WO1997005832A1 - Rheologically modified and osmotically balanced fill material for implant - Google Patents

Rheologically modified and osmotically balanced fill material for implant Download PDF

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Publication number
WO1997005832A1
WO1997005832A1 PCT/US1996/012861 US9612861W WO9705832A1 WO 1997005832 A1 WO1997005832 A1 WO 1997005832A1 US 9612861 W US9612861 W US 9612861W WO 9705832 A1 WO9705832 A1 WO 9705832A1
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WO
WIPO (PCT)
Prior art keywords
fill material
poly
implant
gum
implant fill
Prior art date
Application number
PCT/US1996/012861
Other languages
French (fr)
Inventor
Thomas G. Hayes
Kenneth C. Kredovski
Robert M. Hume, Iii
Original Assignee
Novamed Medical Products Manufacturing, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novamed Medical Products Manufacturing, Inc. filed Critical Novamed Medical Products Manufacturing, Inc.
Priority to EP96926926A priority Critical patent/EP0850029A4/en
Publication of WO1997005832A1 publication Critical patent/WO1997005832A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/12—Mammary prostheses and implants

Definitions

  • the present invention relates generally to implants introduced into the body, particularly to fill material for such implants, and specifically to rheologically modified fill material for implants.
  • silicone has been the fill material of choice.
  • silicone as a fill material has fallen into disfavor. This has prompted efforts to find replacements for silicone. These replacements are often if not always undesirable because such replacements have been unable to match the feel provided by silicone.
  • the inventors of the present invention have investigated the rheoiogical parameters of certain fluid formulations in an effort to provide a fill material having the heretofore unmatched feel of ⁇ ilicone. Thu ⁇ , it is important to understand some basics of rheology to have an understanding of the present invention.
  • Rheology is the science of the deformation and flow of matter. It is concerned with the response of materials to mechanical force. Polymer rheology deals with polymeric materials and biorheology deals with biological fluids.
  • Deformation is the relative di ⁇ placement of points of a body and can be divided into two general types: flow and elasticity. Flow i ⁇ irrever ⁇ ible deformation; when the stress is removed, the material does not revert to its original configuration. Elasticity is reversible deformation; the deformed body recovers its original shape.
  • the usual way of defining the rheoiogical properties of a material is to determine the resistance to deformation. Resistance to deformation is measured by two indexes or yardsticks: 1) viscosity (the index or yardstick for flow; viscosity is the resistance to flow of a liquid) ; and 2) the degree of elasticity (elastic deformation) .
  • a liquid is a material that continues to deform as long as it i ⁇ subjected to a tensile or shear stress. For a liquid under shear, the rate of deformation (shear rate) is proportional to the ⁇ hearing ⁇ tress.
  • Thixotropy is the decrease in visco ⁇ ity with time when ⁇ heared at a con ⁇ tant shear rate.
  • Rheopexy a relatively rare occurrence, is the increase in visco ⁇ ity of a fluid in re ⁇ pon ⁇ e to shear.
  • thixotropy when a shearing action begin ⁇ , such as when one applies a latex house paint with a brush, the viscosity decreases quickly to permit the paint to be easily brushed to a thin film and provide a ⁇ hort period of time for the bru ⁇ hmarks to level.
  • the viscosity of the latex hou ⁇ e paint increa ⁇ e ⁇ to prevent running and ⁇ agging.
  • Thixotropy may be a time dependent effect.
  • a ⁇ ingle fluid may be ⁇ ubject to a number of shear rates.
  • a paint may be pumped during manufacture or immediately prior to application (intermediate shear rate) , sprayed onto a wall (high ⁇ hear rate) , coalesce and flow to form a uniform film (intermediate to low shear rate) , and ⁇ ag or run under gravity (low ⁇ hear rate) .
  • a given liquid or material may work well at one or two of the ⁇ hear rate ⁇ , but fail at other ⁇ hear rate ⁇ .
  • General objects of the present invention include a unique rheologically modified dispersion for an implant for a body and unique methods for filling the implant.
  • Another object of the pre ⁇ ent invention i ⁇ .to provide such a rheologically modified dispersion which uniquely includes an osmotic control agent.
  • Another object of the present invention is to provide such a rheologically modified dispersion wherein the osmotic control agent uniquely includes a poly-N- vinylamide.
  • Another object of the pre ⁇ ent invention is to provide such a rheologically modified dispersion wherein the poly-N-vinylamide uniquely includes polyvinylpyrrolidinone.
  • Another object of the present invention is to provide such an osmotically controlled and rheologically modified disper ⁇ ion wherein the rheoiogical agent uniquely include ⁇ a three-dimen ⁇ ional network.
  • Another object of the present invention i ⁇ to provide such an osmotically controlled and rheologically modified di ⁇ per ⁇ ion wherein the three-dimen ⁇ ional rheoiogical agent uniquely include ⁇ gum.
  • Another object of the pre ⁇ ent invention i ⁇ to provide such an osmotically controlled and rheologically modified dispersion wherein the gum uniquely includes a natural gum.
  • Another object of the present invention i ⁇ to provide ⁇ uch an o ⁇ motically controlled and rheologically modified dispersion wherein the natural gum uniquely includes guar gum or locust bean gum and their derivative ⁇ .
  • Another object of the present invention is to provide such an osmotically controlled and rheologically modified dispersion wherein the gum uniquely includes xanthan and its derivatives.
  • Another object of the present invention is .to provide such an o ⁇ motically controlled and rheologically modified dispersion wherein the gum uniquely includes a synthetic gum.
  • Another object of the present invention i ⁇ to provide ⁇ uch an osmotically controlled and rheologically modified disper ⁇ ion wherein the synthetic gum uniquely includes poly(vinyl alcohol) , polyethylene oxide, polypropylene oxide, polyacrylamide, or copolymers of polyvinylpyrrolidinone.
  • Another object of the present invention is to provide such an osmotically controlled and rheologically modified dispersion which uniquely is a pseudopla ⁇ tic.
  • a pseudoplastic di ⁇ per ⁇ ion mimic ⁇ the rheology of body fluid and ti ⁇ ue.
  • Another object of the present invention is to provide such an osmotically controlled and rheologically modified dispersion in which uniquely all of the components of the dispersion are biocompatible. Accordingly, even in the worst case ⁇ cenario in which the implant bursts, little or minimal danger is presented.
  • An advantage of the pre ⁇ ent invention is that the fill material of an implant is osmotically balanced with its environment. With an osmotic balance, the implant retains its desired volume. Such is in contrast to an implant which include ⁇ a low o ⁇ motic pre ⁇ ure; here, water or another ⁇ olvent flow ⁇ out of the implant, perhap ⁇ cau ⁇ ing fold flaw fracture. A high o ⁇ motic pre ⁇ ure in the implant may lead to a bur ⁇ ting of the implant.
  • Another advantage of the present invention is that the fill material i ⁇ rheologically modified to be pseudoplastic. This provides a feel or responsive fill material which mimics body tis ⁇ ue.
  • Fig. 1 shows a perspective, partially exploded view of a breast implant.
  • Fig. 2 shows a section view of an implant with a dispersion containing a drug to be released over time. All Figures are drawn for ease of explanation of the basic teachings of the present invention only; the extension ⁇ of the Figures with respect to number, po ⁇ ition, relation ⁇ hip, and dimen ⁇ ion ⁇ of the parts to form the preferred embodiment will be explained or will be within the skill of the art after the following description has been read and understood. Further, the exact dimensions and dimensional proportion ⁇ to conform to ⁇ pecific force, weight, ⁇ trength, and ⁇ imilar requirement ⁇ will likewi ⁇ e be within the ⁇ kill of the art after the following de ⁇ cription ha ⁇ been read and under ⁇ tood.
  • the pre ⁇ ent invention relate ⁇ to a ⁇ afe fill material for an implant.
  • the fill material preferably include ⁇ water, an o ⁇ motic control agent such as a poly-N-vinylamide or polyvinylimide, a rheoiogical agent such as a gum.
  • the fill material may include cross-linkers for the rheoiogical agent (i.e. the thixotrope or gellant) and/or other additives such as antioxidants, preservatives such as antimicrobials, wetting agent ⁇ , and lubricant ⁇ .
  • the fill material i ⁇ biocompatible.
  • O ⁇ motic control agent for the purpo ⁇ e ⁇ of the pre ⁇ ent invention, mean ⁇ that which i ⁇ added to the fill material to prevent or minimize o ⁇ mo ⁇ i ⁇ , i.e. flow of ⁇ olvent (water) through the membrane of the implant. O ⁇ mosis i ⁇ minimized by providing interior of the implant with an osmotic pres ⁇ ure which is equal to the osmotic pressure of the environment outside of the implant. Accordingly, osmotic control agent further means that which provide ⁇ an osmotic pressure similar to the body or body tissue or fluid or to the portion of the body into which the implant is to be located.
