The application be the applying date be September in 2012 13, application No. is " 201280055657.7 ", entitled " useIn microgroove treatment dermal augmentation agent composition " application for a patent for invention divisional application.
The priority of the U.S. Provisional Patent Application No.61/534,780 submitted for 14th this application claims September in 2011 andInterests, and be the part continuation application for the U.S. Patent Application Serial Number 13/593,313 that August in 2012 is submitted on the 23rd, the latterIt is the part continuation application for the U.S. Patent Application Serial Number 13/486,754 submitted on June 1st, 2012, requires 2011The U.S. Provisional Patent Application No.61/493 submitted June 3,309 priority and interests, each in these application casesComplete disclosure is integrally incorporated herein by this specific reference.
The present invention relates generally to dermal augmentation agent compositions, and relate more specifically to effective to the microgroove on treatment skinInjectable dermal augmentation agent composition.
Skin aging is a progressive phenomenon, occurs and is influenced by Lifestyle factors as time goes by, such asIt drinks, smoke and sunshine.The aging of atrophy, relaxation and fat characterization skin of face can be used.Atrophy corresponds to skin histology thicknessGreatly reduce.Subcutaneous tissue relaxation causes skin excessive and sagging and leads to cheek and ptosis occur.Obesity refer to becauseIncrease excess weight for face and the swelling of neck bottom.These variation usually to drying, follow the string it is coarse related to skin texture.
Hyaluronic acid (HA), also referred to as hyaluronan are the connective for being distributed widely in entire human body, epithelium and nerve fiberNon sulphate glycosaminoglycan.Hyaluronic acid is all very abundant in different skin layer, and wherein hyaluronic acid has multiple functions, exampleSuch as ensure good aquation, help the composition of extracellular matrix, play packing material and participates in tissue repair mechanisms.However, the amount of other matrix polymers present in hyaluronic acid, collagen, elastin laminin and skin is reduced with the age.ExampleSuch as, being repeated exposure to the (for example) ultraviolet light from the sun causes dermal cell to reduce the generation of its hyaluronan and increaseThe degradation rate of hyaluronan.This material loss leads to various skins, such as corrugates, recess, water loss and hasHelp other undesirable conditions of aging appearance.
Injectable dermal augmentation agent has been used successfully to treatment aging skin.Filler can replace the endogenous parent lost poly-The function of closing object or the existing matrix polymer of enhancing/promotion, to treat these skins.Corium based on hyaluronic acidFiller has become to become more and more popular, because hyaluronic acid is the substance existing for entire human body natural.These fillers are logicalNormal well-tolerated, impermanency, and be the treatment to the suitable low-risk of a variety of skins.
Tyndall effect (Tyndall effect) is to applied one of the dermal augmentation agent based on hyaluronic acid (HA)The adverse events occurred in a little patients.Tyndall effect is characterized in that, is gone out in the skin part for having injected dermal augmentation agentExisting blue variable colour, this indicates to see visible hyaluronic acid by translucent epidermis.Clinical report show filler application technique andSkin properties can influence the performance of this adverse events.High rigidity and elastomeric filler are used successfully to correct the upper such as nose of faceThe regions such as labial groove, cheek and chin, without having any worry to change color, because Material injection is at middle part and deep dermis areaIn.However, when using these packing materials to correct superficial, fine wrinkles, such as tear ditch, glabella line, canthus line, laugh line or precedingVolume, or in upper part of dermis region too superficial mistake in application, being frequently observed the light blue discoloration of skin.This phenomenon,Be considered as Tyndall effect as a result, cause application site semipermanent change colour, and sometimes only applied degradationIt disappears after the hyaluronidase of packing material.Therefore, Tyndall effect is more conventional in the patient for the treatment of superficial fine wrinkles.OnlyGel is wanted to maintain in skin, Tyndall effect performance extends, and usual some months is an original of principal concern in patientCause.
The dermal augmentation gel based on HA has especially been prepared to treat around tear ditch, forehead, canthus line, glabella line etc.It was found that " fine wrinkles ".Commercially available HA " microgroove " gel includes Juv é derm Refine (G '~67Pa；G”/G’~0.59, HA concentration 18mg/ml), Belotero Soft (G '~28Pa；G "/G '~1.1, HA concentration 20mg/ml),Emervel Touch (G '~56Pa；G "/G '~0.64, HA concentration 20mg/ml), Stylage S (G '~192Pa；G "/G '~0.20, HA concentration 16mg/ml), Teosyal First Lines (G ' 59Pa；G "/G '~0.53, HA concentration 20mg/ml),Restylane Touch (G '~489Pa；G "/G '~0.24, HA concentration 18mg/ml).Although (for example) by making linear HA chainsIt is slightly cross-linked and/or reduce the final HA concentration of these gels with a small amount of crosslinking agent, these gels are configured to low elasticityModulus, but most of commercially available " microgroove " gel still shows Tyndall effect among the patients, especiallyWhen superficial is injected, such as in the depth less than about 1mm.
The gel based on collagen can be used in the treatment of superficial wrinkle and seem that Tyndall effect will not be caused.Gel based on collagen, which is not affected by height, to be favored, because their duration in skin are relatively poor and needIt is tested in advance in individual.(calcium hydroxy apetite) is subcutaneous, injectable implant, and key component is synthesis hydroxylBase apatite calcium rather than hyaluronic acid.Different from the dermal augmentation agent based on hyaluronic acid, calcium hydroxy apetite is opaque, becauseThis avoids the complication of Tyndall effect.However, if placement is too shallow, this filler can be considered as under skinWhiteness.In addition, compared with the filler based on hyaluronic acid,Longer syringe needle is needed to inject and lead toOften do not recommend to be used for ocular.
Needs are provided to the noting based on hyaluronic acid for the light blue discoloration that will not show to be attributed to Tyndall effectPenetrate dermal augmentation agent.
The present invention describes preparation and can be applied in the corium of top, does not generate any light blue discoloration of skin, or at leastThe composition and preparation method of the dermal augmentation agent based on HA of not notable or unconspicuous light blue discoloration.Further,It is found that the gel filled duration in vivo of presently described many present invention is obviously commercially available more solidifying than on Vehicles Collected from MarketGlue is longer.In some aspects of the present invention, the optically transparent dermal augmentation agent useful to enhancing skin appearance is provided, is increasedVolume and richness are added, and have reduced the appearance of even fine wrinkles, has not had " Tyndall effect ".This composition can introduceIn the microgroove of skin or even thin skin region and suitable superficial, the dermal augmentation agent transparent with many normal opticals will not be causedRelevant negative blue variable colour.
More specifically, in one aspect of the invention, providing long-acting treatment dermal augmentation agent composition, usually wrapContaining biocompatible polymer, such as cross-linked-hyaluronic acid component and the additive that merges with hyaluronic acid component.
In one embodiment, polymer is polysaccharide, such as hyaluronic acid.Hyaluronic acid includes cross-linking component and canFurther comprise non-crosslinked components.Additive may include vitamin, for example, vitamin C (for example, vitamin C of stable form) orVitamin C derivatives are (for example, L-AA 2- glucosides (AA2G), ascorbic acid 3- aminopropyl phosphate (vitagens(Vitagen)) or STAY-C 50 (AA2P)).
In one aspect of the invention, additive is vitamin derivative, by suitable reaction process, such as be etherified,Amidation or esterification and polymer covalent bond.
At one of present invention aspect extensively, dermal augmentation agent composition is provided, the composition includes and crosslinking groupDivide crosslinked hyaluronic acid component and the additive in addition to the cross-linking component.Hyaluronic acid component can be with additive chemistry knotIt closes.Further, when in the corium area for being administered to patient, relative in addition to no additive, substantially the same groupObject is closed, the composition shows Tyndall effect reduction.The composition can further include other additives, such as anaesthetizeAgent (such as lidocaine).In one embodiment, additive is vitamin C derivatives, such as AA2G.In another embodiment partyIn case, additive is vitagen.
In one embodiment, hyaluronic acid component is combined with additive chemistry, and conjugation is between about 3mol% peace treatiesBetween 40mol, such as between about 3mol% and about 10mol%.
The composition may generally optical clear.G ' the values of the composition are generally between about 40Pa and about 100PaBetween, such as no more than about 100Pa, such as not less than about 40Pa.
In another aspect of this invention, the method for providing the microgroove on treatment patient skin.In one embodiment,The method includes being introduced in the skin to patient comprising hyaluronic acid component, be crosslinked the cross-linking component of the hyaluronic acid and removedThe step of composition of the mixture of additive other than the cross-linking component, the composition generally optical clear, andWherein relative in addition to no additive, substantially the same composition, the composition shows Tyndall effect and subtractsIt is small.
In another aspect of this invention, providing improves the method for face appearance, and the method generally includes the following steps：The generally optically transparent corium for not showing or showing unconspicuous Tyndall effect is applied to the corium area of patientBulking agent compositions.The composition is made through the following steps：Hyaluronic acid is provided, crosslinking agent and vitamin C derivatives are madeReaction, it includes covalently bound that the crosslinking agent reacted, which is added in the hyaluronic acid with vitamin C derivatives to be formed,Ascorbic cross-linked-hyaluronic acid composition；And it homogenizes and neutralizes the cross-linked-hyaluronic acid composition to obtain injectableDermal augmentation agent composition.In some embodiments, vitamin C derivatives are AA2G.In other embodiments, dimension lifePlain C derivatives are vitagens.
In still another aspect of the invention, the method for reducing that microgroove occurs in patient's thin skin area, wherein the method are providedIt is typically included in the depth no more than about 1mm, dermal augmentation agent composition, a kind of generally optical clear are applied to the patientThe dermal augmentation agent composition based on hyaluronic acid comprising vitamin C or vitamin C derivatives.In some embodimentsIn, the composition described in the deeper injection no more than 0.8mm, no more than 0.6mm or no more than 0.4mm.
In still another aspect of the invention, it provides a kind of dermal augmentation agent composition, generally optical clear and leads toOften comprising with the crosslinked hyaluronic acid component of cross-linking component and with the covalently bound vitamin C derivatives of hyaluronic acid component.In one exemplary implementation scheme, the G ' values of the composition are between about 40Pa and about 100Pa.Further, described groupThe hyaluronic acid concentration for closing object may be between about 18mg/g and about 30mg/g.In treatment skin, for example, even very thinIn microgroove or superficial gauffer on skin, such as skin of the thickness no more than about 1mm, these compositions may be particularly useful and be hadEffect.In some embodiments, composition of the invention after introducing skin continue at least three moon, at least six moon or be up to oneYear.
It may be easier to understand and recognize these and other aspects of the invention and excellent with reference to following drawings and detailed descriptionPoint.
Brief description
Fig. 1 is the structural schematic diagram of L-AA 2- glucosides (AA2G).
Fig. 2 is the structural schematic diagram of ascorbic acid 3- aminopropyls phosphate (vitagen).
Fig. 3 is the structural schematic diagram of STAY-C 50 (AA2P).
Fig. 4 is the structural schematic diagram of 1,4-butanediol diglycidyl ether (BDDE).
Fig. 5 is the structural schematic diagram of pentaerythrite glycidol ether (Star-PEG epoxides).
Fig. 6 is the structural schematic diagram of pentaerythrite (3- aminopropyls) ether (Star-PEG amine).
Fig. 7 is the table of the conjugation and G ' values that show various dermal augmentation agent compositions according to the present invention.
Fig. 8 is to show that the conjugation, HA of HA-AA2G according to the present invention (BDDE) dermal augmentation agent composition are denseThe table of degree and G ' values.
Fig. 9 is for 4 kinds of different alpha-glucosaccharase enzyme concentrations, and in terms of the time (Minute), that observes comes fromThe pictorial diagram of the percentage of the AsA releases of solution of the AA2G in PBS.
Figure 10 shows the release profiles schematic diagram of the free AsA from combination dermal augmentation agent according to the present invention(sustained release) (AA2G compared with the reaction time converts mol%).
