WO2006102676A1

WO2006102676A1 - Injectable polyethylene oxide dermal fillers and related devices

Info

Publication number: WO2006102676A1
Application number: PCT/US2006/011201
Authority: WO
Inventors: Edward Perez
Original assignee: Tissue Engineering Refraction, Inc.
Priority date: 2005-03-23
Filing date: 2006-03-23
Publication date: 2006-09-28

Abstract

This description relates to the field of injectable implants useful in supplementing soft tissue, particularly skin. More particularly it relates to dermal filler compositions of biocompatible polyethylene oxides that may be introduced, perhaps by injection, into areas of soft tissue often in need of augmentation. Examples include cosmetic enhancement or correction of facial defects due to scarring, aging and the like. This description also relates to kits containing the described polyethylene oxides and to processes of using these compositions.

Description

INJECTABLE POLYETHYLENE OXIDE DERMAL FILLERS AND RELATED DEVICES

FIELD

[0001] This description relates to the field of injectable implants useful in supplementing soft tissue, particularly skin. More particularly it relates to dermal filler compositions of biocompatible polyethylene oxides that may be introduced, perhaps by injection, into areas of soft tissue often in need of augmentation. Examples include cosmetic enhancement or correction of facial defects due to scarring, aging and the like. This description also relates to kits containing the described polyethylene oxides and to processes of using these compositions.

BACKGROUND

[0002] Injectable dermal fillers are used extensively for the augmentation of soft tissue, such as for removing wrinkles, treating dermal scarring due to trauma, acne, surgery and the like, or for augmenting soft tissue of the lips and nasolabial folds. Injectable fillers have several advantages over traditional surgical techniques for implanting filler materials, such as reduced discomfort, ease of administration, and precise control of the augmentation. Desirable injectable materials are biocompatible, non-immunogenic, non-toxic, non-carcinogenic, and non-resorbable. In addition, they should have the ability to conform to a desired shape and not migrate from the implantation site. They should also be inexpensive, easily sterilized, and have a long storage shelf life. Several materials are currently in use as injectable fillers, for instance, collagen based fillers, hyaluronic acid, synthetic materials such as Silicone or polymethyl methacrylate particles, and autologous materials such as autologous fat (Hotta, Plastic Surgical Nursing 24(1): 14-19, 2004; Ellis et al, Facial Plastic Surgery Clinics of North America 9(3): 405-411, 2001).

[0003] Polyethylene oxides are non-toxic polymers that used in a variety of products, such as cosmetics, shampoos, drug formulations, and laxatives. Polyethylene oxides are available in sizes ranging in molecular weight from less than 1,000 to as high as 10,000,000, for example from Amerchol (Dow) or Polysciences, Inc. (Warrington, PA). These polymers may be linear, branched, or in some instances crosslinked. Although linear polymers are typically water soluble even at high molecular weights, branching and crosslinking of the polymers may result in decreased water solubility such that substantially insoluble solid or gel materials are formed. Crosslinking of polyethylene oxide polymers by a variety of methods is well known, for example, by methods described in U.S. patents 6,323,287 and 6,537,569, among others.

SUMMARY

[0004] This description includes compositions of polyethylene oxide for use as dermal fillers and optionally containing a liquid carrier in which the described polyethylene oxides are substantially insoluble. The term "liquid carrier" is intended to include aqueous fluids, e.g., water and saline solutions, and includes both imbibed liquids where the selected polyethylene oxides are crosslinked and fluids exterior to polyethylene oxides bodies present in an injectable composition. The liquid carrier may further comprise pharmaceutically acceptable excipients, adjuvants, diluents or stabilizers, or combinations thereof. In one variation, the liquid carrier comprises saline or neat water. In one variation, the injectable composition is made up of particles consisting of polyethylene oxide and an aqueous liquid carrier comprising saline or water. In another variation, the injectable composition is made up of particles consisting of polyethylene oxide and the aqueous carrier consists essentially of saline. The polyethylene oxide compositions have a form that is injectable by an injector, such as injectable through a needle. For instance, the form may comprise particles having a particle size and configuration injectable by such injectors. The polyethylene oxide compositions may be substantially non-biodegradable. The polyethylene oxide may be linear or branched and either non-crosslinked or crosslinked. Specifically, the polyethylene oxide may be linear or branched polyethylene oxide that is crosslinked. The crosslinked polyethylene oxide may be in the form of a non-biodegradable hydrogel and in one variation containing such polymer, the composition substantially lacks any organic compound capable of swelling the hydrogel, for example, the composition lacks any organic compound selected from the group consisting of polyethylene glycol having a molecular weight of less than about 10,000, also of less than about 5,000 or less than about 1,000, polyvinyl pyrrolidone, dextran, polyethylene oxide polypropylene oxide copolymer having a molecular weight of less than about 5,000, also of less than about 1,000, polyacrylic acid, polyacrylamide, polyvinyl pyridine, polylysine, polyarginine and oligopeptides. The linear or branched polyethylene oxide may be non-crosslinked with a molecular weight in the range of 100,000 to 10,000,000, also 200,000 to 8,000,000, also 400,000 to 8,000,000, or 1,000,000 to 8,000,000. The linear or branched polyethylene oxide may be crosslinked, wherein prior to crosslinking, the polyethylene oxide has a molecular weight in the range of 20,000 to 10,000,000, also 50,000 to 2,000,000, also 500,000 to 2,000,000, also 50,000 to 1,000,000, or 50,000 to 500,000. The crosslinked polyethylene oxide may be in the form of a non-biodegradable hydrogel.

