APPLICATION
`NUMBER
`61/087,934
`
`FILING or
`37l(c)DATE
`08/11/2008
`
`GRPART
`UNIT
`
`FIL FEE REC'D
`210
`
`51957
`ALLERGAN, INC.
`2525 DUPONT DRIVE, T2-7H
`IRVINE, CA 92612-1599
`
`Ul\TfED STATES DEPA RTME'IT OF COMMERCE
`United States Patent and Trademark Office
`Adiliess. COMMISSIO'JER FOR PATENTS
`PO Box 1450
`Alexandria, Virgmia 22313-1450
`\VVi\V.USpto.gov
`
`ATTY.DOCKET.NO
`18438PROV2 (FAC)
`
`TOT CLAIMS IND CLAIMS
`
`CONFIRMATION NO. 7372
`FILING RECEIPT
`
`111111111111111111111111]~!1]!~1!~1!~111111 IIH~~ll 111111111111111 IIII IIII
`
`Date Mailed: 09/02/2008
`
`Receipt is acknowledged of this provisional patent application. It will not be examined for patentability and will
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
`must include the following identification information: the U.S. APPLICATION NUMBER, FILING DATE, NAME OF
`APPLICANT, and TITLE OF INVENTION. Fees transmitted by check or draft are subject to collection. Please verify
`the accuracy of the data presented on this receipt. If an error is noted on this Filing Receipt, please submit
`a written request for a Filing Receipt Correction. Please provide a copy of this Filing Receipt with the
`changes noted thereon. If you received a "Notice to File Missing Parts" for this application, please submit
`any corrections to this Filing Receipt with your reply to the Notice. When the USPTO processes the reply
`to the Notice, the USPTO will generate another Filing Receipt incorporating the requested corrections
`
`Applicant( s)
`
`Pierre Lebreton, Annecy Le-Vieux, FRANCE;
`Power of Attorney:
`Linda Fox--38883
`
`If Required, Foreign Filing License Granted: 08/28/2008
`
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61/087,934
`Projected Publication Date: None, application is not eligible for pre-grant publication
`
`Non-Publication Request: No
`
`Early Publication Request: No
`Title
`
`Cross-Linked Cohesive Hyaluronic Acid With Lidocaine Gel
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
`
`Since the rights granted by a U.S. patent extend only throughout the territory of the United States and have no
`effect in a foreign country, an inventor who wishes patent protection in another country must apply for a patent
`in a specific country or in regional patent offices. Applicants may wish to consider the filing of an international
`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
`of patent applications on the same invention in member countries, but does not result in a grant of "an international
`page 1 of 3
`
`Exhibit 1028
`Prollenium v. Allergan
`
`

`

`patent" and does not eliminate the need of applicants to file additional documents and fees in countries where patent
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`Almost every country has its own patent law, and a person desiring a patent in a particular country must make an
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`foreign countries to ensure that patent rights are not lost prematurely.
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`Applicants also are advised that in the case of inventions made in the United States, the Director of the US PTO must
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`
`LICENSE FOR FOREIGN FILING UNDER
`
`Title 35, United States Code, Section 184
`
`Title 37, Code of Federal Regulations, 5.11 & 5.15
`
`GRANTED
`
`The applicant has been granted a license under 35 U.S.C. 184, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" followed by a date appears on this form. Such licenses are issued in all applications where
`the conditions for issuance of a license have been met, regardless of whether or not a license may be required as
`set forth in 37 CFR 5.15. The scope and limitations of this license are set forth in 37 CFR 5.15(a) unless an earlier
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`37 CFR 5.13 or 5.14.
`
`This license is to be retained by the licensee and may be used at any time on or after the effective date thereof unless
`it is revoked. This license is automatically transferred to any related applications(s) filed under 37 CFR 1.53(d). This
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`The grant of a license does not in any way lessen the responsibility of a licensee for the security of the subject matter
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`

`

`Security, Department of Commerce (15 CFR parts 730-774); the Office of Foreign AssetsControl, Department of
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`NOT GRANTED
`
`No license under 35 U.S.C. 184 has been granted at this time, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" DOES NOT appear on this form. Applicant may still petition for a license under 37 CFR 5.12,
`if a license is desired before the expiration of 6 months from the filing date of the application. If 6 months has lapsed
`from the filing date of this application and the licensee has not received any indication of a secrecy order under 35
`U.S.C. 181, the licensee may foreign file the application pursuant to 37 CFR 5.15(b).
`
`page 3 of 3
`
`