  • the most preferred osmotic pres ⁇ ure provided by the o ⁇ motic control agent, when combined with the rheoiogical agent of the pre ⁇ ent invention, is between about 250 and about 350 milliosmoles.
  • the osmotic control agent i ⁇ a polymer or polymers or copolymer or copolymers that contributes substantially to the desired osmotic pres ⁇ ure of between about 250 and 350 milliosmoles.
  • the polymeric osmotic control agent is added to the fill material in an amount preferably between about 90% to 99.9% w/w, more preferably between about 95% to 99.9% w/w, and most preferably between about 98% to 99% w/w of the osmotic control agents.
  • salts may be added to fine tune the osmotic pre ⁇ sure of the implant.
  • These salt ⁇ preferably include biocompatible salts such as sodium chloride, sodium lactate and sodium acetate in an amount of between about 1% and 10% w/w of the osmotic control agents.
  • biocompatible salts such as sodium chloride, sodium lactate and sodium acetate in an amount of between about 1% and 10% w/w of the osmotic control agents.
  • ⁇ odium lactate and ⁇ odium acetate are preferred. It ⁇ hould be noted that osmotic pressure is a colligative property that depends on the number of solute particles.
  • osmotic control agents which are preferred provide lubricity to the interior wall of the implant.
  • the osmotic control agent 1) is a polymer or copolymer or blend thereof; 2) is present in an amount effective to provide an osmotic pre ⁇ ure to the implant of between about 250 and 350 millio ⁇ moles without the use of salt ⁇ ; and 3) i ⁇ pre ⁇ ent in an amount effective to provide lubricity to the fill material (i.e. to the interior wall of the implant) .
  • the o ⁇ motic control agent i ⁇ preferably a protective colloid which i ⁇ water- ⁇ oluble or water-di ⁇ persable. ⁇
  • Example ⁇ of preferred colloids include poly-N- vinylamides, poly-N-vinylamide copolymers, polyvinylimides. Poly-N-vinylamide hydrogel ⁇ are most preferred.
  • the poly-N-vinylamides may be either linear or cyclic.
  • Example ⁇ of poly-N-vinylamide ⁇ prepared from linear derivatives include poly(acetamide) , poly(methylacetamide) , poly(ethylacetamide) , poly(phenylacetamide) , poly(methylpropionamide) , poly(ethylpropionamide) , poly(methylisobutyramide) , and poly(methylbenzylamide) .
  • Poly-N-vinylamides derived from cyclic structures are more preferred.
  • polymers examples include polyvinylpyrrolidinone, polyvinylcaprolactam, poly-2-piperidinone, poly-5-methyl- 2-pyrrolidinone, poly-2,2,5-trimethyl-2-pyrrolidinone, and poly-5-methyl-2-pyrrolidinone.
  • Polyvinylpyrrolidinone and polyvinylcaprolactam are even more preferred with polyvinylpyrrolidinone being most preferred.
  • Polyvinylpyrrolidinone (PVP or povidone or poly(N- vinyl-2-pyrrolidinone) ) is one of the few poly-N- vinylamide ⁇ prepared from cyclic ⁇ tructure ⁇ , if not the only one, available in a commercial quantity.
  • Polyvinylcaprolactam has been commercialized to some extent.
  • Poly-N-vinylamide copolymers include poly(vinylpyrrolidinone-co-vinyl acetate) , poly(vinylpyrrolidinone-co-maleic anhydride) , poly(vinylpyrrolidinone-co-methyl methacrylate) , poly(vinylpyrrolidinone-co-dimethylaminoethyl methacrylate) , poly(vinylpyrrolidinone-co-butyl methacrylate) , poly(vinylpyrrolidinone-co-hydroxyethyl methacrylate) , poly(vinylpyrrolidinone-co-ethyl acrylate) , poly(vinylpyrrolidinone-co-ethylhexyl acrylate), poly(vinylpyrrolidinone-co-acrylic acid), poly(vinylpyrrolidinone-co-acrylamide) , poly(vinylpyrrolidinone-co-acrylonit
  • the molecular weight of the osmotic control agent is in the range of preferably about 1000 to about 100,000, more preferably about 1000 to about 40,000, and even more preferably about 3000 to about 20,000, and most preferably about 10,000.
  • Poly-N-vinylamides, such as PVP at molecular weights higher than about 100,000 may not be excretible from the human body.
  • Poly-N- vinylamides, ⁇ uch as PVP, at weights below about 100,000 may be bioexcretable, with tho ⁇ e having molecular weight ⁇ below 30,000 being more likely to be quickly excretable, ⁇ uch as through the human kidney.
  • the molecular weights noted herein are in daltons.
  • a higher molecular weight of the poly-N-vinylamide, such as PVP, generally relates to a higher degree of polymerization and a greater intrinsic visco ⁇ ity.
  • the vi ⁇ co ⁇ ity of the poly-N-vinylamide ( ⁇ uch a ⁇ PVP) in water generally increases with the solid concentration.
  • the osmotic control agent i ⁇ pre ⁇ ent in the range of preferably from about 0.5% to about 60%, more preferably from about 2.5% to about 40%, and most preferably from about 3.5% to about 20% (w/w) .
  • Such a range of concentration when combined with one or more of the rheoiogical agents of the present invention, provide ⁇ an osmolarity of preferably between about 100 milliosmoles and about 500 milliosmole ⁇ , more preferably between about 200 millio ⁇ mole ⁇ and about 400 illio ⁇ mole ⁇ , and mo ⁇ t preferably between about 250 and about 350 millio ⁇ mole ⁇ . It should be noted that such an osmolarity is preferably obtained without the use of salt ⁇ . It should further be noted that PVP, when alone in solution without a three dimensional network, doe ⁇ not provide the de ⁇ ired p ⁇ eudopla ⁇ ticity to the ⁇ olution.
  • Rheoiogical agent mean ⁇ a material which modifie ⁇ the normal ⁇ olution propertie ⁇ to increa ⁇ e or decrea ⁇ e its resistance to flow and to increase or decrea ⁇ e it ⁇ elasticity.
  • Rheoiogical agent further means that which provide ⁇ a p ⁇ eudopla ⁇ ticity to the fill material to the implant.
  • the fill material of the pre ⁇ ent invention a ⁇ a whole is pseudoplastic. In other words, when shear ⁇ tress is applied to the fill material, the viscosity of the fill material is reduced in proportion to the amount of shear. Upon release of the shear, total visco ⁇ ity recovery of the fill material occurs almost instantaneously.
  • the fill material of the present invention is pseudoplastic is advantageous. This feature of decreased apparent viscosity at high shear rates facilitates mixing, pumping, and pouring. Further, when in the body, such pseudopla ⁇ ticity mimics body tissue and fluid, such as the breast body tissue and fluid. For example, the undesired bounce of conventional saline implants is minimized.
  • the rheoiogical agent includes pseudopla ⁇ tic agent ⁇ or thixotropic agent ⁇ . Pseudoplastic agents are preferred.
  • the rheoiogical agent is preferably a polymer which provides a three-dimen ⁇ ional network within the implant.
  • Thi ⁇ three-dimen ⁇ ional network provide ⁇ a backbone for the polymeric osmotic control agent, which may contribute in part to the three-dimensional network.
  • the rheoiogical agent is preferably one which contributes little to the osmotic pressure of the implant.
  • osmotic pre ⁇ ure is a colligative property that depends on the number of solute particles.
  • the polymeric rheoiogical agent and its three-dimensional network behaves like a ⁇ ingle particle. Accordingly, it contribute ⁇ little to the o ⁇ motic balance.
  • a portion of the polymeric o ⁇ motic control agent contributes to the three- dimensional network, while the remaining portion of the polymeric o ⁇ motic control agent dictate ⁇ the o ⁇ motic pre ⁇ ure of the fill material in the implant.
  • the combinations of the present invention are synergistic; that is, the osmotic pressure of the present invention relates little, if at all, to a corresponding amount of an o ⁇ motic control agent di ⁇ per ⁇ ed only in water.
  • the polymeric osmotic control agents of the present invention move through the three-dimensional network relatively slowly.
  • salts are distributed rather quickly even in the presence of a three-dimensional network of the present invention.
  • the rheoiogical agent is preferably a gum which is water-dispersible.
  • examples include gums which are natural polymers and gums which are synthetic polymers.
  • Example ⁇ of natural polymer gum ⁇ include polysaccharides, proteins, and natural rubbers and chemically modified natural polymer ⁇ ⁇ uch a ⁇ hydroxyethylcellulose.
  • Examples of synthetic polymer gums include poly(vinyl alcohol) and polyethylene oxide.
  • a gum is a polymeric substance which, in an appropriate solvent or swelling agent, form highly viscous dispersion ⁇ or gels at low, dry substance content. Gums may or may not be water-soluble.
  • the gum preferably is a water soluble polysaccharide (glycan) .
