U.S. patent application number 12/776313 was filed with the patent office on 2011-01-06 for photoinitiated tissue filler.
This patent application is currently assigned to THE JOHNS HOPKINS UNIVERSITY. Invention is credited to Jennifer H. Elisseeff, Alexander Hillel, H. Janice Lee.
Application Number | 20110002997 12/776313 |
Document ID | / |
Family ID | 40304928 |
Filed Date | 2011-01-06 |
United States Patent
Application |
20110002997 |
Kind Code |
A1 |
Elisseeff; Jennifer H. ; et
al. |
January 6, 2011 |
PHOTOINITIATED TISSUE FILLER
Abstract
Visible light-activated polymer cosmetic filler preparations
useful in a variety of applications are provided. In some
embodiments, the photo-activated polymer composition comprises a
conventional polymeric material, such as HA, together with a
modified, cross-linkable polymer, such as PEG or PEODA, to permit
the formation of crosslinks within the polymer matrix in situ on
exposure to a visible light source, such as an IPL device. The
preparations provide for a more stabilized composition that is
contourable during gelation.
Inventors: |
Elisseeff; Jennifer H.;
(Baltimore, MD) ; Hillel; Alexander; (Baltimore,
MD) ; Lee; H. Janice; (Baltimore, MD) |
Correspondence
Address: |
EDWARDS ANGELL PALMER & DODGE LLP
P.O. BOX 55874
BOSTON
MA
02205
US
|
Assignee: |
THE JOHNS HOPKINS
UNIVERSITY
Baltimore
MD
|
Family ID: |
40304928 |
Appl. No.: |
12/776313 |
Filed: |
May 7, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12185023 |
Aug 1, 2008 |
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12776313 |
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60953375 |
Aug 1, 2007 |
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Current U.S.
Class: |
424/486 ;
424/78.17 |
Current CPC
Class: |
A61K 8/8152 20130101;
A61L 27/26 20130101; A61L 27/26 20130101; A61L 27/26 20130101; A61K
8/02 20130101; A61Q 19/00 20130101; A61K 2800/81 20130101; A61L
27/50 20130101; A61K 2800/91 20130101; C08L 5/08 20130101; C08L
71/02 20130101; A61P 17/02 20180101 |
Class at
Publication: |
424/486 ;
424/78.17 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/74 20060101 A61K031/74; A61P 17/02 20060101
A61P017/02 |
Claims
1-36. (canceled)
37. A method of repairing or augmenting soft tissue in a subject,
the method comprising a. injecting into a subject in need thereof a
composition comprising a biodegradable, polymerizable macromer, the
macromer comprising a water soluble polymer modified with one or
more biodegradable moieties; and b. polymerizing the macromer to
provide a hydrogel wherein the hydrogel to soft tissue have a
normalized compliance ratio of from about 0.05 to about 3, thus
repairing or augmenting the soft tissue.
38. The method of claim 37, wherein the compliance ratio is from
about 0.1 to about 2.0 relative to the soft tissue.
39. The method of claim 38, wherein the compliance ratio is from
about 0.1 to about 1.0 relative to the soft tissue.
40. The method of claim 37, wherein the macromer is polymerized by
irradiating through the skin of the subject with visible light.
41. The method of claim 37, wherein the subject is irradiated with
visible light for from about 10 seconds to about 120 seconds.
42. The method of claim 41, wherein the subject is irradiated with
visible light for at least about 30 seconds.
43. The method of claim 42, wherein the subject is irradiated with
visible light for at least about 40 seconds.
44. The method of claim 37, wherein the macromer is polymerized by
irradiating the subject with blue-green light.
45. The method of claim 37, wherein the macromer is polymerized by
irradiating the subject with thermal energy.
46. The method of claim 37, wherein the water soluble polymer is
PEG.
47. The method of claim 46, wherein the PEG has a molecular weight
of from about 10,000 to about 35,000 Daltons.
48. The method of claim 37, wherein the macromer is
biodegradable.
49. The method of claim 37, wherein the macromer comprises a
plurality of hydrolysable linkages.
50. The method of claim 49, wherein the hydrolyzable linkages are
selected from the group consisting of esters or carbonates.
51. The method of claim 37, wherein the water soluble polymer is
modified with an poly (L-lactide) and poly (trimethylene carbonate)
and an acrylate endcap.
52. The method of claim 51, wherein the water soluble polymer is
PEG.
53. The method of claim 37, wherein the composition further
comprises a photo-initiator.
54. The method of claim 53, wherein the photoinitiator is a
dye.
55. The method of claim 54, wherein the dye is eosin.
56. The method of claim 37, wherein the composition further
comprises a rheology modifier.
57. The method of claim 56, wherein the rheology modifier is HA or
CMC.
58. The method of claim 37, wherein the composition is
substantially free of organic solvent.
59. The method of claim 37, wherein the hydrogel has a strain or
elongation before fracture substantially similar to the expected
strain during normal use of the soft tissue to which it augments or
repairs.
60. The method of claim 37, wherein the hydrogel has a strain or
elongation before fracture greater than the expected strain during
normal use of the soft tissue to which it augments or repairs.
61. The method of claim 37, wherein the hydrogel has a reversible
elongation at least about 150% as great as an expected strain of
the soft tissue which is augments or repairs.
62. The method of claim 37, wherein the hydrogel has an elastic
modulus which is less than about 150 kPa.
63. The method of claim 37, wherein the hydrogen has an ultimate
yield stress of from about 500 to about 2,000 psi.
64. The method of claim 37, wherein the macromer is injected
subdermally.
65. The method of claim 64, wherein the macromer is polymerized by
irradiating least a part of the skin of the subject.
66. The method of claim 65, wherein the skin is irradiated for at
least about 30 seconds.
67. The method of claim 66, wherein the macromer is injected
intradermally.
68. The method of claim 67, wherein the macromer is polymerized by
irradiating at least a part of the skin of the subject.
69. The method of claim 68, wherein the skin is irradiated for at
least about 30 seconds.
70. The method of claim 37, further comprising shaping the
macromer.
71. The method of claim 70, wherein the macromer is shaped during
polymerization of the macromer.
72. The method of claim 71, wherein the macromer is polymerized by
irradiating through the skin of the subject.
73. The method of claim 37, comprising repeating steps a) and b) of
claim 1 at least one time.