[0005] The injectable composition may, in addition to including polyethylene oxides, further comprise crosslinked hyaluronic acid, e.g., bodies or particulates consisting essentially of hyaluronic acid having a particle size and configuration that are injectable by an injector, such as injectable through a needle. The hyaluronic acid materials similarly are substantially insoluble in the liquid carrier. Where particles are used, such hyaluronic acid particles may be in the same size range as that of the polyethylene oxide particles. In one instance, the injectable polyethylene oxide or hyaluronic acid particles may be in a size range and configuration that is injectable through a syringe needle, such as having a dimension with a size range of about 10 to 1,000 μm, also about 20 to 1,000 μm, also about 50 to 1,000 μm, or about 100 to 1,000 μm. In any event, the injectable polyethylene oxide or hyaluronic acid bodies, compositions, and particles should be of a size and configuration such that they are injectable through a syringe needle ranging in size from 18 to 33 gauge, also 24 to 31 gauge, or 27 to 30 gauge.

[0006] Included in this description are dermal filler compositions comprising, consisting essentially of, or consisting of polyethylene oxide and a liquid carrier in which the particles are substantially insoluble. The liquid carrier may be aqueous or non-aqueous. In one instance, the liquid carrier may be aqueous. The aqueous liquid carrier may comprise, consist essentially of, or consist of a saline solution. The liquid carrier may further comprise pharmaceutically acceptable excipients, adjuvants, diluents or stabilizers, or combinations thereof. The liquid carrier may further contain other materials, e.g., antibiotics or local anesthetics, as desired. Suitable local anesthetics include lidocaine (perhaps in the commercial solution known as Xylocaine with or without epinepherine), procaine, benzocaine, tetracaine, chloroprocaine, mepivacane, bupivacaine, etidocaine, prilocaine, etc. and the like.

[0007] Other suitable biocompatible liquids such as DMSO, DMF, propylene glycol, glycerol, plant oils, and ethanol may be included in the injectable composition, if so desired. [0008] Included in this description are dermal filler compositions comprising, consisting essentially of, or consisting of polyethylene oxide and a liquid carrier in which the particles are substantially insoluble. Where the polyethylene oxide polymers are particulate, the particles may have a particle size and configuration that is injectable by an injector, such as injectable through a needle. The polyethylene oxide polymer may be a linear or branched polyethylene oxide that is crosslinked such that it is in the form of a non-biodegradable hydrogel and the composition containing such polymer may substantially lack any organic compound capable of swelling the hydrogel. The composition may substantially lack an organic compound capable of swelling the hydrogel selected from the group consisting of polyethylene glycol having a molecular weight of less than about 10,000, also of less than about 5,000 or less than about 1,000, polyvinyl pyrrolidone, dextran, polyethylene oxide polypropylene oxide copolymer having a molecular weight of less than about 5,000, also of less than about 1,000, polyacrylic acid, polyacrylamide, polyvinyl pyridine, poly lysine, polyarginine and oligopeptides. The linear or branched polyethylene oxide may be crosslinked, wherein prior to crosslinking, the polyethylene oxide has a molecular weight in the range of 20,000 to 10,000,000, also 50,000 to 2,000,000, also 500,000 to 2,000,000, also 50,000 to 1,000,000, or 50,000 to 500,000. The crosslinked linear or branched polyethylene oxide may be a non-biodegradable hydrogel. The injectable compositions may further comprise particulates comprising, consisting essentially of, or consisting of hyaluronic acid having a particle size and configuration that is injectable through a needle. Those hyaluronic particles may be substantially insoluble in the liquid carrier. The hyaluronic acid particles may be in the same size range as that of the polyethylene oxide particles. The particles may be in a size range and configuration that is injectable through a syringe needle, such as having a dimension with a size range of about 10 to 1,000 μm, also about 20 to 1,000 μm, also about 50 to 1,000 μm, or about 100 to 1,000 μm. The particles may be of a size and configuration such that they are injectable through a syringe needle ranging from 18 to 33 gauge, also 24 to 31 gauge, or 27 to 30 gauge. The compositions described herein may be sterile.