  • Examples include seed gums such as corn starch, guar gum, and locust bean gum; tuber and root gums such as potato starch and tapioca starch; seaweed extracts such as algin, carageenan, agar, and furcellaran; plant extracts such as pectin; exudate gum ⁇ ⁇ uch as gum arabic; fermentation (microbial) gum ⁇ such as xanthan (qv) , dextran (qv) and welan (polysaccharide S- 130) ; and derived gums such as carboxymethylcellulose, hydroxyalkylmethylcellulose, methylcellulose, starch acetate, starch phosphate, hydroxyethylstarch, hydroxypropylstarch, oxidized starches, and dextrinized starche ⁇ .
  • seed gums such as corn starch, guar gum, and locust bean gum
  • tuber and root gums such as potato starch and tapioca starch
  • seaweed extracts such as algin
  • Seed gum ⁇ are mo ⁇ t preferred. Of the seed gums, guar gum is most preferred.
  • the glycan is added to the fill material in a concentration of preferably from about 0.1% to about 25%, more preferably from about 0.1% to about 15%, and most preferably from about 0.01% to about 10% (w/w) .
  • Example ⁇ of gum ⁇ which are galactommannans (a polymer of D-galactose and D-mannose) include guaran (the purified poly ⁇ accharide from guar gum) , locust bean gum, and tara gum. Of these guaran is preferred. Guar gum, locust bean, and tara gum al ⁇ o means, for the purpose ⁇ of the present invention, their blends, and the endosperms, high purity split ⁇ , derivative ⁇ , granule ⁇ , and powders of such gums. Examples of guar derivatives include hydroxypropyl-, hydroxyethyl-, sodium carboxymethyl-, sodium carboxymethylhydroxypropyl-, and 2- hydroxypropyl (trimethyl)ammonium guar gums.
  • the galactommannan is added to the fill material in a concentration of preferably from about 0.05% to about 6%, more preferably from about 0.1% to about 4.0%, and mo ⁇ t preferably from about 0.1% to about 2% (w/w) .
  • Chemically modified natural polymers or derived gums preferably include cellulose derivatives such as an hydroxyalkylcellulose.
  • hydroxyalkylcellulose include carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylhydroxyethylcellulo ⁇ e.
  • Xanthan (or xanthan gum) may be u ⁇ ed a ⁇ the ⁇ ole rheoiogical agent of the pre ⁇ ent invention or in combination with locust bean and/or guar gum.
  • xanthan When used alone, xanthan is added to the fill material in a concentration of preferably from about 0.05% to about 6%, more preferably from about 0.1% to about 4.0%, and most preferably from about 0.1% to about 2.0% (w/w).
  • the amount of xanthan in locust bean gum or in a locust bean/guar gum blend may be between about 1% and about 99% w/w.
  • the amount of locust bean or guar gum in ⁇ uch a blend may be between about 1% and about 99% w/w.
  • the xanthan and/or locu ⁇ t bean and/or guar blend is added to the fill material in a concentration preferably from about 0.05% to about 6%, more preferably from about 0.1% to about 4.0%, and most preferably from about 0.1% to about 2% (w/w) .
  • Examples of synthetic polymer gum ⁇ where such form biocompatible water-disper ⁇ able and water- ⁇ oluble gum ⁇ , include poly(vinyl alcohol) , polyether ⁇ ⁇ uch as the poloxamers polyethylene oxide and polypropylene oxide, polyacrylamide, their copolymer ⁇ and blend ⁇ , and copolymer ⁇ of poly-N-vinylamide ⁇ , including copolymers of polyvinylpyrrolidinone such as poly(N-l- vinylpyrrolidone) -co-2-methylaminoethylmethacrylate, poly(1-vinylpyrrolidone) -co-acrylic acid, and poly(l- vinylpyrrolidone) -co-vinylacetate.
  • polyethylene oxide and polypropylene oxide and their copolymers and blends the totality of the Tautvydas et al. U.S. Patent 5,407,445 is hereby incorporated by reference.
  • the synthetic polymer gum is added to the fill material in a concentration of preferably from about 0.5% to about 60%, more preferably from about 0.5% to about 40%, and ⁇ till more preferably from about 0.5% to about 20%(w/w). Still further, in the ca ⁇ e of polyethylene oxide or polypropylene oxide, the mo ⁇ t preferred range i ⁇ about 0.6% to about 5.0% of the fill material. Of the biodegradable ⁇ ynthetic polymer ⁇ , poly(vinyl alcohol) and polyethylene oxide are preferred.
  • the gum of the pre ⁇ ent invention preferably include ⁇ tho ⁇ e gums which have been identified a ⁇ the safest gums for an implant in the body.
  • Such gum ⁇ include guar, a cellulo ⁇ e derivative ( ⁇ elected from the group of carboxymethylcellulose, hydroxyethylcellulo ⁇ e, hydroxypropylcellulose, ethylhydroxyethylcellulose) , xanthan, a xanthan/locust bean mixture, polyethylene oxide, and poly(vinyl alcohol) .
  • Guar, polyethylene oxide, and poly(vinyl alcohol) are mo ⁇ t preferred.
  • the rheoiogical agent of the pre ⁇ ent invention is one which contributes little, if any, to the osmotic pres ⁇ ure of the implant fill material.
  • a ⁇ osmolarity is a function of the number of particle ⁇ , it i ⁇ preferred that the rheoiogical agent have a ⁇ ufficiently high molecular weight.
  • Guar typically include ⁇ a molecular weight between about 200,000 and about 240,000.
  • Locu ⁇ t bean gum typically includes a molecular weight between about 300,000 and 360,000.
  • the compound (or compounds) forming the three-dimen ⁇ ional network include ⁇ a molecular weight preferably between about 4000 and 4,000,000, and more preferably between about 100,000 and 600,000.
  • biocompatible compound which form ⁇ a three-dimen ⁇ ional network but which i ⁇ neither a gum nor a polymer i ⁇ gelatin.
  • Gelatin i ⁇ a heterogeneous mixture of water-soluble proteins of high average molecular weight.
  • Gelatin is not found in nature but i ⁇ derived from collagen. Gelatin may be obtained by boiling skin, tendons, ligaments, bones, etc. with water.
  • Examples of means for preventing microbial growth include irradiation (gamma radiation) of the fill material and antimicrobial preservative ⁇ ⁇ uch a ⁇ benzoate ⁇ and parabens, and non food grade pre ⁇ ervative ⁇ .
  • the preservative ⁇ are added to the fill material in concentration ⁇ at or le ⁇ s than about 1% w/w, or more preferably at or less than about 0.5% w/w, and still more preferably at or les ⁇ than 0.25% w/w.
  • the rheoiogical agent ⁇ of the present invention include tho ⁇ e rheoiogical agent ⁇ which have been irradiated prior to introduction into the dispersion or formation of gum.
  • These pre-irradiated rheoiogical agents include pre-irradiated guar or xanthan gums.
  • pre-irradiated rheoiogical agent ⁇ the totality of the Burgum U.S. Patent No. 5,273,767 i ⁇ hereby incorporated by reference.
  • the fill material include ⁇ a reactant ⁇ uch a ⁇ a cro ⁇ -linking agent for the rheoiogical agent.
  • cros ⁇ -linking agents include A1 2 (S0 4 ) 3 and its analogs, borates such as borax, boric acid and its analogs, titonates, chrome complexe ⁇ , zirconium, and calcium compound ⁇ .
  • the ⁇ e cross-linking agents are added to the fill material in a concentration of preferably at or less than 1% w/w and more preferably at or less than 1% of the concentration of the rheoiogical agent.
  • Cros ⁇ -linking or hydrogen bonding in the three- dimensional network of the present fill material may provide a vi ⁇ coelastic fill material.
  • one object of the present invention is to provide a safer fill material for an implant.
  • a safer fill material is one which include ⁇ the least pos ⁇ ible amount of nontoxic foreign components.
  • the lubricity of the fill material is preferably provided by the polymeric osmotic control agent, such as the colloid, the poly-N- vinylamide, or polyvinylpyrrolidinone.
  • the vi ⁇ cosity, or apparent viscosity, of the fill material is in the range of preferably between about 100 and 20,000 centipoi ⁇ e, more preferably between about 200 and about 10,000 centipoi ⁇ e, and mo ⁇ t preferably between about 400 and about 5000 centipoi ⁇ e.
  • the implant according to the pre ⁇ ent invention may be a brea ⁇ t or te ⁇ tes prosthe ⁇ i ⁇ , a penile implant, or an implant containing a drug to be di ⁇ per ⁇ ed over time.
  • the ⁇ hell of the implant may be permeable or impermeable.
  • the ⁇ hell may be permeable to water vapor or may be impermeable to water vapor, or may be permeable to other fluid ⁇ or compound ⁇ ⁇ uch a ⁇ drugs or pharmaceutical agents.
  • shells which are permeable to water vapor include the shell set forth in U.S. patent application serial no. 08/473,284, filed June 7, 1995, the totality of which is hereby incorporated by reference.
  • Example ⁇ of shells which are permeable to water vapor include the conventional silicone or polyurethane shell.