Figure 11 A and 11B show the additional release data of various dermal augmentation agent according to the present invention.
Figure 12 shows that the present invention is based on the dermal augmentation gels of HA and some commercially available confessions in superficial injectionAfter the gel of microgroove application, the image of skin.
Figure 13 shows the present invention is based on the dermal augmentation gel of HA and certain commercially available is applied for microgrooveThe vision Tyndall score of gel.
Figure 14 show the present invention is based on the dermal augmentation gel of HA and some commercially available applied for microgrooveThe blue light % that gel is emitted from skin.
Figure 15 show implantation the present invention is based on the dermal augmentation gel of HA and some commercially available answered for microgrooveAfter gel 1 week, total % of remaining gel.
Figure 16 is shown implantation is the present invention is based on the dermal augmentation gel of HA and some are commercially available for microgrooveThe gel of application the 0th week, the 12nd week, the 24th week and the 40th week, total % of remaining gel.
It is described in detail
In one aspect of the invention, dermal augmentation agent composition is provided, the composition generally comprises bio-compatibleProperty polymer, for example, polysaccharide (such as cross-linked-hyaluronic acid) and with the covalently bound vitamin C derivatives of the polymer.It is describedComposition provides sustained release for the vitamin C of skin collagen hyperplasia and other treatments or beauty interests.Work as introducingWhen skin, for example, it is intradermal, and the composition is reacted with internal endogenous enzyme, and over time, is enzymatically cleaved off in vivoGenerate bioactive vitamin C.Because vitamin C is discharged from the composition in a few weeks or months so that followingInterests it is available to body.
The polymer can be selected from protein, peptide and polypeptide, polylysine, collagen, procollagen, elastin lamininAnd laminin.
The polymer can be selected from the synthetic polymer with hydroxyl, amine and carboxyl functional group：Poly- (vinyl alcohol), poly- second twoAlcohol, polyvinylamine, polyallylamine, deacetylate polyacrylamide, polyacrylic acid and polymethylacrylic acid.The polymer is optionalFrom dendroid or branched polymer, including dendrimeric polyols and dendroid polyamine.The polymer can be selected from hydroxyl, amineWith the surface of solids of carboxyl functional group.
The polymer can be polysaccharide, such as selected from following group of polysaccharide, including starch and its derivative；Glucan and itsDerivative；Cellulose and its derivates；Chitin, chitosan and alginates and its derivative.
In the exemplary implementation scheme of the present invention, the polymer is glycosaminoglycan.Hydrogel disclosed hereinComposition can further include two or more different Glycosaminoglycan Polymers.As used herein, " osamine is poly- for termSugar " is synonymous with " GAG " and " mucopolysaccharide " and refers to the long linear polysaccharide of repetition disaccharide unit composition.Repetitive unit by with hexosamineThe hexose (hexose) or hexuronic acid composition of (nitrogenous hexose) and its pharmaceutically acceptable salt connection.GAG families atIt is different in the type of hexosamine of the member contained by it, hexose or hexuronic acid unit, for example, glucuronic acid, iduronic acid,Galactolipin, galactosamine, gucosamine and may also be different in the geometric shape of glycosidic inkage.Any Glycosaminoglycan PolymerUseful in hydrogel composition disclosed herein, condition, which is Glycosaminoglycan Polymer, improves skin.GlycosaminoglycanNon-limiting examples include chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronan.The acceptable salt of glycosaminoglycanNon-limiting examples include sodium salt, sylvite, magnesium salts, calcium salt and combinations thereof.For example, in Piron and Tholin,Polysaccharide Crosslinking, Hydrogel Preparation, Resulting Polysaccharides (s)And Hydrogel (s), uses Thereof, U.S. Patent Publication 2003/0148995；Lebreton, Cross-Linkingof Low and High Molecular Weight Polysaccharides Preparation of InjectableMonophase Hydrogels；Lebreton, Viscoelastic Solutions Containing SodiumHyaluronate and Hydroxypropyl Methyl Cellulose, Preparation and Uses, United States Patent (USP)Announce 2008/0089918；Lebreton, Hyaluronic Acid-Based Gels Including Lidocaine, the U.S.Patent disclosure 2010/0028438；With Polysaccharides and Hydrogels thus Obtained, United States Patent (USP) public affairsCloth 2006/0194758；With Di Napoli, Composition and Method for Intradermal Soft TissueIt is described in hydrogel composition disclosed herein and method in Augmentation, international patent publications WO 2004/073759In useful glycosaminoglycan and its resulting polymers, be respectively integrally incorporated accordingly by reference.In hydrogel disclosed hereinUseful GAG is commercially available in composition and method, such as the dermal augmentation agent based on hyaluronan30、Ultra、UltraPlus、Ultra XC andUltra Plus XC (Allergan Inc, Irvine,Califomia).Table 1 lists representative GAG.
The aspect of the present invention provides in part the hydrogel composition for including chondroitin sulfate polymer.As made hereinWith term " chondroitin sulfate polymer " refers to unbranched, the sulfated polymers of variable-length, and it includes two alternating monosaccharideThat is the disaccharides of D-Glucose aldehydic acid (GlcA) and N-ACETYL-D- GALACTOSAMINE (GalNAc) and its pharmaceutically acceptable salt.Chondroitin sulfate polymer may also comprise the D-Glucose aldehydic acid residue that epimerism turns to L- iduronic acids (IdoA), at thisGained disaccharides is known as dermatan sulfate in the case of kind.It is more than 100 individually sugared chains that chondroitin sulfate, which can have, respectively withVariable position and amount sulphation.Chondroitin sulfate polymer is the important feature component of cartilage and provides it and permitted compressionMultiresistance.Any chondroitin sulfate polymer is useful in compositions disclosed herein, and condition is chondroitin sulfate polymerImprove skin.The non-limiting examples of chondroitin sulfate pharmaceutically acceptable salt include that sodium chondroitin sulfate, sulfuric acid are softOssein potassium, chondroitin sulfate magnesium, calcium chondroitin sulfate and combinations thereof.
The hydrogel composition for including keratan sulfate polymer is provided in part in terms of this specification.Such as this paper institutesIt uses, term " keratan sulfate polymer " refers to the polymer of the variable-length comprising disaccharide unit, itself includes β-D- halfLactose and N-ACETYL-D- GALACTOSAMINE (GalNAc) and its pharmaceutically acceptable salt.Two in keratan sulfate duplicate blockSugar may be covered through fucosylation and N-acetyl-neuraminate in the end of chain.Any keratan sulfate polymer is public hereinUseful in the composition opened, condition, which is keratan sulfate polymer, improves skin.Keratan sulfate is pharmaceutically acceptableSalt non-limiting examples include keratan sulfate sodium, keratan sulfate potassium, keratan sulfate magnesium, keratan sulfate calcium and itsCombination.
The hydrogel composition for including hyaluronan polymer is provided in part in terms of this specification.As made hereinWith, term " hyaluronan polymer " is synonymous with " HA polymer ", " hyaluronic acid polymer " and " hyaluronate polymers ",Refer to anion, the non sulphate Glycosaminoglycan Polymer for including disaccharide unit, itself include passing through alternate β-Isosorbide-5-Nitrae and β -1,3 glucosides key connections D-Glucose aldehydic acid together and D-N- acetylglucosamine monomers and its pharmaceutically acceptable salt.It canHyaluronan polymer is purified from animal and non-animal.The polymer sizes range of hyaluronan can from about 5,000Da toAbout 20,000,000Da.Any hyaluronan polymer is useful in compositions disclosed herein, and condition is that hyaluronan changesKind skin.The non-limiting examples of hyaluronan pharmaceutically acceptable salt include hyaluronan sodium, hyaluronan potassium, thoroughlyBright matter alkane magnesium, hyaluronan calcium and combinations thereof.
The hydrogel composition for including crosslinking Glycosaminoglycan Polymer is provided in part in terms of this specification.As hereinIt is used, term " crosslinking " refers to intermolecular linkage, and individual polymer molecule or monomer chain link imaging gel is equally more stableStructure.Thus, crosslinking Glycosaminoglycan Polymer has is connected to another at least one by least one object molecule that is polymerized aloneA intermolecular linkage.The crosslinking of Glycosaminoglycan Polymer typically results in hydrogel and is formed.Such water-setting adhesiveness is high and needs phaseWhen big power squeezes out fine needle.Dialdehyde and disulphide cross-linking agents Glycosaminoglycan Polymer disclosed herein can be used, includingBut it is not limited to multi-functional PEG group crosslinking agent, divinyl sulfone, glycidol ether and di-epoxide, dual-carbodiimide.HyaluronanThe non-limiting examples of crosslinking agent include multi-functional PEG group crosslinking agent, such as four glycidol ether of pentaerythrite (PETGE), diethylBis- (2, the 3- glycidoxy) ethylene (EGDGE) of alkene sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE), 1,2-, 1,2,7,8-- diepoxyoctanes (DEO), (phenylene is double-(ethyl)-carbodiimide and 1,6 hexylidenes bis- (ethyl carbodiimides), oneselfTwo hydrazides (ADH), bis- (sulfosuccinic base) suberates (BS), hexamethylene diamine (HMDA), 1- (2,3- glycidoxy) -2,3- ringsOxygen hexamethylene, lysine, lysine methyl ester or combinations thereof.In Stroumpoulis and Tezel, Tunably CrosslinkedPolysaccharide Compositions are disclosed in the U.S. Patent application 12/910,466 that on October 22nd, 2010 submitsOther useful crosslinking agents are integrally incorporated by reference.For example, in Piron and Tholin, PolysaccharideCrosslinking, Hydrogel Preparation, Resulting Polysaccharides (s) and Hydrogel(s), uses Thereof, U.S. Patent Publication 2003/0148995；Lebreton, Cross-Linking of Low andHigh Molecular Weight Polysaccharides Preparation of Injectable MonophaseHydrogels；Lebreton, Viscoelastic Solutions Containing Sodium Hyaluronate andHydroxypropyl Methyl Cellulose, Preparation and Uses, U.S. Patent Publication 2008/0089918；Lebreton, Hyaluronic Acid-Based Gels Including Lidocaine, U.S. Patent Publication 2010/0028438；With Polysaccharides and Hydrogels thus Obtained, U.S. Patent Publication 2006/0194758；With Di Napoli, Composition and Method for Intradermal Soft TissueThe non-limit of the method for crosslinking Glycosaminoglycan Polymer is described in Augmentation, international patent publications WO 2004/073759Property example processed, and useful Glycosaminoglycan Polymer in compositions disclosed herein and method, respectively accordingly by drawingWith being integrally incorporated.
The water for including the crosslinking Glycosaminoglycan Polymer with certain degree of cross linking is provided in part in terms of this specificationGel combination.As used herein, term " degree of cross linking " refers to Glycosaminoglycan Polymer monomeric unit, such as is combined with crosslinking agentHyaluronan disaccharides monomeric unit percentage.The degree of cross linking is expressed as the weight percent of crosslinking agent and glycosaminoglycan.At thisInvention certain Favourable implementations in, the degree of cross linking between about 3% and about 12%, such as between about 5% and about 10% itBetween.
In one embodiment, hydrogel composition includes to be crosslinked Glycosaminoglycan Polymer, such as cross-linked-hyaluronic acid,The concentration of the crosslinking Glycosaminoglycan Polymer is (for example) between about 18mg/g and about 30mg/ present in the wherein described compositionBetween g.In some embodiments, the hyaluronic acid total concentration of the composition is about 24mg/g or about 25mg/g.
