U.S. patent application number 09/858333 was filed with the patent office on 2002-01-17 for methods for soft tissue augmentation.
This patent application is currently assigned to ENTERIC MEDICAL TECHNOLOGIES, INC.. Invention is credited to Greff, Richard J., Silverman, David E., Stein, Alan.
Application Number | 20020007221 09/858333 |
Document ID | / |
Family ID | 22784078 |
Filed Date | 2002-01-17 |
United States Patent
Application |
20020007221 |
Kind Code |
A1 |
Greff, Richard J. ; et
al. |
January 17, 2002 |
Methods for soft tissue augmentation
Abstract
Disclosed are methods for soft tissue augmentation in a mammal
wherein a composition comprising a biocompatible polymer having a
water equilibrium content of less than about 15% and a
biocompatible solvent is delivered to the tissue of the mammal to
be augmented.
Inventors: |
Greff, Richard J.; (St. Pete
Beach, FL) ; Silverman, David E.; (Palo Alto, CA)
; Stein, Alan; (Moss Beach, CA) |
Correspondence
Address: |
Edward N. Bachand
Flehr Hohbach Test Albritton & Herbert LLP
Suite 3400
Four Embarcadero Center
San Francisco
CA
94111-4187
US
|
Assignee: |
ENTERIC MEDICAL TECHNOLOGIES,
INC.
|
Family ID: |
22784078 |
Appl. No.: |
09/858333 |
Filed: |
May 15, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09858333 |
May 15, 2001 |
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09210736 |
Dec 15, 1998 |
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6231613 |
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Current U.S.
Class: |
623/23.58 ;
424/423; 623/23.72 |
Current CPC
Class: |
A61L 27/54 20130101;
A61L 2430/34 20130101; A61L 2300/44 20130101; A61L 27/16 20130101;
A61L 27/20 20130101; C08L 33/06 20130101; A61L 27/20 20130101; C08L
29/04 20130101; C08L 1/12 20130101; Y10S 623/902 20130101; A61L
27/16 20130101; A61L 27/16 20130101 |
Class at
Publication: |
623/23.58 ;
623/23.72; 424/423 |
International
Class: |
A61F 002/02; A61F
002/28 |
Claims
What is claimed is:
1. A method for soft tissue augmentation in a mammal, which method
comprises delivering a composition comprising a biocompatible
polymer having a water equilibrium content of less than about 15%
and a biocompatible solvent to the tissue of the mammal to be
augmented wherein said delivery is conducted under conditions such
that a polymer precipitate forms in situ in the soft tissue thereby
augmenting the tissue at the delivery site in the mammal.
2. The method according to claim 1 wherein said biocompatible
polymer is selected from the group consisting of cellulose acetate
polymers, ethylene vinyl alcohol copolymers and polyacrylates.
3. The method according to claim 2 wherein said biocompatible
polymer is a cellulose acetate polymer or an ethylene vinyl alcohol
copolymer.
4. The method according to claim 1 wherein said biocompatible
solvent is selected from the group consisting of dimethylsulfoxide,
ethanol, ethyl lactate, and acetone.
5. The method according to claim 4 wherein said biocompatible
solvent is dimethylsulfoxide.
6. The method according to claim 1 wherein the composition further
comprises a contrast agent.
7. The method according to claim 6 wherein said contrast agent is a
water insoluble contrast agent.
8. The method according to claim 7 wherein said water insoluble
contrast agent is selected from the group consisting of tantalum,
tantalum oxide, tungsten, and barium sulfate.
9. The method according to claim 6 wherein said contrast agent is a
water soluble contrast agent.
10. The method according to claim 1 wherein the delivery is
selected from the group consisting of subcutaneous delivery,
intradermal delivery and subdermal delivery.
11. The method according to claim 1 wherein said composition is
delivered into the soft tissue via a needle and syringe.
12. A method for the delivery of a composition comprising a
biocompatible polymer having a water equilibrium content of less
than about 15% and a biocompatible solvent to the soft tissue of
the mammal which tissue already has deposited therein an initial
amount of this composition which method comprises visualizing the
position of the deposited composition in the tissue delivering a
composition comprising a biocompatible polymer having a water
equilibrium content of less than about 15% and a biocompatible
solvent to the tissue of the mammal containing said deposited
composition wherein said delivery is conducted under conditions
such that additional polymer precipitate forms in situ in the
tissue thereby further augmenting the tissue at the delivery site
in the mammal.
13. The method according to claim 12 wherein the initial deposit
was made during a prior procedure.
14. The method according to claim 12 wherein visualization is
conducted by direct visualization, fluoroscopy or ultrasound.
15. The method according to claim 12 wherein the composition
further comprises a contrast agent.
16. A kit of parts comprising: a first member which is a
composition comprising a biocompatible polymer having a water
equilibrium content of less than about 15% and a biocompatible
solvent; and a second member which is a needle selected from the
group consisting of a puncture needle, a spinal needle and a needle
tipped catheter.