  • a breast implant is shown in Fig. 1. It includes a shell 11, a fill material 12 of the present invention, and a closure or joint 13 for closing the ⁇ hell 11 and sealing the fill material therein.
  • the clo ⁇ ure 13 i ⁇ a room temperature vulcanized ⁇ ilicone button ⁇ eal.
  • the closure 13 is formed of the same material as the shell 11 and includes an inner disk shaped silicone layer 20 having a greater diameter than the outer disk shaped layer 22 such that an annular portion 24 of the inner layer 20 extends beyond the outer layer 22.
  • the outer surface of the annular portion 24 is bonded via a vulcanized weld to the inner surface of the shell 11.
  • the outer disk shaped layer 22 has a diameter substantially equal to the diameter of the opening 26 formed by the mandrel in the manufacture of the ⁇ hell 11.
  • the leaf valve assembly 28 includes an outlet 30 and an inlet disposed adjacent to the center of the disk shaped portion 20.
  • the opposing flap sides of the leaf valve as ⁇ embly 28 cling together to minimize pa ⁇ age of fluid through the assembly 28.
  • the clo ⁇ ure 13 may alternatively include a valve ⁇ uch as compression valve or septa.
  • the shell 11 may be of a material which i ⁇ permeable or impermeable to water vapor.
  • the ⁇ hell ll may be ⁇ ilicone, polyurethane, or another ela ⁇ tomeric material.
  • the implant 40 includes a ⁇ pherical ovoid or coin-like ⁇ hell 44 which i ⁇ permeable or semipermeable relative to the agent 42.
  • the agent include silicone permeable hormone ⁇ ⁇ uch as progesterone, E ⁇ tradiol including 17-B-E ⁇ tradiol, Melatonin, and evonorge ⁇ trel, ⁇ ilicone permeable narcotic analgesics such as Fentanyl and morphine sulfate, and silicone permeable antianginal agents or vasodilator ⁇ ⁇ uch a ⁇ nitroglycerin.
  • Procedure ⁇ for filling the implants include the following method.
  • the temperature of double distilled water is adju ⁇ ted to 35°F (1.67°C).
  • the component ⁇ are then preferably added to the double di ⁇ tilled water in the following order: the pre ⁇ ervative if de ⁇ ired, the cro ⁇ -linking agent if desired, the osmotic control agent, and then the rheoiogical agent.
  • the di ⁇ per ⁇ ion i ⁇ agitated and the temperature of the dispersion is permitted to rise in an environment at room temperature until the desired swelling has occurred.
  • the dispersion is then injected into the implant.
  • the implant is then rotated such that the dispersion remains uniformly dispersed, thereby allowing the rheoiogical agent to fully hydrate (and cross-link if a cross-linking agent has been added to provide a three dimensional network if the rheoiogical agent alone does not provide such) .
  • biocompatible mean ⁇ that which remain ⁇ in unchanged form in the body without cau ⁇ ing adver ⁇ e reaction, that which may be metabolized, and/or that which may be excreted without being metabolized.
  • the fill material of the present invention is radiolucent.
  • the fill material is not radiographically dense, nor does the fill material result in under-exposure of x-ray film.
  • the fill material includes an optical density from about 1.2 to about 1.3 and an x-ray penetrance of from about 9.2 to about 30 illiroentgens.
  • the osmotic control agents and rheoiogical agents of the present invention include elements with relatively low atomic numbers which do not interfere with radiolucency.
  • Example 1 (PVP and guar) Eight hundred (800) grams of high purity water were mixed with 200 g of PVP [poly(2-vinylpyrrolidone) ,
  • Example 7 PVP and polyethylene oxide
  • PVP poly(pol (2-vinylpyrrolidone)
  • PVP poly(pol (2-vinylpyrrolidone)
  • Polyox 303 polyethylene oxide, Union Carbide
  • Example 8 PVP and polyethylene oxide
  • PVP poly(2-vmylpyrrolidone)
  • Example 9 PVP and polyethylene oxide
  • Example 9 Four hundred grams of deionized water and one hundred grams of PVP (poly(2-vmylpyrrolidone) ) were mixed with vigorous stirring.
  • Six grams of Polyox 303 polyethylene oxide, Union Carbide) were added. The rapid formation of a responsive gel wa ⁇ noted.
  • Example 10 (PVP and polyethylene oxide) Eight hundred gram ⁇ of deionized water and one hundred grams of PVP (poly(2-vinylpyrrolidone) ) were mixed with vigorous stirring. To this ⁇ olution twenty- five gram ⁇ of Polyox 303 (polyethylene oxide, Union Carbide) were added. The rapid formation of a re ⁇ pon ⁇ ive gel wa ⁇ noted.
  • Example 11 (PVP and PVP copolymer)
  • Example 12 PVP and PVP copolymer
  • Example 13 PVP and PVP copolymer

Abstract

An implant (10) including a shell (11), fill material (12), and a joint (13) for closing the shell (11), is disclosed. The joint (13) is formed from the same material as the shell (11), and includes an inner disk shaped silicone layer (20) having a greater diameter than the outer disk shaped layer (22), such that the annular portion (24) is bonded via a vulcanized weld to the inner surface of the shell (11). The fill material (12) is composed of a rheologically modified, osmotically balanced dispersion including an osmotic control agent, such as polyvinyl pyrrolidine, and a rheological agent, such as guar gum.

Description

IDEOLOGICALLY MODIFIED AND OSMOTICALLY BALANCED FILL MATERIAL FOR IMPLANT
BACKGROUND OF THE INVENTION The present invention relates generally to implants introduced into the body, particularly to fill material for such implants, and specifically to rheologically modified fill material for implants.
For implants such as breast and testes prosthesis as well as other implants and prosthesis, silicone has been the fill material of choice. However, silicone as a fill material has fallen into disfavor. This has prompted efforts to find replacements for silicone. These replacements are often if not always undesirable because such replacements have been unable to match the feel provided by silicone. The inventors of the present invention have investigated the rheoiogical parameters of certain fluid formulations in an effort to provide a fill material having the heretofore unmatched feel of εilicone. Thuε, it is important to understand some basics of rheology to have an understanding of the present invention.
Rheology is the science of the deformation and flow of matter. It is concerned with the response of materials to mechanical force. Polymer rheology deals with polymeric materials and biorheology deals with biological fluids.
Deformation is the relative diεplacement of points of a body and can be divided into two general types: flow and elasticity. Flow iε irreverεible deformation; when the stress is removed, the material does not revert to its original configuration. Elasticity is reversible deformation; the deformed body recovers its original shape.
The usual way of defining the rheoiogical properties of a material is to determine the resistance to deformation. Resistance to deformation is measured by two indexes or yardsticks: 1) viscosity (the index or yardstick for flow; viscosity is the resistance to flow of a liquid) ; and 2) the degree of elasticity (elastic deformation) . A liquid is a material that continues to deform as long as it iε subjected to a tensile or shear stress. For a liquid under shear, the rate of deformation (shear rate) is proportional to the εhearing εtress.
Thixotropy is the decrease in viscoεity with time when εheared at a conεtant shear rate. Rheopexy, a relatively rare occurrence, is the increase in viscoεity of a fluid in reεponεe to shear. For example, as to thixotropy, when a shearing action beginε, such as when one applies a latex house paint with a brush, the viscosity decreases quickly to permit the paint to be easily brushed to a thin film and provide a εhort period of time for the bruεhmarks to level. When the shearing action stopε, such as when the paint leaves the brush and clings to the wall, the viscosity of the latex houεe paint increaεeε to prevent running and εagging. Thixotropy may be a time dependent effect.
A εingle fluid may be εubject to a number of shear rates. For example, a paint may be pumped during manufacture or immediately prior to application (intermediate shear rate) , sprayed onto a wall (high εhear rate) , coalesce and flow to form a uniform film (intermediate to low shear rate) , and εag or run under gravity (low εhear rate) . A given liquid or material may work well at one or two of the εhear rateε, but fail at other εhear rateε.
SUMMARY OF THE INVENTION General objects of the present invention include a unique rheologically modified dispersion for an implant for a body and unique methods for filling the implant.
Another object of the preεent invention iε .to provide such a rheologically modified dispersion which uniquely includes an osmotic control agent.
Another object of the present invention is to provide such a rheologically modified dispersion wherein the osmotic control agent uniquely includes a poly-N- vinylamide. Another object of the preεent invention is to provide such a rheologically modified dispersion wherein the poly-N-vinylamide uniquely includes polyvinylpyrrolidinone.
Another object of the present invention is to provide such an osmotically controlled and rheologically modified disperεion wherein the rheoiogical agent uniquely includeε a three-dimenεional network.
Another object of the present invention iε to provide such an osmotically controlled and rheologically modified diεperεion wherein the three-dimenεional rheoiogical agent uniquely includeε gum.
Another object of the preεent invention iε to provide such an osmotically controlled and rheologically modified dispersion wherein the gum uniquely includes a natural gum.
