (KOH ), sodium bicarbonate
120 ° C. to about 130 ° C. and/or pressures of at least about (NaHCO3), lithium hydroxide (LiOH ), and the like . In
12 pounds per square inch (PSI) to about 20 PSI during
autoclaving for a period of at least about 1 minute to about 5 anotherous
embodiment, the suitable alkaline solution is aque
solutions containing NaOH . The resulting alkaline gel
15 minutes. will have a pH above 7.5 . The pH of the resulting alkaline
The present products and compositions also remain stable gel can have a pH greater than 9, or a pH greater than 10 , or
when stored for long periods of time at room temperature . a pH greater than 12 , or a pH greater than 13 .
Preferably , the present compositions remain stable for a
period of at least about two months, or at least about six 10 stepTheof next step in the manufacturing process involves the
months, or at least about 9 months, or at least about 12 suitable crosslinkingtheagent
crosslinking hydrated , alkaline NaHA gel with a
. The crosslinking agent may be
months, or at least about 36 months, at temperatures of at any agent known to be suitable for crosslinking polysaccha
least about 25 ° C. In a specific embodiment, the composi rides and their derivatives via their hydroxyl groups . Suit
tions are stable at a temperature up to about 45 ° C. for a
period of at least two months . 15 able crosslinking agents include , but are not limited to ,
The manufacturing process includes, in one embodiment, 1,4 -butanediol diglycidyl ether (or 1,4 -bis (2,3 -epoxy
the initial step of providing raw HA material in the form of propoxy )butane or 1,4 -bisglycidyloxybutane, all of which
dry HA fibers or powder. The raw HA materialmay be HA , are commonly known as BDDE ), 1,2- bis(2,3 -epoxy
its salts and/ ormixtures thereof. In a preferred embodiment, propoxy )ethylene and 1-( 2,3-epoxypropyl) -2,3 - epoxycyclo
the HA material comprises fibers or powder of NaHA , and 20 hexane. The use of more than one crosslinking agent or a
even more preferably , bacterial -sourced NaHA . In some different crosslinking agent is not excluded from the scope
aspects of the present description , the HA material may be of the present disclosure . In one aspect of the present
animal derived . The HA material may be a combination of disclosure , the HA gels described herein are crosslinked
raw materials including HA and at least one other polysac using BDDE.
charide, for example , glycosaminoglycan (GAG ). 25 The step of crosslinking may be carried out using any
In some embodiments , the HA material in the composi means known to those of ordinary skill in the art. Those
tions nearly entirely comprises or consists of high molecular skilled in the art appreciate how to optimize conditions of
weight HA . That is, nearly 100 % of the HA material in the crosslinking according to the nature of the HA , and how to
present compositions may be high molecular weight HA as carry out crosslinking to an optimized degree .
defined above . In other embodiments , the HA material in the 30 Degree of crosslinking for purposes of the present dis
compositions comprises a combination of relatively high closure is defined as the percent weight ratio of the cross
molecular weight HA and relatively low molecular weight linking agentto HA -monomeric units within the crosslinked
HA , as defined above . portion of the HA based composition . It is measured by the
The HA material of the compositions may comprise weightratio ofHA monomers to crosslinker (HA monomers:
between about 5 % to about 95 % high molecular weightHA 35 crosslinker ).
with the balance of the HA material including low molecular The degree of crosslinking in the HA component of the
weight HA . In one embodiment of the invention , the ratio of present compositions is at least about 2 % and is up to about
high molecular weight to low molecular weight HA is at 20 % .
least about, and preferably greater than 2 (w /w22 ) with the In other embodiments, the degree of crosslinking is
high molecular weight HA having a molecular weight of 40 greater than 5 % , for example, is about 6 % to about 8 % .
above 1.0 MDa . In some embodiments , the degree of crosslinking is
It will be appreciated by those of ordinary skill in the art between about 4 % to about 12 % . In some embodiments, the
that the selection of high and low molecular weight HA degree of crosslinking is less than about 6 % , for example , is
material and their relative percentages or ratios is dependent less than about 5 % .
upon the desired characteristics, for example , extrusion 45 In some embodiments , the HA component is capable of
force , elastic modulus, viscous modulus and phase angle absorbing at least about one time its weight in water. When
expressed as the ratio of viscousmodulus to elastic modulus, neutralized and swollen , the crosslinked HA component and
cohesivity, etc. of the final HA -based product. For additional water absorbed by the crosslinked HA component is in a
information that may be helpful in understanding this and weight ratio of about 1: 1. The resulting hydrated HA -based
other aspects of the present disclosure, see Lebreton , U.S. 50 gels have a characteristic of being highly cohesive .
Patent Application Publication No. 2006/0194758 , the entire The HA -based gels in accordance with some embodi