Provided in part in terms of this specification the hyaluronan polymer comprising low molecular weight, high molecular weight it is transparentThe hydrogel composition of matter alkane polymer or the hyaluronan polymer of low molecular weight and high molecular weight.As used herein, whenTerm " high molecular weight " refers to average molecular weight and polymerize for 1,000,000Da or higher hyaluronans when referring to " hyaluronan "Object.The non-limiting examples of high molecular weight hyaluronan polymer include about 1,500,000Da, about 2,000,000Da, about 2,500,000Da, about 3,000,000Da, about 3,500,000Da, about 4,000,000Da, about 4,500,000Da and about 5,000,The hyaluronan polymer of 000Da.As used herein, when referring to " hyaluronan ", term " low molecular weight " refers to mean moleculeHyaluronan polymer of the amount less than 1,000,000Da.The non-limiting examples of low molecular weight hyaluronan polymer include about200,000Da, about 300,000Da, about 400,000Da, about 500,000Da, about 600,000Da, about 700,000Da, about 800,The hyaluronan polymer of 000Da and about 900,000Da.
In one embodiment, composition includes the cross-linked transparent matter alkane polymer of low molecular weight.In the embodimentAspect, composition include average molecular weight be (for example) about 100,000Da, about 200,000Da, about 300,000Da, about 400,The cross-linked transparent of 000Da, about 500,000Da, about 600,000Da, about 700,000Da, about 800,000Da or about 900,000DaMatter alkane polymer.In the other aspects of the embodiment, composition include average molecular weight be (for example) at most 100,000Da,At most 200,000Da, at most 300,000Da, at most 400,000Da, at most 500,000Da, at most 600,000Da, at mostThe cross-linked transparent matter alkane polymer of 700,000Da, at most 800,000Da, at most 900,000Da or at most 950,000Da.At thisThe other aspects of embodiment, composition include that average molecular weight is (for example) about 100,000Da to about 500,000Da, about200,000Da to about 500,000Da, about 300,000Da to about 500,000Da, about 400,000Da to about 500,000Da, about500,000Da to about 950,000Da, about 600,000Da to about 950,000Da, about 700,000Da to about 950,000Da, about800,000Da to about 950,000Da, about 300,000Da to about 600,000Da, about 300,000Da to about 700,000Da, aboutThe cross-linked transparent matter alkane polymer of 300,000Da to about 800,000Da or about 400,000Da to about 700,000Da.
In another embodiment, composition includes the cross-linked transparent matter alkane polymer of high molecular weight.In the embodimentAspect, composition include average molecular weight be (for example) about 1,000,000Da, about 1,500,000Da, about 2,000,000Da,About 2,500,000Da, about 3,000,000Da, about 3,500,000Da, about 4,000,000Da, about 4,500,000Da or about 5,The cross-linked transparent matter alkane polymer of 000,000Da.In the other aspects of the embodiment, composition is comprising average molecular weight(for example) at least 1,000,000Da, at least 1,500,000Da, at least 2,000,000Da, at least 2,500,000Da, at least 3,000,000Da, at least 3,500,000Da, at least 4,000,000Da, at least 4,500,000Da or at least 5,000,000Da'sCross-linked transparent matter alkane polymer.In the other aspects of the embodiment, composition includes that average molecular weight is (for example) about 1,000,000Da to about 5,000,000Da, about 1,500,000Da to about 5,000,000Da, about 2,000,000Da to about 5,000,000Da, about 2,500,000Da are to about 5,000,000Da, about 2,000,000Da to about 3,000,000Da, about 2,500,000DaTo the cross-linked transparent matter alkane polymer of about 3,000,000Da.
In another embodiment, composition includes cross-linked transparent matter alkane polymer, wherein the cross-linked transparent matter alkane polymerizeObject includes the combination of the high molecular weight hyaluronan polymer and low molecular weight hyaluronan polymer of different proportion.In the implementationThe aspect of scheme, composition includes cross-linked transparent matter alkane polymer, wherein the cross-linked transparent matter alkane polymer is comprising ratioAbout 20: 1, about 15: 1, about 10: 1, about 5: 1, about 1: 1, about 1: 5, about 1: 10, about 1: 15 or about 1: 20 high molecular weight hyalomitomeThe combination of alkane polymer and low molecular weight hyaluronan polymer.
The hydrogel composition for including uncrosslinked Glycosaminoglycan Polymer is provided in part in terms of this specification.Such as thisText is used, and term " uncrosslinked " refers to the intermolecular linkage for lacking and connecting individual Glycosaminoglycan Polymer molecule or monomer chain.CauseAnd uncrosslinked Glycosaminoglycan Polymer is not connect by intermolecular linkage with any other Glycosaminoglycan Polymer.In the embodiment partyThe aspect of case, composition include uncrosslinked chondroitin sulfate polymer, uncrosslinked dermatan sulfate polymer, uncrosslinked sulfuric acid angleQuality polymer, uncrosslinked heparan polymer, uncrosslinked Heparan sulfate polymer or the polymerization of uncrosslinked hyaluronanObject.Uncrosslinked Glycosaminoglycan Polymer is water-soluble and usually keeps mobility in itself.Thus, uncrosslinked glycosaminoglycanPolymer often mixes with the hydrogel composition based on Glycosaminoglycan Polymer as lubricant thin to promote composition to pass throughThe extrusion of needle.
In one embodiment, composition includes uncrosslinked Glycosaminoglycan Polymer, wherein the uncrosslinked osamine is poly-A concentration of (for example) about 2mg/g, about 3mg/g, about 4mg/g, about 5mg/g, about 6mg/g, about 7mg/g existing for glycopolymers, about8mg/g, about 9mg/g, about 10mg/g, about 11mg/g, about 12mg/g, about 13mg/g, about 13.5mg/g, about 14mg/g, about 15mg/G, about 16mg/g, about 17mg/g, about 18mg/g, about 19mg/g, about 20mg/g, about 40mg/g or about 60mg/g.In the embodiment partyThe other aspects of case, composition includes uncrosslinked glycosaminoglycan, wherein a concentration of (example existing for the uncrosslinked glycosaminoglycanAs) at least 1mg/g, at least 2mg/g, at least 3mg/g, at least 4mg/g, at least 5mg/g, at least 10mg/g, at least 15mg/g, extremelyFew 20mg/g, at least 25mg/g, at least 35mg/g or at least 40mg/g.In the other aspects of the embodiment, composition includesUncrosslinked glycosaminoglycan, wherein a concentration of (for example) at most 1mg/g, at most 2mg/g existing for the uncrosslinked glycosaminoglycan, extremelyMore 3mg/g, at most 4mg/g, at most 5mg/g, at most 10mg/g, at most 15mg/g, at most 20mg/g or at most 25mg/g.At thisThe other aspects of embodiment, composition includes uncrosslinked glycosaminoglycan, wherein concentration existing for the uncrosslinked glycosaminoglycanFor (for example) about 1mg/g to about 60mg/g, about 10mg/g to about 40mg/g, about 7.5mg/g to about 19.5mg/g, about 8.5mg/gTo about 18.5mg/g, about 9.5mg/g to about 17.5mg/g, about 10.5mg/g to about 16.5mg/g, about 11.5mg/g to about15.5mg/g or about 12.5mg/g are to about 14.5mg/g.
The hydrogel composition substantially free of crosslinking Glycosaminoglycan Polymer is provided in part in terms of this specification.As used herein, term substantially free (or " substantially by ... form "), which refers to, wherein only can detect micro friendshipJoin the composition of matrix polymer.In the one side of the embodiment, composition includes substantially free of crosslinking chondroitin sulfateThe chondroitin sulfate of plain polymer, substantially free of crosslinking dermatan sulfate polymer dermatan sulfate, substantially free of friendshipKeratan sulfate, the heparan, substantially substantially free of crosslinking heparan polymer for joining keratan sulfate polymerHeparan sulfate without crosslinking Heparan sulfate polymer or the sulfuric acid substantially free of cross-linked transparent matter alkane polymerHyaluronan.
The hydrogel composition for being entirely free of crosslinking Glycosaminoglycan Polymer is provided in part in terms of this specification.Such asUsed herein, term " being entirely free of " refers to composition within the scope of the instrument or fabrication evaluation used, cannot detect crosslinkingGlycosaminoglycan Polymer not can confirm that its presence.In the one side of the embodiment, composition includes to be entirely free of crosslinkingThe chondroitin sulfate of chondroitin sulfate polymer, the dermatan sulfate, completely not for being entirely free of crosslinking dermatan sulfate polymerContaining crosslinking keratan sulfate polymer keratan sulfate, be entirely free of crosslinking heparan polymer heparan, completelyIt is saturating without the Heparan sulfate for being crosslinked Heparan sulfate polymer or the sulfuric acid for being entirely free of cross-linked transparent matter alkane polymerBright matter alkane.
It is provided in part in terms of this specification comprising a certain proportion of crosslinking Glycosaminoglycan Polymer and uncrosslinked sugarThe hydrogel composition of amine chitosan polymer.This ratio of crosslinking and uncrosslinked Glycosaminoglycan Polymer is alternatively referred to as gel:Fluid ratio.Any gel in preparing compositions disclosed herein: fluid ratio is useful, condition are that the generation of this ratio is disclosed hereinImprovement skin as disclosed herein composition.Gel in the present composition: fluid than non-limiting examples packetInclude 100: 0,98: 2,90: 10,75: 25,70: 30,60: 40,50: 50,40: 60,30: 70,25: 75,10: 90；2: 98 and 0:100。
In terms of the embodiment, composition includes crosslinking Glycosaminoglycan Polymer and the polymerization of uncrosslinked glycosaminoglycanObject, wherein gel: fluid ratio be (for example) about 0: 100, about 1: 99, about 2: 98, about 3: 97, about 4: 96, about 5: 95, about 6: 94,About 7: 93, about 8: 92, about 9: 91 or about 10: 90.In the other aspects of the embodiment, composition includes that crosslinking glycosaminoglycan is poly-Close object and uncrosslinked Glycosaminoglycan Polymer, wherein gel: fluid ratio is (for example) at most 1: 99, at most 2: 98, at most 3: 97,At most 4: 96, at most 5: 95, at most 6: 94, at most 7: 93, at most 8: 92, at most 9: 91 or at most 10: 90.In the embodimentOther aspects, composition includes crosslinking Glycosaminoglycan Polymer and uncrosslinked Glycosaminoglycan Polymer, wherein gel: fluid ratioIt is (for example) about 0: 100 to about 3: 97, about 0: 100 to about 5: 95 or about 0: 100 to about 10: 90.
In the other aspects of the embodiment, composition includes that crosslinking Glycosaminoglycan Polymer and uncrosslinked glycosaminoglycan are poly-Close object, wherein gel: fluid ratio is (for example) about 15: 85, about 20: 80, about 25: 75, about 30: 70, about 35: 65, about 40: 60,About 45: 55, about 50: 50, about 55: 45, about 60: 40, about 65: 35, about 70: 30, about 75: 25, about 80: 20, about 85: 15, about 90:10, about 95: 5, about 98: 2 or about 100: 0.In the other aspects of the embodiment, composition includes crosslinking Glycosaminoglycan PolymerWith uncrosslinked Glycosaminoglycan Polymer, wherein gel: fluid ratio be (for example) at most 15: 85, at most 20: 80, at most 25: 75,At most 30: 70, at most 35: 65, at most 40: 60, at most 45: 55, at most 50: 50, at most 55: 45, at most 60: 40, at most 65:35, at most 70: 30, at most 75: 25, at most 80: 20, at most 85: 15, at most 90: 10, at most 95: 5, at most 98: 2 or at most100∶0.In the other aspects of the embodiment, composition includes crosslinking Glycosaminoglycan Polymer and the polymerization of uncrosslinked glycosaminoglycanObject, wherein gel: fluid ratio be (for example) about 10: 90 to about 70: 30, about 15: 85 to about 70: 30, about 10: 90 to about 55: 45,About 80: 20 to about 95: 5, about 90: 10 to about 100: 0, about 75: 25 to about 100: 0 or about 60: 40 to about 100: 0.
Hydrogel composition disclosed herein, which can further include, to be provided when to individual applying said compositions beneficial to workAnother reagent or reagent combination.Such beneficial agent includes but not limited to antioxidant, antipruritic, the fat agent that disappears, anti-scar(such as hemostat or anti-fiber are molten for trace agent, anti-inflammatory agent, anesthetic, counter-stimulus, vasoconstrictor, vasodilator, antihaemorrhagics agentSolve protein agent), remover, tensioning agent, anti-acne agent, pigmentation agent, anti-pigmentation agent or moisturizer.