74. The method of claim 37, comprising repeating steps a) and b) of
claim 1 at least two times.
75. The method of claim 37, wherein the subject is a mammal.
76. The method of claim 75, wherein the subject is a human.
77. The method of claim 37, the method comprising repairing facial
tissue.
78. The method of claim 77, the method comprising decreasing the
appearance of at least one facial line, wrinkle, crease, or
fold.
79. The method of claim 37, the method comprising augmenting
breast, lip, cheek, chin, forehead, buttocks, hand, neck or earlobe
tissue in a subject.
80. The method of claim 37, the method comprising decreasing the
appearance of a dermal dimple.
81. The method of claim 80, wherein the dimple is a component of a
scar.
82. The method of claim 37, wherein the composition is administered
with a red tinted syringe.
83. The method of claim 37, wherein the soft tissue remains
substantially augmented or repaired for at least about 1 month.
84. The method of claim 83, wherein the soft tissue remains
substantially augmented or repaired for at least about 2
months.
85. The method of claim 84, wherein the soft tissue remains
substantially augmented or repaired for at least about 6
months.
86. The method of claim 37, wherein the hydrogel elicits a mild
fibrotic response in the subject.
87. The method of claim 37, wherein the composition comprises a two
part system, and wherein the polymerization is initiated via a
redox system.
88. The method of claim 87, wherein the polymerization occurs over
a period of from about 30 seconds to about 2 minutes.
89. The method of claim 37, wherein the composition further
comprises a drug such as an non-steroidal anti-inflammatory, an
analgesic, a vitamin such as E, C, A, D or K, an anti-oxidant, an
alpha hydroxyl acid such as lactic acid or a polymer capable of
releasing such drug, vitamin, anti oxidant or alpha-hydroxyacid or
any combination thereof.
90. A method of repairing or augmenting soft tissue in a subject,
the method comprising a. injecting into a subject in need thereof a
composition comprising a biodegradable, polymerizable macromer, the
macromer comprising a water soluble polymer modified with one or
more biodegradable moieties; and b. polymerizing the macromer to
provide a hydrogel, thus repairing or augmenting the soft tissue.
Description
[0001] This application claims the benefit of U.S. provisional
application No. 60/953,375 filed Aug. 1, 2007, which is
incorporated herein by reference in its entirety.
BACKGROUND OF INVENTION
[0002] Hyaluronic acid (HA), which can be crosslinked, and
collagens are biomaterials used in the fields of surgery and
dermatology as fillers to recontour/reconstruct tissues. The market
of cosmetic fillers for soft tissue augmentation has increased in
recent years and there is a need to create longer lasting materials
that are retained at the site of application. Physicians also would
like to improve control over the final result and allow for
subsequent correction to optimize patient satisfaction.
[0003] Hydrogels hold the promise of creating dermal fillers that
maintain aesthetic corrections longer than currently available
fillers. The term, "hydrogel," refers to a broad class of polymeric
materials that contain water but do not dissolve in water.
Generally hydrogels are cross-linked and networked polymer chains.
If there are two or more crosslinks per polymer chain, a network is
formed that is able to absorb large amounts of solvent. Hydrogels
are of particular interest in the field of tissue engineering
because of their tissue-like water content, which allows nutrient
and waste transport.
[0004] There are a number of methods to form polymers and to
crosslink polymers. One such method involves light-reactive
reagents and light-induced reactions which create reactive species
in a monomer solution, wherein the monomers are polymerized to form
chains, monomers, polymers and chains, which in turn can form
networks.
[0005] Currently used cosmetic fillers are generally derived from
biological polymers, such as collagen or hyaluronic acid. Since
these compounds are biological in nature, they tend to be sensitive
to degradation even if crosslinked. Hence, the esthetic duration of
an enhancement/correction achieved with such materials is limited
in time, and frequently requires the recipient to undergo
additional and expensive repeat injections/treatments to maintain a
desired effect. Another drawback of conventional cosmetic fillers
is the lack of malleability and contourability to maintain a
desired and/or corrective formation after injection, such as, for
example, in human cheek bone or chin manipulations. Thus, for these
types of and other similar procedures, a more invasive approach is
used wherein plastic implants are inserted while a patient is under
general anesthesia. Hence, a need continues to exist in the
cosmetic reconstructive arts for improved polymeric fillers that
are contourable and longer lasting.
[0006] Synthetic polymers have highly controllable physical and
degradation properties, making them suitable for creating an
implant with specific properties. Poly(ethylene glycol), PEG, is an
example of a frequently used biocompatible synthetic polymer. PEG,
and other synthetic polymers, can be modified to react with
functional groups to allow crosslinking and to form hydrogels.
[0007] A PEG derivative, poly(ethylene oxide) diacrylate (PEODA),
can be injected into the body as a solution and can be polymerized
to form a crosslinked, insoluble gel [1-5]. To induce
photopolymerization by free radical formation, various
photoinitiators have been used. In particular, Hubbell and his
colleagues previously created PEODA hydrogels using Eosin
Y/triethylamine via argon ion laser (514 nm, 70 mW/cm.sup.2, 2 s
exposure; American Laser, Salt Lake City) [6]. Eosin Y is a good
candidate as a transdermal photoinitiator because of its adsorption
range in visible blue light [7,8]. The advantage of visible light,
as compared to UV, is that the longer visible wavelength can
penetrate deeper into the skin. Moreover, high doses of UV light
have been implicated as a cause for erythema and different types of
skin cancers [9]. Therefore, photopolymerization using a visible
light source would be suitable for the proposed cosmetic
applications. Feasibility of PEODA photopolymerization with visible
light using Eosin Y as the initiator under human skin, however, is
yet to have been established.
[0008] Intense pulsed light (IPL) devices are a common visible
light source in a dermatology office for photorejuvenation and
photoepilation procedures [10-13]. The compatibility of Eosin Y
photoinitiation with an IPL device, however, has not been
established.
[0009] These and other deficiencies in the art of cosmetically
useful preparations are satisfied with the present invention.