[0009] Further, the description includes injectable crosslinked linear or branched polyethylene oxide hydrogel compositions containing imbibed or free liquid carrier in which the hydrogel is substantially insoluble. The hydrogel may be added to the injector device in forms or sizes that functionally allow the user to inject the hydrogel and carrier fluid from the injector device through, e.g., the attached needle. The composition of the injectable material may further include the crosslinked HA described above. Further, the makeup of the carrier fluid may be as described above. Finally, the injectable crosslinked linear or branched polyethylene oxide hydrogel compositions may be crosslinked within the injector in a form that is ready for use.

[0010] Also described are kits comprising one or more subcutaneous injectors, such as a syringe and needle, sterile or sterilizable packaging, and a composition as described herein. Methods of making the kits are also described. The kit components, such as the syringe, needle and composition may be sterile. The subcutaneous injector or syringe and needle combination may be sized to cooperate with a chosen composition to allow introduction of the composition by flow through the entry component into a treatment site in the human body. The composition may be contained within the injector or syringe ready for use, perhaps with the attachment of an included needle. The composition may be within a container separate from the syringe, such as in a vial. The needle may be in a size range such as 18 to 33 gauge, 24 to 31 gauge, or 27 to 30 gauge.

[0011] The kit may comprise a composition having particles in a size range of about 50-

1,000 μm. The kit may comprise one or more of a composition having particles in a size range of about 50 to 400 μm or about 100 to 300 μm, a composition having particles in a size range of about 100 to 600 μm or about 200 to 500 μm, or a composition having particles in a size range of about 500 to 1,000 μm or about 700 to 1,000 μm.

[0012] The kit may comprise injectable crosslinked linear or branched polyethylene oxide hydrogel compositions containing imbibed or free liquid carrier in which the hydrogel is substantially insoluble. The injectable crosslinked linear or branched polyethylene oxide hydrogel compositions may be added to the injector before the injector is placed in packaging, added to the injector after the injector is removed from kit packaging, or may be crosslinked in the injector either before or after placement in the kit packaging..

[0013] The kit packaging may be of a type that seals the included components and is capable of maintaining the sterility of the enclosed components until the packaging is opened for use. [0014] The description includes methods of treating or augmenting soft tissue, such as methods of treating fine rhytids, wrinkles, periorbital lines, perioral lines, facial folds, scars, nasolabial folds, oral commisures or other conditions requiring augmentation of soft tissue, or to provide tissue enhancement, such as methods of enhancing lips. These methods involve introducing, such as by injecting, the composition into a treatment site in a mammal, such as a human. The methods may involve using an injector, perhaps a syringe, to inject the composition into a treatment site in a mammal. Variations of the methods include a step of loading a composition from a vial into the injector and injecting the composition, perhaps through a needle, into the treatment site of a mammal. Other variations include introducing a pre-loaded composition into the treatment site.