For the purposes of the present invention, unless otherwise stated, " % " otherwise in formula is defined as weight (that is, w/w) percentageThan.
The aspect of the present invention provides in part the hydrogel composition disclosed herein that can optionally include anesthetic.AnesthesiaAgent is preferably local anesthetic, that is, causes invertibity local anaesthesia and lose the anesthetic of nociception, such as amino amides officeAnesthetic and amino ester local anesthetic.The amount for the anesthetic that compositions disclosed herein includes is being applied to mitigating individualIt is effectively measured with the pain experienced after the composition.Thus, the anesthesia that composition disclosed in the present specification includesThe amount of agent is between by between general composition weight meter about 0.1% to about 5%.The non-limiting examples of anesthetic include benefit cardCause, ambucaine (ambucaine), amolanone (arnolanone), amylocaine (amylocaine), OxybuprocaineBecause of (benoxinate), benzocainum (benzocaine), betoxycaine (betoxycaine), xenysalate(biphenamine), bupivacaine (bupivacaine), butacaine (butacaine), butamben (butamben), clothSmooth cacaine (butanilicaine), butethamine (butethamine), butoxycaine (butoxycaine), carticaine(carticaine), chloroprocanine (chloroprocaine), hexyl benzoic acid Ai Kangyin (cocaethylene), cocaine(cocaine), cyclomethycaine (cyclomethycaine), cinchocaine (dibucaine), quotane(dimethysoquin), dimethocaine (dimethocaine), the piperazine winter (diperodon), bentyl (dycyclonine),Water sprout is gone to subtract (ecgonidine), bud subtracts (ecgonine), chloroethanes, Etidocaine (etidocaine), betaeucaine(beta-eucaine), Euprocin (euprocin), fenalcomine (fenalcomine), formocaine, Hexylcaine(hexylcaine), hydroxytetracaine (hydroxy teracaine), cycloform, leucinocaine mesylate(leucinocaine mesylate), Levoxadrol (Ievoxadrol), lidocaine, mepivacaine (mepivacaine),Meprylcaine (meprylcaine), metabutoxycaine (metabutoxycaine), chloromethanes, myrtecaine (myrtecaine),Receive her cacaine (naepaine), Octacaine (octacaine), Orthocaine (orthocaine), Mucaine(oxethazaine), parethoxycaine (parethoxycaine), phenacaine hydrochloride (phenacaine), phenol, piperocaine(piperocaine), Piridocaine (piridocaine), polidocanol (polidocanol), pramoxine(pramoxine), prilocaine (prilocaine), procaine (procaine), Propanocaine (propanocaine), thirdU.S. cacaine (proparacaine), Bing Veins cacaines (propipocaine), propoxycaine (propoxycaine), d-pseudococaine(psuedococaine), Pyrrocaine (pyrrocaine), Ropivacaine (ropivacaine), saligenin, totokaine(tetracaine), Tolycaine (toIycaine), trimecaine (trimecaine), zolamine (zolamine), a combination thereofAnd its salt.Amino ester local anesthetic includes procaine, chloroprocanine, cocaine, cyclomethycaine, cimethocaine(larocaine (larocaine)), propoxycaine, procaine (procaine hydrochloride (novocaine)), proparacaine, totokaine(amethocaine (amethocaine)).The non-limiting examples of amino amides local anesthetic include Articaine(articaine), bupivacaine, cinchocaine (cinchocaine) (cinchocaine), Etidocaine, chirocaine(levobupivacaine), lidocaine (lignocaine (lignocaine)), mepivacaine, piperocaine, prilocaine,Ropivacaine and trimecaine.Compositions disclosed herein may include single anesthesia agent or a variety of anesthetic.Combine local anaesthesiaThe non-limiting examples of medicine are lidocaine/prilocaine (EMLA).
Therefore in one embodiment, compositions disclosed herein includes anesthetic and its salt.In the embodimentAspect, compositions disclosed herein include amino amides local anesthetic and its salt or amino ester local anesthetic and its salt.The other aspects of the embodiment, compositions disclosed herein include procaine, chloroprocanine, cocaine, cyclomethycaine,Cimethocaine, propoxycaine, procaine, proparacaine, totokaine or its salt or any combination thereof.In the embodimentOther aspects, compositions disclosed herein include Articaine, bupivacaine, cinchocaine, Etidocaine, left Bu BikaCause, lidocaine, mepivacaine, piperocaine, prilocaine, Ropivacaine, trimecaine or its salt or any combination thereof.The other aspect of the embodiment, compositions disclosed herein include lidocaine/prilocaine combination.
In the other aspects of the embodiment, compositions disclosed herein includes to be measured as (example based on the weight of total compositionAs) about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0% or about 10%Anesthetic.At other aspect, compositions disclosed herein includes to be measured as (for example) at least based on the weight of total composition0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%,At least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least7.0%, at least 8.0%, at least 9.0% or at least 10% anesthetic.In also other aspects, compositions disclosed herein packetContaining based on the weight of total composition, measure as (for example) at most 0.1%, at most 0.2%, at most 0.3%, at most 0.4%, at most0.5%, at most 0.6%, at most 0.7%, at most 0.8%, at most 0.9%, at most 1.0%, at most 2.0%, at most 3.0%,At most 4.0%, at most 5.0%, at most 6.0%, at most 7.0%, at most 8.0%, at most 9.0% or at most 10% anesthesiaAgent.In other aspects, compositions disclosed herein includes and is measured as (for example) about 0.1% to about based on the weight of total composition0.5%, about 0.1% to about 1.0%, about 0.1% to about 2.0%, about 0.1% to about 3.0%, about 0.1% to about 4.0%, about0.1% to about 5.0%, about 0.2% to about 0.9%, about 0.2% to about 1.0%, about 0.2% to about 2.0%, about 0.5% to about1.0% or about 0.5% to about 2.0% anesthetic.
In another embodiment, compositions disclosed herein does not include anesthetic.
In one aspect of the invention, injectable dermal augmentation agent is provided, it includes polymer, such as glycosaminoglycan are poly-Close object, such as hyaluronic acid polymer, for example, at least a part of crosslinked hyaluronic acid and additive or with the polymer groupThe beneficial agent of conjunction.
Beneficial agent with the combination of polymers includes vitamin, such as vitamin C.It is suitble to the ascorbic of formNon-limiting examples include the fat of sodium salt, sylvite and the calcium salt of ascorbic acid and ascorbic acid, ascorbic acid and long chain fatty acidsSolubleness ester (ascorbyl palmitate or ascorbyl stearate), magnesium ascorbyl phosphate (MAP), ascorbic acid phosphoric acidSodium (SAP) and ascorbic acid 2- glucosides (AA2GTM), STAY-C 50 (AA2P), ascorbic acid disodium sulfate and anti-Bad hematic acid 3- aminopropyls phosphate (vitagen).
In a particularly advantageous embodiment, beneficial agent and the polymer covalent bond.For example, beneficial agentCan be vitamin C or vitamin C derivatives, with the polymer covalent bond and based on the weight of total composition, in groupClose object present in amount between about 0.04% to about 5.0%, such as based on the weight of total composition between about 0.1% to aboutBetween 4.0%, such as based on the weight of total composition between about 0.2% to about 2.0%.In one embodiment, originallyThe ascorbic amount that composition disclosed in text includes is based on the weight of total composition between about 0.3% to about 1.2%.
Preferably, include following at least one with the covalently bound vitamin C of the composition：Ascorbic acid, L- are anti-badHematic acid, L-AA 2- sulfuric esters (AA-2S) and L-AA 2- phosphates (AA-2P), ascorbic acid 2-O- glucoseGlycosides (AA-2G), 6-O- acyl group -2-O- α-D- glucopyranosyls-L-AA (6- acyl groups-AA-2G), (ascorbic acid 3-Aminopropyl phosphate, ascorbyl palmitate), its derivative and combination.Compositions disclosed herein may include single dimension lifePlain C reagents or multivitamin C reagents.
In another embodiment of the present invention, dermal augmentation agent is provided, wherein hyaluronic acid is crosslinked with BDDE.At thisIn a embodiment, conjugation can be between about 3mol% and about 10mol%, between about 15mol% to about 40mol%.
In some embodiments, dermal augmentation agent has lasting bioavailability.The mankind are being introduced for example, providingWhen in skin, be released effectively ascorbic acid or other vitamins at least about 1 month to the mankind or it is long of about 20 months or longer whenBetween dermal augmentation agent.
The aspect of the present invention provides in part display complex modulus, elasticity modulus, viscous modulus and tan disclosed hereinThe hydrogel composition of δ.When applied force (stress, deformation), compositions disclosed herein has viscoplasticity, because composition has(liquid for example uncrosslinked glycosaminoglycan is poly- for elastic component (solid-like is for example crosslinked Glycosaminoglycan Polymer) and sticky ingredientClose object or carrier phase).The rheological attributes for describing the property are complex modulus (G*), define composition to the total anti-of deformationProperty.Complex modulus is the plural number for having real and imaginary parts：G*=G '+iG ".The absolute value of G* is Abs (G*)=Sqrt (G '2+G″2).Complex modulus can be defined as to the summation of elasticity modulus (G ') and viscous modulus (G ").Falcone etc., TemporaryPolysaccharide Dermal Fillers：A Model for Persistence Based on PhysicalProperties, Dermatol Surg.35 (8)：1238-1243(2009)；Tezel, ibid, 2008；Kablik, ibid,2009；Beasley, ibid, 2009；It is respectively integrally incorporated accordingly by reference.
Elasticity modulus or modulus of elasticity refer to the ability of hydrogel material resistance to deformation, or on the contrary, when to its applied forceTendency of the object to impermanency deformation.Elasticity modulus characterizes the fastness of composition, and because it is described from groupThe energy storage for closing object movement, so also referred to as storage modulus.Elasticity modulus describes the phase interaction between elasticity and intensityWith (G '=stress/strain), and thus provide the quantitative measurment to composition hardness or pliability.By the elasticity modulus of objectIt is defined as the slope of its load-deformation curve in elastic deformation area：λ=stress/strain, wherein λ are Pascal's theoremsElasticity modulus in (Pascal ' s)；Stress is transmutative force divided by the area of applied force；And it is that stress causes to strainVariation and the ratio between object original state.Although depending on the speed of applied force, composition is harder, and the elasticity modulus having is got overIt is high and so that material is deformed in distance to a declared goal the power of flower bigger, such as inject.It illustrates how to measure stress, including direction, permitPerhaps the elasticity modulus of many types is defined.3 primary resilient modulus are stretch modulus, modulus of shearing and bulk modulus.
Viscous modulus is also referred to as loss modulus, because it describes the energy being lost with viscous dissipation.Tan δ are viscosityThe ratio between modulus and elasticity modulus, tan δ=G "/G '.Falcone, ibid, 2009.For tan δ disclosed in the present specificationValue, tan δ are obtained by the dynamic modulus under 1Hz frequencies.Lower tan δ correspond to harder, firmer or more flexibleComposition.