SUMMARY OF THE INVENTION
[0010] In part, the present disclosure provides novel cosmetic
fillers activated by visible light that comprise a crosslinkable
polymeric material or functional derivatives thereof. The polymers
and derivatized polymeric materials may be further described as
containing modified reactive groups that facilitate polymerization,
attachment and crosslinking of the polymeric material on exposure
to light. By exposure to visible light, the liquid form of the
synthetic polymer filler in the cosmetic preparation takes on a
semisolid or gel form, and is amenable to desired contouring and
manipulation to result in a desired, solid and/or semisolid
polymerized form in situ. Moreover, the use of derivatized monomers
and polymers provides for more stable polymers and networks that
are more resistant to biodegradation.
[0011] Virtually any polymeric material that may be modified to
include a light-activated derivatized reactive group may be used in
the preparation of the present cosmetic fillers. By way of example,
and not limitation, and in particular embodiments, the polymer can
comprise synthetic reactants and comprises poly(ethylene glycol)
(PEG) or a derivative thereof. In some embodiments, the polymer
derivative comprises poly(ethylene oxide) diacrylate (PEODA) or
poly(ethylene glycol) diacrylate (PEGDA).
[0012] In another aspect, the invention provides for a method for
forming an implant in vivo. In particular embodiments, the method
comprises administering a liquid derivatized monomeric material
into a desired site in a host, inducing gelation to form a
polymeric material by exposing said liquid derivatized monomeric
material to light, and contouring said gelling and gelled polymeric
material into a desired conformation to provide an implant.
[0013] In particular applications, the liquid derivatized polymeric
material comprises a combination of a PEODA/Restylene.RTM. (a
commercially available filler, U.S. Pat. No. 5,827,937) solution.
In some embodiments, the PEODA/Restylene.RTM. solution comprises
10% PEODA, 15% PEODA, 20% PEODA, 25% PEODA, 30% PEODA, 35% PEODA,
40% PEODA, 45% PEODA, 50% PEODA, 60% PEODA, 70% PEODA or even up to
80% PEODA.
[0014] In some embodiments, a photoinitiator is included in the
method or in a reagent of the method. In some embodiments, the
photoinitiator will be one responsive to visible light, such as one
with an absorption maximum in the visible blue light range. An
example of such a photoinitiator having an absorption maximum in
the visible blue light range is Eosin Y.
[0015] In specific applications of the method, a 10% PEODA or a 20%
PEODA solution will be used in combination with 200 mM
triethylamine and 50 uL/ml Eosin Y initiator.
[0016] In some embodiments of the method, the illumination means
used is an intense pulsed light (IPL) source. In some embodiments
of the method, a combination of Eosin Y/triethylamine and an IPL
light source is used to provide a tissue filler or implant. In some
embodiments, the illumination means is one wherein the light
penetrates the skin, that is, the illumination means is placed
above or on the skin, and the visible light is applied to the skin
surface.
[0017] Compositions of the present disclosure may further comprise
a cell, or encapsulated cells, tissues and/or engineered cells and
tissues.
[0018] The present invention is envisioned to embrace any number of
different combinations and concentrations/amounts of synthetic
polymers, biodegradable polymers, photoinitiators, proton
acceptors, visible light sources and pulse intensity and schedule
regimens, and is expected to vary depending on the particular
subject being treated, the particular type and location of cosmetic
implant/cosmetic filler sought to be achieved, the viscosity and
specific physical properties of the cosmetic filler suitable for
the specific application being made, as well as other variables
associated with clinical procedures of this type known to those of
ordinary skill in the cosmetic and medical arts.
[0019] One advantage of the present materials/methods is an
increased residence/lifetime of fillers and implants in vivo,
Another advantage is an improved non-invasive method for providing
an implant or filler that may be contoured to a particular subject
and/or tissue site in situ. Yet another advantage is the use of
visible light which can be applied to the skin surface.
[0020] In particular aspects, a composition suitable for tissue
augmentation is provided that comprises: (a) modified hyaluronic
acid; (b) PEODA; and (c) accelerant of polymerization of the PEODA.
Preferably, the PEODA has a molecular weight (e.g. weight average
molecular weight) in excess of 2000, 2500, or 3000, with a
molecular weight (e.g. weight average molecular weight) of about
3400 being particularly preferred for many applications. Suitable
accelerants may include e.g. N-vinyl pyrrolidinone. A particularly
preferred modified hyaluronic acid is Restylane.TM.. Such preferred
compositions also may suitably comprise an initiator e.g. Eosin Y
as well as co-initiator (i.e. a composition that has at least two
distinct initiators) such as an amine e.g. a tertiary amine. A
trialkyl amine such as triethyl amine or other
tri(C.sub.1-C.sub.16alkyl)amine can be a preferred co-initiator. In
such compositions the weight ratios of PEODA to modified hyaluronic
acid can suitably vary rather widely, preferably with PEODA being
present in a weight excess relative to the modified hyaluronic acid
component, e.g. where the w/w ratio of PEODA:modified hyaluronic
acid is from about 2:1 to 10:1. Particularly suitable w/w ratios of
PEODA:modified hyaluronic acid include 10:1, 5:1 and 2:1.
[0021] In a further particularly preferred aspect, methods are
provided for augmenting a soft tissue site comprising: (a)
administering to the soft tissue site a composition comprising:
PEODA monomers, modified hyaluronic acid, and an accelerant; and
(b) applying light to the tissue site to induce polymerization of
the PEODA monomers. The soft tissue site is suitably that of a
mammal, particularly a primate such as a human, e.g. the neck,
orbital groove, breast, cheek and/or nose of such a subject.
Suitably the light may be applied externally to the subject.
Preferably, such methods also may comprise shaping the soft tissue
site by external manipulation. The composition may be administered
to the soft tissue site by any of a number of suitable means, such
as by injection under the skin. Preferably, the PEODA has a
molecular weight (e.g. weight average molecular weight) in excess
of 2000, 2500, or 3000, with a molecular weight (e.g. weight
average molecular weight) of about 3400 being particularly
preferred for many applications. Suitable accelerants may include
e.g. N-vinyl pyrrolidinone. A particularly preferred modified
hyaluronic acid is Restylane.TM..
[0022] Other aspects of the invention are disclosed infra.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIGS. 1A and 1B--HA-based filler with PEG crosslinked using
light in a subcutaneous space of a mouse retained more volume over
the 140 days studied (FIG. 1A). Specific comparison after 28 days
(FIG. 1B) defines more clearly the differences between the two
groups.
