Ready-to-use cosmetic compositions

Abstract

To provide an immediately usable composition for subcutaneous or intradermal injection, and a method for performing restoration or cosmetic dermatology treatment.SOLUTION: Provided is an immediately usable injectable composition containing polymeric microspheres or fine particles originated from non-animal, hydrogel containing water and cellulose derivative gelatinizer, and polysorbate 80. Further provided is a method for using an immediately usable injectable composition for restoration or formation surgery, cosmetic dermatology, contour formation of a face, contour formation of a body, and gum augmentation.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority of U.S. Application No. 62 / 926,935, filed October 28, 2019, the entire disclosure of which is incorporated herein by reference.

[0002] Field The present disclosure relates to an implant that is ready for use for subcutaneous or intradermal injection. This can be used as a skin filler in humans for reconstructive or cosmetic surgery, and in aesthetic dermatology, to fill wrinkles, to fill fine lines, to fill skin cracks, to fill scars, to fill gingival tissue, to change the shape of various areas of the body, and to change the shape of the face.

Background Art

[0003] Background The applicant sells a product under the trade name SCULPTRA, which is supplied as a sterile lyophilized powder in a glass vial. Each vial contains poly - L - lactic acid (PLLA), sodium carboxymethyl cellulose (CMC), and mannitol. Prior to administration, the contents of the vial need to be reconstituted by adding an aqueous solution or water to the vial. See U.S. Patent Nos. 7,731,758 (Patent Document 1) and 8,414,657 (Patent Document 2).

[0004] If there is contamination in the case of non - sterile volume of the liquid added to the vial, or if there is no consistency in the concentration of the final product when an excessive or insufficient volume is used to reconstitute the contents of the vial, the need to reconstitute the contents of the vial causes a potential for error.

[0005] The purpose of this disclosure is to further stabilize ready-to-use products for storage before administration in a ready-to-use form by overcoming the possibility of errors or inconsistencies when reconstituting the contents of vials and by reducing foaming and sedimentation of ready-to-use products. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] U.S. Patent No. 7,731,758 [Patent Document 2] U.S. Patent No. 8,414,657 [Overview of the Initiative]

[0007] Summary of this disclosure This disclosure, as a whole, relates to stable, ready-to-use, injectable implants and methods for performing restorative or cosmetic dermatological surgery using implants.

[0008] In one embodiment, the present disclosure relates to a composition comprising (a) microspheres or fine particles of at least one non-animal polymer selected from the group consisting of lactic acid polymers, glycolic acid polymers, and lactic acid-glycolic acid copolymers; (b) a hydrogel comprising water and a cellulose derivative gelling agent; and (c) 0.05% to 1% by weight of polysorbate 80.

[0009] In some embodiments, at least one polymer is lactic acid selected from poly-L-lactic acid, poly-D-lactic acid, and mixtures thereof. In some embodiments, at least one polymer is poly-L-lactic acid. In some embodiments, at least one polymer is present in an amount of 5 mg / mL to 50 mg / mL.

[0010] In some embodiments, the cellulose derivative gelling agent is carboxymethylcellulose or hydroxypropylmethylcellulose. In some embodiments, the cellulose derivative gelling agent is carboxymethylcellulose. In some embodiments, carboxymethylcellulose is sodium carboxymethylcellulose. In some embodiments, the cellulose derivative gelling agent is present in an amount of 0.5% to 4% by weight. In some embodiments, the cellulose derivative gelling agent is present in an amount of 2% by weight. In some embodiments, polysorbate 80 is present in an amount of 0.05% by weight.

[0011] In some embodiments, the composition exhibits a viscosity of less than 100 mPas. In some embodiments, the composition exhibits a viscosity of less than 60 mPas. In some embodiments, the composition exhibits a viscosity of 5 to 45 mPas.

[0012] In some embodiments, the ratio of cellulose derivative gelling agent to polysorbate 80 is 100:1 to 1:1. In some embodiments, the ratio of cellulose derivative gelling agent to polysorbate 80 is 50:1 to 10:1.

[0013] In some embodiments, the microspheres or particles are bioabsorbable. In some embodiments, the microspheres or particles are bioabsorbable for a period of about 1 to 3 years.

[0014] In some embodiments, the composition contains microspheres or fine particles at a concentration of 5 to 20 mg / mL. In some embodiments, the composition contains microspheres or fine particles at a concentration of 17 to 18 mg / mL. In some embodiments, the microspheres or fine particles are approximately 20 to 100 μm in size. In some embodiments, the microspheres or fine particles exhibit a median particle size of approximately 40 μm. In some embodiments, the microspheres or fine particles exhibit a molecular weight of 70 to 500 kDa. In some embodiments, the microspheres or fine particles exhibit a molecular weight of 70 to 200 kDa.