In another embodiment, hydrogel composition disclosed herein shows elasticity modulus.In the embodimentAspect, hydrogel composition show (for example) about 25Pa, about 50Pa, about 75Pa, about 100Pa, about 125Pa, about 150Pa, about175Pa, about 200Pa, about 250Pa, about 300Pa, about 350Pa, about 400Pa, about 450Pa, about 500Pa, about 550Pa, about600Pa, about 650Pa, about 700Pa, about 750Pa, about 800Pa, about 850Pa, about 900Pa, about 950Pa, about 1,000Pa, about 1,200Pa, about 1,300Pa, about 1,400Pa, about 1,500Pa, about 1,600Pa, about 1700Pa, about 1800Pa, about 1900Pa, about 2,The elasticity modulus of 000Pa, about 2,100Pa, about 2,200Pa, about 2,300Pa, about 2,400Pa or about 2,500Pa.In the embodiment partyThe other aspects of case, hydrogel composition show (for example) at least 25Pa, at least 50Pa, at least 75Pa, at least 100Pa, extremelyFew 125Pa, at least 150Pa, at least 175Pa, at least 200Pa, at least 250Pa, at least 300Pa, at least 350Pa, at least400Pa, at least 450Pa, at least 500Pa, at least 550Pa, at least 600Pa, at least 650Pa, at least 700Pa, at least 750Pa,At least 800Pa, at least 850Pa, at least 900Pa, at least 950Pa, at least 1,000Pa, at least 1,200Pa, at least 1,300Pa,At least 1,400Pa, at least 1,500Pa, at least 1,600Pa, at least 1700Pa, at least 1800Pa, at least 1900Pa, at least 2,The elasticity modulus of 000Pa, at least 2,100Pa, at least 2,200Pa, at least 2,300Pa, at least 2,400Pa or at least 2,500Pa.At the other aspect of the embodiment, hydrogel composition shows (for example) at most 25Pa, at most 50Pa, at most75Pa, at most 100Pa, at most 125Pa, at most 150Pa, at most 175Pa, at most 200Pa, at most 250Pa, at most 300Pa, extremelyMore 350Pa, at most 400Pa, at most 450Pa, at most 500Pa, at most 550Pa, at most 600Pa, at most 650Pa, at most700Pa, at most 750Pa, at most 800Pa, at most 850Pa, at most 900Pa, at most 950Pa, at most 1,000Pa, at most 1,The elasticity modulus of 200Pa, at most 1,300Pa, at most 1,400Pa, at most 1,500Pa or at most 1,600Pa.The embodimentOther aspect, hydrogel composition show (for example) about 25Pa to about 150Pa, about 25Pa to about 300Pa, about 25Pa extremelyAbout 500Pa, about 25Pa to about 800Pa, about 125Pa to about 300Pa, about 125Pa to about 500Pa, about 125Pa to about 800Pa, about500Pa to about 1,600Pa, about 600Pa to about 1,600Pa, about 700Pa to about 1,600Pa, about 800Pa to about 1,600Pa, about900Pa to about 1,600Pa, about 1,000Pa to about 1,600Pa, about 1,100Pa to about 1,600Pa, about 1,200Pa to about 1,600Pa, about 500Pa are to about 2,500Pa, about 1,000Pa to about 2,500Pa, about 1,500Pa to about 2,500Pa, about 2,000PaTo about 2,500Pa, about 1,300Pa to about 1,600Pa, about 1,400Pa to about 1,700Pa, about 1,500Pa to about 1,800Pa, about1,600Pa to about 1,900Pa, about 1,700Pa to about 2,000Pa, about 1,800Pa to about 2,100Pa, about 1,900Pa to about 2,The springform of 200Pa, about 2,000Pa to about 2,300Pa, about 2,100Pa to about 2,400Pa or about 2,200Pa to about 2,500PaAmount.
In another embodiment, hydrogel composition disclosed herein shows viscous modulus.In the embodimentAspect, hydrogel composition show (for example) about 10Pa, about 20Pa, about 30Pa, about 40Pa, about 50Pa, about 60Pa, about70Pa, about 80Pa, about 90Pa, about 100Pa, about 150Pa, about 200Pa, about 250Pa, about 300Pa, about 350Pa, about 400Pa, aboutThe viscous modulus of 450Pa, about 500Pa, about 550Pa, about 600Pa, about 650Pa or about 700Pa.In other sides of the embodimentFace, hydrogel composition show (for example) at most 10Pa, at most 20Pa, at most 30Pa, at most 40Pa, at most 50Pa, at most60Pa, at most 70Pa, at most 80Pa, at most 90Pa, at most 100Pa, at most 150Pa, at most 200Pa, at most 250Pa, at most300Pa, at most 350Pa, at most 400Pa, at most 450Pa, at most 500Pa, at most 550Pa, at most 600Pa, at most 650Pa orThe at most viscous modulus of 700Pa.At the other aspect of the embodiment, hydrogel composition shows (for example) about 10PaTo about 30Pa, about 10Pa to about 50Pa, about 10Pa to about 100Pa, about 10Pa to about 150Pa, about 70Pa to about 100Pa, about50Pa to about 350Pa, about 150Pa are to about 450Pa, about 250Pa to about 550Pa, about 350Pa to about 700Pa, about 50Pa to about150Pa, about 100Pa to about 200Pa, about 150Pa to about 250Pa, about 200Pa to about 300Pa, about 250Pa to about 350Pa, about300Pa to about 400Pa, about 350Pa are to about 450Pa, about 400Pa to about 500Pa, about 450Pa to about 550Pa, about 500Pa to aboutThe viscous modulus of 600Pa, about 550Pa to about 650Pa or about 600Pa to about 700Pa.
In another embodiment, hydrogel composition disclosed herein shows tan δ.In terms of the embodiment,Hydrogel composition shows (for example) about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1,About 2.2, about 2.3, about 2.4 or about 2.5 tan δ.In the other aspects of the embodiment, hydrogel composition shows (exampleAs) at most 0.1, at most 0.2, at most 0.3, at most 0.4, at most 0.5, at most 0.6, at most 0.7, at most 0.8, at most 0.9, extremelyMore 1.0, at most 1.1, at most 1.2, at most 1.3, at most 1.4, at most 1.5, at most 1.6, at most 1.7, at most 1.8, at most1.9, at most 2.0, at most 2.1, at most 2.2, at most 2.3, at most 2.4 or at most 2.5 tan δ.The embodiment in additionOther aspects, hydrogel composition show (for example) about 0.1 to about 0.3, about 0.3 to about 0.5, about 0.5 to about 0.8, about 1.1To about 1.4, about 1.4 to about 1.7, about 0.3 to about 0.6, about 0.1 to about 0.5, about 0.5 to about 0.9, about 0.1 to about 0.6, about0.1 to about 1.0, about 0.5 to about 1.5, about 1.0 to about 2.0 or about 1.5 to about 2.5 tan δ.
The hydrogel group with the transparency and/or translucence disclosed herein is provided in part in terms of this specificationClose object.Optical transparence is to allow physical property of the visible light by material, and translucence is (also referred to as translucent or translucentDegree) only light diffusion is allowed to pass through.Opposite property is opacity.Transparent material is limpid, and trnaslucent materials cannot be clearlyUnderstand thoroughly.Hydrogel disclosed herein is preferably optical clear or at least translucent.
In one embodiment, hydrogel composition optical clear disclosed herein.In terms of the embodiment, waterGel Compositions diffusion conducts (for example) about 75% light, about 80% light, about 85% light, about 90% light, about 95%Light or about 100% light.In the other aspects of the embodiment, hydrogel combination diffusion conducts (for example) at least 75%Light, at least 80% light, at least 85% light, at least 90% light or at least 95% light.The embodiment it is other itsIts aspect, the conduction of hydrogel combination the diffusion (for example) light of about 75% to about 100%, the light of about 80% to about 100%, aboutThe light of the light of 85% to about 100%, the light of about 90% to about 100% or about 95% to about 100%.In one embodiment,Hydrogel composition optical clear disclosed herein and the visible light of conduction 100%.
Hydrogel composition disclosed herein and optionally and carrier can be further processed by the way that hydrogel is worn into particleMutually such as water or saline solution mixing are to form injectable or topical substance, such as solution, oil, washing lotion, gel, ointment, emulsifiable paste, slurryMaterial, ointment or paste.Thus, disclosed hydrogel composition can be single-phase or heterogeneous compositions.Hydrogel can be milled into directlyThe granularity that about 10 μm to about 1000 μm of diameter, for example, about 15 μm to about 30 μm, about 50 μm to about 75 μm, about 100 μm to about 150 μm,About 200 μm to about 300 μm, about 450 μm to about 550 μm, about 600 μm to about 700 μm, about 750 μm to about 850 μm or about 900 μmTo about 1,000 μm.
The aspect of the present invention provides in part the composition of injectable disclosed herein.As used herein, term " canInjection ", which refers to material, has injection device of the use with fine needle to property necessary to composition described in individual's skin Zoned application.As used herein, term " fine needle " refers to 27G or smaller needles.It can be by determining hydrogel particle as discussed aboveSize realize compositions disclosed herein syringeability.
In terms of the embodiment, hydrogel composition disclosed herein can be injected by fine needle.In the embodimentOther aspects, hydrogel composition disclosed herein can be injected by the needle of (for example) about 27G, about 30G or about 32G.At thisThe other aspect of embodiment, hydrogel composition disclosed herein can by (for example) 22G or smaller, 27G or smaller,30G or smaller or 32G or smaller needle are injected.In the other aspect of the embodiment, hydrogel combination disclosed hereinObject can be by (for example) about 22G to about 35G, about 22G to about 34G, about 22G to about 33G, about 22G to about 32G, about 22G to aboutThe needle of 27G or about 27G to about 32G are injected.
In terms of the embodiment, hydrogel composition disclosed herein can use about 60N, about 55N, about 50N, about 45N,The extruding force of about 40N, about 35N, about 30N, about 25N, about 20N or about 15N, with the speed injection of 100mm/min.In the embodiment partyThe other aspects of case, hydrogel composition disclosed herein can be by 27G needles, with about 60N or smaller, about 55N or smaller, about50N or smaller, about 45N or smaller, about 40N or smaller, about 35N or smaller, about 30N or smaller, about 25N or smaller, about 20N orSmaller, about 15N or smaller, about 10N or smaller or the injection of about 5N or smaller extruding forces.In the other side of the embodimentFace, hydrogel composition disclosed herein can be by 30G needles, with about 60N or smaller, about 55N or smaller, about 50N or smaller, about45N or smaller, about 40N or smaller, about 35N or smaller, about 30N or smaller, about 25N or smaller, about 20N or smaller, about 15N orSmaller, about 10N or smaller or about 5N or smaller extruding force are injected.At the other aspect of the embodiment, it is disclosed hereinHydrogel composition can by 32G needles, with about 60N or smaller, about 55N or smaller, about 50N or smaller, about 45N or smaller,About 40N or smaller, about 35N or smaller, about 30N or smaller, about 25N or smaller, about 20N or smaller, about 15N or smaller, about 10NOr smaller or about 5N or smaller extruding forces are injected.
The aspect of the present invention provides in part the hydrogel composition disclosed herein for showing cohesiveness.Cohesiveness,Also referred to as cohesion adhesion gravitation, bonding force or compressing force, are played between similar molecules in material by the work of molecule synthesis oneThe physical property of material caused by intermolecular attraction.Cohesiveness is indicated with fors (gmf).Among other things, caking propertyBy initial free Glycosaminoglycan Polymer molecular weight than remaining free sugar after, the degree of cross linking of Glycosaminoglycan Polymer, crosslinkingThe amount of amine chitosan polymer and the pH of hydrogel composition influence.Composition should have enough caking property, to remain in applicationPart.In addition, in some applications, enough caking property keeps its shape to composition, and mechanical load therefore is occurringIt is critically important for keeping functional when cycle.Thus, in one embodiment, hydrogel composition disclosed herein is shownCohesiveness, with water peer-level.In yet another embodiment, gel combination disclosed herein shows enough cohesiveness to protectIt holds positioned at using part.In yet another embodiment, gel combination disclosed herein shows enough cohesiveness to keep itShape.In yet another embodiment, gel combination disclosed herein shows enough cohesiveness to keep its shape and functionProperty.