DETAILED DESCRIPTION
[0024] The instant invention relates, in part, to cosmetic and
medical polymer-based fillers that form a moldable gel or gel-like
composition on photoactivation with a visible light source. The
polymer may be naturally occurring or synthetic.
[0025] Significant to a product of interest is the advantage of
permitting in situ formation of a custom, contoured filler or
implant without invasive surgical intervention or general
anesthesia. Generally, the product of interest is introduced under
the skin (that is, under the epidermis) and polymerization is
induced by exposure to visible light applied to the skin surface,
that is, from outside of the body or outside of the skin, or to the
epidermis.
[0026] The instant invention addresses the problem of limited
lifetime of cosmetic filler materials, particularly polymeric
implantable materials. In some embodiments, the in vivo lifetime of
implants and/or other formations made with the present
polymer-based preparations, such as PEODA, is increased by 50% or
more, such as by 60%, by 70%, by 75%, by 80%, by 85%, by 90% or
even up to 100%, compared to conventional implant materials.
[0027] The instant invention provides for in situ polymerization
techniques to provide cosmetic and medical corrective and/or
enhancement procedures using conventional polymeric materials that
include a polymer component capable of forming an insoluble
crosslinked and crosslinking network on activation with a visible
light source.
[0028] For example, the instant disclosure provides a cosmetic
filler that comprises PEG, or a derivative thereof, such as PEODA,
either alone or together with another polymer, such as HA, which
may be crosslinked, to provide a cosmetic filler that forms a water
insoluble, crosslinked polymer preparation in situ on visible light
activation in the presence of a photoinitiator, such as Eosin Y,
optionally, in the presence of a proton acceptor, such as,
triethylamine.
[0029] A biological surface refers to an external (relative to a
tissue or organ, for example), exposed portion of a biological
material or entity, such as a skin surface, cell, tissue, organ and
the like, to which a preparation comprising the light-activated
crosslinkable monomer preparation of interest can be exposed or is
applied and then said preparation is induced to form a gel in situ
on said surface for cosmetic and/or corrective use.
[0030] A biologically compatible polymer refers to a polymer which
is functionalized to serve as a composition for applying to a
biological surface. The polymer is one that is a naturally
occurring polymer or one that is not toxic to the host, The polymer
may be a homopolymer where all monomers are the same or a
heteropolymer containing two or more kinds of monomers. The terms,
"biocompatible polymer," "biocompatible cross-linked polymer
matrix" and "biocompatibility," when used in relation to the
instant polymers are art-recognized and are considered equivalent
to one another, including, "biologically compatible polymer." For
example, biocompatible polymers include polymers that are naturally
occurring, or are polymers that can be synthetic, and which are
neither toxic to the host (e.g., an animal or human) nor degrade
(if the polymer degrades) at a rate or that produces monomeric or
oligomeric subunits or other byproducts at toxic concentrations or
which are toxic in the host.
[0031] In certain embodiments of the present invention,
biodegradation generally involves degradation of the polymer in an
organism, e.g., into its monomeric subunits, which may be known to
be effectively non-toxic. Intermediate oligomeric products
resulting from such degradation may have different toxicological
properties, however, or biodegradation may involve oxidation or
other biochemical reactions that generate molecules other than
monomeric subunits of the polymer. Consequently, in certain
embodiments, toxicology of a biodegradable polymer intended for in
vivo use, such as implantation or injection into a patient, may be
determined after one or more toxicity analyses. It is not necessary
that any subject composition have a purity of 100% to be deemed
biocompatible; indeed, it is only necessary that the subject
compositions be biocompatible as set forth above, Hence, a subject
composition may comprise polymers comprising 99%, 98%, 97%, 96%,
95%, 90%, 85%, 80%, 75% or even less of biocompatible polymers,
e.g., including polymers and other materials and excipients
described herein, and overall still be biocompatible and minimally
or not toxic.
[0032] To determine whether a polymer or other material is
biocompatible, it may be necessary to conduct a toxicity analysis.
Such assays are well known in the art. One example of such an assay
may be performed with live cells, such as HeLa, 293, CHO and the
like. The polymer sample is partially or completely degraded as
known in the art, using for example, chemical means or enzymatic
means. An aliquot of the treated sample products is placed in
culture plates previously seeded with the cells. The sample
products are incubated with the cells. The results of the assay may
be plotted as % relative growth vs. concentration of degraded
sample. Non-degraded polymer, monomers, networks and the like can
be tested as well.
[0033] In addition, monomers, polymers, polymer matrices, and
formulations of the present invention may also be evaluated by
well-known in vivo tests, such as subcutaneous implantation in rats
to confirm that the materials of interest do not cause significant
levels of, for example, irritation or inflammation at the
subcutaneous implantation sites,
[0034] An "active agent" and a "biologically active agent" are
phrases used interchangeably herein to refer a chemical or
biological compound that induces a desired pharmacological or
physiological effect, wherein the effect may be prophylactic or
therapeutic. The terms also encompass pharmaceutically acceptable,
pharmacologically active derivatives of those active agents
specifically mentioned herein, including, but not limited to,
salts, esters, amides, prodrugs, active metabolites, analogs and
the like. When the terms "active agent," "pharmacologically active
agent" and "drug" are used, it is to be understood that the
invention includes the active agent per se, as well as
pharmaceutically acceptable, pharmacologically active salts,
esters, amides, prodrugs, metabolites, analogs etc. The active
agent can be a biological entity, such as a virus or cell, whether
naturally occurring or manipulated, such as transformed.
[0035] Crosslinked herein refers to a composition containing
intermolecular links and, optionally, intramolecular links, arising
from the formation of covalent bonds. Covalent bonding between two
crosslinkable components may be direct, in which case, an atom in
one component is directly bound to an atom in the other component,
or it may be indirect, that is, for example, through a linking
group. A crosslinked gel or polymer matrix may, in addition to
covalent bonds, also include intermolecular and/or intramolecular
noncovalent bonds such as hydrogen bonds and electrostatic (ionic)
bonds.
[0036] Functionalized refers to a modification of an existing
molecular segment to generate or introduce a new reactive or more
reactive group (e.g., an amine, ester or imide group) that is
capable of undergoing reaction with another molecule, polymer or
functional group (e.g., an amine, an ester or a carboxyl group) to
form a covalent bond. For example, carboxylic acid groups can be
functionalized by reaction with a carbodiimide and an imide reagent
using known procedures to provide a new reactive functional group
in the form of an imide group substituting for the hydrogen in the
hydroxyl group of the carboxyl function.