17. The kit of parts according to claim 16 wherein said
biocompatible polymer is selected from the group consisting of
cellulose acetates, ethylene vinyl alcohol copolymers,
polyalkyl(C.sub.1-C.sub.6) acrylates, acrylate copolymers, and
polyalkyl alkacrylates wherein the alkyl and the alk groups contain
no more than 6 carbon atoms.
18. The kit of parts according to claim 17 wherein said
biocompatible polymer is a cellulose acetate polymer or an ethylene
vinyl alcohol copolymer.
19. The kit of parts according to claim 17 wherein said
biocompatible solvent is selected from the group consisting of
ethyl lactate, dimethylsulfoxide, ethanol, and acetone.
20. The kit of parts according to claim 19 wherein said
biocompatible solvent is dimethylsulfoxide.
21. The kit of parts according to claim 16 wherein the composition
further comprises a contrast agent.
22. The kit of parts according to claim 21 wherein said contrast
agent is a water insoluble contrast agent.
23. The kit of parts according to claim 22 wherein said water
insoluble contrast agent is selected from the group consisting of
tantalum, tantalum oxide, tungsten, and barium sulfate.
24. The kit of parts according to claim 16 further comprising a
syringe.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention is directed to methods for soft tissue
augmentation in mammals generally and humans in particular. In
these methods, a composition comprising a biocompatible polymer and
a biocompatible solvent is delivered to the tissue of a mammal.
[0003] The biocompatible polymer is selected to be soluble in the
biocompatible solvent, but insoluble in the tissue. The
biocompatible solvent is miscible or soluble in the fluids of this
tissue and, upon contact with such fluids, the biocompatible
solvent quickly diffuses away whereupon the biocompatible polymer
precipitates to augment the tissue at the delivery site in the
mammal.
REFERENCES
[0004] The following publications are cited in this application as
numbers in brackets ([ ]):
[0005] 1. "Plastic Surgery: The Booming Business of Age
Retardation", Med. Data Intl., Inc., pp. 278-281 (Nov./Dec.
1997).
[0006] 2. Costantino, P. D., et al., "Soft-Tissue Augmentation and
Replacement in the Head and Neck", Otol. Clin. No. Am., 27(1):1-12
(Feb. 1994).
[0007] 3. Matton, G., et al., "The History of Injectable
Biomaterials and the Biology of Collagen", Aesth. Plast. Surg.,
9:133-140 (1985).
[0008] 4. Elson, M. L., "Dermal Filler Materials", Derma. Clin.,
11(2):361-367 (April 1993).
[0009] 5. Ford, C. N., et al., "Role of Injectable Collagen in the
Treatment of Glottic Insufficiency: A Study of 119 Patients", Ann.
Otol. Rhinol. LaryngoL, 101:237-247 (1992).
[0010] 6. Remacle, M., et al., "Further Morphologic Studies on
Collagen Injected into Canine Vocal Folds", Ann. Otol. Rhinol.
Laryngol., 100: 1007-1014 (1991).
[0011] 7. Cukier, J., et al., "Association between Bovine Collagen
Dermal Implants and a Dermatomyositis or a Polymyositis-like
Syndrome", Ann. Intern. Med., 118:920-928 (1993).
[0012] 8. Overholt, M. A., et al., "Granulomatous Reaction to
Collagen Implant: Light and Electron Microscopic Observations",
Cutis, 51:95-98 (Feb. 1993).
[0013] 9. Hanke, C. W., et al., "Abscess formation and local
necrosis after treatment with Zyderm or Zyplast Collagen Implant",
Amn. Acad. Derm., 2(1):319-326 (Aug. 1991).
[0014] 10. Piacquadio, D. J., "Epitomes--Important Advances in
Clinical Medicine", Section on Dermatology, Calif. Med. Assn.
[0015] 11. Takayama, E., et al., "Is injectable collagen truly
safe?", J. Laryngol. Oto., 106:704-708 (Aug. 1992).
[0016] 12. Mladick, R. A., "Twelve Months of Experience with
Bioplastique", Aesth. Plast. Surg., 16:69-76 (1992).
[0017] 13. Pieyre, J. -M., "Collagen Injections: Two Years'
Experience", Aesth. Plast. Surg., 9:153-154 (1985).
[0018] 14. Tolleth, H., "Long-Term Efficacy of Collagen", Aesth.
Plast. Surg., 9:155-158 (1985).
[0019] 15. Nicolle, F. V., "Correction of Age- and Disease-Related
Contour Deficiencies of the Face", Aesth. Plast. Surg., 9:159-162
(1985).
[0020] 16. Jost, G., "Experience with Collagen Injection for the
Correction of Contour Deficiencies", Aesth. Plast. Surg., 9:163-165
(1985).
[0021] 17. Ersek, R. A., et al., "Bioplastique: A New Textured
Copolymer Microparticle Promises Permanence in Soft-Tissue
Augmentation", Plast. Recon. Surg., 87(4):693-702 (April 1991).
[0022] 18. Ersek, R. A., et al., "Bioplastique.TM.: A New Biphasic
Polymer for Minimally Invasive Injection Implantation", Aesth.
Plast. Surg., 16:59-65 (1992).
[0023] 19. Ersek, R. A., "Bioplastique: Specific Technical Advice
on Its Use and Possible Complications", Aesth. Plast. Surg.,
16:67-68 (1992).