Another object of the present invention iε to provide εuch an oεmotically controlled and rheologically modified dispersion wherein the natural gum uniquely includes guar gum or locust bean gum and their derivativeε.
Another object of the present invention is to provide such an osmotically controlled and rheologically modified dispersion wherein the gum uniquely includes xanthan and its derivatives.
Another object of the present invention is .to provide such an oεmotically controlled and rheologically modified dispersion wherein the gum uniquely includes a synthetic gum.
Another object of the present invention iε to provide εuch an osmotically controlled and rheologically modified disperεion wherein the synthetic gum uniquely includes poly(vinyl alcohol) , polyethylene oxide, polypropylene oxide, polyacrylamide, or copolymers of polyvinylpyrrolidinone.
Another object of the present invention is to provide such an osmotically controlled and rheologically modified dispersion which uniquely is a pseudoplaεtic. Such a pseudoplastic diεperεion mimicε the rheology of body fluid and tiεεue.
Another object of the present invention is to provide such an osmotically controlled and rheologically modified dispersion in which uniquely all of the components of the dispersion are biocompatible. Accordingly, even in the worst case εcenario in which the implant bursts, little or minimal danger is presented.
An advantage of the preεent invention is that the fill material of an implant is osmotically balanced with its environment. With an osmotic balance, the implant retains its desired volume. Such is in contrast to an implant which includeε a low oεmotic preεεure; here, water or another εolvent flowε out of the implant, perhapε cauεing fold flaw fracture. A high oεmotic preεεure in the implant may lead to a burεting of the implant.
Another advantage of the present invention is that the fill material iε rheologically modified to be pseudoplastic. This provides a feel or responsive fill material which mimics body tisεue. Theεe and further objectε and advantageε of the preεent invention will become clearer in light of the following detailed deεcription of the illuεtrative embodimentε of this invention described in connection with the drawings. BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows a perspective, partially exploded view of a breast implant.
Fig. 2 shows a section view of an implant with a dispersion containing a drug to be released over time. All Figures are drawn for ease of explanation of the basic teachings of the present invention only; the extensionε of the Figures with respect to number, poεition, relationεhip, and dimenεionε of the parts to form the preferred embodiment will be explained or will be within the skill of the art after the following description has been read and understood. Further, the exact dimensions and dimensional proportionε to conform to εpecific force, weight, εtrength, and εimilar requirementε will likewiεe be within the εkill of the art after the following deεcription haε been read and underεtood. Where used in the various figures of the drawings, the same numeralε designate the same or εimilar parts. Furthermore, when the terms "inner", "outer", and "upper" and similar terms are used herein, it should be understood that these terms have reference only to the structure shown in the drawings as it would appear to a person viewing the drawings and are utilized only to facilitate describing the preferred embodimentε.
DESCRIPTION In general, the preεent invention relateε to a εafe fill material for an implant. The fill material preferably includeε water, an oεmotic control agent such as a poly-N-vinylamide or polyvinylimide, a rheoiogical agent such as a gum. Optionally, the fill material may include cross-linkers for the rheoiogical agent (i.e. the thixotrope or gellant) and/or other additives such as antioxidants, preservatives such as antimicrobials, wetting agentε, and lubricantε. The fill material iε biocompatible. Oεmotic control agent, for the purpoεeε of the preεent invention, meanε that which iε added to the fill material to prevent or minimize oεmoεiε, i.e. flow of εolvent (water) through the membrane of the implant. Oεmosis iε minimized by providing interior of the implant with an osmotic presεure which is equal to the osmotic pressure of the environment outside of the implant. Accordingly, osmotic control agent further means that which provideε an osmotic pressure similar to the body or body tissue or fluid or to the portion of the body into which the implant is to be located. The most preferred osmotic presεure provided by the oεmotic control agent, when combined with the rheoiogical agent of the preεent invention, is between about 250 and about 350 milliosmoles.
Still further, the osmotic control agent iε a polymer or polymers or copolymer or copolymers that contributes substantially to the desired osmotic presεure of between about 250 and 350 milliosmoles. Such a substantial contribution is made when the polymeric osmotic control agent is added to the fill material in an amount preferably between about 90% to 99.9% w/w, more preferably between about 95% to 99.9% w/w, and most preferably between about 98% to 99% w/w of the osmotic control agents. If required, salts may be added to fine tune the osmotic preεsure of the implant. These saltε preferably include biocompatible salts such as sodium chloride, sodium lactate and sodium acetate in an amount of between about 1% and 10% w/w of the osmotic control agents. For radiolucency, εodium lactate and εodium acetate are preferred. It εhould be noted that osmotic pressure is a colligative property that depends on the number of solute particles.
Still further, it should be noted that osmotic control agents which are preferred provide lubricity to the interior wall of the implant. In sum, it is preferred that the osmotic control agent: 1) is a polymer or copolymer or blend thereof; 2) is present in an amount effective to provide an osmotic preεεure to the implant of between about 250 and 350 millioεmoles without the use of saltε; and 3) iε preεent in an amount effective to provide lubricity to the fill material (i.e. to the interior wall of the implant) .
The oεmotic control agent iε preferably a protective colloid which iε water-εoluble or water-diεpersable. δ
Exampleε of preferred colloids include poly-N- vinylamides, poly-N-vinylamide copolymers, polyvinylimides. Poly-N-vinylamide hydrogelε are most preferred. The poly-N-vinylamides may be either linear or cyclic. Exampleε of poly-N-vinylamideε prepared from linear derivatives include poly(acetamide) , poly(methylacetamide) , poly(ethylacetamide) , poly(phenylacetamide) , poly(methylpropionamide) , poly(ethylpropionamide) , poly(methylisobutyramide) , and poly(methylbenzylamide) . Poly-N-vinylamides derived from cyclic structures are more preferred. Examples of these polymers include polyvinylpyrrolidinone, polyvinylcaprolactam, poly-2-piperidinone, poly-5-methyl- 2-pyrrolidinone, poly-2,2,5-trimethyl-2-pyrrolidinone, and poly-5-methyl-2-pyrrolidinone.
Polyvinylpyrrolidinone and polyvinylcaprolactam are even more preferred with polyvinylpyrrolidinone being most preferred. Polyvinylpyrrolidinone (PVP or povidone or poly(N- vinyl-2-pyrrolidinone) ) is one of the few poly-N- vinylamideε prepared from cyclic εtructureε, if not the only one, available in a commercial quantity. Polyvinylcaprolactam has been commercialized to some extent.
Poly-N-vinylamide copolymers include poly(vinylpyrrolidinone-co-vinyl acetate) , poly(vinylpyrrolidinone-co-maleic anhydride) , poly(vinylpyrrolidinone-co-methyl methacrylate) , poly(vinylpyrrolidinone-co-dimethylaminoethyl methacrylate) , poly(vinylpyrrolidinone-co-butyl methacrylate) , poly(vinylpyrrolidinone-co-hydroxyethyl methacrylate) , poly(vinylpyrrolidinone-co-ethyl acrylate) , poly(vinylpyrrolidinone-co-ethylhexyl acrylate), poly(vinylpyrrolidinone-co-acrylic acid), poly(vinylpyrrolidinone-co-acrylamide) , poly(vinylpyrrolidinone-co-acrylonitrile) , polyvinylpyrrolidinone-co-styrene) , poly(vinylpyrrolidinone-co-ethylene) , and poly(vinylpyrrolidinone-co-crotonic acid) and their derivatives. For the purposes of the present invention, the molecular weight of the osmotic control agent is in the range of preferably about 1000 to about 100,000, more preferably about 1000 to about 40,000, and even more preferably about 3000 to about 20,000, and most preferably about 10,000. Poly-N-vinylamides, such as PVP, at molecular weights higher than about 100,000 may not be excretible from the human body. Poly-N- vinylamides, εuch as PVP, at weights below about 100,000 may be bioexcretable, with thoεe having molecular weightε below 30,000 being more likely to be quickly excretable, εuch as through the human kidney. The molecular weights noted herein are in daltons.
A higher molecular weight of the poly-N-vinylamide, such as PVP, generally relates to a higher degree of polymerization and a greater intrinsic viscoεity.
Further, the viεcoεity of the poly-N-vinylamide (εuch aε PVP) in water generally increases with the solid concentration.
In the fill material according to the present invention, the osmotic control agent iε preεent in the range of preferably from about 0.5% to about 60%, more preferably from about 2.5% to about 40%, and most preferably from about 3.5% to about 20% (w/w) .