disclosure of which is incorporated herein by this reference . ments of the invention may have sufficient cohesivity such
The HA - based gels can be prepared according to the that the gels will not undergo substantial phase separation
present description by first cleaning and purifying dry or raw after centrifugation of the gel at 2000 rd /min for 5 minutes .
HA material having a desired high / low molecular weight 55 In another embodiment, the gels have the characteristic of
ratio . These steps generally involve hydrating the dry HA being capable of absorbing at least one time their weight of
fibers or powder in the desired high /low molecular weight water and have sufficient cohesivity such that when swollen
ratio , for example , using pure water , and filtering themate with water at a gel/water weight ratio of about 1: 1, the gels
rial to remove large foreign matters and/or other impurities . maintain their integrity, for example , when subjected to
The filtered , hydrated material is then dried and purified . The 60 centrifugation .
high and low molecular weight HÀ may be cleaned and The hydrated crosslinked , HA gels may be swollen to
purified separately, ormay be mixed together, for example, obtain the desired cohesivity . This step can be accomplished
in the desired ratio , just prior to crosslinking . by neutralizing the crosslinked , hydrated HA gel, for
In one aspect of the present disclosure, pure, dry NaHA example by adding an aqueous solution containing of an
fibers are hydrated in an alkaline solution to produce an free 65 acid , such as HC1. The gels are then swelled in a phosphate
NaHA alkaline gel. Any suitable alkaline solution may be buffered saline (PBS) solution for a sufficient time and at a
used to hydrate the NaHA in this step , for example, but not low temperature.
US 10,485,896 B2
11 12
In one embodiment, the resulting swollen gels are highly determine the correct syringe dimensions and needle gauge
cohesive with no visible distinct particles, for example, no required to arrive at a particular extrusion force requirement.
visibly distinct particles when viewed with the naked eye. In The extrusion forces displayed by the HA / lidocaine com
one embodiment, the gels have no visibly distinct particles positions described herein using the needle dimensions
under a magnification of less than 35x . 5 described above are at an injection speeds that are comfort
The cohesive , substantially single -phase gels are now able to a patient. Comfortable to a patient is used to define
purified by conventional means such as, dialysis or alcohol a rate of injection that does not injure or cause excess pain
precipitation , to recover the crosslinked material, to stabilize to a patient upon injection to the soft tissue . One skilled in
the pH of the material and to remove any un -reacted the art will appreciate that comfortable as used herein
crosslinking agent. Additional water or a slightly alkaline 10 includes not only patient comfort, but also comfort and
aqueous solution can be added to bring the concentration of ability of the physician or medical technician injecting the
the NaHA to a desired concentration . HA / lidocaine compositions. Although certain extrusion
The pH of the purified , substantially pH neutral , cross forces may be achievable with the HA /lidocaine composi
linked HA gels are preferably adjusted to cause the gels to tions of the present description , one skilled in the art
become slightly alkaline such that the gels have a pH of 15 understands that high extrusion forces can lead to lack of
greater than about 7.2 , for example, about 7.5 to about 8.0 . control during injection and that such lack of controlmay
This step may be accomplished by any suitable means, for result in additional pain to the patient. Extrusion forces of
example, by adding a suitable amount of dilute NaOH , the present HA / lidocaine compositions can be from about 8
KOH , NaHCO3 or LiOH , to the gels or any other alkaline N to about 15 N , or more preferably from about 10 N to
molecule , solution and/or buffering composition know by 20 about 13 N , or about 11 N to about 12 N , for example, at an
one skilled in the art. extrusion rate of about 12.5 mm /min .
An effective amount of lidocaine, such as lidocaine HCI, Sterilization , as used herein comprises any method known
is then added to the purified cohesive NaHA gels. For in the art to effectively kill or eliminate transmissible agents ,
example , in some embodiments, the lidocaine HCl is pro preferably without substantially altering of degrading the
vided in a powder form which is solubilized using water for 25 HA /lidocaine compositions .
injection (WFI). The gels are kept neutral with a buffer or by One preferable method of sterilization of the filled
adjustment with diluted NaOH in order that the final HA / li syringes is by autoclave. Autoclaving can be accomplished
docaine composition will have a desired , substantially neu by applying a mixture of heat, pressure and moisture to a
tral pH . The final HA -based filler compositions including sample in need of sterilization .Many different sterilization
lidocaine have a lidocaine concentration of between at least 30 temperatures, pressures and cycle times can be used for this
about 0.1 % and about 5 % , for example, about 2 % w /w of the step . For example , the filled syringes may be sterilized at a