DETAILED DESCRIPTION

[0015] Polyethylene oxides are formed by the polymerization of ethylene oxide with, for example, an alcohol or water initiator. The characteristics of the polymers will depend on their size. When polymerization is initiated by water, linear polyethylene oxides are terminated by hydroxyl groups at the ends. The ends may also be suitably modified, either by modification of the hydroxyl group or by initiation with a suitable alcohol such that the initiation end terminates in other than a hydroxyl group. Polyethylene oxides with one or more reactive termini are available and may be suitably reacted to form branched polyethylene oxides. Further, linear and branched polyethylene oxides may be crosslinked, for example by reacting with a suitable crosslinking agent (e.g. a chemical agent or radiation) to link polyethylene oxides together along the chain, or by reaction of two sets of polymers with suitably reactive termini. The branching and crosslinking reactions may be selected to provide stable linkages, such that the resulting materials are substantially nonbiodegradable. Linear polyethylene oxides tend to be water soluble, even at high molecular weight. Water solubility may be decreased, for instance, by branching and/or crosslinking of the linear polymers. Water insoluble polyethylene oxides may be suitable as dermal filler materials, since they are generally biocompatible, non-immunogenic, non-toxic, non-carcinogenic, and non- resorbable. [0016] These polymers may be formulated as injectable particles or bodies that are substantially water insoluble and that have a desired shape that does not substantially migrate from an injection site. Polymers suitable for the compositions include polyethylene oxides that are terminated with non-reactive groups, such as hydroxyl groups, and include linear, branched and crosslinked polyethylene oxides. The described compositions may comprise, consist essentially of, or consist of polyethylene oxide particles, where the particles themselves comprise, consist essentially of, or consist of polyethylene oxide. The terms "comprise", "consist essentially of or "consist of polyethylene oxide encompass branched or crosslinked polyethylene oxides. Further, particles comprising, consisting essentially of, or consisting of polyethylene oxides include particles or bodies that are primarily made up of polyethylene oxide chains, but the chains may include additional linking groups, such as branching groups and crosslinking groups, or may have non- reactive termini other than hydroxyl groups, such as methoxy, other alkoxy, or similarly non- reactive groups. Often, the branching groups, crosslinking groups, or non-reactive termini are chosen so that the resulting particles are substantially non-biodegradable. The polyethylene oxide particles or bodies may also be suitably reactive, such as having reactive termini, crosslinking groups and the like described above, such that they can be further reacted in situ. In one instance, suitably sized particles for injection into a treatment site, such as soft tissue, may be mixed with a suitable agent, such as a crosslinking agent, such that upon injection into the treatment site, the particles react further to provide additional structure to the injected material. The additional structure may be a particle network structure or an increase in the particle size at the injection site relative to the particles injected.

[0017] Substantially water insoluble particles or bodies comprising polyethylene oxide, whether linear, branched, crosslinked, or non-crosslinked, or combinations thereof, may be formulated for use in the described compositions. Substantially water insoluble particles or bodies are "insoluble in water" in the sense that they maintain a shape in aqueous solution or are not solvated by the water. Particles "insoluble in water" may also be referred to as not substantially soluble in water. The particle or body may comprise a gel-like material, as with hydrogels, or the particle may be of a more rigid material. The particles and bodies are also substantially insoluble in body fluids and, as such, do not dissolve substantially over time at a site of injection, such as in an area of soft tissue. Preferably the particles are substantially non-biodegradable. Substantially "nonbiodegradable" particles will not readily break down in the body once injected. Substantially water insoluble, non-biodegradable examples of the described compositions will remain at or in the vicinity of the injection site for extended periods, periods such as: greater than 6 months, also 1 year, also 2 years or longer.

[0018] For linear or branched polyethylene oxide, the molecular weight may be in the range of 100,000 to 10,000,000, also 200,000 to 8,000,000, also 400,000 to 8,000,000, or 1,000,000 to 8,000,000. For crosslinked polyethylene oxide, the molecular weight of the material prior to crosslinking may be in the range of 20,000 to 10,000,000, also 50,000 to 2,000,000, also 500,000 to 2,000,000, also 50,000 to 1,000,000, or 50,000 to 500,000. Generally, upon certain forms of crosslinking, the polyethylene oxide polymer is a hydrogel: the crosslinking results in a three dimensional polymer network that swells on absorbing or imbibing water but does not dissolve in water. A crosslinked polyethylene oxide polymer suitable for the injectable composition is one that is substantially non-biodegradable. Solid, semi-solid, gel, or hydrogel materials of polyethylene oxide polymers may be, if desired, comminuted to a selected size by grinding, chopping, microsizing, etc. or other suitable physical process for reducing larger materials to smaller sizes. If a smaller composition is needed for a specific procedure, that material may generally be sized to a suitable size range that is injectable through a selected injector, e.g. a needle using a syringe, to the treatment site. Additionally, for comminuting of hydrogels, the particles may first be lyophilized or frozen while hydrated. If the water is removed from hydrogels before sizing, the dry particle size is selected to provide the desired particle size upon swelling. The particles may also be formulated in the dry state, or in a liquid, perhaps an aqueous liquid, or as a suspension in a carrier liquid, perhaps an aqueous carrier liquid, or in other suitable forms.