[0037] Gel refers to a state of matter between liquid and solid,
and is generally defined as a polymer network swollen in a liquid
medium. Typically, a gel is a two-phase colloidal dispersion
containing both solid and liquid, wherein the amount of solid is
greater than that in the two-phase colloidal dispersion referred to
as a "sol." As such, a "gel" has some of the properties of a liquid
(i.e., the shape is resilient and deformable) and some of the
properties of a solid (i.e., the shape is discrete enough to
maintain three dimensions on a two-dimensional surface). "Gelation
time," also referred to herein as "gel time," refers to the time it
takes for a composition to become non-flowable under modest stress.
This is generally exhibited as reaching a physical state in which
the elastic modulus, G', equals or exceeds the viscous modulus,
G'', i.e., when tan(A) becomes 1 (as may be determined using
conventional rheological techniques).
[0038] A gel that is "moldable" is one that is conformable to a
shape before or during exposure to the light, and which can be
contoured or shaped to assume and to retain a particular shape.
Thus, following instillation or administration in a space and
illumination to catalyze gelation, a composition of interest can be
shaped by external manipulation, using, for example, a shaping
means, such as, a surgical depressor or other tool or instrument
with a flat or curved surface, fingers, the palm, a knuckle and so
on.
[0039] A hydrogel is a water-swellable polymeric matrix that can
absorb water to form elastic gels. Hydrogels consist of hydrophilic
polymers crosslinked to from a water-swollen, insoluble polymer
network. Crosslinking can be initiated by many physical or chemical
mechanisms, for example, such as, a light-induced reaction.
[0040] A "matrix" is a three-dimensional network of macromolecules
held together by covalent or noncovalent crosslinks. On placement
in an aqueous environment, dry hydrogels swell to the extent
allowed by the viscosity, the gel state and/or degree of
crosslinking in the polymer or network. A matrix can be a
network.
[0041] Photopolymerization is a method to covalently crosslink
polymer chains, whereby a photoinitiator and polymer solution
(termed "pre-gel" or monomer solution) are exposed to a light
source specific to the photoinitiator. On activation, the
photoinitiator reacts with specific functional groups in the
polymer chains, linking the functional groups to form the hydrogel.
The reaction generally is rapid (3-5 minutes) and can proceed at
room or body temperature. Photoinduced gelation enables spatial and
temporal control of scaffold formation, permitting shape
manipulation after injection and during gelation in vivo. Cells and
bioactive factors can be incorporated into the hydrogel scaffold by
simply mixing same in and with the polymer solution prior to
gelation.
[0042] Hydrogels of interest can be semi-interpenetrating networks
that promote cell, tissue and organ repair while discouraging scar
formation. The hydrogels of interest are derivatized to contain a
reactive group to facilitate polymerization and linking. The
hydrogels of interest also can carry a reactive group or a
functional group reactive with a biological surface, an artificial
surface and/or a second polymer or network. The latter form of
reactivity also can anchor a gel of interest at and to a site of
interest, Hydrogels of interest also are configured to have a
viscosity that will enable the gelled hydrogel to remain or reside
in place for longer periods of time. Viscosity can be controlled by
the monomers and polymers used, the degree of crosslinking, by the
level of water trapped in the hydrogel and by incorporated
thickeners, such as biopolymers, such as proteins, lipids,
saccharides and the like. An example of such a thickener is HA,
whether crosslinked or not.
[0043] Polymer is used to refer to molecules composed of repeating
monomer units, including homopolymers, block copolymers,
heteropolymers, random copolymers, graft copolymers and so on.
"Polymers" also include linear polymers as well as branched
polymers, with branched polymers including highly branched,
dendritic, comb-burst and starburst polymers.
[0044] A monomer is the basic repeating unit in a polymer. A
monomer may itself be a monomer or may be dimer or oligomer of at
least two same or different monomers, and each dimer or oligomer is
repeated in a polymer. A macromer, a macromolecular weight monomer,
is generally a polymer or oligomer with a reactive group, often at
a terminus, which enables the molecule to act as a monomer.
[0045] A polymerizing initiator refers to any substance that can
initiate polymerization of monomers or macromers by, for example,
free radical generation. The polymerizing initiator often is an
oxidizing agent. Exemplary polymerizing initiators include those
which are activated by exposure to, for example, electromagnetic
radiation, such as visible light.
[0046] Certain monomeric subunits of the present invention may
exist in particular geometric or stereoisomeric forms. In addition,
polymers and other compositions of the present invention may also
be optically active. The present invention contemplates all such
compounds, including cis-isomers and trans-isomers, R-enantiomers
and S-enantiomers, diastereomers, (d)-isomers, (1)-isomers, the
racemic mixtures thereof, and other mixtures thereof, as falling
within the scope of the invention. Additional asymmetric carbon
atoms may be present in a substituent, such as an alkyl group. All
such isomers, as well as mixtures thereof, are intended to be
included in the invention.
[0047] The terms "substituted," "functional group" and "reactive
group" are contemplated to include all permissible substituents of
organic compounds on the monomers, polymers and networks of
interest. In a broad aspect, the permissible substituents include
acyclic and cyclic, branched and unbranched, carbocyclic and
heterocyclic, aromatic and nonaromatic substituents of organic
compounds. Illustrative substituents include, for example, carboxy
groups, amine groups, amide groups, hydroxyl groups and so on, as
known in the art. The permissible substituents may be one or more
and the same or different for appropriate organic compounds. For
purposes of this invention, the heteroatoms such as nitrogen may
have hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valences of
the heteroatoms. This invention is not intended to be limited in
any manner by the permissible substituents of organic
compounds.
[0048] A functional group or a moiety capable of mediating
formation of a polymer or network can be added to a naturally
occurring molecule or a synthetic molecule practicing methods known
in the art. Functional groups include the various radicals and
chemical entities taught herein, and include alkenyl moieties such
as acrylates, methacrylates, dimethacrylates, oligoacrylates,
oligomethacrylates, ethacrylates, itaconates or acrylamides.