composition , or in another example about 0.3 % . temperature of at least about 120° C. to about 130 ° C. or
After the addition of the lidocaine HC or alternatively , greater. Moisture may or may not be utilized . The pressure
during the addition of the lidocaine HCl, the HA /lidocaine applied is in some embodiments depending on the tempera
gels, or compositions, are homogenized to create highly 35 ture used in the sterilization process. The sterilization cycle
homogenous cohesive HA /lidocaine gels having a desired may be at least about 1 minute to about 20 minutes or more .
consistency and stability. The homogenization step may Another method of sterilization incorporates the use of a
comprise mixing, stirring , or beating the gels with a con gaseous species which is known to kill or eliminate trans
trolled shearing force to obtain a substantially homogenous missible agents. Preferably , ethylene oxide is used as the
mixture. 40 sterilization gas and is known in the art to be useful in
The HA /lidocaine compositions described herein display sterilizing medical devices and products .
a viscosity which is dependent on the composition's prop A further method of sterilization incorporates the use of
erties and the presence of at least one anesthetic agent. The an irradiation source which is known in the art to kill or
viscosity of the HA/lidocaine compositions can be from eliminate transmissible agents. A beam of irradiation is
about 50 Pa* s to about 450 Pa* s. In other embodiments , the 45 targeted at the syringe containing the HA /lidocaine solution ,
viscosity can be from about 50 Pa * s to about 300 Pa * s, from and the wavelength of energy kills or eliminates the
about 100 Pa * s to about 400 Pa* s , or about 250 Pa * s to unwanted transmissible agents. Preferable energy useful
about 400 Pa's, or about 50 Pa * s to about 250 Pa* s . include, but is not limited to ultraviolet (UV ) light, gamma
After homogenization , the HA /lidocaine compositions are irradiation , visible light, microwaves, or any other wave
introduced into syringes and sterilized . Syringes useful 50 length or band of wavelengths which kills or eliminates the
according to the present description include any syringe unwanted transmissible agents, preferably without substan
known in the art capable of delivering viscous dermalfiller tially altering of degrading the HA/lidocaine composition .
compositions. The syringes generally have an internal vol Further described are In another embodiment,methods of
ume of about 0.4 mL to about 3 mL , more preferably manufacturing cohesive HA -based compositions generally
between about 0.5 mL and about 1.5 mL or between about 55 comprising the steps of providing a crosslinked HA -based
0.8 mL and about 2.5 mL . This internal volume is associated gel without an anesthetic , (hereinafter, sometimes, a precur
with an internal diameter of the syringe which plays a key sor gel) adjusting the pH of the precursor gel to obtain a gel
role in the extrusion force needed to inject high viscosity having a pH of between about 7.2 and 8.0 , and adding a
dermalfiller compositions. The internal diameters are gen suitable amountof lidocaine , or other anesthetic agent, to the
erally about 4 mm to about 9 mm , more preferably from 60 pH -adjusted gels to obtain cohesive HA -based compositions
about 4.5 mm to about 6.5 mm or from about 4.5 mm to that include an anesthetic agent. In one embodiment, the
about 8.8 mm . Further, the extrusion force needed to deliver precursor gel is a highly cohesive , substantially single phase
the HA /lidocaine compositions from the syringe is depen gel comprising no greater than about 1 % to about 10 % free
dent on the needle gauge. The gauges of needles used HA by volume, for example, no greater than about 10 % free
generally include gauges between about 18 G and about 40 65 HA by volume. In another embodiment, the precursor gel is
G , more preferably about 25 G to about 33 G or from about a relatively less cohesive gel comprising at least 10 % to
16 G to about 25 G. A person of ordinary skill in the art can about 20 % or more free HA by volume.
US 10,485,896 B2
13 14
Example 1 several days with regular changes of the bath , in order to
remove the un -reacted crosslinker, to stabilize the pH close
Method for Testing for Cohesivity of Gel to neutrality (pH = 7.2 ) and to ensure proper osmolarity of the
HA gel . The osmolarity of the resulting cohesive HA gel is
For purposes of example only and not to be considered as 5 between about 200 mOsmol and about 400 mOsmol,most
limiting the present invention in any way, the following tests preferably about 300 mOsmol.
may be performed in order to evidence or quantify cohe After dialysis , the resulting cohesive HA gel has a sub
sivity of a HA -based gel composition. stantially neutral pH , preferably about 7.2 , and no visibly
First, 0.2 g or 0.4 g of a gel composition to be tested is distinct particles in a fluidic media when viewed at a
placed in a glass syringe . Next, 0.2 g or more of phosphate 10 magnification of less than about 35x .
buffer is added to the syringe and the mixture is thoroughly Lidocaine chlorhydrate ( lidocaine HCl) in powder form is
mixed for about 1 hour to obtain a homogenous mixture. first solubilized in WFI and filtered through a 0.2 um filter.