[0019] The carrier liquid may comprise pharmaceutically acceptable organic liquids, including, but not limited to, DMSO, DMF, propylene glycol, glycerol, and plant oils. Crosslinked polyethylene oxide particles or compositions may be swelled or imbibed with water or saline solutions and formulated in that swelled state to provide an injectable composition. The carrier liquid in the composition may be aqueous in nature but normally need not consist only of water, although it may be so. The carrier liquid may comprise saline or other pharmaceutically acceptable additives, or may be non-aqueous.

[0020] For many or all of the hydrogels, certain organic, water soluble materials that act to swell the particle may be specifically excluded. For example, such optionally excluded, water soluble organic compounds include polyethylene glycol having a molecular weight of less than about 10,000 (also of less than about 5,000 or less than about 1,000), polyvinyl pyrrolidone, dextran, polyethylene oxide polypropylene oxide copolymer (e.g. Pluronic) having a molecular weight of less than about 5,000 (also of less than about 1,000), polyacrylic acid, polyacrylamide, polyvinyl pyridine, polylysine, polyarginine, and oligopeptides (e.g. polyaspartic acid or polyglutaniic acid).

[0021] The described compositions, in addition to the polyethylene oxide particles or bodies, may also contain hyaluronic acid based materials, which may be polymerized or non-polymerized, and/or crosslinked or non-crosslinked. Hyaluronic acid is a polysaccharide that may be used in gel form as a dermal filler. Commercially available materials include Restylane or Hyaloform. In any described compositions, hyaluronic acid gel particles or bodies may be mixed with the polyethylene oxide composition particles or bodies to provide a suitable material for injection. The hyaluronic acid co-composition sometimes provides advantages, such as lubrication of the injected materials for easier injection and providing an implant that potentially better conforms to a desired shape. Hyaluronic acid containing particles may be dry-mixed and then formulated in a carrier liquid suitable for injection, or may be formulated in a liquid separately and the mixtures or suspensions mixed to provide the desired mixture. The sizes of the polyethylene oxide and hyaluronic acid bodies may be in the same size range if so desired, or may be of different size.

[0022] As noted elsewhere, the individual polymeric particles or bodies utilized in any of the described injectable compositions may comprise, consist essentially of, or consist of polyethylene oxide or of a mixture of polyethylene oxide and one or more other suitable polymers. Other suitable polymers include, but are not limited to, synthetic polymers such as polyalkylene oxides (e.g. other polyethylene oxides, polypropylene oxides, polyethylene oxide-polypropylene oxide copolymers), polyols, polyacrylics, polymethacrylics, polyacrylamides, polymaleic acid, polyolefϊnic alcohols (e.g. polyvinylalcohol), poly N-vinyl lactams (e.g. polyvinylpyrrolidone), polyamino acids (e.g. polylysine), polyoxazolines, and polyvinylamines, and naturally occurring polymers, such as polysaccharides, proteins, proteoglycans, glycosaminoglycans and the like. Suitable naturally occurring polymers include, but are not limited to, hyaluronic acid, dextran, collagen, fibrinogen, elastin, heparin, and albumin. Also included are synthetic versions of such naturally occurring polymers, such as synthetic collagen, heparin, hyaluronic acid, etc. Injectable compositions comprising, consisting essentially of, or consisting of polyethylene oxides in combination with other suitable polymers may be formed in various ways. One procedure entails mixing component polymer particles or bodies such that they are simply physically associated. In another variation, particles or bodies of one type of polymer may be mixed with bodies of another type of polymer, and the mixture reacted to crosslink the polymer types such that the resulting mixture comprises both polymers. The resulting materials may be comminuted, if desired, to provide a desired size range of polymers comprising, consisting essentially of, or consisting of more than one polymer.