[0024] 20. Simons, G., et al., "Utilization of Injectable
Microimplants in Aesthetic Facial Surgery", Aesth. Plast. Surg.,
16:77-82 (1992).
[0025] 21. Beisang, A. A. III, et al., "Mammalian Response to
Subdermal Implantation of Textured Microimplants", Aesth. Plast.
Surg., 16:83-90 (1992).
[0026] 22. Rosen T., et al., "Use of gelatin matrix implant in
patients hypersensitive to bovine collagen", J. Amn. Acad. Dermat.,
p. 848.
[0027] 23. Planas, J., et al., "Twenty Years of Experience with
Particulate Silicone in Plastic Surgery", Aesth. Plast. Surg.,
16:53-57 (1992).
[0028] 24. Kinugasa, et al., "Direct Thrombosis of Aneurysms with
Cellulose Acetate Polymer", J. Neurosurg., 77:501-507 (1992).
[0029] 25. Kinugasa, et al., "Early Treatment of Subarachnoid
Hemorrhage After Preventing Rerupture of an Aneurysm", J.
Neurosurg., 83:34-41 (1995).
[0030] 26. Kinugasa, et al., "Prophylactic Thrombosis to Prevent
New Bleeding and to Delay Aneurysm Surgery", Neurosurg., 36:661
(1995).
[0031] 27. Greff, et al., U.S. Pat. No. 5,580,568 for "Cellulose
Diacetate Compositions for Use in Embolizing Blood Vessels", issued
Dec. 3, 1996.
[0032] 28. Greff, et al., U.S. Pat. No. 5,667,767 for "Compositions
for Use in Embolizing Blood Vessels", issued Sep. 16, 1997.
[0033] 29. Taki, et al., "Selection and Combination of Various
Endovascular Techniques in the Treatment of Giant Aneurysms", J.
Neurosurg., 77:37-42 (1992).
[0034] 30. Park, et al., "New Polymers for Therapeutic
Embolization", Poster #47, Meeting of Radiological Society of North
America (1993).
[0035] 31. Stoy, et al., U.S. Pat. No. 4,631,188, "Injectable
Physiologically-acceptable Polymeric Composition", issued Dec. 23,
1986.
[0036] 32. Dunn, et al., U.S. Pat. No. 4,938, 763, "Biodegradable
In-Situ Forming Inplants and Methods of Producing the Same", issued
Jul. 3, 1990.
[0037] The disclosure of each of the above publications is herein
incorporated by reference in its entirety to the same extent as if
each individual publication was specifically and individually
indicated to be incorporated herein by reference in its
entirety.
[0038] 2. State of the Art
[0039] Soft tissue augmentation to correct defects and counteract
the effects of aging is becoming increasingly important. Currently,
soft tissue augmentation may be achieved by the use of such means
as injectable collagen, fat injections, silicone injections,
insertion of shaped polyethylene based plugs, insertion of
hollow-shaped tubes composed of expanded polytetrafluoroethylene or
the injection of hydrogel based polymer compositions [1, 31].
[0040] The ideal material for soft tissue augmentation would have
the following properties: it must not be capable of causing a
chronic inflammatory response or foreign body reaction; it must not
be immunogenic or carcinogenic over time; its physical properties
(compressibility, stress resistance, compressive strength, etc.)
must appropriately match the local tissue environment at the
delivery site; it should be possible to contour the material to the
desired shape for augmentation; it should be non-resorbable; it
should be available in adequate quantities; it should not degrade
in the body and should be sufficiently durable that it does not
wear out or generate particles that could cause an inflammatory
response over time; it should remain in position and should not
migrate from the implantation site; it should not change in shape
or volume over time; and it should be cost effective [2].
[0041] Injectable collagen has been used extensively for soft
tissue augmentation [3-8,10-16]. It has been used for filling
wrinkles, earlobe and lip augmentation, correction of scarring,
treatment of glottic insufficiency, rehabilitating the vocal folds
and larynx, correction of atrophies, correction of contour
deficiencies, and the like.
[0042] However, when using collagen for soft tissue augmentation,
overcorrection (i.e., injection of more material than just the
amount needed to fill a defect) is needed due to rapid resorption
of the liquid carrier which represents a large percentage of the
injected volume [3, 11, 13]. Hypersensitivity, including erythema,
induration and possibly pruritis, may also be a problem [4, 10,
12-15] and an association between collagen implants and autoimmune
diseases such as dermatomyositis has been shown [7, 10].
Granulomatous reactions to collagen implants have been observed
[8], as have abscess formation and local necrosis [9, 10]. Collagen
injection to the vocal folds has resulted in chronic inflammation
of the larynx [11]. In some cases, correction of atrophy using
collagen injection has resulted in an unacceptable pustulous
appearance [16]. In addition to the above, collagen is bioabsorbed
in vivo and complete absorption usually occurs within 12 to 18
months. Such bioabsorption necessitates, of course, reinjection of
additional collagen composition. Dunn, et al. [32] discloses other
bioabsorbable polymer compositions for in vivo use which similarly
suffer from the same deficiencies.