Such a range of concentration, when combined with one or more of the rheoiogical agents of the present invention, provideε an osmolarity of preferably between about 100 milliosmoles and about 500 milliosmoleε, more preferably between about 200 millioεmoleε and about 400 illioεmoleε, and moεt preferably between about 250 and about 350 millioεmoleε. It should be noted that such an osmolarity is preferably obtained without the use of saltε. It should further be noted that PVP, when alone in solution without a three dimensional network, doeε not provide the deεired pεeudoplaεticity to the εolution. Rheoiogical agent meanε a material which modifieε the normal εolution propertieε to increaεe or decreaεe its resistance to flow and to increase or decreaεe itε elasticity. Rheoiogical agent further means that which provideε a pεeudoplaεticity to the fill material to the implant. The fill material of the preεent invention aε a whole is pseudoplastic. In other words, when shear εtress is applied to the fill material, the viscosity of the fill material is reduced in proportion to the amount of shear. Upon release of the shear, total viscoεity recovery of the fill material occurs almost instantaneously.
That the fill material of the present invention is pseudoplastic is advantageous. This feature of decreased apparent viscosity at high shear rates facilitates mixing, pumping, and pouring. Further, when in the body, such pseudoplaεticity mimics body tissue and fluid, such as the breast body tissue and fluid. For example, the undesired bounce of conventional saline implants is minimized.
The rheoiogical agent includes pseudoplaεtic agentε or thixotropic agentε. Pseudoplastic agents are preferred.
The rheoiogical agent is preferably a polymer which provides a three-dimenεional network within the implant. Thiε three-dimenεional network provideε a backbone for the polymeric osmotic control agent, which may contribute in part to the three-dimensional network.
The rheoiogical agent is preferably one which contributes little to the osmotic pressure of the implant. As noted above, osmotic preεεure is a colligative property that depends on the number of solute particles. With the present invention, even though it is a massive "particle", the polymeric rheoiogical agent and its three-dimensional network behaves like a εingle particle. Accordingly, it contributeε little to the oεmotic balance. Converεely, a portion of the polymeric oεmotic control agent contributes to the three- dimensional network, while the remaining portion of the polymeric oεmotic control agent dictateε the oεmotic preεεure of the fill material in the implant. It iε believed that the combinations of the present invention are synergistic; that is, the osmotic pressure of the present invention relates little, if at all, to a corresponding amount of an oεmotic control agent diεperεed only in water.
Advantageouεly, it should be noted that the polymeric osmotic control agents of the present invention move through the three-dimensional network relatively slowly. In contrast, salts are distributed rather quickly even in the presence of a three-dimensional network of the present invention.
The rheoiogical agent is preferably a gum which is water-dispersible. Examples include gums which are natural polymers and gums which are synthetic polymers. Exampleε of natural polymer gumε include polysaccharides, proteins, and natural rubbers and chemically modified natural polymerε εuch aε hydroxyethylcellulose. Examples of synthetic polymer gums include poly(vinyl alcohol) and polyethylene oxide. Generally, the rheoiogical agent iε added to the fill material in a concentration of preferably from about 0.05% to about 36%, more preferably from about 0.1% to about 24%, even more preferably from about 0.1% to about 12%, and moεt preferably from about 0.1% to about 2.0% (w/w).
A gum is a polymeric substance which, in an appropriate solvent or swelling agent, form highly viscous dispersionε or gels at low, dry substance content. Gums may or may not be water-soluble. The gum preferably is a water soluble polysaccharide (glycan) . Examples include seed gums such as corn starch, guar gum, and locust bean gum; tuber and root gums such as potato starch and tapioca starch; seaweed extracts such as algin, carageenan, agar, and furcellaran; plant extracts such as pectin; exudate gumε εuch as gum arabic; fermentation (microbial) gumε such as xanthan (qv) , dextran (qv) and welan (polysaccharide S- 130) ; and derived gums such as carboxymethylcellulose, hydroxyalkylmethylcellulose, methylcellulose, starch acetate, starch phosphate, hydroxyethylstarch, hydroxypropylstarch, oxidized starches, and dextrinized starcheε. Seed gumε are moεt preferred. Of the seed gums, guar gum is most preferred. The glycan is added to the fill material in a concentration of preferably from about 0.1% to about 25%, more preferably from about 0.1% to about 15%, and most preferably from about 0.01% to about 10% (w/w) .
Exampleε of gumε which are galactommannans (a polymer of D-galactose and D-mannose) include guaran (the purified polyεaccharide from guar gum) , locust bean gum, and tara gum. Of these guaran is preferred. Guar gum, locust bean, and tara gum alεo means, for the purposeε of the present invention, their blends, and the endosperms, high purity splitε, derivativeε, granuleε, and powders of such gums. Examples of guar derivatives include hydroxypropyl-, hydroxyethyl-, sodium carboxymethyl-, sodium carboxymethylhydroxypropyl-, and 2- hydroxypropyl (trimethyl)ammonium guar gums.
The galactommannan is added to the fill material in a concentration of preferably from about 0.05% to about 6%, more preferably from about 0.1% to about 4.0%, and moεt preferably from about 0.1% to about 2% (w/w) .
Chemically modified natural polymers or derived gums preferably include cellulose derivatives such as an hydroxyalkylcellulose. Examples of hydroxyalkylcellulose include carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylhydroxyethylcelluloεe. The derived gum iε added to the fill material in a concentration of preferably from about 0.5% to about 30%, more preferably from about 5% to about 25%, and moεt preferably from about 8% to about 15% (w/w) . Xanthan (or xanthan gum) may be uεed aε the εole rheoiogical agent of the preεent invention or in combination with locust bean and/or guar gum. When used alone, xanthan is added to the fill material in a concentration of preferably from about 0.05% to about 6%, more preferably from about 0.1% to about 4.0%, and most preferably from about 0.1% to about 2.0% (w/w). The amount of xanthan in locust bean gum or in a locust bean/guar gum blend may be between about 1% and about 99% w/w. The amount of locust bean or guar gum in εuch a blend may be between about 1% and about 99% w/w. The xanthan and/or locuεt bean and/or guar blend is added to the fill material in a concentration preferably from about 0.05% to about 6%, more preferably from about 0.1% to about 4.0%, and most preferably from about 0.1% to about 2% (w/w) .
Examples of synthetic polymer gumε, where such form biocompatible water-disperεable and water-εoluble gumε, include poly(vinyl alcohol) , polyetherε εuch as the poloxamers polyethylene oxide and polypropylene oxide, polyacrylamide, their copolymerε and blendε, and copolymerε of poly-N-vinylamideε, including copolymers of polyvinylpyrrolidinone such as poly(N-l- vinylpyrrolidone) -co-2-methylaminoethylmethacrylate, poly(1-vinylpyrrolidone) -co-acrylic acid, and poly(l- vinylpyrrolidone) -co-vinylacetate. As to polyethylene oxide and polypropylene oxide and their copolymers and blends, the totality of the Tautvydas et al. U.S. Patent 5,407,445 is hereby incorporated by reference.
The synthetic polymer gum is added to the fill material in a concentration of preferably from about 0.5% to about 60%, more preferably from about 0.5% to about 40%, and εtill more preferably from about 0.5% to about 20%(w/w). Still further, in the caεe of polyethylene oxide or polypropylene oxide, the moεt preferred range iε about 0.6% to about 5.0% of the fill material. Of the biodegradable εynthetic polymerε, poly(vinyl alcohol) and polyethylene oxide are preferred.
The gum of the preεent invention preferably includeε thoεe gums which have been identified aε the safest gums for an implant in the body. Such gumε include guar, a celluloεe derivative (εelected from the group of carboxymethylcellulose, hydroxyethylcelluloεe, hydroxypropylcellulose, ethylhydroxyethylcellulose) , xanthan, a xanthan/locust bean mixture, polyethylene oxide, and poly(vinyl alcohol) . Guar, polyethylene oxide, and poly(vinyl alcohol) are moεt preferred.
It εhould be noted that it iε preferred that the rheoiogical agent of the preεent invention is one which contributes little, if any, to the osmotic presεure of the implant fill material. Aε osmolarity is a function of the number of particleε, it iε preferred that the rheoiogical agent have a εufficiently high molecular weight. Guar, for example, typically includeε a molecular weight between about 200,000 and about 240,000. Locuεt bean gum typically includes a molecular weight between about 300,000 and 360,000. The compound (or compounds) forming the three-dimenεional network includeε a molecular weight preferably between about 4000 and 4,000,000, and more preferably between about 100,000 and 600,000.
An example of a biocompatible compound which formε a three-dimenεional network but which iε neither a gum nor a polymer iε gelatin. Gelatin iε a heterogeneous mixture of water-soluble proteins of high average molecular weight. Gelatin is not found in nature but iε derived from collagen. Gelatin may be obtained by boiling skin, tendons, ligaments, bones, etc. with water.
Examples of means for preventing microbial growth include irradiation (gamma radiation) of the fill material and antimicrobial preservativeε εuch aε benzoateε and parabens, and non food grade preεervativeε. The preservativeε are added to the fill material in concentrationε at or leεs than about 1% w/w, or more preferably at or less than about 0.5% w/w, and still more preferably at or lesε than 0.25% w/w.
It εhould be noted that the rheoiogical agentε of the present invention include thoεe rheoiogical agentε which have been irradiated prior to introduction into the dispersion or formation of gum. These pre-irradiated rheoiogical agents include pre-irradiated guar or xanthan gums. As to pre-irradiated rheoiogical agentε, the totality of the Burgum U.S. Patent No. 5,273,767 iε hereby incorporated by reference.