`

`18438PROV2 (FAC)
`
`CROSS-LINKED COHESIVE HY ALURONIC ACID WITH LIDOCAINE GEL
`
`By Inventor Pierre Lebreton
`
`The present invention generally relates to injectable soft tissue fillers and more
`
`5
`
`specifically relates to hyaluronic acid-based dermal and subdermal fillers including lidocaine gel.
`
`As a person ages, the face begins to show the effects of gravity, sun-exposure, and years
`
`of facial muscle movement, such as smiling, frowning, chewing and squinting. The underlying
`
`tissues that keep the skin appearing youthful begin to break down, often resulting in laugh lines,
`
`10
`
`smile lines, "crow's feet" and facial creases.
`
`Soft tissue fillers have been developed to help fill in facial lines and depressions, and for
`
`restoring volume of tissues due to fat loss, thereby temporarily restoring a smoother, more
`
`youthful appearance.
`
`Ideally, a filler will be long-lasting, soft, smooth and natural appearing when implanted in
`
`the skin or beneath the skin. Further, the filler will be easy to implant into a patient using a fine
`
`gauge needle and will require low extrusion force for injection. Ideal fillers would also cause no
`
`adverse reaction of effects, and would be injectable with minimal or no discomfort to the patient.
`
`15
`
`20
`
`For more than 20 years, bovine collagen-based fillers were the only U.S. Food and Drug
`
`Administration (FDA)-approved dermal fillers. Because these dermal fillers are bovine based,
`
`one of the main disadvantages has been the potential for allergic reaction in patients.
`
`It is
`
`believed that approximately 3-5% of human subjects show serious allergic reactions to bovine
`
`25
`
`collagen, thus requiring careful testing before using these fillers in any particular person. In
`
`February 2003, human derived collagens received FDA approval. These collagens provide the
`
`advantaged a significantly reduced risk of allergic reactions.
`
`The search for fillers that do not provoke allergic reactions has brought about the
`
`30
`
`development of hyaluronic acid (HA)-based products. In December 2003, the first HA-based
`
`filler was approved by the FDA. This was soon followed by other HA-based fillers.
`
`1
`
`

`

`18438PROV2 (FAC)
`
`Hyaluronic acid, also known as hyaluronan, is a naturally occurnng, water soluble
`
`polysaccharide, specifically a glycosaminoglycan, which is a major component of the extra(cid:173)
`
`cellular matrix and is widely distributed in animal tissues. Hyaluronic acid has excellent
`
`5
`
`biocompatibility and does not cause allergic reaction when implanted into a patient. In addition,
`
`hyaluronic acid has the ability to bind to large amounts of water, making it an excellent
`
`volumizer of soft tissues.
`
`The development of HA-based fillers which exhibit ideal in vivo properties as well as
`
`10
`
`ideal surgical usability has proven difficult. For example, HA-based fillers that exhibit desirable
`
`stability properties in vivo, can be so highly viscous that injection through fine gauge needles is
`
`difficult. Conversely, HA-based fillers that are relatively easily injected through fine gauge
`
`needles often have relatively inferior stability properties in vivo.
`
`15
`
`Crosslinked HA is formed by reacting uncrosslinked HA with a crosslinking agent under
`
`suitable reaction conditions. Methods of preparing HA based soft tissue fillers including both
`
`crosslinked and uncrosslinked HA are well known.
`
`It has been proposed to incorporate certain therapeutic agents, for example, anesthetic
`
`20
`
`agents such as lidocaine, into injectable HA-based compositions. Unfortunately, HA-based
`
`injectable compositions which incorporate lidocaine during the manufacturing process are prone
`
`to partial or almost complete degradation prior to injection, particularly during high temperature
`
`sterilization steps and/or when placed in storage for any significant length of time.
`
`25
`
`Sadozai et al., U.S. Patent Application Publication No. 2005/0136122, discloses a process
`
`for making an HA-based composition including lidocaine which includes hydrating dried HA
`
`particles with a phosphate buffer containing lidocaine.
`
`Wohlrab, U.S. Patent Application Publication No. 2006/0122147 discloses a combination
`
`30
`
`preparation comprising hyaluronic acid and a local anesthetic for example lidocaine, and further
`
`2
`
`