[0043] Textured dimethylsiloxane particles suspended in a hydrogel,
such as Bioplastique.TM., have been injected for soft tissue
augmentation [12, 17-20]. The gel carrier is rapidly dispersed and
a fibrotic capsule forms around the particles to create a stable
implant [18]. However, this material is best used under, not in,
the skin and therefore is not useful to correct wrinkles [12, 19].
Also, problems may arise if the particles migrate before fibrosis
is complete [17]. Overcorrection with this material may cause cord
like subcutaneous indurations and the product remains palpable
wherever it is injected [20]. This product may also cause a foreign
body reaction in the host [21].
[0044] Other materials have been used for soft tissue augmentation.
These include gelatin matrix implants, which have been used in
patients hypersensitive to collagen [4, 22]. These materials,
however, may cause an immune response in the implanted
patients.
[0045] Autologous fat injections have also been used, but produce
only temporary results [12]. Paraffin has a long history of use in
soft tissue augmentation, but often results in unacceptable
deformaties [3]. Pastes comprising Teflon.TM. particles have also
been used, but may migrate and/or cause inflammation [5, 6].
Similarly, liquid and particulate silicones have been used in soft
tissue augmentation [3, 23].
[0046] Use of hydrogel polymer compositions such as those described
by Stoy, et al. [31] have been proposed for use in soft tissue
augmentation. Upon injection, these hydrogel compositions absorb
water from the surrounding tissue and, accordingly, can cause
osmotic shock and death to the cells in contact with the
hydrogel.
[0047] In addition to the various problems associated with many of
the substances used for soft tissue augmentation, the methods
currently employed for delivering injectable materials to the
tissue have certain disadvantages. In particular, the amount of
material necessary for augmentation must typically be estimated
based mostly on the skill and experience of the physician
particularly when resorbable materials such as collagen and
autologous fat are used. If an insufficient amount of material is
injected in the first procedure or when resorption occurs, top-up
injections administered in subsequent procedures are almost always
necessary. Such subsequent injections, often as many as three to
six, may not smoothly interface with the original injection,
resulting in unsightly surface irregularities. Accordingly, it
would be advantageous to be able to more accurately monitor the
size of the occlusion formed by the injected material to ensure
that it is sufficient to augment the tissue. Additionally, if
follow-up injections are necessary, it would be advantageous to be
able to locate accurately the site of the material previously
injected. Further, compositions comprising materials such as Telfon
and collagen have high viscosities and must be injected through
large bore needles.
[0048] In view of the above, it is evident that there is an ongoing
need in the art for new methods of soft tissue augmentation in
mammals. Preferably, such methods would allow an occlusion-forming
substance to be delivered accurately to the tissue. The substance
employed would preferably conserve its volume in vivo, be
non-migratory and be substantially non-immunogenic.
[0049] This invention is directed to the discovery that soft tissue
augmentation can be accomplished in mammals by delivering
sufficient amounts of a composition comprising a biocompatible
polymer and a biocompatible solvent to the tissue under conditions
such that a polymer precipitate forms in situ in the tissue. The
polymeric compositions of this invention are non-biodegradable and,
accordingly, do not substantially decrease in volume over time and
the polymers employed in these compositions have a water
equilibrium content of less than about 15% and, accordingly, do not
hydrate, swell or cause osmotic shock. Moreover, the injection
process provides for a coherent mass, not particulates, which mass
is non-migratory.
[0050] When a contrast agent is included in the compositions
employed in this invention, the contrast agent permits monitoring
of the injection by conventional methods while it is taking place
to ensure that it is being carried out properly and that proper
placement is obtained. The contrast agent also allows monitoring
post-injection by conventional methods to ensure correct placement
of the mass months or even years after injection. Conventional
monitoring methods include, by way of example, fluoroscopy,
ultrasound, and in some cases visual detection.
SUMMARY OF THE INVENTION
[0051] This invention is directed to the discovery that unexpected
and surprising results are achieved when soft tissue augmentation
in mammals is performed using a composition comprising a
biocompatible polymer having a water equilibrium content of less
than about 15% and a biocompatible solvent. In particular,
deficiencies associated with the prior art procedures are reduced
by the invention. Such deficiencies include, for example, problems
associated with migration of particulates over time, the
biodegradation of the injected mass (e.g., collagen type materials)
employed to augment the tissue of the mammal, development of an
immune response or hypersensitivity to the material used for
augmentation, osmotic shock associated with hydration of the
hydrogel polymer, problems associated with the accurate delivery of
such substances, and problems associated with post-delivery
monitoring of the deposited materials.
[0052] Accordingly, in one of its method aspects, this invention is
directed to a method for soft tissue augmentation in a mammal,
which method comprises delivering a composition comprising a
biocompatible polymer having a water equilibrium content of less
than about 15% and a biocompatible solvent to the tissue of the
mammal to be augmented, wherein said delivery is conducted under
conditions such that a polymer precipitate forms in situ in the
tissue at the delivery site in the mammal. The composition may
comprise a contrast agent.