Optionally, the fill material includeε a reactant εuch aε a croεε-linking agent for the rheoiogical agent. These crosε-linking agents include A12(S04)3 and its analogs, borates such as borax, boric acid and its analogs, titonates, chrome complexeε, zirconium, and calcium compoundε. Generally, theεe cross-linking agents are added to the fill material in a concentration of preferably at or less than 1% w/w and more preferably at or less than 1% of the concentration of the rheoiogical agent. Crosε-linking or hydrogen bonding in the three- dimensional network of the present fill material may provide a viεcoelastic fill material.
It should be noted that one object of the present invention is to provide a safer fill material for an implant. A safer fill material is one which includeε the least posεible amount of nontoxic foreign components.
It should be noted that the lubricity of the fill material is preferably provided by the polymeric osmotic control agent, such as the colloid, the poly-N- vinylamide, or polyvinylpyrrolidinone. The amount of the polymeric oεmotic control agent effective to provide an osmotic pressure to the implant of between about 250 and 350 milliosmoleε iε more than required to provide lubricity to the fill material.
The viεcosity, or apparent viscosity, of the fill material is in the range of preferably between about 100 and 20,000 centipoiεe, more preferably between about 200 and about 10,000 centipoiεe, and moεt preferably between about 400 and about 5000 centipoiεe.
The implant according to the preεent invention may be a breaεt or teεtes prostheεiε, a penile implant, or an implant containing a drug to be diεperεed over time. The εhell of the implant may be permeable or impermeable. For example, the εhell may be permeable to water vapor or may be impermeable to water vapor, or may be permeable to other fluidε or compoundε εuch aε drugs or pharmaceutical agents. Examples of shells which are permeable to water vapor include the shell set forth in U.S. patent application serial no. 08/473,284, filed June 7, 1995, the totality of which is hereby incorporated by reference. Exampleε of shells which are permeable to water vapor include the conventional silicone or polyurethane shell. A breast implant is shown in Fig. 1. It includes a shell 11, a fill material 12 of the present invention, and a closure or joint 13 for closing the εhell 11 and sealing the fill material therein. The cloεure 13 iε a room temperature vulcanized εilicone button εeal. The closure 13 is formed of the same material as the shell 11 and includes an inner disk shaped silicone layer 20 having a greater diameter than the outer disk shaped layer 22 such that an annular portion 24 of the inner layer 20 extends beyond the outer layer 22. The outer surface of the annular portion 24 is bonded via a vulcanized weld to the inner surface of the shell 11. The outer disk shaped layer 22 has a diameter substantially equal to the diameter of the opening 26 formed by the mandrel in the manufacture of the εhell 11. A leaf valve assembly or primary cloεure 28 iε fixed to the inner surface of the disk shaped portion 20. The leaf valve assembly 28 includes an outlet 30 and an inlet disposed adjacent to the center of the disk shaped portion 20. The opposing flap sides of the leaf valve asεembly 28 cling together to minimize paεεage of fluid through the assembly 28. After the closure 13 haε been vulcanized to the εhell 11 to close the shell 11, a needle filled with the filling material 12 penetrates the closure 13 and extendε into the inlet of the leaf assembly 28. The needle is then operated to puεh the fill material 12 into the shell 11. After the shell has been filled, a pocket of air typically existε in the upper portion of the shell 11. This air may be withdrawn by operation of the needle. The hole formed in the center of the closure 13 by the penetration of the needle is then sealed with a biocompatible silicone to form the domed button seal or secondary closure 32. It εhould be noted that the cloεure 13 may alternatively include a valve εuch as compression valve or septa. As noted above, the shell 11 may be of a material which iε permeable or impermeable to water vapor. The εhell ll may be εilicone, polyurethane, or another elaεtomeric material. Fig. 2 shows an implant 40 containing the fill material 12 and a drug or pharmaceutical or therapeutic agent 42 to be dispersed over time. The implant 40 includes a εpherical ovoid or coin-like εhell 44 which iε permeable or semipermeable relative to the agent 42. When the shell is silicone, examples of the agent include silicone permeable hormoneε εuch as progesterone, Eεtradiol including 17-B-Eεtradiol, Melatonin, and evonorgeεtrel, εilicone permeable narcotic analgesics such as Fentanyl and morphine sulfate, and silicone permeable antianginal agents or vasodilatorε εuch aε nitroglycerin.
Procedureε for filling the implants include the following method. The temperature of double distilled water is adjuεted to 35°F (1.67°C). The componentε are then preferably added to the double diεtilled water in the following order: the preεervative if deεired, the croεε-linking agent if desired, the osmotic control agent, and then the rheoiogical agent. Then the diεperεion iε agitated and the temperature of the dispersion is permitted to rise in an environment at room temperature until the desired swelling has occurred. The dispersion is then injected into the implant. The implant is then rotated such that the dispersion remains uniformly dispersed, thereby allowing the rheoiogical agent to fully hydrate (and cross-link if a cross-linking agent has been added to provide a three dimensional network if the rheoiogical agent alone does not provide such) .
It should be noted that "biocompatible" meanε that which remainε in unchanged form in the body without cauεing adverεe reaction, that which may be metabolized, and/or that which may be excreted without being metabolized.
It should further be noted that the fill material of the present invention is radiolucent. The fill material is not radiographically dense, nor does the fill material result in under-exposure of x-ray film. The fill material includes an optical density from about 1.2 to about 1.3 and an x-ray penetrance of from about 9.2 to about 30 illiroentgens. The osmotic control agents and rheoiogical agents of the present invention include elements with relatively low atomic numbers which do not interfere with radiolucency. Example 1 (PVP and guar) Eight hundred (800) grams of high purity water were mixed with 200 g of PVP [poly(2-vinylpyrrolidone) ,
Povidone K-17, (ISP Povidone C-15)] at room temperature to form a yellow liquid. Two and one half grams of methyl-4-hydroxybenzoate and two and one half grams of propyl-4-hydroxybenzoate were added to the PVP solution with vigorouε εtirring. Fifteen gramε of Jaguar 8600 guar gum (Rhone-Poulenc, Specialty Chemical Diviεion, Proεpect Plainε Road, Cranberry NJ) were added by carefully diεpersing the gum into the vortex of a rapidly (ca 2000 rpm) εtirring laboratory mixer to form a reεponsive gel. Example 2 (PVP and guar)
Eight hundred (800) grams of high purity water were mixed with 200 g of PVP (poly(2-vinylpyrrolidone) ) , at room temperature to form a yellow liquid. Two and one half grams of methyl-4-hydroxybenzoate and two and one half grams of propyl-4-hydroxybenzoate were added to the PVP solution with vigorous stirring. Thirty grams of Jaguar 8600 guar gum were added by carefully dispersing the gum into the vortex of a rapidly (ca 2000 rpm) stirring laboratory mixer to form a responεive gel.
Example 3 (PVP and guar)
Eight hundred (800) grams of high purity water were mixed with 200 g of PVP (poly(2-vmylpyrrolidone) ) at room temperature to form a yellow liquid. Two and one half grams of methyl-4-hydroxybenzoate and two and one half grams of propyl-4-hydroxybenzoate were added to the PVP solution with vigorouε εtirring. Forty-five gramε of Jaguar 8600 guar gum were added by carefully diεperεing the gum into the vortex of a rapidly (ca 2000 rpm) εtirring laboratory mixer to form a reεponsive gel.
Example 4 (PVP and guar)
Eight hundred (800) gramε of high purity water were mixed with 200 g of PVP (poly(2-vinylpyrrolidone) ) at room temperature to form a yellow liquid. Two and one half grams of methyl-4-hydroxybenzoate and two and one half grams of propyl-4-hydroxybenzoate were added to the PVP solution with vigorous stirring. Fifty-five grams of Jaguar 8600 guar gum were added by carefully dispersing the gum into the vortex of a rapidly (ca 2000 rpm) εtirring laboratory mixer to form a reεponεive gel. Example 5 (PVP and pectin)
Two hundred grams of a 20% w/w solution of PVP (poly(2-vinylpyrrolidone) ) (with a base of high purity water) were mixed with Carex F/G Arabinose Galactan (a pectin from the larch tree) by adding the Galactan to the vortex of rapidly stirred water. The temperature was raised slowly, over the course of one hour, to 97°C with moderate stirring to form a reεponεive gel. Example 6 (PVP and gelatin) Gelatin (Knox houεehold gelatin) waε added to a 20% (w/w) PVP (poly(2-vinylpyrrolidone) ) εolution aε deεcribed in Example 1. The dispersion was heated until all the gelatin dissolved forming a clear solution. Upon cooling a responsive gel formed. Several concentrations were prepared using this same technique to provide gelε of varying conεistency.