The aspect of the present invention, which provides in part, disclosed herein shows the infiltration of physiologically acceptable volume moleculeThe hydrogel composition of concentration (osmolarity).As used herein, term " volume molecule osmotic concentration " refers in solutionThe concentration of osmotically active solute.As used herein, term " physiologically acceptable volume molecule osmotic concentration " refers to and livesThe normal function of organism is consistent or its distinctive volume molecule osmotic concentration.Thus, when being administered to mammal, using thisHydrogel composition disclosed in text shows the volume molecule osmotic concentration generally without long-term or permanent adverse effect.HoldProduct gram molecule osmotic concentration is indicated with the osmol(e) (Osmol/L or Osm/L) of osmotically active solute in every liter of solvent.VolumeGram molecule osmotic concentration is different from molar concentration because it measure the molal quantity of osmotically active solute particle rather thanThe molal quantity of solute.Because certain compounds can dissociate in the solution, and others cannot, so there is difference.It can be underRow expression formula calculates the volume molecule osmotic concentration of solution：WhereinFor infiltration coefficient, sayThe Non Ideal Degree of solution is illustrated；η be molecular dissociation at particle (such as ion) quantity；And C is the mole dense of soluteDegree；And i is the index for indicating specific solute homogeneity.The conventional method for measuring solution can be used to measure hydrogel disclosed hereinThe volume molecule osmotic concentration of composition.
In one embodiment, hydrogel composition disclosed herein shows physiologically acceptable volume moleculeOsmotic concentration.As used herein, term " osmolality " refers to osmotically active solute in internal every kilogram of solventConcentration.As used herein, term " physiologically acceptable osmolality " refers to and the normal machine of living organismIt can be consistent or its distinctive osmolality.Thus, when being administered to mammal, using water-setting disclosed hereinGlue composition shows the osmolality generally without long-term or permanent adverse effect.Weight molar concentration is permeatedConcentration is indicated with the osmol(e) (osmol/kg or Osm/kg) of osmotically active solute in every kilogram of solvent and molten equal to thisThe summation of the weight-molality of all solutes present in liquid.Osmometer can be used to measure the weight molar concentration infiltration of solutionConcentration.Most common instrument, which is freezing point, in modern laboratory reduces osmometer.The apparatus measures are oozed with weight molar concentrationSaturating concentration increases the variation (freezing point reduction osmometer) that freezing point occurs in solution or increases solution with osmolalityThe variation (the low osmometer of steam drop) that middle vapour pressure occurs.
In terms of the embodiment, hydrogel composition shows (for example) about 100mOsm/L, about 150mOsm/L, about200mOsm/L, about 250mOsm/L, about 300mOsm/L, about 350mOsm/L, about 400mOsm/L, about 450mOsm/L or aboutThe volume molecule osmotic concentration of 500mOsm/L.In the other aspects of the embodiment, hydrogel composition is shown (for example)At least 100mOsm/L, at least 150mOsm/L, at least 200mOsm/L, at least 250mOsm/L, at least 300mOsm/L, at leastThe volume molecule osmotic concentration of 350mOsm/L, at least 400mOsm/L, at least 450mOsm/L or at least 500mOsm/L.At thisThe other aspect of embodiment, hydrogel composition show (for example) at most 100mOsm/L, at most 150mOsm/L, extremelyMore 200mOsm/L, at most 250mOsm/L, at most 300mOsm/L, at most 350mOsm/L, at most 400mOsm/L, at mostThe volume molecule osmotic concentration of 450mOsm/L or at most 500mOsm/L.In the other aspect of the embodiment, water-settingGlue composition show (for example) about 100mOsm/L to about 500mOsm/L, about 200mOsm/L to about 500mOsm/L, about200mOsm/L to about 400mOsm/L, about 300mOsm/L to about 400mOsm/L, about 270mOsm/L to about 390mOsm/L, about225mOsm/L to about 350mOsm/L, about 250mOsm/L are to about 325mOsm/L, about 275mOsm/L to about 300mOsm/L or aboutThe volume molecule osmotic concentration of 285mOsm/L to about 290mOsm/L.
The aspect of the present invention provides in part the hydrogel composition disclosed herein for showing substantial equalization.Such as thisText is used, and term " stability " or " stabilization " refer to composition and are being administered to when referring to hydrogel composition disclosed hereinBefore individual, be not easy to degrade, decompose or be crushed in storage it is any generally or significant degree.As used herein,Term " substantially thermal stability ", " generally thermostabilization ", " autoclave stabilization " or " steam sterilizing stabilization " refer to water disclosed hereinGel combination is generally stablized when by heat treatment as disclosed herein.
It can be by making hydrogel composition heat-treated, such as under normal pressure or pressurization (for example, high pressure sterilization)Steam sterilizing measures the stability of hydrogel composition disclosed herein.Hot place is carried out at a temperature of preferably at least about 100 DEG CReason about 1 minute to about 10 minutes.The substantial equalization of hydrogel composition disclosed herein can be assessed in the following manner：1) it surveysThe extruding force variation (Δ F) of hydrogel composition disclosed herein after fixed sterilizing, wherein by (having the hydrogel of specified additiveThe extruding force of composition) (extruding force of not additivated hydrogel composition) measurement is subtracted, the variation of extruding force is less than 2NShow that hydrogel composition is generally stablized；And/or 2) measure the rheological characteristic change of hydrogel composition disclosed herein after sterilizingChange, is surveyed wherein subtracting (the not tan δ 1Hz of the gel preparation of additive) by (the tan δ 1Hz for having the gel preparation of additive)The variation of amount, tan δ 1Hz shows that hydrogel composition is generally stablized less than 0.1.Thus, generally stabilization disclosed hereinHydrogel composition maintains following one or more characteristics after sterilization：Uniformity, extruding force, caking property, hyaluronan are denseOther rheological behaviors before degree, reagent concentration, volume molecule osmotic concentration, pH or heat treatment needed for hydrogel.
In one embodiment, the use of maintain the heat treatment process of required hydrogel properties disclosed herein include osamineThe hydrogel composition of chitosan polymer and at least one reagent disclosed herein.In terms of the embodiment, (example is usedSuch as) about 100 DEG C, about 105 DEG C, about 110 DEG C, about 115 DEG C, about 120 DEG C, about 125 DEG C or about 130 DEG C of heat treatment process includes sugarThe hydrogel composition of amine chitosan polymer and at least one reagent disclosed herein.In the other aspects of the embodiment, makeWith (for example) at least 100 DEG C, at least 105 DEG C, at least 110 DEG C, at least 115 DEG C, at least 120 DEG C, at least 125 DEG C or at least 130DEG C heat treatment process include the hydrogel composition of Glycosaminoglycan Polymer and at least one reagent disclosed herein.In the realityThe other aspect for applying scheme, using (for example) about 100 DEG C to about 120 DEG C, about 100 DEG C to about 125 DEG C, about 100 DEG C to about130 DEG C, about 100 DEG C to about 135 DEG C, about 110 DEG C to about 120 DEG C, about 110 DEG C to about 125 DEG C, about 110 DEG C to about 130 DEG C, about110 DEG C to about 135 DEG C, about 120 DEG C to about 125 DEG C, about 120 DEG C to about 130 DEG C, about 120 DEG C to about 135 DEG C, about 125 DEG C to about130 DEG C or about 125 DEG C to about 135 DEG C of heat treatment process includes Glycosaminoglycan Polymer and at least one reagent disclosed hereinHydrogel composition.
Can be by making hydrogel composition heat-treated, such as be stored in about 45 DEG C of environment about 60 days, it measures public hereinThe long-time stability for the hydrogel composition opened.The long-term steady of hydrogel composition disclosed herein can be assessed in the following mannerIt is qualitative：1) estimate the clarity and color of hydrogel composition after 45 DEG C of heat treatments, hydrogel composition is limpid and uncolored tableSubject hydrogel compositions are generally stablized；2) extruding force for measuring hydrogel composition disclosed herein after being heat-treated at 45 DEG C becomesChange (Δ F), wherein subtracting (45 DEG C by (before 45 DEG C of heat treatments, there is the extruding force of the hydrogel composition of specified additive)After heat treatment, there is the extruding force of the hydrogel composition of specified additive) it measures, the variation of extruding force shows water-setting less than 2NGlue composition is generally stablized；And/or 3) the rheological characteristic variation of hydrogel composition disclosed herein after sterilizing is measured, wherein logicalCrossing and (before 45 DEG C of heat treatments, there is the tan δ 1Hz of the gel preparation of specified additive) to subtract (after 45 DEG C of heat treatments, has specifiedThe tan δ 1Hz of the gel preparation of additive) it measures, the variation of tan δ 1Hz shows that hydrogel composition is generally steady less than 0.1It is fixed.Thus, maintain following one or more feature evaluations hydrogel composition disclosed herein after 45 DEG C of heat treatmentLong-time stability：Clarity (transparent and translucent), uniformity and caking property.
In terms of the embodiment, hydrogel composition is generally stablized (for example) about 3 months, about 6 at room temperatureMonth, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, about33 months or about 36 months.In the other aspects of the embodiment, hydrogel composition is generally stablized (for example) at room temperatureAt least three moon, at least six moon, at least nine moon, at least 12 months, at least 15 months, at least 18 months, at least 21 months, extremelyIt is 24 months, at least 27 months, at least 30 months, at least 33 months or at least 36 months few.In the other aspects of the embodiment,Hydrogel composition is generally stablized (for example) about 3 months to about 12 months, about 3 months to about 18 months, about 3 at room temperatureMonth to about 24 months, about 3 months to about 30 months, about 3 months to about 36 months, about 6 months to about 12 months, about 6 months extremelyAbout 18 months, about 6 months to about 24 months, about 6 months to about 30 months, about 6 months to about 36 months, about 9 months to about 12A month, about 9 months to about 18 months, about 9 months to about 24 months, about 9 months to about 30 months, about 9 months to about 36 months,About 12 months to about 18 months, about 12 months to about 24 months, about 12 months to about 30 months, about 12 months to about 36 months,About 18 months to about 24 months, about 18 months to about 30 months or about 18 months to about 36 months.
This composition can optionally include but not limited to other pharmaceutically acceptable components, including but not limited to buffer,Preservative, tension regulator, salt, antioxidant, osmolality modifier, emulsifier, wetting agent etc..
Pharmaceutically acceptable buffer is the buffer that can be used for preparing hydrogel composition disclosed herein, and condition isGained preparation is pharmaceutically subjected to.The non-limiting examples of pharmaceutically acceptable buffer include acetate buffer, boronHydrochlorate buffer, citrate buffer agent, neutral buffered saline, phosphate buffer and phosphate buffered saline (PBS).It can will be anyThe pharmaceutically acceptable buffer of concentration is using the slow of effective concentration for preparing pharmaceutical composition disclosed herein, conditionElectuary resumes treatment a effective amount of active constituent.The non-limiting examples of physiologically acceptable buffer concentration are present in aboutWithin the scope of 0.1mM to about 900mM.The pH of pharmaceutically acceptable buffer is adjusted, condition is that gained preparation is pharmaceuticallyIt is acceptable.It should be understood that acid or alkali can be used to adjust the pH of pharmaceutical composition as needed.The pH levels of any buffering can be used forCompounding pharmaceutical composition, condition are to resume treatment a effective amount of matrix polymer using effective pH levels.Physiologically it is subjected toThe non-limiting examples of pH be present in the range of about pH 5.0 to about pH 8.5.For example, hydrogel combination disclosed hereinThe pH of object can be about 5.0 to about 8.0 or about 6.5 to about 7.5, about 7.0 to about 7.4 or about 7.1 to about 7.3.
Pharmaceutically acceptable preservative includes but not limited to sodium pyrosulfite, sodium thiosulfate, acetylcysteine, fourthHydroxyl anisole and Butylated Hydroxytoluene.Pharmaceutically acceptable preservative includes but not limited to benzalkonium chloride, methaform, thimerosal, vinegarSour benzene mercury, phenylmercuric nitrate stabilize oxygen chlorine composition, such as(Allergan, Inc.Irvine, CA) and chelatingAgent, such as DTPA or DTPA- bisamides, DTPA calcium and CaNaDTPA- bisamides.