[0053] In another aspect, the invention provides a method for the
delivery of a composition comprising a biocompatible polymer having
a water equilibrium content of less than about 15% and a
biocompatible solvent to the soft tissue of the mammal which tissue
already has deposited therein an initial amount of this composition
which method comprises visualizing the position of the deposited
composition in the tissue; delivering a composition comprising a
biocompatible polymer and a biocompatible solvent to the tissue of
the mammal containing said deposited composition, wherein said
delivery is conducted under conditions such that additional polymer
precipitate forms in situ in the tissue thereby further augmenting
the tissue at the delivery site in the mammal.
[0054] The methods of this invention are preferably practiced using
a kit of parts comprising a first member which is a polymeric
composition comprising a biocompatible polymer having a water
equilibrium content of less than about 15% and a biocompatible
solvent; and a second member which is a needle selected from the
group consisting of a puncture needle, a spinal needle and a needle
tipped catheter.
[0055] In the compositions employed herein, the biocompatible
polymer having a water equilibrium content of less than about 15%
is preferably an ethylene vinyl alcohol copolymer or a cellulose
acetate polymer. In a particularly preferred embodiment, the
biocompatible polymer is selected to be substantially
non-immunogenic. The biocompatible solvent is preferably ethyl
lactate or dimethylsulfoxide (DMSO).
DETAILED DESCRIPTION OF THE INVENTION
[0056] This invention is directed to methods for soft tissue
augmentation in mammals, which methods comprise delivering a
composition comprising a biocompatible polymer having a water
equilibrium content of less than about 15% and a biocompatible
solvent to the tissue of the mammal to be augmented.
[0057] Prior to discussing this invention in further detail, the
following terms will first be defined:
[0058] The term "soft tissue augmentation" includes, but is not
limited to, the following: dermal tissue augmentation; filling of
lines, folds, wrinkles, minor facial depressions, cleft lips and
the like, especially in the face and neck; correction of minor
deformaties due to aging or disease, including in the hands and
feet, fingers and toes; augmentation of the vocal cords or glottis
to rehabilitate speech; dermal filling of sleep lines and
expression lines; replacement of dermal and subcutaneous tissue
lost due to aging; lip augmentation; filling of crow's feet and the
orbital groove around the eye; breast augmentation; chin
augmentation; augmentation of the cheek and/or nose; filling of
indentations in the soft tissue, dermal or subcutaneous, due to,
e.g., overzealous liposuction or other trauma; filling of acne or
traumatic scars and rhytids; filling of nasolabial lines,
nasoglabellar lines and infraoral lines.
[0059] The term "biocompatible polymer" refers to polymers which
have a water equilibrium content of less than about 15% and which,
in the amounts employed, are non-toxic, non-peptidyl, chemically
inert, and substantially non-immunogenic when used internally in
the mammal and which are substantially insoluble in the tissue. The
biocompatible polymers do not substantially decrease in volume over
time and, since the polymer forms a solid inert mass, it does not
migrate to distant organs within the body. Suitable biocompatible
polymers include, by way of example, cellulose acetates [24-26]
(including cellulose diacetate [27]), ethylene vinyl alcohol
copolymers [28, 29], polyalkyl(C.sub.1-C.sub.6) acrylates, acrylate
copolymers, polyalkyl alkacrylates wherein the alkyl and the alk
groups contain no more than 6 carbon atoms, and the like.
Additional biocompatible polymers are disclosed in U.S. patent
application Ser. No. 08/655,822 entitled "Novel Compositions for
Use in Embolizing Blood Vessels" and U.S. patent application Ser.
No. 09/109,041 entitled "Vascular Embolizing Compositions
Comprising Ethyl Lactate and Methods for Their Use" which
applications are incorporated herein by reference in their
entirety. Further examples of biocompatible polymers are provided
by Park, et al. [30]. Preferably, the biocompatible polymer is also
non-inflammatory when employed in vivo.
[0060] The particular biocompatible polymer employed is not
critical and is selected relative to the viscosity of the resulting
polymer solution, the solubility of the biocompatible polymer in
the biocompatible solvent, and the like. Such factors are well
within the skill of the artisan.
[0061] As noted above, the biocompatible polymers do not
appreciably absorb water upon contact with the fluid of the tissue
and typically will have an equilibrium water content of less than
about 15% water and preferably less than about 10% water.
[0062] Particularly preferred biocompatible polymers include
cellulose diacetate and ethylene vinyl alcohol copolymer. Cellulose
diacetate polymers are either commercially available or can be
prepared by art-recognized procedures. In a preferred embodiment,
the number average molecular weight, as determined by gel
permeation chromatography, of the cellulose diacetate composition
is from about 25,000 to about 100,000; more preferably from about
50,000 to about 75,000; and still more preferably from about 58,000
to 64,000. The weight average molecular weight of the cellulose
diacetate composition, as determined by gel permeation
chromatography, is preferably from about 50,000 to 200,000 and more
preferably from about 100,000 to about 180,000. Preferably, the
cellulose diacetate is selected such that a solution of 6% w/v
(weight/volume) in ethyl lactate or DMSO has a viscosity of 80 or
less centipoise at 20.degree. C. As is apparent to one skilled in
the art, with all other factors being equal, cellulose diacetate
polymers having a lower molecular weight will impart a lower
viscosity to the composition as compared to higher molecular weight
polymers. Accordingly, adjustment of the viscosity of the
composition can be readily achieved by mere adjustment of the
molecular weight of the polymer composition.