`

`18438PROV2 (FAC)
`
`additives. The preparations are used in the medical treatment of diseases of the joints, cartilage
`
`and bones.
`
`Romeo et al., U.S. Patent No. 6,224,857 discloses pharmaceutical preparations containing
`
`5
`
`salts of hyaluronic acid with a basis anesthetic, particularly, salts with benzydamine or
`
`bupuvacaine.
`
`Additional helpful information may be found in the following: U.S. Patent No. 5,143,724,
`
`U.S. Patent No. 5,356,883 and U.S. Patent No. 6,013,679.
`
`The entire disclosure of each of the patents and publications cited in the present patent
`
`application is incorporated herein by this specific reference.
`
`DESCRIPTION OF THE INVENTION
`
`10
`
`15
`
`The present invention generally relates to soft tissue fillers, for example, dermal and
`
`subdermal fillers, based on hyaluronic acids (HA) and pharmaceutically acceptable salts of HA,
`
`for example, sodium hyaluronate.
`
`In one aspect of the invention, HA-based compositions
`
`including a therapeutically effective amount of an anesthetic agent, for example, lidocaine, are
`
`20
`
`provided. The present HA-based compositions including lidocaine have an enhanced stability,
`
`relative to conventional HA-based compositions including lidocaine, for example when
`
`subjected to high temperatures and pressures, for example, those experienced during heat and/or
`
`pressure sterilization techniques, for example, autoclaving, and/or for example, when stored at
`
`ambient temperature for at least 2 years. Methods or processes of preparing such HA-based
`
`25
`
`compositions are also provided as well as products made by such methods or processes.
`
`Generally, concentration of sodium hyaluronate in the compositions of the present
`
`invention is preferably at least lOmg/ml and up to about 40 mg/ml. For example, the
`
`concentration of NaHA in some of the compositions is in a range between about 20 mg/ml and
`
`30
`
`about 30 mg/ml. For example, in some embodiments, the compositions have a NaHA
`
`concentration of about 22 mg/ml, about 24 mg/ml, about 26mg/ml, or about 28mg/ml.
`
`In
`
`3
`
`

`

`18438PROV2 (FAC)
`
`addition, the concentration of lidocaine, for example in the form of lidocaine HCl, is in an
`
`amount of between about 0.1 % and about 5%, or in any suitable amount effective to mitigate
`
`pain experienced upon injection of the composition.
`
`5
`
`In one aspect of the invention, a method is provided for prepanng a HA-based
`
`composition including and effective amount of lidocaine wherein the method compnses
`
`providing a precursor composition comprising a cohesive crosslinked HA-based gel, adding a
`
`solution containing lidocaine HCl thereto and homogenizing the mixture to obtain a cohesive, at
`
`least partially crosslinked HA-based composition including
`
`lidocaine that is stable to
`
`10
`
`autoclaving. More specifically, the cohesive, crosslinked HA-based gel includes substantially no
`
`uncrosslinked HA carrier, and is substantially monophasic in nature. For example, the gel
`
`comprises no greater than about 1 % of uncrosslinked HA by volume.
`
`Without wishing to be bound by any particular theory of operability, it is believed that the
`
`15
`
`high cohesivity of the precursor composition acts to substantially or entirely prevent or impede
`
`any breakdown or degradation of the crosslinked HA in the composition with the addition of
`
`lidocaine HCl. This is in contrast to conventional knowledge in the art which has recognized
`
`that the addition of lidocaine HCl to crosslinked HA-based gels causes degradation, for example,
`
`complete degradation, of the crosslinked HA gel, including loss of viscosity and possibly loss of
`
`20
`
`stability in vivo.
`
`It is believed by the inventor of the present invention that such degradation may primarily
`
`occur because many, perhaps most crosslinked HA based gels are conventionally manufactured
`
`in a manner that produces gels which are "biphasic" in nature, and are not sufficiently cohesive
`
`25
`
`to prevent such degradation when lidocaine HCl is added. It has now been discovered that the
`
`addition of lidocaine HCl to sufficiently cohesive crosslinked HA-based compositions does not
`
`cause any substantial or significant degradation of the compositions, and the compositions
`
`maintain their integrity, in terms of rheology, viscosity, appearance and other characteristics
`
`even when stored for a lengthy period of time and even when subjected to heat and pressure
`
`30
`
`sterilization, for example, autoclaving.
`
`4
`
`