Example 7 (PVP and polyethylene oxide) Four hundred grams of deionized water and one hundred grams of PVP (pol (2-vinylpyrrolidone) ) were mixed with vigorous stirring. To this solution three grams of Polyox 303 (polyethylene oxide, Union Carbide) were added. The rapid formation of a responεive gel waε noted.
Example 8 (PVP and polyethylene oxide) Four hundred gramε of deionized water and one hundred grams of PVP (poly(2-vmylpyrrolidone) ) were mixed with vigorous stirring. To this solution three gramε of Polyox 303 (polyethylene oxide, Union Carbide) were added. The rapid formation of a responsive gel was noted. Example 9 (PVP and polyethylene oxide) Four hundred grams of deionized water and one hundred grams of PVP (poly(2-vmylpyrrolidone) ) were mixed with vigorous stirring. To this solution six grams of Polyox 303 (polyethylene oxide, Union Carbide) were added. The rapid formation of a responsive gel waε noted.
Example 10 (PVP and polyethylene oxide) Eight hundred gramε of deionized water and one hundred grams of PVP (poly(2-vinylpyrrolidone) ) were mixed with vigorous stirring. To this εolution twenty- five gramε of Polyox 303 (polyethylene oxide, Union Carbide) were added. The rapid formation of a reεponεive gel waε noted. Example 11 (PVP and PVP copolymer)
Two hundred gramε of a 20% solution of poly(N-l- vinylpyrrolidone) -co-2-methylaminoethylmethacrylate were mixed with two hundred and fifty-eight grams of high purity water to form a responεive gel. Thirty εix gramε of PVP (poly(2-vmylpyrrolidone) ) were added to the mixture. Upon εtanding a reεponsive viscouε gel waε formed.
Example 12 (PVP and PVP copolymer) Nine hundred forty-nine gramε of 20% (w/w) PVP (poly(2-vinylpyrrolidone) ) εolution were mixed with fifty-one grams of poly(1-vinylpyrrolidone) -co-acrylic acid were mixed together and heated at 70°C for one hour to form a responεive gel.
Example 13 (PVP and PVP copolymer) One hundred grams of poly(1-vinylpyrrolidone) -co- vinylacetate were mixed with eight hundred and thirty grams of deionized water and mixed with vigorous stirring. Seventy grams of PVP (poly(2- vinylpyrrolidone) ) were added to the mixture with vigorous stirring to form a responsive gel.
Thus since the invention disclosed herein may be embodied in other specific forms without departing from the spirit or general characteristics thereof, some of which forms have been indicated, the embodimentε deεcribed herein are to be considered in all respectε illuεtrative and not reεtrictive. The scope of the invention is to be indicated by the appended claims, rather than by the foregoing description, and all changes which come within the meaning and range of equivalents of the claims are intended to be embraced therein.

Claims

1. A safe, rheologically modified, osmotically balanced, biocompatible, lubricating, water based, implant fill material for an implant for the body, the implant having an inner face, the implant fill material comprising, in combination: an aqueous disperεion of a polymeric oεmotic control agent and a polymeric rheoiogical agent, with the polymeric oεmotic control agent being present in the dispersion in an amount effective to subεtantially balance the osmotic preεεure of the implant with the oεmotic preεεure of the portion of the body into which it iε implanted, with the oεmotic control agent further being a lubricant to lubricate an inner face of the implant, with the polymeric rheoiogical agent forming a three-dimensional network and being present in the dispersion in an amount effective such that the fill material is pseudoplaεtic, with the polymeric oεmotic control agent being movable through the three-dimenεional network, and with the fill material being biocompatible.
2. The implant fill material of claim 1 wherein the oεmotic control agent compriεes a poly-N-vinylamide.
3. The implant fill material of claim 1 wherein the osmotic control agent is selected from the group consisting of poly-N-vinylamides, poly-N-vinylamide copolymers, and polyvinylimideε.
4. The implant fill material of claim 3 wherein the poly-N-vinylamide is derived from a linear structure.
5. The implant fill material of claim 4 wherein the poly-N-vinylamide is selected from the group consiεting poly(acetamide) , poly(methylacetamide) , poly(ethylacetamide) , poly(phenylacetamide) , poly(methylpropionamide) , poly(ethylpropionamide) , poly(methyliεobutyramide) , and poly(methylbenzylamide) .
6. The implant fill material of claim 3 wherein the poly-N-vinylamide iε derived from a cyclic εtructure.
7. The implant fill material of claim 6 wherein the poly-N-vinylamide iε εelected from the group conεiεting of polyvinylpyrrolidinone, polyvinylcaprolactam, poly(2- piperidinone) , poly(5-methyl-2-pyrrolidinone) , poly(2,2,5-trimethyl-2-pyrrolidinone) , and poly(5-methyl- 2-pyrrolidinone) .
8. The implant fill material of claim 7 wherein the poly-N-vinylamide is polyvinylpyrrolidinone.
9. The implant fill material of claim 8 wherein the polyvinylpyrrolidinone has a molecular weight from about 3000 to about 40,000 daltons.
10. The implant fill material of claim 7 wherein the poly-N-vinylamide is polyvinylcaprolactam.
11. The implant fill material of claim 1 wherein the osmotic control agent is present in an amount effective to provide the dispersion with an osmolarity of between about 250 and about 350 millioεmoleε.
12. The implant fill material of claim 1 wherein the rheoiogical agent comprises a gum.
13. The implant fill material of claim 12 wherein the gum is selected from the group consiεting of natural polymer gums and synthetic polymer gums.
14. The implant fill material of claim 13 wherein the natural polymer gum is a polysaccharide.
15. The implant fill material of claim 13 wherein the natural polymer gum iε a galactommannan.
16. The implant fill material of claim 15 wherein the galactommannan gum iε selected from the group consiεting of guar gum or a derivative of guar gum, locust bean gum, and tara gum.
17. The implant fill material of claim 16 wherein the galactommannan is guar gum or a derivative of guar gum.
18. The implant fill material of claim 16 wherein the galactommannan gum is locust bean gum.
19. The implant fill material of claim 12 wherein the gum is xanthan.
20. The implant fill material of claim 19 wherein the gum is a blend of xanthan and locust bean gum.
21. The implant fill material of claim 12 wherein the gum iε a cellulose derivative.
22. The implant fill material of claim 21 wherein the cellulose derivative is a hydroxyalkylcellulose.
23. The implant fill material of claim 22 wherein the hydroxyalkylcellulose is selected from the group consisting of carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and ethylhydroxyethylcellulose.
24. The implant fill material of claim 13 wherein the synthetic polymer gum is selected from the group consiεting of poly(vinyl alcohol), polyethylene oxide, polypropylene oxide, polyacrylamide, and copolymerε of polyvinylpyrrolidinone.
25. The implant fill material of claim 12 wherein the gum iε εelected from the group conεiεting of seed gums, tuber and root gums, seaweed extracts, plant extractε, and exudate gumε, fermentation gums, and derived gums.
26. The implant fill material of claim 12 wherein the gum is selected from the group conεiεting of guar gums, cellulose derivative gums, xanthan, a blend of xanthan/locust bean gum, and poly(vinyl alcohol) .
27. The implant fill material of claim 1 wherein the fill material is radiolucent.
28. The implant fill material of claim 1 further comprising means for treating the disperεion to prevent microbial growth.
29. The implant fill material of claim 28 wherein the meanε for treating the diεperεion to prevent microbial growth comprises an antimicrobial.
30. The implant fill material of claim 28 wherein the means for treating the dispersion to prevent microbial growth compriseε irradiating the diεpersion after the disperεion is sealed in the implant.
31. An implant fill material comprising a PVP dispersion, with the disperεion being pseudoplastic.
32. The implant fill material of claim 31 wherein the pseudoplastic disperεion haε an oεmolarity of between about 250 and about 350 millioεmoleε.
33. The implant fill material of claim 32 wherein the pεeudoplaεtic diεperεion iε free of εaltε.
34. The implant fill material of claim 31 further comprising a gum in an effective amount to provide pseudoplasticity to the diεperεion.
35. An implant fill material compriεing, in combination: an aqueouε dispersion of polyvinylpyrrolidinone, and guar gum or a derivative of guar gum, with the polyvinylpyrrolidinone and guar gum or the derivative of guar gum being present in an amount effective such that the dispersion haε an oεmolarity of between about 250 and about 350 millioεmoleε and is pseudoplastic.
36. An implant fill material compriεing, in combination: an aqueouε dispersion of a poly-N- vinylamide and a water disperεable biodegradable three dimenεional network formed by one or more polymeric compoundε, with the poly-N-vinylamide and polymeric compound or compounds being present in amounts effective εuch that the diεpersion has an osmolarity of between about 250 and about 350 milliosmoles and is pεeudoplastic.
37. The implant fill material of claim 36 wherein the compound or compounds compriseε a gum.
PCT/US1996/012861 1995-08-08 1996-08-06 Rheologically modified and osmotically balanced fill material for implant WO1997005832A1 (en)

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US5997574A (en) 1999-12-07
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