[0063] Ethylene vinyl alcohol copolymers comprise residues of both
ethylene and vinyl alcohol monomers. Small amounts (e.g., less than
5 mole percent) of additional monomers can be included in the
polymer structure or grafted thereon provided such additional
monomers do not significantly alter the physical or solidifying
properties of the composition. Such additional monomers include, by
way of example only, maleic anhydride, styrene, propylene, acrylic
acid, vinyl acetate, and the like. Ethylene vinyl alcohol
copolymers are either commercially available or can be prepared by
artrecognized procedures. Preferably, the ethylene vinyl alcohol
copolymer composition is selected such that a solution of 8% w/v of
the ethylene vinyl alcohol copolymer in DMSO has a viscosity equal
to or less than 60 centipoise at 20.degree. C. As is apparent to
one skilled in the art, with all other factors being equal,
copolymers having a lower molecular weight will impart a lower
viscosity to the composition as compared to higher molecular weight
copolymers. Accordingly, adjustment of the viscosity of the
composition as necessary for catheter or needle delivery can be
readily achieved by mere adjustment of the molecular weight of the
copolymer composition.
[0064] As is also apparent, the ratio of ethylene to vinyl alcohol
in the copolymer affects the overall hydrophobicity/hydrophilicity
of the composition which, in turn, affects the relative solubility
of the composition in the biocompatible solvent as well as the rate
of precipitation of the copolymer in an aqueous solution (e.g.,
body fluids). In a particularly preferred embodiment, the
copolymers employed herein comprise a mole percent of ethylene of
from about 25 to about 60 and a mole percent of vinyl alcohol of
from about 40 to about 75. More preferably, these copolymers
comprise from about 40 to about 60 mole percent of vinyl alcohol
and from about 60 to 40 mole percent of ethylene. These
compositions provide for requisite precipitation rates suitable for
soft tissue augmentation in mammals.
[0065] The term "contrast agent" refers to a biocompatible
(non-toxic) radiopaque material capable of being monitored during
injection into a mammalian subject by, for example, radiography or
fluoroscopy. The contrast agent can be either water soluble or
water insoluble. Examples of water soluble contrast agents include
metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and
meglumine.
[0066] The term "water insoluble contrast agent" refers to a water
insoluble (i.e., has a water solubility of less than 0.01 mg/mL at
20.degree. C.), radiopaque material capable of being monitored
during injection into a mammalian subject by, for example,
radiography. Examples of water insoluble contrast agents include
tantalum, tantalum oxide, tungsten, and barium sulfate, which are
commercially available in the proper form for in vivo use. Other
water insoluble contrast agents include gold, tungsten and
platinum.
[0067] The term "biocompatible solvent" refers to an organic
material liquid at least at body temperature of the mammal in which
the biocompatible polymer is soluble and, in the amounts used, is
substantially non-toxic. Suitable biocompatible solvents include,
by way of example, ethyl lactate, analogues/homologues/isomers of
ethyl lactate, dimethylsulfoxide, analogues/homologues of
dimethylsulfoxide, ethanol, acetone, and the like. Aqueous mixtures
with the biocompatible solvent can also be employed provided that
the amount of water employed is sufficiently small that the
dissolved polymer precipitates upon contact with tissue fluids.
Preferably, the biocompatible solvent is ethyl lactate or
dimethylsulfoxide.
[0068] Compositions
[0069] The polymer compositions employed in the methods of this
invention are prepared by conventional methods whereby each of the
components is added and the resulting composition mixed together
until the overall composition is substantially homogeneous.
[0070] For example, polymer compositions can be prepared by adding
sufficient amounts of the biocompatible polymer to the
biocompatible solvent to achieve the effective concentration for
the polymer composition. Preferably, the polymer composition will
comprise from about 2.5 to about 8.0 weight percent of the
biocompatible polymer based on the total weight of the polymer
composition and more preferably from about 4 to about 7.0 weight
percent. If necessary, gentle heating and stirring can be used to
effect dissolution of the biocompatible polymer into the
biocompatible solvent, e.g., 12 hours at 50.degree. C.
[0071] When a contrast agent is used, sufficient amounts of the
contrast agent are then added to the solution to achieve the
effective concentration for the complete polymer composition.
Preferably, the polymer composition will comprise from about 10 to
about 40 weight percent of the contrast agent and more preferably
from about 20 to about 40 weight percent and even more preferably
about 30 weight percent each based on the total weight of the
polymer composition including the biocompatible polymer and the
biocompatible solvent. When the contrast agent is not soluble in
the biocompatible solvent, stirring is employed to effect
homogeneity of the resulting suspension. In order to enhance
formation of the suspension, the particle size of the contrast
agent is preferably maintained at about 10 .mu.m or less and more
preferably at from about 1 to about 5 .mu.m (e.g., an average size
of about 2 .mu.m).