[0023] In another variation, compositions described herein may be further modified in situ to provide additional structure to the implanted materials. In one instance, compositions described herein are combined with a suitable agent or agents prior to injecting into a treatment site, such that the injected material results in structural changes to some or all of the particles. Such structural changes include, but are not limited to, crosslinking within an injected dermal filler body or to an adjacent filler body. In one instance, the structural changes may result in a filler body network, or in the formation of larger bodies from smaller ones. Such structural changes may result in reduced migration of injected material from the injection site. Further, the structural change may result in a substantially less biodegradable implant, such that the implanted material remains at the injection site for longer periods of time.

[0024] An injectable composition comprising, consisting essentially of, or consisting of the polymeric dermal filler components described herein may also comprise agents that will react with the particles to physically link the polymeric materials in situ. Such agents include crosslinking agents. In one instance, solid, semi-solid, gel, or hydrogel materials described herein may be comminuted to a selected particle size and combined with suitable agent or agents, such as crosslinking agents, prior to injecting. Such an injected mixture results in a network at the injection site or in larger filler bodies at the injection site than those injected.

[0025] The compositions discussed above may be formulated for injection. The hydrogel compositions may vary over a large size range while remaining injectable. Several of the other compositions may be tailored with particle sizes in a desirable range for injection. Suitable particles may range from about 10 to 1,000 μm, also about 20 to 1,000 μm, also about 50 to 1,000 μm, or about 100 to 1,000 μm. Suitable needle gauges for injection depend on the desired particle size, and are typically 18 or smaller, such as ranging from 18 to 33, also 24 to 31, or 27 to 30 gauge. The desired size range depends to some extent on the intended use, such as whether they will be injected into the superficial dermis, mid dermis or deep dermis. Particles for injection into the superficial dermis, such as for treating fine rhytids, periorbital lines and the like may be in a range of about 50 to 400 μm, also about 100 to 300 μm. Particles for injection into the mid dermis, such as for treating perioral lines, facial folds, shallow scars and the like may be in a range of about 100 to 600 μm, also about 200 to 500 μm. Particles for injection into the deep dermis, such as for treating nasolabial folds, oral commissures, lip enhancement and the like may be in a range of about 500 to 1,000 μm, also about 700 to 1,000 μm. The particles may be placed in a liquid carrier, perhaps an aqueous liquid, such as neat water, a solution comprising saline, which may contain pharmaceutically acceptable excipients, adjuvants, diluents, or stabilizers such as those described, for example, in Gennaro, ed., Remington's The Science and Practice of Pharmacy, 20^th edition, Lippincott Williams &Wilkins. The compositions may also include one or more local anesthetics. Such local anesthetics include, but are not limited to, lidocaine, procaine, prilocaine, mepivicaine, articaine, bupivacaine, benzocaine, chloroprocaine, tetracaine, propoxycaine, and etidocaine. One suitable composition consists essentially of particles consisting of polyethylene oxide in an aqueous saline carrier. Compositions may be suitably sterilized by well known methods, such as electron beam, heat sterilization, or chemical sterilization.

[0026] In addition to the compositions described herein, methods of use of these compositions and kits comprising these compositions are also described. The described kits may comprise at least one injector, such as one or more hypodermic syringe barrel and body and one or more hypodermic needle, and one or more of the injectable compositions described elsewhere herein. The injector, syringe, needle, and composition may be suitably sterilized, variously by chemical sterilants such as ethylene oxide or by radiation sterilization, as by "e-beam" in any packaging or prior to placement in the packaging. The kits may comprise the composition contained within the injector, such as a syringe, or contained in a separate container, such as a vial. The dermal filler composition may be loaded into the injector or into the syringe through a needle, or in a cartridge placed directly into the injector or syringe for injection through the needle.

[0027] In one variation, the vial or injector designated to hold the composition may be used as an in situ reactor for a polyethylene oxide hydrogel composition as described above. The vial or injector is loaded with crosslinkable linear or branched polyethylene oxide and irradiated using ionizing radiation in an appropriate amount, to produce a hydrogel. See, for instance, the compositions and irradiation levels noted in U.S. Pat. No. 3,419,006, the entirety of which is incorporated by reference.

[0028] The kit may comprise one or more needles of a size range of 18 to 33 gauge, also 24 to 31 gauge, or 27 to 30 gauge.

[0029] The kit may comprise suitable packaging as is commonly used to package medical devices. Of interest is the design utilizing a tray that holds the components and cooperates with a lidding material of, e.g., foil, paper, polymeric materials (such as Tyvek), polymeric films, etc., to maintain the components in a sterile state. Such packaging is well known and is easily opened by the user. Such materials may be selected to be resistant or tolerant to chemical sterilants and sterilizing radiation should the materials be sterilized in the packaging. Similarly, the packaging may be selected to be tolerant of ionizing radiation if the hydrogel composition is crosslinked in situ.