[0015] In some embodiments, the composition further comprises a local anesthetic. In some embodiments, the local anesthetic is an amide or ester type local anesthetic. In some embodiments, the local anesthetic is bupivacaine, butanilicaine, calticaine, cincocaine (dibucaine), cribucaine, parapiperidinoacetylaminobenzoate ethyl, etidocaine, lignocaine (lidocaine), mepivacaine, oxethazaine, prilocaine, ropivacaine, tricaine, trimecaine, budocaine, alticaine, levobupivacaine, amylocaine, cocaine, propano Selected from the group consisting of caine, chlormecaine, cyclomethicine, proximetacaine, ametokine (tetracaine), benzocaine, butacaine, butoxycaine, butyl aminobenzoate, chloroprocaine, dimethokine (larocaine), oxybuprocaine, pipelocaine, paretoxycaine, procaine (novocaine), propoxycaine, and tricaine, or combinations thereof.

[0016] In some embodiments, the composition is sterile. In some embodiments, sterility is achieved by irradiation or heat sterilization.

[0017] In some embodiments, the composition further comprises sodium chloride, phosphate buffer, and a pharmaceutically acceptable carrier. In some embodiments, the composition exhibits a sodium chloride concentration of 0.9% w / v.

[0018] In some embodiments, the composition is injectable. In some embodiments, the injectable composition is an injectable implant. In other embodiments, the disclosure relates to a pre-filled syringe or vial containing any one of the compositions described.

[0019] In another embodiment, the disclosure relates to an injectable implant comprising any one of the compositions described herein. In some embodiments, the injectable implant is for intradermal or subcutaneous injection into the body of a subject requiring it.

[0020] In another aspect, the present disclosure provides a method for performing a restorative or cosmetic dermatological procedure, the method comprising injecting a composition of any one of the described aspects into a subject.

[0021] In some aspects, the injection is intradermal, subdermal, subcutaneous, intramuscular, submuscular, or intramuscular. In some aspects, the injection is within one or more tissues of the oral cavity.

[0022] In some aspects, the injection is for skin filling, body contouring, facial contouring, and gum filling. In some aspects, skin filling is selected from filling of wrinkles, fine lines, skin cracks, scars, and combinations thereof. In some aspects, gum filling includes filling gaps between the bases of teeth. In some aspects, facial and body contouring is selected from creating a protrusion which is a structural feature, correcting concave deformations, correcting age-related facial grooves, and augmenting or repairing contour deficiencies of hard or soft tissues of the face and body due to aging, due to injury, and due to acquired or congenital deformations of the face or body.