Further functional groups include aldehydes. Other functional
groups may include ethylenically unsaturated monomers including,
for example, alkyl esters of acrylic or methacrylic acid such as
methyl methacrylate, ethyl methacrylate, butyl methacrylate, ethyl
acrylate, butyl acrylate, hexyl acrylate, n-octyl acrylate, lauryl
methacrylate, 2-ethylhexyl methacrylate, nonyl acrylate, benzyl
methacrylate, the hydroxyalkyl esters of the same acids such as
2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, and
2-hydroxypropyl methacrylate, the nitrite and amides of the same
acids such as acrylonitrile, methacrylonitrile, and methacrylamide,
vinyl acetate, vinyl propionate, vinylidene chloride, vinyl
chloride, and vinyl aromatic compounds such as styrene, t-butyl
styrene and vinyl toluene, dialkyl maleates, dialkyl itaconates,
dialkyl methylene-malonates, isoprene and butadiene. Suitable
ethylenically unsaturated monomers containing carboxylic acid
groups include acrylic monomers such as acrylic acid, methacrylic
acid, ethacrylic acid, itaconic acid, maleic acid, fumaric acid,
monoalkyl itaconate including monomethyl itaconate, monoethyl
itaconate, and monobutyl itaconate, monoalkyl maleate including
monomethyl maleate, monoethyl maleate, and monobutyl maleate,
citraconic acid and styrene carboxylic acid. Suitable
polyethylenically unsaturated monomers include butadiene, isoprene,
allylmethacrylate, diacrylates of alkyl dials such as butanediol
diacrylate and hexanediol diacrylate, divinyl benzene and the
like.
[0049] It will be understood that substitution or substituted with
includes the implicit proviso that such substitution is in
accordance with the permitted valency of the substituted atom and
the substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo
transformation, such as by rearrangement, cyclization, elimination
or other reaction.
[0050] For purposes of the invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 67th Ed.,
1986-87.
[0051] In some embodiments, the disclosure is directed to a
composition comprising a cosmetic filler generally derived from
biological polymers such as collagen or hyaluronic acid. In some
embodiments, the polymers are generally linked to produce desired
viscosity and physical properties. Those starting molecules are
natural components of extracellular matrices. Other suitable
polymers include those which also are naturally occurring, such as
a glycosaminoglycans, mucopolysaccharides, collagens or
proteoglycan components, such as hyaluronic acid, heparin sulfate,
glucosamines, dermatans, keratins, heparins, hyalurunan, aggrecan
and the like. In general, any biologically compatible polymer can
be used as the polymer of interest.
[0052] Suitable hydrophilic polymers to serve as polymer of
interest include synthetic polymers such as poly(ethylene glycol),
poly(ethylene oxide), partially or fully hydrolyzed poly(vinyl
alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline),
polyethylene oxide)-co-poly(propylene oxide) block copolymers
(poloxamers and meroxapols), poloxamines, carboxymethyl cellulose,
and hydroxyalkylated celluloses such as hydroxyethyl cellulose and
methylhydroxypropyl cellulose, and natural polymers, such as,
polysaccharides or carbohydrates such as Ficoll.TM., polysucrose,
dextran, heparan sulfate, chondroitin sulfate or alginate, and
polypeptides or proteins such as gelatin, collagen, albumin or
ovalbumin, or copolymers or blends thereof. As used herein,
"celluloses" includes cellulose and derivatives of the types
described above; "dextran" includes dextran and similar derivatives
thereof.
[0053] In some embodiments, a monomeric unit of a biologically
compatible polymer may be functionalized through one or more thio,
carboxylic acid or alcohol moieties located on a monomer of the
biopolymer. For example, in the case of chondroitin sulfate, a
carbonyl group can be derivatized with a imide group using, for
example, carbodiimide chemistry. An alcohol group can be
derivatized using, for example, the Mitsunobu reaction, Procter et
al., Tetra. Lett. 47(29) 5151-5154, 2006.
[0054] Polysaccharides that are very viscous liquids or that are
thixotropic, and form a gel over time by the slow evolution of
structure, are also useful. For example, hyaluronic acid, which can
form an injectable gel with a consistency like a hair gel, may be
utilized. Modified hyaluronic acid derivatives are particularly
useful. As used herein, the term "modified hyaluronic acids" refers
to chemically modified hyaluronic acids. Modified hyaluronic acids
may be designed and synthesized with preselected chemical
modifications to adjust the rate and degree of linking and
biodegradation. For example, modified hyaluronic acids may be
designed and synthesized to be esterified with a relatively
hydrophobic group such as propionic acid or benzylic acid to render
the polymer more hydrophobic and gel-forming, or which are grafted
with amines to promote electrostatic self-assembly. Modified
hyaluronic acids thus, may be synthesized which are injectable, to
flow under stress, but maintain a gel-like structure when not under
stress. Hyaluronic acid and hyaluronic derivatives are available
from Genzyme, Cambridge, Mass. and Fidia, Italy.
[0055] Methods for the synthesis of the polymers described above
are known to those skilled in the art, see, for example Concise
Encyclopedia of Polymer Science and Polymeric Amines and Ammonium
Salts, E. Goethals, ed. (Pergamen Press, Elmsford, N.Y. 1980). Many
polymers, such as poly(acrylic acid), are commercially available.
Naturally occurring polymers can be isolated from biological
sources, as known in the art, or are commercially available.
Naturally occurring and synthetic polymers may be modified using
chemical reactions available in the art and described, for example,
in March, "Advanced Organic Chemistry," 4th Edition, 1992,
Wiley-Interscience Publication, New York.
[0056] Numerous chemical options are available for modifying
polymers that may then undergo a radical polymerization. For
example, methacrylic anhydride, methacryloyl chloride and glycidyl
methacrylate may be used to add methacrylate groups to one or more
monomers of a polymer chain. Glycidyl methacrylate may be used, for
example, for efficiency of reaction. Further, the modification
reagents may be chosen to optimize a lack of cytotoxic
byproducts.