[0030] The selected or chosen polyethylene oxide compositions placed in these kits and used as injectable dermal fillers for the augmentation of soft tissue may be selected for specific treatments, such as for treating rhytids, wrinkles, periorbital lines, perioral lines, facial folds, dermal scarring due to trauma, acne, surgery and the like, nasolabial folds, oral commisures, and other conditions, and for enhancing soft tissue such as for lip, chin, and cheek enhancement. The compositions may be used in any mammal, including humans.

[0031] A method of treating or augmenting soft tissue may include the step of injecting the composition through an injector, such as a needle and syringe combination, into a treatment site. The method may further include loading the composition into a syringe and injecting the composition into the treatment site through a suitable gauge needle. The method may involve injection through a needle having a size range of 18 to 33 gauge, also 24 to 31 gauge, or 27 to 30 gauge.

[0032] The disclosures of all references cited herein, including all patents cited, are hereby incorporated by reference in their entirety.

Claims

CLAIMSI claim as my invention:

1. A method of preparing a polyethylene oxide dermal filler kit, comprising the steps of :

providing an amount of a dermal filler gel consisting essentially of polyethylene oxide and water;

providing at least one transdermal injector device selected to controllably introduce a polyethylene oxide dermal filler gel transdermally through human skin,

providing packaging suitable for sealingly and releasingly enclosing at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel and maintaining said at least one said transdermal injector device and polyethylene oxide dermal filler gel in a sterilized condition while sealingly enclosed, and

sealingly enclosing the at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel to form the polyethylene oxide dermal filler kit.

2. The method of claim 1 where the step of providing an amount of a dermal filler gel comprises providing dermal filler gel consisting of polyethylene oxide and water.

3. The method of claim 1 further comprising the step of sterilizing the at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel.

4. The method of claim 3 wherein the step of sterilizing the at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel is prior to the step of sealingly enclosing the at least one said transdermal injector device and polyethylene oxide dermal filler gel.

5. The method of claim 3 wherein the step of sterilizing the at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel is subsequent to the step of sealingly enclosing the at least one said transdermal injector device and polyethylene oxide dermal filler gel.

6. The method of claim 3 wherein the step of sterilizing the at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel comprises contacting the at least one said transdermal injector device and polyethylene oxide dermal filler gel with a chemical sterilant.

7. The method of claim 6 wherein the chemical sterilant.comprises ethylene oxide.

8. The method of claim 3 wherein the step of sterilizing the at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel comprises contacting the at least one said transdermal injector device and polyethylene oxide dermal filler gel with sterilizing radiation.

9. The method of claim 1 wherein the steps of providing an amount of a dermal filler gel consisting essentially of polyethylene oxide and water and providing at least one transdermal injector device comprises providing the polyethylene oxide dermal filler gel preloaded within the at least one transdermal injector device.

10. The method of claim 1 wherein the step of providing the at least one transdermal injector device comprises providing at least one hypodermic needle barrel and at least one hypodermic needle selected to attach to at least one such barrel for controllably introducing the polyethylene oxide dermal filler gel transdermally through human skin.

11. The method of claim 1 wherein the step of providing the at least one transdermal injector device comprises providing at least one hypodermic needle barrel and at least one detached hypodermic needle selected to attach to at least one such barrel for controllably introducing the polyethylene oxide dermal filler gel transdermally through human skin.

12. The method of claim 1 wherein the step of providing the at least one transdermal injector device comprises providing at least one hypodermic needle barrel and at least one hypodermic needle attached to at least one such barrel for controllably introducing the polyethylene oxide dermal filler gel transdermally through human skin,

13. The method of claim 1 wherein the step of providing the packaging suitable for sealingly and releasingly enclosing at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel comprises providing a tray for holding the at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel and sealingly enclosing said device and gel in cooperation with a removable tray liding and providing said removable tray lidding.

14. The method of claim 1 wherein the step of providing an amount of a dermal filler gel consisting essentially of polyethylene oxide further comprises the additional steps of providing reactable polyethylene oxide polymers in said injector and crosslinking said reactable polyethylene oxide polymers to form a polyethylene oxide hydrogel.