Include but not limited to salt for the pharmaceutically acceptable tension regulator in hydrogel composition disclosed hereinSuch as sodium chloride and potassium chloride；And glycerine.The composition can be provided as salt and can together be formed with many acid, includingBut it is not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid etc..Salt tends to than corresponding free alkali shapeFormula is more soluble in water or other proton solvents.It should be understood that may include in pharmaceutical composition disclosed herein in pharmaceutical fieldThese and other substance known.Other non-limiting examples of pharmaceutically acceptable component can in such as Ansel, ibid,(1999)；Gennaro, ibid, (2000)；Hardman, ibid, (2001)；And Rowe is ibid found, thus in (2003)It will wherein each be integrally incorporated by reference.
The aspect of the present invention provides in part soft group by application hydrogel composition disclosed herein treatment individualThe method for knitting situation.As used herein, term " treatment " refers to be mitigated or eliminated in individual and is characterized in that soft tissue defect, lacksThe beauty of the soft tissue condition of damage, disease and/or illness or clinical symptoms；Or it is characterized in that soft tissue in delay or prevention individualDefect, defect, the beauty of the situation of disease and/or illness or onset of clinical symptoms.For example, term " treatment " can refer to mitigate featureBe the symptom of the situation of soft tissue defects, disease and/or illness, for example, at least 20%, at least 30%, at least 40%, at least50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%.Can by observe one or more beauty,It clinical symptoms and/or is characterized in that in treatment with the relevant physiological index determining of situation hydrogel composition disclosed hereinEffect in the situation of soft tissue defects, disease and/or illness.It also can be by showing that soft tissue lacks to the needs reduction of synchronous therapyDamage, disease and/or illness improve.Those skilled in the art will be appreciated that related to specific soft tissue defects, disease and/or illnessAppropriate symptom or index and will appreciate how determine individual whether treated with compound or composition disclosed hereinCandidate.
Hydrogel composition according to the present invention is applied to individual.Individual is typically any age, gender or raceThe mankind.In general, any individual for being the candidate of conventional program treatment soft tissue condition is also the time of method disclosed hereinIt chooses.Although the subject for experiencing skin aging sign is adult, the premature aging or other for being suitble to treatment is experiencedThe subject of skin (for example, scar) can also be treated with hydrogel composition disclosed herein.In addition, presently disclosed waterGel combination and method can be applied to seek body part or the small/moderate in region is expanded, change in shape or profile changeIndividual, this technically can not possibly or cannot aesthetically be received with existing soft tissue implanted prosthetics.Public affairs are assented except informing comprehensivelyIt opens outside all relevant risks and interests of described program, preoperative evaluation generally includes conventional history and physical examination.
Hydrogel composition disclosed herein and method are useful to treatment soft tissue condition.Soft tissue condition includes but unlimitedIn soft tissue defect, defect, disease and/or illness.The non-limiting examples of soft tissue condition include breast defect, defect, diseaseDisease and/or illness, such as breast increases, breast reconstruction, breast is fixed, breast is too small, breast development is not complete, Poland's Cotard(Poland ' s syndrome), the defect caused by complication of implant such as pouch are shunk and/or rupture；Facial defects lackDamage, disease or illness, such as face increases, face reproduces, U.S. rope therapy, parry-Romberg syndrome (Parry-RombergSyndrome), lupus erythematosus profundus, corium point, scar, have sunken cheeks, after thin lip, nose defect or defect, socket of the eye defect orDefect, facial fold, microgroove and/or wrinkle, such as glabella line, muffle line, mouth week line and/or corners of the mouth line, and/or face is otherProfile deformity or defect；Neck defect, defect, disease or/or illness；Skin defect, defect, disease or/or illness；It is other softTissue defects, defect, disease or/or illness, for example, it is upper arm, underarm, hand, shoulder, back, trunk (including abdomen), buttocks, bigThe increase of leg, shank (including calf), foot (including vola fat pad), eyes, genitals or other body parts, region or areaOr reconstruction, or influence the disease or illness of these body parts, region or area；Aconuresis, incontinence of faces, other formsIncontinence；With gastroesophageal reflux disease (GERD).As used herein, term " U.S. rope therapy " refers to the No operation beauty therapeutic of skinTechnology, involve to epidermis, dermal-epidermal junction and/or corium through in epidermis, intradermal and/or be subcutaneously injected in multiple smallThe reagent of drop application.
Usually by based on required change and/or improvement, the mitigation of required soft tissue condition symptom and/or elimination, individual and/Or the body part or region of clinical and/or cosmetic result and treatment needed for doctor determine together with any method disclosed hereinThe amount of the hydrogel composition used.The effect of composition application can use following one or more clinical and/or beauty measurement marksStandard indicates：Soft tissue shape changes and/or improves, soft tissue size changes and/or improves, soft tissue profile changes and/or changesKind, function of organization changes and/or improves, tissue ingrowth is supported and/or new collagen deposition, composition continuous infusion,Patient satisfaction and/or quality of life improve and the use of implantable foreign matter is reduced.
The effect of the composition and method treatment facial soft tissue can use following one or more clinical and/or beauty degreeMeasure canonical representation：Size, shape and/or the profile of facial characteristics improve, size, shape such as lip, cheek or ocularAnd/or profile improves；Size, shape and/or the profile of facial characteristics change, size, shape such as lip, cheek or ocularShape and/or profile change；Wrinkle, fold or microgroove on skin reduce or eliminate；Have to wrinkle, fold or the microgroove on skinResistance；Skin moisturizing；Skin elasticity increases；Pachylosis is mitigated or eliminated；Skin tautness increases and/or improves；Drag lineOr striae of pregnancy reduces or eliminates；The colour of skin, gloss, brightness and/or honorable enhancing and/or improvement；Skin color enhances and/or changesKind, ochrodermia is mitigated or eliminated；Composition continuous infusion；Side effect is reduced；Patient satisfaction and/or quality of life improve.
As another example, for aconuresis operation, the effect for composition and method that sphincter is supportedFruit can use following one or more clinical measures canonical representations：The reduction of incontinence frequency, continuous infusion, patient satisfaction and/or lifeQuality advance living and the use that can plant external filler are reduced.
In terms of the embodiment, the amount of the hydrogel composition of application is (for example) about 0.01g, about 0.05g, about0.1g, about 0.5g, about 1g, about 5g, about 10g, about 20g, about 30g, about 40g, about 50g, about 60g, about 70g, about 80g, about 90g,About 100g, about 150g or about 200g.It is (for example) about in the amount of the other aspects of the embodiment, the hydrogel composition of application0.01g to about 0.1g, about 0.1g are to about 1g, about 1g to about 10g, about 10g to about 100g or about 50g to about 200g.In the implementationThe other aspect of scheme, the amount of the hydrogel composition of application is (for example) about 0.01mL, about 0.05mL, about 0.1mL, about0.5mL, about 1mL, about 5mL, about 10mL, about 20mL, about 30mL, about 40mL, about 50mL, about 60mL, about 70g, about 80mL, about90mL, about 100mL, about 150mL or about 200mL.It is in the amount of the other aspects of the embodiment, the hydrogel composition of application(for example) about 0.01mL to about 0.1mL, about 0.1mL are to about 1mL, about 1mL to about 10mL, about 10mL to about 100mL or about 50mLTo about 200mL.
Usually by body part or region based on beauty and/or clinical effectiveness and treatment needed for individual and/or doctorMeasure the duration for the treatment of.In terms of the embodiment, soft tissue can be treated using hydrogel composition disclosed hereinSituation, for example, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months,About 14 months, about 15 months, about 18 months or about 24 months.In the other aspects of the embodiment, using water disclosed hereinGel combination can treat soft tissue condition, for example, at least 6 months, at least seven moon, at least eight moon, at least nine moon, at least 10A month, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 18 months or at least24 months.In the other aspects of the embodiment, soft tissue condition can be treated using hydrogel composition disclosed herein, such asAbout 6 months to about 12 months, about 6 months to about 15 months, about 6 months to about 18 months, about 6 months to about 21 months, about 6Month to about 24 months, about 9 months to about 12 months, about 9 months to about 15 months, about 9 months to about 18 months, about 9 months extremelyAbout 21 months, about 6 months to about 24 months, about 12 months to about 15 months, about 12 months to about 18 months, about 12 months to about21 months, about 12 months to about 24 months, about 15 months to about 18 months, about 15 months to about 21 months, about 15 months to about24 months, about 18 months to about 21 months, about 18 months to about 24 months or about 21 months to about 24 months.
The aspect of the present invention is provided in part using hydrogel composition disclosed herein.As used herein, term" application " be directed toward individual provide compositions disclosed herein any delivery mechanism, potentially resulted in clinically, treatingUpper or experimentally beneficial result.Actual delivery mechanism for applying from composition to individual can pass through ordinary skill peopleMember considers to include but not limited to below because usually determining：The type of skin, the position of skin, skin originalBecause the seriousness of, skin, needed for alleviate degree, needed for the duration alleviated, the particular composition used, the spy that usesOther compounds that the drug effect of the excretion rate, the particular composition used of determining composition, the particular composition used includeProperty, particular route of administration, specific feature, individual medical history and risk factors (such as age, weight, health status etc.) or itsWhat is combined.In the one side of the embodiment, by injecting the skin area to individual using compositions disclosed herein.
It is usually that body part or region based on beauty and/or clinical effectiveness and treatment needed for individual and/or doctor is trueOrient the approach that individual patient applies hydrogel composition.Compositions disclosed herein can be by those of ordinary skill in the artAny mode known is applied, including but not limited to band needle injection, pistol (for example, hydropneumatic compression pistol), conduit, partOr it is implanted by Direct Surgery.Hydrogel composition disclosed herein can be applied to skin area, such as corium area or rim surface zone.For example, injecting water disclosed herein from about 4mm to the needle of about 14mm using diameter about 0.26mm to about 0.4mm and length rangeGel combination.Optionally, needle can be 21-32G and length is about 4mm to about 70mm.Preferably, needle is disposableNeedle.The needle can be combined with syringe, conduit and/or pistol.
In addition, compositions disclosed herein can be applied once or several times.Finally, the timing used will be according to nursing qualityStandard.For example, hydrogel composition disclosed herein can be applied a primary or point several periods, period interval a few days or a few weeks.ExampleSuch as, individual can apply hydrogel composition disclosed herein in every 1,2,3,4,5,6 or 7 day or every 1,2,3 or 4 week.It is applied to individualWith hydrogel composition disclosed herein can one month or two months it is primary every 3,6,9 or application in 12 months it is primary.
The aspect of the present invention provides in part corium area.As used herein, term " corium area " refers to true comprising epidermis-The region of the skin of skin intersection and corium including superficial corium (mamillary region) and deep dermis (webbed region).Skin is by threeMain layer composition：Epidermis provides water proofing property and as the barrier of infection；Corium is used as the position of cutaneous appendage；With subcutaneous tissue (subcutaneous layer of fat).Epidermis is free of blood vessel, and by being nourished from the diffusion of corium.Form the main of epidermisCell type is keratinocyte, melanocyte, Langerhans cell (Langerhans cell) and Merkel cell (Merkelscell)。
Corium is the skin layer being made of connective tissue under epidermis and is giving of body stress and strain.Corium is logical with epidermisBasement membrane is crossed to be tightly coupled.It also includes many mechanoreceptor/nerve endings for providing sense of touch and thermal sensation.It contains hairinessCapsule, sweat gland, sebaceous glands, apocrine gland, lymphatic vessel and blood vessel.Blood vessel in the dermis provides nutrition and the cell from ownAnd remove waste from the basal layer of epidermis.Corium is divided into the areas Liang Ge in structure：Neighbouring epidermis, the superficial area for being known as mamillary regionThe thicker area in deep of referred to as webbed region.
Mamillary region is made of the areolar connective tissue that relaxes.It is referred to as nipple because of its finger-like projection object, prolongs to epidermisIt stretches.Nipple provides " rugged " surface to intermesh with epidermis for corium, strengthens the connection between two layers of skin.Webbed region is located at mamillary region depths, and usually thick very much.It is made of fine and close irregular connective tissue, and by weaving itsCollagen, elasticity and the reticular fibre of dense concentrations are gained the name.These azelons give corium intensity, ductility and elastic property.It is root of hair, sebaceous glands, sweat gland, receptor, nail and blood vessel also to be located within webbed region.Tattoo ink is retained in coriumIn.The striae of pregnancy generated by pregnancy also is located in corium.