[0072] The particular order of addition of components to the
biocompatible solvent is not critical and stirring of the resulting
composition is conducted as necessary to achieve homogeneity of the
composition. Preferably, mixing/stirring of the composition is
conducted under an anhydrous atmosphere (e.g., dry nitrogen or
argon) at ambient pressure. The resulting composition may be heat
sterilized and then stored preferably in sealed bottles (e.g.,
amber vials) until needed. Alternatively, if the composition is a
true solution (i.e., not a suspension), sterilization of the
composition can be achieved by aspectic filling procedures
typically employing a small pore biofilter.
[0073] Each of the polymers recited herein is commercially
available but can also be prepared by methods well known in the
art. For example, polymers are typically prepared by conventional
techniques such as radical, thermal, UV, .gamma. irradiation, or
electron beam induced polymerization employing, as necessary, a
polymerization catalyst or polymerization initiator to provide for
the polymer composition. The specific manner of polymerization is
not critical and the polymerization techniques employed do not form
a part of this invention.
[0074] In order to maintain solubility in the biocompatible
solvent, the polymers described herein are preferably not
cross-linked.
[0075] Methods
[0076] The compositions described above are then employed in
methods for soft tissue augmentation in mammals. In these methods,
the composition is introduced to the tissue via conventional needle
tip catheter or needle technology using, for example, techniques
similar to those used to introduce collagen based soft tissue
augmentation materials. Specifically, the injection may be
performed through a puncture needle or spinal needle placed
directly in the dermis or other tissue to be augmented.
Alternatively, in certain situations, the tissue can be exposed
surgically and the composition injected directly into the
tissue.
[0077] Upon discharge of the composition from the catheter or the
needle into the tissue, the biocompatible solvent dissipates into
the fluid of the tissue resulting in the precipitation of the
biocompatible polymer which precipitate forms a coherent mass. The
formed precipitate in the tissue augments the tissue at the
delivery site.
[0078] The particular amount of polymer composition employed is
dictated by various factors such as the size of the correction to
be made, the volume to be injected, the rate of precipitation
(solids formation) of the polymer, etc. Such factors are well
within the skill of the artisan.
[0079] The methods of this invention are particularly advantageous,
when a contrast agent is used in the composition, it permits
monitoring of the delivery of the biocompatible polymer while
deposition is taking place either by fluoroscopy, ultrasound, or
visually. In this way, one can ensure that the biocompatible
polymer is being delivered to the optimal location in the tissue as
well as determine whether the size of the polymer precipitate
thus-formed will be sufficient to augment the tissue.
[0080] Moreover, the treatment process can be modified by altering
the rate of precipitation of the polymer which can be controlled
merely by changing the overall hydrophobicity/hydrophilicity of the
polymer. As is understood in the art, faster precipitation rates
are achieved by a more hydrophobic polymer composition.
[0081] When delivery of the polymeric composition to the tissue is
conducted with a small diameter medical catheter (e.g.-, via a
cytoscope), the catheter employed is not critical provided that
polymeric catheter components are compatible with the polymeric
composition (i.e., the catheter components will not readily degrade
or leach in the polymer composition and none of the components of
the polymer compositions will readily degrade in the presence of
the catheter components). In this regard, it is preferred to use
polyethylene in the catheter components because of its inertness in
the presence of the polymeric composition described herein. Other
materials compatible with the composition can be readily determined
by the skilled artisan and include, for example, other polyolefins,
fluoropolymers (e.g., polytetrafluoroethylene, perfluoroalkoxy
resin, fluorinated ethylene propylene polymers), silicone, etc.
[0082] When introduced into the tissue, the biocompatible solvent
rapidly diffuses into the fluids of this tissue leaving a solid
precipitate. The precipitate is a coherent mass of the
biocompatible polymer. Without being limited to any theory, it is
believed that this precipitate augments the soft tissue.
[0083] Another advantage of this invention is that the precipitate
forms a coherent mass which is substantially retained at the site
of injection thereby obviating prior art concerns with migration of
injected particulates. Moreover, the polymeric compositions of this
invention are non-biodegradable and, accordingly, do not
substantially decrease in volume over time.
[0084] Still another advantage of this invention is that the
polymer employed can be selected to be non-immunogenic thereby
obviating concerns raised by use of collagen-type materials which
can produce ar immune response in vivo.
[0085] Yet another advantage of this invention, in particular when
a water insoluble contrast agent is used, is the formation of a
polymeric mass in the tissue which may be monitored by the
physician over time to assure proper retention of the mass in the
tissue. Additionally, if a subsequent injection is necessary to
further augment the soft tissue in the mammal, placement of the
additional polymeric material is facilitated when the material
previously implanted can be visualized by, for example,
fluoroscopy, ultrasound, and the like. A subsequent injection can
occur at any time after the initial injection including, for
example, months or years later.
[0086] In view of the above, the methods of this invention are
preferably practiced using a kit of parts which kit contains a
first member which is a polymeric composition comprising a
biocompatible polymer having a water equilibrium content of less
than about 15% and a biocompatible solvent, and a second member
which is a needle selected from the group consisting of a puncture
needle, a spinal needle and a needle tipped catheter.