`

`18438PROV2 (FAC)
`
`It is a surprising discovery that highly cohesive, monophasic formulations of crosslinked
`
`HA-based compositions including lidocaine can be manufactured in a manner to produce
`
`autoclave-stable, injectable HA/lidocaine compositions.
`
`5
`
`In another aspect of the invention, a method of preparing a stable HA-based composition
`
`containing an effective amount of lidocaine comprises preparing a cohesive, monophasic,
`
`crosslinked HA-based gel, adding lidocaine chlorhydrate to the gel to form a HA/lidocaine gel
`
`mixture, homogenizing the mixture, to obtain a crosslinked HA-based composition that is stable
`
`to autoclaving.
`
`10
`
`In a more specific aspect of the invention, a method of preparing a stable HA-based
`
`composition containing an effective amount of lidocaine generally comprises the steps of
`
`providing purified sodium hyaluronate (NaHA) material, for example, in the form of fibers,
`
`hydrating the material, and crosslinking the hydrated material with a suitable crosslinking agent
`
`15
`
`to form an effectively cohesive, crosslinked HA-based gel. The method further comprises the
`
`steps of neutralizing and swelling the gel, and adding to the gel a solution containing lidocaine,
`
`preferably an acidic salt of lidocaine, for example, lidocaine chlorhydrate, to form a
`
`HA/lidocaine gel. The method further comprises homogenizing the HA/lidocaine gel and
`
`packaging the homogenized HA/lidocaine gel, for example, in syringes for dispensing. The
`
`20
`
`syringes are then sterilized, for example by autoclaving at an effective temperature and pressure.
`
`In accordance with the invention, the packaged, sterilized NaHA/lidocaine gel exhibits enhanced
`
`stability relative to HA-based compositions including lidocaine which are made usmg
`
`conventional methods and relatively less cohesive, or biphasic HA-based compositions.
`
`25
`
`Without being limited thereto, stabilized HA/lidocaine compositions in accordance with
`
`the present invention include cross-linked HA-based compositions and at least partially cross(cid:173)
`
`linked HA-based compositions.
`
`The term "autoclave stable" or "stable to autoclaving" in the context of the present
`
`30
`
`invention is generally meant herein to mean that the product, or composition, is resistant to
`
`degradation such that the product or composition maintains at least one of, and preferably all of,
`
`5
`
`

`

`18438PROV2 (FAC)
`
`the following aspects after effective autoclave sterilization: transparent appearance, acceptable
`
`pH, acceptable extrusion
`
`force and/or
`
`rheological characteristics, acceptable NaHA
`
`concentration, acceptable sterility, acceptable osmolarity, and acceptable lidocaine concentration.
`
`Further, the present products and compositions are considered to be "stable" within the scope of
`
`5
`
`the invention when exposed to temperatures of at least about 120 degrees C to about 130 degrees
`
`C and/or pressures of at least about 3 bars during autoclaving for a period of at least about 1
`
`minute to about 15 minutes. Preferably, the present compositions remain stable for a period of at
`
`least about 2 months, for example, at least about 6 months, more preferably at least about 12
`
`months, more preferably at least about 36 months, at temperatures of at least 25 degrees C. In a
`
`10
`
`specific embodiment, the compositions are stable at a temperature up to about 45 degrees C for a
`
`period of at least two months.
`
`In a specific embodiment, the manufacturing process of the present invention includes the
`
`initial step of providing raw HA material, for example in the form of dry HA fibers or powder.
`
`15
`
`The raw HA material may be hyaluronic acid, its salts and/or mixtures thereof.
`
`In a preferred
`
`embodiment, the HA material comprises fibers or powder of sodium hyaluronate (NaHA), and
`
`even more preferably, bacterial-sourced sodium hyaluronate.
`
`In other embodiments, the HA
`
`material may be animal derived. In some embodiments, the HA material is a combination of raw
`
`materials including HA and at least one other polysaccharide, for example, glycosaminoglycan
`
`20
`
`(GAG).
`
`In accordance with the present disclosure, high molecular weight HA is understood to
`
`mean that the HA material has a molecular weight of at least about 1.0 million Daltons (mw 2:
`106 Da) to about 4.0 million Da (mw 4 X 106 Da). For example, the high molecular weight HA
`in the present compositions may have a molecular weight of about 2.0 million Da (Mw 2 X 106
`
`25
`
`Da). In another example, the high molecular weight HA may have a molecular weight of about
`2.8 million Da (Mw 2.8 x 106 Da).
`
`In addition, for purposes of the present disclosure, relatively low molecular weight HA
`
`30 may have a relatively lower molecular weight, for example, a molecular weight of less than 1.0
`
`million Da.
`
`In some embodiments, the relatively low molecular weight HA has a molecular
`
`6
`
`