Subcutaneous tissue is located at below corium.It is that connection dermis of skin area is carried with following bone and muscle and for it that it, which is acted on,Feeder vessels and nerve.It is made of loose connective tissue and elastin laminin.Main cell type is fibroblast, macrophage is thinBorn of the same parents and lipocyte (subcutaneous tissue contains 50% body fat).Fat is used as the bedding and padding (padding) and thermal insulation material of body.
In the one side of the embodiment, is injected by the corium area in subcutaneously region, applied to the skin area of individualWith hydrogel composition disclosed herein.In terms of the embodiment, by (for example) epidermal-dermal junctional area, nippleArea, webbed region or any combination thereof injection, to individual corium area apply hydrogel composition disclosed herein.
Advantageously, some compositions of the present invention it is particularly useful to the appearance for reducing microgroove (for example) in patient's thin skin area andEffectively.For example, the method for providing microgroove treatment, is included in the depth no more than about 1mm, elsewhere herein to patient's applicationThe step of dermal augmentation agent composition of description.
The method that the other aspects of this specification partly disclose treatment skin, includes to skinThe step of individual application hydrogel composition disclosed herein, wherein applying said compositions improve skin, to controlSkin is treated.In the one side of the embodiment, the method for (skin is) treatment skin dehydration include toThe individual of skin dehydration is applied the step of hydrogel composition disclosed herein, and wherein applying said compositions are skin moisturizing,To treat skin dehydration.In the another aspect of the embodiment, the treatment inelastic method of skin includes to skinThe step of inelastic individual of skin applies hydrogel composition disclosed herein, wherein applying said compositions increase skinElasticity lacks flexibility to treat skin.At the another aspect of the embodiment, the method for treating pachylosis includes to troubleThere is the step of individual of pachylosis applies hydrogel composition disclosed herein, wherein applying said compositions reduce skinIt is coarse, to treat pachylosis.At the another aspect of the embodiment, method that treatment skin lacks tautness include toLack the step of individual of tautness is using hydrogel composition disclosed herein with skin, wherein applying said compositions makeSkin is tighter, lacks tautness to treat skin.
At the another aspect of the embodiment, the method for treating skin stretch line or striae of pregnancy includes to skin stretchThe individual of line or striae of pregnancy applies the step of hydrogel composition disclosed herein, and wherein applying said compositions reduce or eliminateSkin stretch line or striae of pregnancy, to having treated skin stretch line or striae of pregnancy.In the another aspect of the embodiment, treatmentThe method of ochrodermia includes the steps that applying hydrogel composition disclosed herein to the individual with ochrodermia, wherein applyingThe colour of skin or brilliance are enhanced with the composition, to treat ochrodermia.In the another aspect of the embodiment, skin is treatedThe method of skin wrinkle includes the steps that applying hydrogel composition disclosed herein to the individual with wrinkle of skin, wherein applyingThe composition reduce or eliminates wrinkle of skin, to treat wrinkle of skin.In the another aspect of the embodiment, treatmentThe method of wrinkle of skin includes the steps that applying hydrogel composition disclosed herein to individual, and wherein applying said compositions makeThe anti-wrinkle of skin of skin, to treat wrinkle of skin.
In some embodiments, dermal augmentation agent has lasting bioavailability.The mankind are being introduced for example, providingWhen in skin, (for example, through intradermal or subcutaneous introducing mankind to correct the soft tissue hole defect on face) are anti-to mankind's releaseBad hematic acid (or other vitamins) at least about 1 month or the long dermal augmentation agent of about 20 months or longer time.
For example, to predict that the vitamin C consistent with the filler duration continues effect, conjugation is assessed.ThisKind assessment is based on the etherified preparations combined with HA of AA2G.The preparation is stablized in physiological conditions, but starts by being attached toAlpha-glucosidase on cell membrane starts to discharge ascorbic acid (AsA).Since alpha-glucosidase is attached on cell membrane, instituteOccurred in filler/Cellular interfaces with the release of AsA.Further, AsA will degrade from the release of HA-AA2G with HA so thatIt is available to fibroblast to obtain AA2G.Therefore AA2G conjugation and duration of the release of AsA depending on HA.Conjugation is aboutThe gel of 5mol% can be at least up to 1 month, such as active vitamin C is discharged within about 3~5 month periods；10mol%The gel of conjugation can at least be up to release active vitamin C in 6~8 months periods；The gel of 15mol% conjugations can beAt least it is up to release active vitamin C in 10~a month period；30mol% is up to a year and a half.
* the parameter based on gel：Volume, 0.1cc；Concentration, 24mg/ml.(0.1 × 24 × 3% × 1000)/(338*0.1)=2.13 (mM)
* assumes：
AsA is discharged with constant rate of speed.
The effective concentration of AsA is 0.05mM and keeps 2 days 2.13*2/ (0.05*30)=2.8 (a month) of effective ＞
In one embodiment of the invention, provide a kind of dermal augmentation agent, it includes with Star-PEG epoxidationsThe crosslinked hyaluronic acid of object and with being combined with hyaluronic acid with the conjugation between about 3mol% and about 40mol%Vitamin C derivatives are for example, AA2G (ascorbic acid 2- glucosides), vitagen (3- aminopropyls-L-AA phosphoric acidOne of ester) and SAP (STAY-C 50).
Prepare this dermal augmentation agent method include make pentaerythrite glycidol ether (Star-PEG epoxides) withAscorbic acid 2- glucosides (AA2G) react by a certain percentage, and reaction temperature and reaction time are suitble to obtain containing by 4- armletsThe composition of the capped AA2G of oxide (AA2G-4 armlets oxide), unreacted 4 armlet oxide and free AA2G.4- armsThe capped AA2G of epoxides (AA2G-4 armlets oxide) is combined through epoxy group with hyaluronic acid.Unreacted 4 armlet oxidationObject is used as crosslinking agent with cross-linked-hyaluronic acid and as bonding agent with further combined with AA2G.
In another embodiment of the present invention, a kind of dermal augmentation agent is provided, it includes crosslinked transparent with BDDEMatter is sour and derives with the vitamin C combined with hyaluronic acid with the conjugation between about 3mol% and about 10mol%Object is for example, AA2G (ascorbic acid 2- glucosides), vitagen (3- aminopropyls-L-AA phosphate) and SAP are (anti-badOne of hematic acid sodium phosphate).
The method for preparing this dermal augmentation agent includes making BDDE with ascorbic acid 2- glucosides (AA2G) by certain ratioExample reaction, reaction temperature and reaction time are suitble to obtain containing by the capped AA2G of BDDE (AA2G-BDDE), unreacted BDDEWith the composition of free AA2G.The capped AA2G of BDDE (AA2G-BDDE) are combined through epoxy group with hyaluronic acid.It is unreactedBDDE is used as crosslinking agent with cross-linked-hyaluronic acid and as bonding agent with further combined with AA2G.
Fig. 9 is the table for showing influence of the alpha-glucosaccharase enzyme concentration to discharging AsA from AA2G-PBS solution.AA2G is to AsAConversion depending on alpha-glucosidase concentration.When a concentration of 6.3 units/g gels of alpha-glucosidase, AA2G is several in 15minIt is fully converted to AsA.When a concentration of 4.7 units/g gels of alpha-glucosidase, 30min is needed to be fully converted to AA2GAsA.Further decreasing alpha-glucosidase concentration causes AA2G slow to the conversion of AsA.
Figure 10 shows the release profiles schematic diagram of the free AsA from combination dermal augmentation agent according to the present invention(sustained release) (AA2G compared with the reaction time converts mol%).AA2G is complete in 40min in AA2G/HA mixturesIt is converted into AsA.AA2H/HA conjugates show that AA2G is converted into the time dependence of AsA.
Figure 11 A and 11B show the additional release data of various dermal augmentation agent according to the present invention.More specificallyGround, AA2G depends on alpha-glucosidase concentration to the conversion of AsA in HA-AA2G gels.High alpha-glucosidase concentration cause AA2G toAsA rapid conversions.For specified alpha-glucosidase concentration, different preparations show the heterogeneity that AA2G is converted to AsA.
In one aspect of the invention, dermal augmentation agent is provided, it is especially effective to the appearance for treating and eliminating microgroove,Such as with respect to the gauffer of superficial on skin, such as, but not limited to eyes, the areas Lei Gou, the microgroove near forehead, canthus line, glabella lineDeng.
It is that some corium are filled out blue variable colour (Tyndall effect) occur in the skin part for having injected dermal augmentation agentFill the great adverse events of agent patient experience.Tyndall effect is more conventional in the patient for the treatment of superficial fine wrinkles.It has groundEmbodiment of the present invention is sent out, providing can inject in superficial to treat microgroove and wrinkle, or even in relatively thin skinSkin is injected in region, without long-acting, the translucent filler of any blue variable colour generated by Tyndall effect.Microgroove or superficialWrinkle be generally understood as it is usually most thin in skin, i.e., the dermis thickness of skin be less than 1mm facial area (forehead, outer canthus, lipRed edge/mouth contour) in find skin on wrinkle or gauffer.In forehead, average dermis thickness is for normal skinAbout 0.95mm and be about 0.81mmm for the skin that wrinkles.Corium around outer canthus is even more thin (such as normal skinFor about 0.61mm and for the skin that wrinkles about 0.41mm).30 or 32G needles (needle for being commonly used in microgroove gel application)Mean outside diameter is about 0.30 and about 0.24mm.
The present invention provides the dermal augmentation agent groups that will not lead to Tyndall effect being for example described elsewhere hereinClose object.For example, the composition of the present invention includes and the hyaluronic acid component of cross-linking agents, the additive in addition to cross-linking component；When in the corium area for being administered to patient, relative in addition to no additive, substantially the same composition, the combinationObject shows Tyndall effect reduction.The composition can generally optical clear.
In one embodiment, additive is vitamin C derivatives, for example, can with it is described elsewhere herein transparentThe chemically combined AA2G of matter acid.
In some embodiments, cross-linking component is BDDE and conjugation between about 3mol% and about 10mol%,Or up to 15mol% or higher.In some embodiments, the composition is further included suitable for being carried after injection for patientFor the anesthetic comfortably measured, such as lidocaine.
The method for additionally providing the microgroove on treatment patient skin.The method generally includes to introduce example into patient skinThe step of composition as described herein.Such as the composition includes the crosslinking group of hyaluronic acid component, cross-linked-hyaluronic acidPoint and additive in addition to cross-linking component mixture, the composition generally optical clear；And wherein relative to except not havingHave outside the additive, substantially the same composition, dermal augmentation agent composition shows Tyndall effect reduction.
In some embodiments of the present invention, the composition includes using EDC chemistry and diamines or polyamine crosslinkersCrosslinked hyaluronic acid component.For example, the crosslinking agent can be HMDA.
In certain embodiments of the present invention that crosslinking agent is HMDA, the G ' of the composition is up to about 70Pa, G "/G 'Between about 0.65 and about 0.75, extruding force about 24N or smaller, and final HA concentration is between about 24mg/g and about 25mg/gBetween.
In certain embodiments of the present invention that additive is HA-AA2G conjugates or HA- vitagen conjugates, knotIt is right between about 3mol% and about 10mol%, or up to about 15mol%, or up to about 40mol%.These compositionsG ' is from least about 30Pa, and more preferably at least about 40Pa to about 100Pa, G "/G ' are between about 0.30 and about 0.50, and extruding force is about27N or smaller, and final HA concentration is between about 24mg/g and about 25mg/g.
For the purposes of the present invention, as used herein " conjugation " is defined as the molar percentage of combination, such asAA2G and hyaluronic acid repetitive unit (for example, HA dimers).Therefore, 10mol% conjugations mean every 100 HA repetitive unitsThe AA2G combined containing 10.The method illustrated in following example 2 or other methods well known by persons skilled in the art can be usedCalculations incorporated degree.