[0057] A variety of photolabile compounds are available, including,
but not limited to, disulfides, benzoins and benzyls for use as a
photoinitiator of interest. A non-limiting list of exemplary
photoinitiators includes benzophenone, trimethylbenzophenone,
thioxanthone, 2-chlorothioxanthone, 9,10-anthraquinone,
bis-4,4-dimethylaminobenzophenone, benzoin ethers, benzilketals,
.alpha.-dialkoxyacetophenones, .alpha.-hydroxyalkylphenones,
.alpha.-amino alkylphenones, acylphosphine oxides,
benzophenones/amines, thioxanthones/amines, titanocenes,
2,2-dimethoxy acetophenone, 1-hydroxycyclohexyl phenyl ketone,
2-methyl-1-[4-(methylthio)phenyl]-2-(4-morpholinyl)-1-propanone,
2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone,
.alpha.-hydroxy-ketones and benzilidimethyl-ketals, e.g. Irgacure
651 and 184, and Darocur 1173, marketed by Ciba Chemicals, Rose
Bengal, camphorquinone, erythrosine, and mixtures thereof, and so
on.
[0058] The pregel, monomer solution can comprise a photoinitiator
in an amount of, for example, 0.05 to about 1.5% by weight, 0.1 to
1.0% by weight or 0.08 to 0.5% by weight, based on the entire
polymerizable component to be gelled, the degree of polymerization
and/or networking desired, the rate of polymerization and/or
networking desired and so on, as a design choice.
[0059] The monomer solution can contain the photoinitiator, the
photoinitiator can be mixed with the monomer prior to use or
applied separately.
[0060] Optionally, a proton acceptor is included. Suitable such
proton acceptors are known in the art. An example of such a
suitable proton acceptor is an amine, such as a tertiary amine,
such as, triethylamine.
[0061] An illuminating means can be a light source suitable for
activating the photoinitiator used, and which can activate the
photoinitiator from outside of the body. While thermal initiators
can be used and thus, an infrared source used, and
ultraviolet-activated initiators can be used, and thus, a suitable
ultraviolet source used, a preferred light source is a white light
source. Thus, a suitable photoinitiator is used, such as Eosin Y,
so that the maximum absorption of the initiator and the light
source are tuned. As mentioned hereinabove, one such visible light
source is an IPL device. A commonly used commercially available IPL
carries a xenon flash lamp. Other suitable light sources can be
used so long as gelation occurs in the body, at the site, under the
skin surface and so on, such as, by applying the electromagnetic
radiation to the body, to the site as needed, or from above the
skin surface. The electromagnetic radiation is applied at an
intensity, for a time and for a duration that enables gelation. The
light source can be situated above the skin surface or directly on
the skin surface.
[0062] The monomer solution of interest also can contain any of a
variety of other materials, such as, inert materials, such as,
preservatives, fillers, excipients or diluents, pharmacologically
active molecules or agents, such as a small molecule or a
biological, cells and so on, as known in the pharmaceutic arts.
Thus, a suitable inert or biologically active agent can be added to
the monomer solution. In the case of the latter, the active agent
may exert a pharmacologic action locally at the site or in the
vicinity of the polymerized or networked structure of interest, or
can be released from the formed scaffold, matrix or network to move
though the adjoining tissue spaces or may enter the circulatory
system for a less local effect.
[0063] As discussed above, the functionalized monomer of interest
also can be used in combination with other dermatology, orthopedic,
cosmetic and so on fillers, patches and so on, such as those which
are commercially available. Examples include Restylane.sup.4p,
comprising a crosslinked HA, Juvederm (Allergan) comprising HA,
Zyderm, comprising collagen, Radiesse.TM. comprising microspheres
in a collagen and so on. Thus, the monomer solution of interest can
be mixed with a known filler to provide a composition which is
moldable, contourable, has a long residence time and so on.
[0064] By way of example, polymer matrix compositions of the
invention can be used to block or fill various lumens and voids
just below a skin surface. Thus, the instant invention relates to a
method of tissue augmentation in a host, such as a human patient,
wherein said monomer solution of interest is introduced at a site
of interest using methods known in the art, such as injecting a
monomer at or in a tissue site in need of augmentation and once
applied, exposing the body surface to a visible light to cause
polymerization of the deposited monomer solution. A kit containing
the injectable monomer, and a delivery means, such as a syringe, as
well as an optional light source, a photoinitiator and proton
acceptor, is also provided.
[0065] "Augmentation" means the repair, prevention or alleviation
of defects, particularly defects due to loss or absence of tissue,
by providing, augmenting, or replacing such tissue with a polymer
or network or interest. Augmentation is also meant to include
supplementation of a natural structure or feature, that is, a
building of adding to an existing body part, for example, to
increase the size thereof, such a lips, nose, breast, ears,
portions of the reproductive organs, eyebrows, chin, cheeks and so
on. While the invention is designed primarily for soft tissue
augmentation, hard tissue augmentation is encompassed as the
injectable compositions of the invention can be applied to a hard
tissue and can be used in combination with, for example, materials
to promote mineralization or bone formation. Thus, tissue
augmentation can include the filling of lines, folds, wrinkles,
minor facial depressions, cleft lips, superficial wrinkles and the
like, such as, in the face and neck; the correction of minor
deformities due to aging or disease, including in the hands and
feet, fingers and toes; the augmentation of the vocal cords or
glottis to rehabilitate speech; the dermal filling of sleep lines
and expression lines; the replacement of dermal and subcutaneous
tissue lost due to aging; the augmentation of lips; the filling of
wrinkles and the orbital groove around the eye; the augmentation of
the breast; the augmentation of the chin; the augmentation of the
cheek and/or nose; the filling of indentations in soft tissue,
dermal or subcutaneous, due to, e.g., overzealous liposuction or
other trauma; the filling of acne or traumatic scars and rhytids;
the filling of nasolabial lines, nasoglabellar lines and infraoral
lines and so on.
[0066] The monomer solution of interest is one which has a
viscosity suitable for ready extrusion through a delivery means,
such as a fine surgical needle (e.g., needles having a gauge of at
least 22, at least 27 or finer) at the temperature of use. Thus, a
solution that is, "injectable" is one having a texture and
viscosity which permits flow through a suitable delivery device,
such as, a surgical needle, other surgical instrument, or other
delivery means such as a equipment used in endoscopic or
percutaneous dissectomy procedures, by employing typical injection
pressures. The monomer solution of interest thus is injectable
through a suitable applicator, such as a catheter, a cannula, a
needle, a syringe, tubular apparatus and so on, as known in the
art.
[0067] The viscosity of the monomer solution can be varied as a
design choice to suit the intended use. For example, for
application to superficial sites or little tissue space volume, a
less viscous monomer solution can be used to ensure flowability of
the solution. In other sites, such as larger tissue spaces or
deeper sites, a more viscous monomer solution can be used to
facilitate retention of the monomer solution at the site prior to
and during exposure to the photoinitiator and light.