15. The method of claim 1 wherein the step of crosslinking said reactable polyethylene oxide polymers to form a polyethylene oxide hydrogel comprises irradiating the reactable polyethylene oxide polymers with an effective amount of ionizing radiation.

16. A polyethylene oxide dermal filler kit, comprising:

an amount of a dermal filler gel consisting essentially of polyethylene oxide and water;

at least one transdermal injector device selected to controllably introduce a polyethylene oxide dermal filler gel transdermally through human skin,

packaging sealingly and releasingly enclosing at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel and maintaining said at least one said transdermal injector device and polyethylene oxide dermal filler gel in a sterilized condition while sealingly enclosed

17. The kit of claim 16 where dermal filler gel consists of polyethylene oxide and water.

18. The kit of claim 16 the at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel are sterilized.

19. The kit of claim 16 wherein the at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel and packaging are selected to be tolerant of sterilizing radiation.

20. The kit of claim 16 wherein the dermal filler gel is preloaded within the at least one transdermal injector device.

21. The kit of claim 16 wherein the at least one transdermal injector device comprises at least one hypodermic needle barrel and at least one hypodermic needle selected to attach to at least one such barrel for controllably introducing the polyethylene oxide dermal filler gel transdermally through human skin.

22. The kit of claim 16 wherein the at least one transdermal injector device comprises at least one hypodermic needle barrel and at least one detached hypodermic needle selected to attach to at least one such barrel for controllably introducing the polyethylene oxide dermal filler gel transdermally through human skin.

23. The kit of claim 16 wherein the at least one transdermal injector device comprises at least one hypodermic needle barrel and at least one hypodermic needle attached to the at least one such barrel.

24. The kit of claim 16 wherein the packaging suitable for sealingly and releasingly enclosing at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel comprises a tray for holding the at least one said transdermal injector device and said amount of polyethylene oxide dermal filler gel and sealingly enclosing said device and gel in cooperation with a removable tray lidding and said attached removable tray lidding.

25. The kit of claim 21 wherein the needle is in a size range of 18 to 33 gauge.

26. The kit of claim 21 wherein the needle is in a size range of 27 to 30 gauge.

27. A dermal filler composition comprising a liquid carrier and polyethylene oxide particles having particle sizes and shapes whereby the composition is injectable through an injector into a human body.

28. The composition of claim 27 wherein the liquid carrier is aqueous.

29. The composition of claim 28 wherein the aqueous liquid carrier is a saline solution.

30. The composition of claim 27 wherein the composition is adapted for injection into facial soft tissue.

31. The composition of claim 27 wherein the particles are not substantially soluble in water.

32. The composition of claim 27 wherein the particles are not hydrogels.

33. The composition of claim 27 wherein the polyethylene oxide consists essentially of a substantially non-biodegradable hydrogel of crosslinked linear or branched polyethylene oxide.

34. The composition of claim 33 wherein the composition substantially lacks an organic compound capable of swelling the hydrogel selected from the group consisting of polyethylene glycol having a molecular weight of less than about 1,000, polyvinyl pyrrolidone, dextran, polyethylene oxide polypropylene oxide copolymer having a molecular weight of less than about 1,000, polyacrylic acid, polyacrylamide, polyvinyl pyridine, polylysine, polyarginine, and oligopeptides.

35. The composition of claim 34 wherein the composition substantially lacks any organic compound capable of swelling the hydrogel.

36. The composition of claim 33 wherein the polyethylene oxide prior to crosslinking has a molecular weight of at least 20,000.

37. The composition of claim 33 wherein the polyethylene oxide prior to crosslinking has a molecular weight in the range of 500,000 to 2,000,000.

38. The composition of claim 27 wherein the particles have a size range of 10 to 1000 μM.

39. The composition of claim 27 further comprising hyaluronic acid gel particles.

40. The composition of claim 39 wherein the hyaluronic acid gel particles are substantially insoluble in the liquid carrier.

41. The composition of claim 27 wherein the composition is injectable through a needle having a size in the range of 18 to 33 gauge.

42. The composition of claim 27 wherein the particulates consist essentially of polyethylene oxide having particle sizes injectable into the human body through an injector.

43. The composition of claim 27 wherein the particles have a size range of 10 to 1000 μM.

44. The composition of claim 27 wherein the particulates consist of polyethylene oxide having particle sizes injectable into the human body through an injector.