`

`18438PROV2 (FAC)
`
`weight of between about 200,000 Da (mw 0.2 Xl0 6 Da) to less than 1.0 million Da, (mw less
`than 106 Da ), for example, between about 300,000 Da ( 0.3 X 106 Da)
`(mw 0.75 X 106 Da ).
`
`to about 750,000 Da.
`
`5
`
`In some embodiments of the invention, the HA material in the compositions nearly
`
`entirely comprises or consists of high molecular weight HA. That is, nearly 100% of the HA
`
`material in the present compositions may be high molecular weight HA as defined above.
`
`In other embodiments of the invention, the HA material in the compositions comprises a
`
`10
`
`combination of relatively high molecular weight HA and relatively low molecular weight HA, as
`
`defined above.
`
`For example, in some embodiments, the HA material of the compositions compnses
`
`between about 5% to about 95% high molecular weight HA with the balance of the HA material
`
`15
`
`comprising or consisting of low molecular weight HA. In a typical embodiment of the invention,
`
`the ratio of high molecular weight to low molecular weight HA is at least about, and preferably
`
`greater than 2 (that means: Mw HMw I Mw LMw 2: 2) with the high molecular weight HA
`
`having a molecular weight of above 1.0 million Da.
`
`20
`
`It will be appreciated by those of skill in the art that the selection of high and low
`
`molecular weight HA material and their relative percentages or ratios is made dependent upon
`
`the desired characteristics, for example, extrusion force, elastic modulus and/or viscous modulus
`
`and/or phase angle expressed as the ration of viscous modulus to elastic modulus, cohesivity, etc.
`
`of the final HA-based product. For additional information that may be helpful in understanding
`
`25
`
`this and other aspects of the present invention, see Lebreton, U.S. Patent Application Publication
`
`No. 2006/0194758, the entire disclosure of which is incorporated herein by this reference.
`
`Typically, raw HA material is cleaned and purified. These steps generally involved
`
`hydrating the dry HA fibers in the desired high/low molecular weight ratio, for example, using
`
`30
`
`pure water, and filtering the material to remove large foreign matters and other impurities. The
`
`filtered, hydrated material is then dried and purified. The high and low molecular weight may be
`
`7
`
`