Then , the homogenized mixture is centrifuged for 5 min at Dilute NaOH solution is added to the cohesive HA gel in
2000 tr/min to remove the air bubbles and to allow the order to reach a slightly basic pH ( for example, a pH of
decantation of any particles. The syringe is then held in a 15 between about 7.5 and about 8 ). The lidocaine HCl solution
vertical position and one drop of eosin colorant is deposited is then added to the slightly basic gel to reach a final desired
at the surface of the gel by means of a syringe and an 18 G concentration , for example , a concentration of about 0.3 %
needle . After 10 min , the dye has slowly diffused through the ( w /w ). The resulting pH of the HA / lidocaine mixture is then
gel. about 7 and the HA concentration is about 24 mg/mL .
After dilution ofthe gel, homogenization and decantation , 20 Mechanical mixing is performed in order to obtain a proper
a relatively low cohesivity gel shows a phase separation (an homogeneity in a standard reactor equipped with an appro
upper diluted less viscous phase without particles and a priate blender mechanism . The resulting composition is
lower one composed of decanted particles that are visible cohesive.
with the naked eye or under microscope ). Under the same If desired , a suitable amount of free HA gelmay be added
conditions, a highly cohesive gel shows substantially no 25 to the HA /lidocaine gel mixture with the advantage of
phase separation , and the dye is prevented from diffusing increasing the kinetics of lidocaine delivery . For example ,
into the cohesive formulation . A relatively less cohesive gel, free HA fibers are swollen in a phosphate buffer solution , in
on the other hand, shows a clear phase separation . order to obtain a homogeneous viscoelastic gel. This free
Example 2 30
HA gel is then added to the crosslinked HA /lidocaine gel
(for example , at about 5 % , w /w ). The resulting gel is then
Synthesis of a Soft Tissue Filler with Lidocaine filled into sterile syringes and autoclaved at sufficient tem
peratures and pressures for sterilization for at least about 1
minute .
NaHA fibers or powder are hydrated in an alkaline
solution , for example , an aqueous solution containing 35 agedAfterandautoclaving , the final HA / lidocaine product is pack
distributed to physicians. The product manufac
NaOH . The mixture is mixed at ambient temperature , about tured in accordance with this method exhibits one or more
23 ° C., to form a substantially homogenous, alkaline HA gel. characteristics of stability as defined elsewhere herein . For
A crosslinking agent, BDDE, is diluted in an aqueous example , the autoclaved HA/ lidocaine product has a viscos
solution and added to the alkaline HA gel . The mixture is ity, cohesivity, and extrusion force that are acceptable . No
homogenized for several minutes. 40
degradation of the HA / lidocaine gel product is found during
Alternatively, BDDE can be added directly to the HA testing of the product after the product has spent several
fibers (dry state ) at the beginning of the process , prior to the months in storage.
hydration . The crosslinking reaction will then start relatively
slowly at ambient temperature , ensuring even better homo Example 3
geneity and efficacy of the crosslinking. Methods of cross- 45
linking polymers in the dry state using a polyfunctional Properties of Soft Tissue Fillers
crosslinking agent such as BDDE are described in , for
example , Piron et al., U.S. Pat . No. 6,921,819 which is Properties of HA /lidocaine compositions manufactured in
incorporated herein by reference in its entirety as if it were accordance with methods described herein are shown in the
part of the present specification . 50 Table 1 below . Extrusion force for example was measured
The resulting crosslinked HA gel mixture is then heated at using an INSTRON® Advanced Materials Testing System
about 50 ° C. for about 2.5 hours . The material is now a Model 5564 (Instron , Norwood , Mass .) running BLUE
highly crosslinked HA /BDDE gel ( aspect= solid gel). This HILL® software version 2.11 ( Instron , Norwood , Mass .).
crosslinked gel is then neutralized with a suitable acidic Other rheological data was collected using a Versa test
solution . The neutralized HA gel is then swollen in a 55 Column with a MECMESIN® dynamometer AGF 100 N
phosphate buffer at a cold temperature , for example a (Mecmesin Limited , West Sussex , United Kingdom ) run
temperature of about 5 ° C., to obtain a highly cohesive HA ning Emperor software and a THERMO FISHER SCIEN
gel. In this specific example , the phosphate buffered saline TIFIC® Rheometer RS600 ( Thermo Fisher Scientific , Inc.
solution contains water- for -injection (WFI), disodium Corp., Waltham , Mass.).
hydrogen phosphate, and sodium dihydrogen phosphate . 60
When neutralized and swollen , the crosslinked HA compo TABLE 1
nent and water absorbed by the crosslinked HA component
is in a weight ratio of about 1: 1 . HA /lidocaine Composition
The cohesive swollen HA gel is then mechanically stirred Appearance Homogeneous transparent gel
and filled into dialysis membranes and dialyzed against a 65 pH 7.2
phosphate buffer. The HA gel is then filled into dialysis Extrusion force (N ) 10.8N
membranes and dialyzed against a phosphate buffer for up to