[0068] The instant invention also provides kits for enabling
performing the method of the invention. Such kits can be prepared
from readily available materials and reagents and can come in a
variety of embodiments as known in the pharmaceutic and medical
arts. For example, such kits can comprise, in an amount sufficient
for at least one treatment, a photoactivatable monomer solution,
optionally, sterilized buffers or water, other reagents necessary
or helpful to perform the method, and instructions. Instructions
include a tangible expression describing reagent concentration or
at least one method parameter, such as the amount of reagent to be
used, stability conditions of the reagent(s) and the like, to allow
the user to carry out the method of the instant invention. In one
embodiment, a kit comprises a means for delivery in which is placed
a monomer of interest, which often is pre-sterilized. Such delivery
means can include, by way of illustration and not limitation, a
small syringe (for example, 22 to 27 gauge), a large syringe (for
example, 13 to 19 gauge) or equipment used in endoscopic or
percutaneous discectomy procedures, The delivery means can be
pre-sterilized and encased in a sterile containing means, such as a
plastic wrapper. The reagents can be provided in solution, as
suspensions, or as a substantially dry powder, e.g., in lyophilized
form, either independently or in a mixture of components to improve
ease of use and stability. Where a degradable reagent is provided,
conditions are selected which maximize stability of the reagent(s),
e.g., storage at lower temperature, addition of stabilizing agents
(e.g., glycerol or a reducing agent) and so on, as known in the
art. Unstable reagents can be provided together with or separately
from the more stable components of the kit. The reagents and
instructions can be placed and carried in a container means for
immobilizing the reagents therein thereby providing support and
protection for the contents, providing stackability of units,
providing insulation, providing a transporting form and so on.
[0069] The reagents are manufactured, kitted, stored and so on in a
manner acceptable in the pharmaceutic arts, practicing methods and
using reagents that are suitable for in vivo use, as known in the
art, see for example, Remington: The Science and Practice of
Pharmacy, latest edition.
[0070] The invention now being generally described, it will be more
readily understood by reference to the following examples which are
included merely for purposes of illustration of certain aspects and
embodiments of the present invention, and are not intended to limit
the invention.
Example 1
Dermal Filler Comprising PEG and HA
[0071] The present example demonstrates the utility of the present
invention for providing a light-activated injectable cosmetic
filler comprising a modified crosslinkable polymer together with
HA.
[0072] A range of concentrations of PEG in HA filler
(Restylane.RTM.) were examined. A blue dye was incorporated in the
PEG to better visualize the implant and the degradation thereof.
Without PEG present, the HA quickly dissolved in the buffer
solution. As more PEG was added to the filler, the shape (and
incorporated dye) was maintained longer.
[0073] A suitable obtained concentration of PEG-HA was then
translated to in vivo studies, which demonstrated that
incorporation of a crosslinked polymer with a commercially
available dermal filler extended the lifetime of that filler. The
data summarized and presented in FIG. 1 demonstrated an enhanced
retention of a dermal photofiller, that includes a combination of
HA (Restylane) and PEG, by almost 100%, compared to HA
(Restylane.RTM.) alone.
Example 2
Cosmetic Filler Comprising PEODA and HA
[0074] The present example demonstrates the utility of the present
invention for providing a cosmetic filler composition that
comprises HA and PEODA.
[0075] A number of polymer combinations were tested including
varying polymer concentrations and compositions. Those factors can
play a role in the monomer properties, such as viscosity,
crosslinking density and subsequent swelling and mechanical
properties of the hydrogel.
[0076] Macromer solutions: PEODA/HA (Restylene.RTM.) macromer
solution was prepared by mixing 200 mM triethylamine (Sigma
Aldrich),
50 pl/mL Eosin Y (Sigma Aldrich), N-vinylpyrrolidone (Sigma
Aldrich), and PEODA (SunBio, Seoul, South Korea, molecular weight:
3400 g/mol) in Restylene.RTM.. Three different concentrations of
PEODA were used: 4 and 10% PEODA and 20% 4-arm PEODA.
[0077] Then, the macromer solution was injected under the skin of a
78 year-old female cadaver and was photopolymerized by IPL exposure
(intensity per pulse, -5 J/cm.sup.2) under three different
conditions.
[0078] Subcutaneous mold: Macromer solution of approximately 100 pL
was put in a mold and placed under the skin. IPL light was shone,
and the number of IPL pulses required for polymerization of
macromer solution was counted and recorded (Table 1).
[0079] Dermal pocket: Under the skin, a constrained space with a
smooth surface was created, and macromer solution of approximately
500 pL was placed in the pocket without a mold. IPL light was
shone, and the number of IPL pulses required for polymerization of
macromer solution was counted and recorded (Table 1).
[0080] Intradermal injection: Macromer solution was injected under
the skin.
[0081] Solidification of the macromer solutions was observed after
different IPL pulses were applied. Polymerization was confirmed
following excision of the site.
[0082] The distance from which the IPL light source was held from
the skin had an effect on polymerization, and macromer solutions
were not polymerized if the IPL source was held further than
approximately 3 cm from the cadaver skin surface. Therefore, the
IPL light source was kept about 1 cm from the skin, and the amount
of energy required for photopolymerization of macromer solutions
was determined (Table 1). The results indicated that the
PEODA/Restylene.RTM. macromer solution indeed can be polymerized in
dermal and intradermal spaces using Eosin Y initiator and IPL light
source.
TABLE-US-00001 TABLE 1 Pulses Total Group Procedure (5 J/cm.sup.2
per (J/cm.sup.2) Polymerization Restylene .RTM. + Subcutaneous 12
60 + 10% PEODA Mold Dermal 10 50 + Pocket Intradermal 18 90 +
Injection Restylene .RTM. + Subcutaneous 12 60 + 4% PEODA Mold
Dermal 14 70 - Pocket 18 90 + Intradermal 30 150 + Injection
Restylene .RTM. + Subcutaneous 8 40 + 20% 4 arm Mold PEODA Dermal 6
30 + Pocket Intradermal 10 50 + Injection
[0083] All publications and patents mentioned herein are hereby
incorporated by reference in their entirety as if each individual
publication or patent was specifically and individually indicated
to be incorporated by reference.
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