`

`18438PROV2 (FAC)
`
`cleaned and purified separately, and they may also be mixed together, for example, in the desired
`
`ratio, just before being crosslinked.
`
`In a preferred embodiment of the invention, the pure, dried NaHA fibers are hydrated in
`
`5
`
`an alkaline solution to produce an uncrosslinked NaHA alkaline gel. Any suitable alkaline
`
`solution may be used to hydrate the NaHA in this step, for example, but not limited to an
`
`aqueous solution containing NaOH. The resulting alkaline gel will have a pH above 7.5, for
`
`example, a pH above 9, for example, a pH above 10, for example, a pH above 12, for example, a
`
`pH above 13 or greater.
`
`10
`
`The next step in the manufacturing process compnses the step of crosslinking the
`
`hydrated, alkaline NaHA gel with a suitable crosslinking agent. The crosslinking agent may be
`
`any agent known to be suitable for crosslinking polysaccharides and their derivatives via their
`
`hydroxyl groups. Suitable crosslinking agents include but are not limited to, for example, 1,4-
`
`15
`
`butanediol
`
`diglycidyl
`
`ether
`
`(or
`
`1,4-bis(2,3-epoxypropoxy)butane
`
`or
`
`1,4-
`
`bisglycidyloxybutane=BDDE), 1,2-bis(2,3-epoxypropoxy)ethylene and 1-(2,3-epoxypropyl)-2,3-
`
`epoxycyclohexane. The use of more than one crosslinking agent or a different crosslinking agent
`
`is not excluded from the scope of the present invention. In is particularly preferred embodiment,
`
`the crosslinking agent comprises or consists of 1,4-butanediol diglycidyl ether (BDDE).
`
`20
`
`The step of crosslinking may be carried out using means known to those of skill in the art. Those
`
`skilled in the art appreciate how to optimize the conditions of crosslinking according to the
`
`nature of the HA, and how to carry out the crosslinking to an optimized degree. The degree of
`
`crosslinking is preferably sufficient for the final hydrogel composition obtained from the present
`
`25 methods to remain implanted at the injection site without excessive diffusion away from this
`
`injection site. In some embodiments of the present invention, the degree of crosslinking is at
`
`least about 2% to about 20%, and more preferably is about 4% to about 12%, wherein the degree
`
`of crosslinking is defined as the percent weight ratio of the crosslinking agent to HA-monomeric
`
`units in the composition.
`
`30
`
`8
`
`

`

`18438PROV2 (FAC)
`
`The crosslinked, HA-based gel compnses a crosslinked HA component capable of
`
`absorbing at least about one time its weight in water. When neutralized and swollen, the
`
`crosslinked HA component and water absorbed by the crosslinked HA component is in a weight
`
`ratio of about 1: 1.
`
`5
`
`Importantly, the resulting gel has a characteristic of being highly cohesive. Using a
`
`different terminology, the resulting HA-based gel can also be considered substantially
`
`"monophasic".
`
`10
`
`Monophasic HA-based gel, at least for purposes of the present disclosure, are to be
`
`distinguished from HA-based gels that are not monophasic in character, for example, those gels
`
`which are "biphasic" or heterogeneous in character.
`
`Crosslinked HA-based gels which are considered to be "biphasic" or heterogeneous are
`
`15
`
`those HA-based gels which are relatively particulate in nature, and comprise particles of
`
`crosslinked HA material dispersed in a carrier of uncrosslinked HA material. When analyzed
`
`with the naked eye or microscopically, for example, at a magnification of up to 35X, biphasic or
`
`heterogeneous HA-based gels appear particulate in nature. Such dispersed "particles" are often
`
`but not always perceptible by touch (tactilely) when felt with the fingers. These gels are usually
`
`20 manufactured by pressing a mass of crosslinked HA-based gel through a sieve or a mesh to
`
`create crosslinked HA particles of generally uniform size and/or shape. To form the biphasic
`
`gel, these particles are then mixed with a carrier material, usually an amount of uncrosslinked
`
`HA, to produce a "biphasic" gel. Examples off such biphasic gels are manufactured by QMed
`
`and marketed under the names Perlane and Restylane, for example.
`
`25
`
`The HA-based gel at this step of the present process has a sufficient cohesivity such that
`
`the gel will not undergo substantial phase separation after centrifugation of the gel at 2000
`
`rd/min for 5 minutes. Even more preferably, the gel preferably has the characteristic of being
`
`capable of absorbing at least one time its weight of water and has a sufficient cohesivity such
`
`30
`
`that when swollen with water at a gel/water weight ratio of about 1: 1, the gel maintains its
`
`integrity when subjected to centrifugation.
`
`9
`
`