US 10,485,896 B2
15 16
TABLE 1 - continued Each of Samples 1-6 was prepared as follows:
HA /lidocaine Composition
Test 1: About 20 g of each of Samples 1-6 was individu
ally mixed with a solution of lidocaine chlorhydrate and
NaHA Content 23.7 mg/g homogenized . In this test, during the addition of the lido
Sterility Sterile (SAL < 10-6 5 caine chlorhydrate , the pH of the sample gel is substantially
Osmolarity 321 mOsml/kg neutral and is not adjusted , for example , with the addition of
Lidocaine Content ( % ) 0.29 %
2,6 - dimethylaniline content Conforms sodium hydroxide solution . Each of the Samples was then
filled into syringes and autoclaved .
In order to ensure that product specifications were main- 10 Test 2 : About 20 g of each of Samples 1-6 was individu
tained throughout the shelf life of the composition , multiple ally mixed with a solution of lidocaine chlorhydrate, and the
studies were performed . In addition , 2,6 -dimethylaniline pH was adjusted to 7.2 using NaOH solution as described in
content was measured in order to confirm the absence of Example 2 above. Each of the Samples was then filled into
lidocaine degradation . syringes and autoclaved.
Table 2 provides a summary of stability testing results on 15 Test 3 : About 20 g ofeach of Samples 1-6 was mixed with
the composition manufactured as described herein . an equivalent amount of WFI to take into account dilution
effect. No lidocaine was added . Each of the Samples was
TABLE 2 then filled into syringes and autoclaved .
HA / lidocaine Composition
Results : For each of the Samples in Tests 1-3 , rheological
20 measurements were performed using the rheological mea
3 month 6 month 9 month surement equipment described in Example 3. The results are
Test results results results generally shown graphically in accompanying FIGS. 1-8 .
Aspect Transparent and Conforms Conforms Conforms Definitions of symbols and units in Table 3 generally apply
homogeneous to FIGS. 1-8 .
pH 7.2 7.2 7.2 25
Extrusion Force ( N ) 11.9 11.1 11.9
TABLE 3
NaHA Concentration 23.8 23.1 24.2
(mg/ g ) Symbol Name Units Description
Sterility Conforms Conforms Conforms
Osmolarity (mOsm /kg) 349 329 342 G' Elastic Pa Quantifies the solid -like behavior or
Lidocaine Content ( % ) 0.29 0.29 0.29 30 Modulus resistance to permanent deformation .
2,6 -dimethylaniline content Conforms Conforms Conforms G" Viscous Pa Quantifies the liquid - like behavior or
Modulus resistance to flow .
(G " /G ') Tan Delta (G " /G ') the ratio of the viscous
It was discovered that at 9 months ' time (from manufac modulus to the elastic modulus and use
ture date ), the composition continues to meet the product ful
for quantifying the extent of elasticity .
specifications 35
A value is below 1 means that the fluid
is
Example 4 more elastic conversely a value above 1
means the fluid is more viscous.
Stability of Soft Tissue Fillers
40
As a general guideline, a stable Sample including lido
The following sterilized HA formulations ( Samples 1-6 ) caine prepared according to Test 1 or 2 would exhibit similar
were obtained for testing . viscosity , when subjected to shear across a range of frequen
Sample 1 is a free HA mixture 13.5 mg/g , with hydroxyl cies , as the Samples prepared according to Test 3 which
propyl methyl cellulose (HPMC) 5.5 mg/g.
Sample 2 is contains 5.5-6.5 mg/mL of high molecular 45 contain no lidocaine .
weight HA (about 4-6 MDa) and a degree of elasticity (G ') lidocaine discovered
It was that neither of Samples 1 and 2 with
was stable to autoclaving and as a result , degrade
of about 200 .
Sample 3 is a non -commercial gel made of distinct gel and 2.
becomesubstantially less viscous in both Test 1 and Test
FIGS . 1 and 2 in particular illustrate that Samples 1 and
particlesmixed with free HA (80/20 , w /w ). The HÀ particles
(80 % ) is obtained by disintegration of a “ solid ” heavily 50 2 have a lowered viscosity , and hence were less stable to
crosslinked HA gel . The particles have different shapes and sheer when the product was prepared with lidocaine as
dimensions (several microns to several mm ). compared to the product without lidocaine, even when the
Sample 4 is a cohesive crosslinked HA formulation . Sample was prepared according to Test 2 wherein a pH
Sample 4 has a HA concentration of about 18 mg/mL , less adjustment was performed .
than 6 % crosslinking , a G ' of about 60 and a high molecular 55 With regard to viscosity, Sample 3 and Sample 4 were
weight to low molecular weightHA ratio from about 95 % to found to be stable to autoclaving in Test 2 but were not stable
about 5 % , to about 100 % high molecular weight HA . in Test 1. Sample 6 was found to be stable to autoclaving in
Sample 5 is a cohesive crosslinked HA formulation . both Test 1 and Test 2. FIGS. 3 and 4 illustrate that Samples
Sample 5 has a HA concentration of about 24 mg/mL , about 3 and 4 were stable when prepared with lidocaine and with
6 % crosslinking , a G ' of about 170 and a high molecular 60 pH adjustment, but were not stable when lidocaine was
weightto low molecular weight HA ratio from about 95 % to added and the pH not adjusted . FIG . 6 illustrates that Sample
5 % to about 100 % high molecular weight HA . 5 prepared with lidocaine and pH control had similar viscous