[0087] Utility
[0088] The methods described herein are useful in treating mammals
requiring soft tissue augmentation. Accordingly, these methods find
use in human and other mammalian subjects requiring such treatment.
Soft tissue augmentation includes subcutaneous delivery,
intradermal delivery and subdermal delivery of the compositions
described herein. In addition, delivery of the compositions to
sphincter sites in vivo is contemplated including delivery to the
esophageal sphincter, the anal sphincter, and the like. Sphincter
delivery bulks the sphincter in a manner which permits coappation
thereby retaining its sphincter function.
[0089] The following examples are set forth to illustrate the
claimed invention and are not to be construed as a limitation
thereof.
EXAMPLES
[0090] Unless otherwise stated, all temperatures are in degrees
Celsius. Also, in these examples and elsewhere, the following
abbreviations have the following meanings:
[0091] cc=cubic centimeter
[0092] cm=centimeter
[0093] DMSO=dimethylsulfoxide
[0094] EVOH=ethylene vinyl alcohol copolymer
[0095] g=gram
[0096] GPC=gel permeation chromatography
[0097] HEPA=high efficiency particulate air
[0098] min.=minute
[0099] mL=milliliter
[0100] mm=millimeter
[0101] M.sub.w=weight average molecular weight
[0102] .mu.m=micron
[0103] w/v=weight to volume
[0104] In the following examples, Examples 1-2 illustrate the
preparation of polymer compositions useful in the methods described
herein which polymer compositions comprise EVOH and cellulose
acetate. Example 3 demonstrates the biocompatibility, non-migratory
and bulking properties of an EVOH polymer in vivo.
Example 1
[0105] An EVOH polymer composition was prepared by combining 8
grams of EVOH (44 mole percent ethylene) (M.sub.w 108,000 GPC), 30
grams of tantalum having an average particle size of about 3 .mu.m
(narrow size distribution), and 100 mL of anhydrous DMSO. Heating
at about 50.degree. C. for about 12 hours was used to aid
dissolution. The composition was mixed until homogeneous.
[0106] Tantalum having an average particle size of about 3 .mu.m
(narrow size distribution) was prepared by fractionation wherein
tantalum, having an average particle size of less than about 20
.mu.m, was added to ethanol (absolute) in a clean environment.
Agitation of the resulting suspension was followed by settling for
approximately 40 seconds to permit the larger particles to settle
faster. Removal of the upper portion of the ethanol followed by
separation of the liquid from the particles results in a reduction
of the particle size which is confirmed under a microscope (Nikon
Alphaphot.TM.). The process was repeated, as necessary, until an
average 3 .mu.m particle size was reached.
Example 2
[0107] A composition comprising 7% (w/v) of cellulose diacetate in
ethyl lactate with 30% (w/v) tantalum powder was prepared in a HEPA
clean hood in a 20 cc screw cap bottle with Teflon cap liner as
follows: 1.05 g of cellulose diacetate (U.S.P. grade--39% acetyl
content) was added to 15 mL of ethyl lactate (Aldrich E3410-2),
using a pipet for transfer. The bottle was briefly flushed with
filtered, dry, prepurified nitrogen and capped. Exposure of ethyl
lactate to air was minimized. The composition was shaken gently to
dissolve. Then, 4.5 g of tantalum micronized powder (average
particle size was 2 microns) was added to the bottle, which was
flushed with nitrogen, capped and shaken gently for 1 min. Then,
2.5 cc aliquots were transferred into six 3.0 cc vials, flushed
with nitrogen, capped and sterilized at 125.degree. C. for 60
minutes.
Example 3
[0108] The purpose of this example is to demonstrate the
biocompatibility of an EVOH polymer composition with the soft
tissue of a mammal and to illustrate the non-migratory properties
of such a polymer composition.
[0109] A 125 pound female sheep was anesthetized with an
intramuscular injection of Ketamine and maintained on a respirator
with oxygen (O.sub.2)/halothane. The right inner thigh of the sheep
was shaved and prepped with a Betadine scrub. A composition
comprising ethylene vinyl alcohol prepared as in Example 1 above
was shaken to disperse the tantalum contrast agent. Afterwards,
about 0.8 cc of the composition was withdrawn into a 1 cc syringe
fitted with a 26 gage needle. The shaved skin of the thigh was
punctured with the needle and about 0.25 cc of the composition was
injected intradermally. A visible bleb or dome (12 mm in
width.times.2 mm in height) formed at the injection site. About 3
cm beneath this site another 0.25 cc of the composition was
injected subdermally, with similar results.
[0110] The animal was then awakened from the anesthesia with no ill
effects. The two raised skin sites from the injections were
unchanged after 4 hours. The animal was examined at 48 hours
post-injection. There was some reddening observed around the two
injection sites, which resolved within one week. The animal was
sacrificed four (4) weeks later and the tissue adjacent the
injection sites wa examined which examination revealed no
inflammation (i.e., reddening or swelling of the tissue) nor
migration of the solid mass from the site of the injection.
[0111] From the foregoing description, various modifications and
changes in the composition and method will occur to those skilled
in the art. All such modifications coming within the scope of the
appended claims are intended to be included therein.
* * * * *