`

`18438PROV2 (FAC)
`
`The hydrated crosslinked, HA gel may be swollen to facilitate obtaining the desired
`
`cohesivity. This step may be accomplished by neutralizing the crosslinked, hydrated HA gel, for
`
`example by adding an aqueous solution containing HCl. The gel is then swelled in a phosphate
`
`5
`
`buffered saline solution for a sufficient time and at a low temperature. The resulting swollen gel
`
`is highly cohesive with no visible distinct particles, for example, no visibly distinct particles
`
`when viewed with the naked eye. In a preferred embodiment, the gel has no visibly distinct
`
`particles under a magnification of less than 35X.
`
`10
`
`The cohesive, monophasic gel is now purified by conventional means for example,
`
`dialysis or alcohol precipitation, to recover the crosslinked material, to stabilize the pH of the
`
`material and remove any unreacted crosslinking agent. Additional water or slightly alkaline
`
`aqueous solution can be added to bring the concentration of the N aHA in the composition to a
`
`desired concentration. In some embodiments, the concentration of NaHA in the composition is
`
`15
`
`in a range between about 10 mg/ml to about 30 mg/ml.
`
`The pH of the purified, substantially pH neutral crosslinked HA gel is preferably adjusted
`
`to cause the gel to become slightly alkaline, for example, such that the gel has a pH of greater
`
`than about 7.2, for example, about 7.5 to about 8.0. This step may be accomplished by any
`
`20
`
`suitable means, for example, by adding a suitable amount of dilute sodium hydroxide (NaOH)
`
`solution to the gel or any other alkaline molecule and/or buffering composition know by
`
`l'homme de l'art.
`
`An effective amount of lidocaine, preferably in the form of lidocaine HCl, is then added
`
`25
`
`to the purified cohesive NaHA gel. For example, in some embodiments, the lidocaine HCl is
`
`provided in a powder form which is solubilized using water for injection (WFI). The gel is kept
`
`neutral with a "strong" buffer or by adjustment with diluted sodium hydroxide in order that the
`
`final HA/lidocaine composition will have a desired substantially neutral pH. Preferably, the
`
`final HA-based filler composition including lidocaine will have a lidocaine concentration of
`
`30
`
`between at least about 0.1 % and about 5%, for example, about 2% by weight of the composition,
`
`or in another example about 0.3%.
`
`10
`
`

`

`18438PROV2 (FAC)
`
`After the addition of the lidocaine HCl, or alternatively, during the addition of the
`
`lidocaine HCl, the HA/lidocaine gel is homogenized to create a highly homogenous cohesive
`
`HA/lidocaine gel having a desired consistency and stability. Preferably, the homogenization
`
`5
`
`step comprises mixing, stirring, or beating the gel with a controlled shear force to obtain a
`
`substantially homogenous mixture.
`
`After homogenization, the HA/lidocaine composition is introduced into synnges and
`
`sterilized. Sterilization comprises sterilization of the filled syringes by moist heat. Many
`
`10
`
`different sterilization temperatures and cycle times can be used for this step. For example, the
`
`filled syringes may be sterilized at a temperature of at least about 120 degrees C to about 130
`
`degrees C or greater. The sterilization cycle may be at least about 1 minute to about 20 minutes
`
`or more.
`
`15
`
`Swelling Test/Centrifugation Test/Dye Test
`
`The following Tests may be performed in order to evidence a sufficient cohesivity of a
`
`HA-based gel composition for purposes of the present disclosure.
`
`Method for testing for sufficient cohesivity of gel:
`
`20
`
`0.2 g or 0.4g of a gel composition to be tested is placed in a glass synnge. 0.2g
`
`(resp.0.4g) or more of phosphate buffer is added to the syringe and the mixture is thoroughly
`
`mixed for about 1 hour to obtain a homogenous mixture. The homogenized mixture is then
`
`centrifuged for 5 min at 2000tr/min to remove the air bubbles and to allow the decantation of any
`
`particles. The syringe is then held in a vertical position and one drop of eosin colorant (dye) is
`
`25
`
`deposit at the surface of the gel by means of a syringe and an 18G needle. A photo (Figure IA)
`
`is taken after 10 min to show diffusion of the dye through the gel.
`
`After dilution of the gel, homogenization and decantation, a biphasic or heterogeneous
`
`gel shows a phase separation ( an upper diluted less viscous phase without particles and a lower
`
`11
`
`

`

`18438PROV2 (FAC)
`
`one composed of decanted particles that are visible with the naked eye or under microscope).
`
`Under the same conditions, a monophasic cohesive gel shows substantially no phase separation.
`
`The dye is prevented from diffusing into the cohesive formulation. A biphasic, non-cohesive gel
`
`shows a clear phase separation.
`
`5
`
`EXAMPLE 1
`
`Sodium hyaluronate fibers or powd