Sample 6 is a cohesive crosslinked HA formulation . and elastic properties (G " /G ') to Sample 5 prepared without
Sample 6 has a HA concentration of about 20 mg/mL , about lidocaine . When Sample 5 was prepared with lidocaine and
5 % crosslinking , a G ' of about 450 and a high molecular 65 no pH adjustment, the viscous and elastic properties
weight to low molecular weight HA ratio from about 10 % to changed an insubstantial amount (FIG . 6 ). FIGS. 7 and 8
90 % . illustrate that Sample 6 was stable and had similar viscous
US 10,485,896 B2
17 18
and elastic properties (G "/G ') when prepared with lidocaine, without departing from the scope of the invention , as here
both with and without pH control. inafter claimed .
FIGS. 1-5 and 7 show changes in viscosity between the Unless otherwise indicated , all numbers expressing quan
autoclaved Samples without lidocaine (“ No Lido ” ) and the tities of ingredients, properties such as molecular weight,
autoclaved Samples with lidocaine (“ Lido no pH control” ). 5 reaction conditions, and so forth used in the specification
More specifically , as shown in FIGS . 1-3 , the viscosity at 0.1 and claims are to be understood as being modified in all
Hz of Samples 1 , 2 and 3 decreased at least about 35 % when instances by the term “ about.” Accordingly , unless indicated
lidocaine was added . As shown in FIGS. 4 , 5 and 7, the
viscosity at 0.1 Hz of cohesive Samples 4 , 5 and 6 , in tospecificationthe contrary, the numerical parameters set forth in the
and attached claims are approximations that
accordance with the invention , did not decrease to any 10 may vary depending upon the desired properties sought to be
appreciable extent (not greater than about 30 % ) when lido obtained by the present invention . At the very least, and not
caine was added and the combination was autoclaved .
Sample 6 was found to be stable to autoclaving in both of equivalents to the scopethe ofapplication
as an attempt to limit
the claims
of the doctrine of
, each numerical
Test 1 and Test 2. FIG . 7 illustrates that Sample 6 , no matter
how it is produced , had similar viscosity and hence little 15 ofparameter should at least be construed in light of the number
reported significant digits and by applying ordinary
shear comparison between preparation protocols . FIG . 8
further illustrates that Sample 6 retained similar viscous and rounding techniques. Notwithstanding that the numerical
elastic properties no matter how it was produced . ranges and parameters setting forth the broad scope of the
Example 5
invention are approximations, the numerical values set forth
20 in the specific examples are reported as precisely as possible.
Any numerical value , however, inherently contains certain
Kinetic Release errors necessarily resulting from the standard deviation
found in their respecti testing measurements .
The following example illustrates the kinetic ofrelease of The terms “ a ,” “ an ,” “ the ” and similar referents used in
lidocaine from cohesive HA gels according to the present 25 the context of describing the invention (especially in the
description . The aim of the Example is to show that the
lidocaine contained in cohesive HA gels according to the context of the following claims) are to be construed to cover
present description is freely released from the gels when both the singular and the plural, unless otherwise indicated
placed in the skin . herein or clearly contradicted by context. Recitation of
ranges of values herein is merely intended to serve as a
Dialysis was performed for different periods of time
(about 10 g of gel were placed in a small dialysis bag and 30 shorthand method of referring individually to each separate
then put in 30 g of water). After each dialysis was stopped value falling within the range. Unless otherwise indicated
at a given time, the gel was homogenized with a spatula and herein , each individual value is incorporated into the speci
the amount of lidocaine was determined by UV method . The fication as if it were individually recited herein . Allmethods
final concentration of the dialysis bath met the theoretical 35 described herein can be performed in any suitable order
concentration of lidocaine which indicates the free release of unless otherwise indicated herein or otherwise clearly con
lidocaine from the gel. tradicted by context. The use of any and all examples, or
Table 3 illustrates lidocaine concentration in % (w /w ), exemplary language ( e.g., " such as" ) provided herein is
correction of the value and determination of the % of intended merely to better illuminate the invention and does
released lidocaine. Additionally , FIG . 9 graphically illus- 40 not pose a limitation on the scope of the invention otherwise
trates the results tabulated in Table 4 below . Within FIG . 9 claimed . No language in the specification should be con
is indicated the theoretical equilibrium concentration of strued as indicating any non -claimed element essential to the
lidocaine that would exist if the lidocaine were retained in practice of the invention .
the gel or if it were to be freely released . As is graphically Groupings of alternative elements or embodiments of the
illustrated therein , the data suggest that the lidocaine is invention disclosed herein are not to be construed as limi
freely released from the gel. tations . Each group member may be referred to and claimed
TABLE 4
MMA4031 MMA4031 MMA4031 MMA4031 MMA4031 MMA4029
MMA3056 EC6 EC2 EC3 EC4 EC5 EC7
Dialysis 0 hr 1 hr 30 5 hr 7 hr 23 hr 48 hr 72 hr
time (h ) min
[lidocaine ] 0.29 0.20 0.16 0.15 0.08 0.07 0.07
(%)
The concentration profile of lidocaine in Sample 5 from individually or in any combination with other members of
Example 4 (FIG . 9 ) shows that over time it reaches an the group or other elements found herein . It is anticipated
equilibrium that corresponds to free release of lidocaine. that one or more members of a group may be included in , or
This in vitro study shows that lidocaine is freely released 60 patentability
deleted from .,When
a groupanyforsuchreasons of convenience
inclusion and /or,
or deletion occurs
from the gel and not retained in the gel once implanted . the specification is deemed to contain the group as modified
Although the invention has been described and illustrated thus fulfilling the written description of all Markush groups
with a certain degree of particularity, it is understood that the used in the appended claims.
present disclosure has been made only by way of example, 65 Certain embodiments of this invention are described
and that numerous changes in the combination and arrange herein , including the bestmode known to the inventors for
ment of parts can be resorted to by those skilled in the art carrying out the invention . Of course , variations on these
US 10,485,896 B2
19 20
described embodiments will become apparent to those of 8. The dermal filler of claim 7, wherein the process further
ordinary skill in the art upon reading the foregoing descrip comprises adding free HA gel to the crosslinked HA com
tion . The inventor expects skilled artisans to employ such position after the crosslinked HA composition has been
variations as appropriate , and the inventors intend for the passed through the sieve .
invention to be practiced otherwise than specifically 5 9. The dermal filler of claim 7 , wherein the crosslinked
described herein . Accordingly , this invention includes all HA composition , after being passed through the sieve,
modifications and equivalents of the subjectmatter recited in comprises particles of crosslinked HA having an average
the claims appended hereto as permitted by applicable law .
Moreover , any combination of the above -described elements particle size of at least about 200 um .
10. The dermal filler of claim 7 , wherein the crosslinked
in all possible
invention unlessvariations
otherwisethereof is encompassed
indicated by the
herein or otherwise 10 HA composition , after being passed through the sieve,
clearly contradicted by context. comprises particles of crosslinked HA having an average
Furthermore , numerous references have been made to particle size of at least about 250 um .
patents and printed publications throughout this specifica 11. The dermal filler of claim 7 , wherein the crosslinked
tion. Each of the above-cited references and printed publi- 15 comprises
HA composition , after being passed through the sieve,
particles of crosslinked HA having an average
cations are individually incorporated herein by reference in particle size of less than about 200 um .
their entirety.
Specific embodiments disclosed herein may be further 12. The dermal filler of claim 1 , wherein the process
limited in the claims using consisting of or and consisting further comprises homogenizing the crosslinked HA com
essentially of language . When used in the claims, whether as 20 position before adding the lidocaine .
filed or added per amendment, the transition term " consist 13. The dermal filler of claim 1, wherein the dermal filler
ing of” excludes any element, step , or ingredient not speci has a lidocaine concentration of between about 0.1 % and
fied in the claims. The transition term “ consisting essentially about 5.0 % w / w .
of" limits the scope of a claim to the specified materials or 14. The dermal filler of claim 1 , wherein the dermal filler
steps and those that do not materially affect the basic and 25 has a HA concentration between about 20 mg/mL and about
novel characteristic (s ). Embodiments of the invention so 30 mg/mL .
claimed are inherently or expressly described and enabled 15. The dermal filler of claim 1 , having a lidocaine
herein . concentration of 0.3 % w / w and a HA concentration between
In closing, it is to be understood that the embodiments of about 20 mg/mL and about 30 mg/mL .
the invention disclosed herein are illustrative of the prin- 30 16. A dermal filler composition comprising:
ciples of the present invention . Other modifications thatmay a composition comprising hyaluronic acid (HA ) cross
be employed are within the scope of the invention . Thus, by linked with 1,4 butanediol diglycidyl ether (BDDE ),
way of example, but not of limitation , alternative configu wherein the HA is not crosslinked to a non -HA biopo
rations of the present invention may be utilized in accor lymer, and lidocaine ;
dance with the teachings herein . Accordingly, the present 35 wherein the dermal filler is made by a process comprising:
invention is not limited to that precisely as shown and crosslinking HA with BDDE to obtain a crosslinked
described . HA ;
adding lidocaine to the crosslinked HA ; and
What is claimed is : heat sterilizing the crosslinked HA with added lido
1. A dermal filler comprising: 40 caine to obtain a sterile dermal filler.
hyaluronic acid (HA ) crosslinked with 1,4 butanediol 17. The dermal filler of claim 16 , wherein the process
diglycidyl ether (BDDE ), and further comprises adjusting the pH of the crosslinked HA to
lidocaine ; obtain an alkaline crosslinked HA .
wherein the lidocaine is freely released in vivo; 18. The dermal filler of claim 17 , wherein the adjusting
wherein the dermal filler is sterile ; and 45 the pH is performed before adding the lidocaine .
wherein the dermal filler is made by a process comprising: 19. The dermal filler of claim 16 , wherein adding the
crosslinking HA with BDDE to obtain a crosslinked lidocaine comprises adding a solution containing lidocaine
HA composition ; HC1.
adding lidocaine to the crosslinked HA composition ; 20. The dermal filler of claim 16 , wherein the crosslinked
and 50 HA comprises particles of crosslinked HA having an average
heat sterilizing the crosslinked HA composition with particle size of at least about 200 um .
added lidocaine to obtain a sterile dermal filler. 21. The dermal filler of claim 16 , wherein the crosslinked
2. The dermal filler of claim 1, wherein the process further HA comprises particles of crosslinked HA having an average
comprises adjusting the pH of the crosslinked HA compo particle size of less than about 200 um .
sition to obtain an alkaline crosslinked HA composition . 55 22. The dermal filler of claim 16 , wherein the dermal filler
3. The dermal filler of claim 2 , wherein the pH adjustment has a lidocaine concentration of between about 0.1 % and
is performed before adding the lidocaine. about 5.0 % w / w .
4. The dermal filler of claim 2 , wherein the pH adjustment 23. The dermal filler of claim 16 , wherein the dermal filler
comprises adjusting the pH to about 7.5 to about 8.0 . has a HA concentration of between about 20 mg/mL and
5. The dermal filler of claim 2 , wherein the pH adjustment 60 about 30 mg/mL .
comprises adjusting the pH to above about 7.5 . 24. A dermal filler composition comprising:
6. The dermal filler of claim 1, wherein the adding the a hyaluronic acid (HA ) crosslinked with 1,4 butanediol
lidocaine comprises adding a solution containing lidocaine diglycidyl ether (BDDE ), and about 0.3 % lidocaine by
HC1. weight,wherein the lidocaine is freely released in vivo
7. The dermal filler of claim 1 , wherein the process further 65 and wherein the composition is sterile ;
comprises passing the crosslinked HA composition through wherein the composition is made by a process compris
a sieve before adding the lidocaine. ing:
US 10,485,896 B2
21 22
crosslinking HA with BDDE to obtain a crosslinked packaging the crosslinked HA containing lidocaine in a
HA ; syringe; and
adding a free HA gel to the crosslinked HA ; autoclaving the syringe containing the crosslinked HA
adding a solution of lidocaine HCl to the crosslinked containing lidocaine to obtain a dermal filler product .
HA ; and 5
26. The dermal filler product of claim 25 , wherein the
autoclaving the crosslinked HA having free HA gel and sterile composition contained in the syringe has a volume
lidocaine HCl added thereto , to obtain a sterile between about 0.8 mL and about 2.5 mL .
dermal filler composition . 27. The dermal filler product of claim 25 , wherein the
25. A dermal filler product comprising : sterile composition has a HA concentration of about 20
a dermal filler composition comprising a hyaluronic acid 10
mg/mL to about 30 mg/mL .
(HA ) crosslinked with 1,4 butanediol diglycidyl ether 28. The dermal filler product of claim 25 , wherein the
(BDDE ), and between about 0.1 % to about 5.0 % lido sterile composition is stable at ambient temperature for at
caine by weight, wherein the HA is not crosslinked to least about 6 months .
a non -HA biopolymer, and wherein the composition is 29. The dermal filler product of claim 25 , wherein the
sterile ; 15
sterile composition comprises particles of crosslinked HA
a syringe containing the sterile composition ; having an average particle size of at least about 200 um .
wherein the product is made by a process comprising: 30. The dermal filler product of claim 25 , wherein the
crosslinking HA with BDDE to obtain a crosslinked sterile composition comprises particles of crosslinked HA
??;
adding lidocaine to the crosslinked HA to obtain a having an average particle size of less than about 200 um .
crosslinked HA containing lidocaine ; and

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US010485896B2

( 12 ) United States Patent ( 10 ) Patent No.: US 10,485,896 B2

( 56 ) References Cited 8,357,795 B2 * 1/2013 Lebreton A61K 8/42

( 56 ) References Cited 2013/0203696 Al 8/2013 Liu

( 56 ) References Cited Summary of Safety and Effectiveness Data of Juvederm 30 , 24HV

( 56 ) References Cited Park et al., “ Biological Characterization ofEDC -crosslinked Collagen

( 56 ) References Cited EP 2323617 Communication Pursuant to Rule 114 ( 2 ) EPC Third

( 56 ) References Cited Defendants ' Answer and Counterclaims to Plaintiff's Complaint,

500 Lido no pH control

DODOC 2009 DOGS

12 AURA Lido with pH control

Lido with pH control

Visco ity 300

0.30 theoreucal result if lidocaine is

0.15 theoretical result if lidocaine

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