[0023] [Invention 1001] (a) Microspheres or microparticles of at least one non-animal-derived polymer selected from the group consisting of a lactic acid polymer, a glycolic acid polymer, and a lactic acid-glycolic acid copolymer, (b) A hydrogel comprising water and a cellulose derivative gelling agent, (c) Polysorbate 80 in an amount of 0.05% to 1% by weight and a composition comprising. [Invention 1002] The composition of Invention 1001, wherein the at least one polymer is lactic acid selected from poly-L-lactic acid, poly-D-lactic acid, and mixtures thereof. [Invention 1003] The composition of Invention 1002, wherein the at least one polymer is poly-L-lactic acid. [Invention 1004] The composition of the present invention 1001, wherein the at least one polymer is present in an amount of 5 mg / mL to 50 mg / mL. [The present invention 1005] The composition of the present invention 1001, wherein the cellulose derivative gelling agent is carboxymethyl cellulose or hydroxypropyl methyl cellulose. [The present invention 1006] The composition of the present invention 1005, wherein the cellulose derivative gelling agent is carboxymethyl cellulose. [The present invention 1007] The composition of the present invention 1006, wherein the carboxymethyl cellulose is sodium carboxymethyl cellulose. [The present invention 1008] The composition of the present invention 1006, wherein the cellulose derivative gelling agent is present in an amount of 0.5% to 4% by weight. [The present invention 1009][[ID=,20]] The composition of the present invention 1008, wherein the cellulose derivative gelling agent is present in an amount of 2% by weight. [The present invention 1010] The composition of the present invention 1001, wherein the polysorbate 80 is present in an amount of 0.05% by weight. [The present invention 1011] [[ID=,29]]The composition of the present invention 1001, which exhibits a viscosity of less than 100 mPas. [The present invention 1012] The composition of the present invention 1011, which exhibits a viscosity of less than 60 mPas. [The present invention 1013] The composition of the present invention 1001, which exhibits a viscosity of 5 to 45 mPas. [The present invention 1014] The composition of the present invention 1001, wherein the ratio of the cellulose derivative gelling agent to the polysorbate 80 is 100:1 to 1:1. [The present invention 1015] The composition of the present invention 1014, wherein the ratio of the cellulose derivative gelling agent to the polysorbate 80 is 50:1 to 10:1. [The present invention 1016] The composition of the present invention 1001, wherein the microspheres or microparticles are biodegradable. [Invention 1017] The composition of the present invention 1016, wherein the microspheres or fine particles are bioabsorbable within a period of about 1 to 3 years. [Invention 1018] A composition according to the present invention 1001, comprising microspheres or fine particles at a concentration of 5 to 20 mg / mL. [Invention 1019] A composition according to the present invention 1018, comprising microspheres or fine particles at a concentration of 17-18 mg / mL. [Invention 1020] The composition of the present invention 1001, wherein the microspheres or fine particles are approximately 20 to 100 μm in size. [Invention 1021] The composition of the present invention 1020, wherein the microspheres or fine particles exhibit a median particle size of approximately 40 μm. [Invention 1022] The composition of the present invention 1001, wherein the microspheres or fine particles have a molecular weight of 50 to 500 kDa. [Invention 1023] The composition of the present invention 1022, wherein the microspheres or fine particles have a molecular weight of 50 to 200 kDa. [Invention 1024] A composition according to any one of the present invention 1001 to 1023, further comprising a local anesthetic. [Invention 1025] The composition of the present invention 1024, wherein the local anesthetic is an amide-type or ester-type local anesthetic. [Invention 1026] The aforementioned local anesthetics include bupivacaine, butanilicaine, calticaine, cincocaine (dibucaine), cribucaine, parapiperidinoacetylaminobenzoate ethyl, etidocaine, lignocaine (lidocaine), mepivacaine, oxethazaine, prilocaine, ropivacaine, tricaine, trimecaine, budocaine, alticaine, levobupivacaine, amylocaine, cocaine, propanocaine, chlormecaine, and s A composition of the present invention 1024 or 1025, selected from the group consisting of clomethicaine, proximetacaine, amethokine (tetracaine), benzocaine, butacaine, butoxycaine, butyl aminobenzoate, chloroprocaine, dimethokine (larocaine), oxybuprocaine, pipelocaine, paretoxycaine, procaine (novocaine), propoxycaine, and tricaine, or a combination thereof. [Invention 1027] A sterile composition according to any of the present invention 1001 to 1026. [Invention 1028] A composition of the present invention 1027, wherein a sterile state is achieved by irradiation or heat sterilization. [Invention 1029] A composition according to any one of the present invention 1001 to 1028, further comprising sodium chloride, phosphate buffer, and a pharmaceutically acceptable carrier. [Invention 1030] A composition according to any of the present invention 1001 to 1029, exhibiting a sodium chloride concentration of 0.9% w / v. [Invention 1031] A composition according to any of the present invention 1001 to 1030, which is injectable. [Invention 1032] The composition of the present invention 1031, wherein the injectable composition is an injectable implant. [Invention 1033] A pre-filled syringe or vial containing any of the compositions of the present invention 1001 to 1032. [Invention 1034] An injectable implant comprising any composition of invention 1001 to 1032. [Invention 1035] An injectable implant according to the present invention 1034, for intradermal or subcutaneous injection into the body of a person requiring it. [Invention 1036] A method for performing a reparative or cosmetic dermatological procedure, comprising injecting a subject with any of the compositions 1001 to 1032 of the present invention. [Invention 1037] The method of the present invention 1036, wherein the injection is intradermal, subdermal, subcutaneous, intramuscular, submuscular, or intragingival. [Invention 1038] The method of the present invention 1036, wherein the injection is administered into one or more tissues of the oral cavity. [Invention 1039] The method according to any one of the invention 1036 to 1038, wherein the injection is for skin filling, body contouring, facial contouring, and gingival filling. [Invention 1040] The method of the present invention 1039, wherein the skin filling is selected from wrinkle filling, fine line filling, skin crack filling, scar filling, and combinations thereof. [Invention 1041] A method according to the present invention 1039, wherein gingival filling includes filling the gap between the bases of teeth. [Invention 1042] The method of the present invention 1039, wherein facial and body contouring is selected from creating structural features (pronouncements), correcting concave deformities, correcting age-related facial grooves, and augmenting or repairing contour defects of the hard or soft tissues of the face and body resulting from age-related, injury-related, and acquired or congenital deformities of the face or body. The following detailed description is illustrative and explanatory and is intended to provide further explanation of the invention. [Brief explanation of the drawing]

[0024] [Figure 1]Raw Turbiscan data is shown (of sample PLLA-2.25%CMC-0.05%PS80-S2). Transmittance (top) and backscattering (bottom) of the sample solution at different heights (x-axis) of the vial containing the sample. [Figure 2] This shows the backscattering time by foam or effervescence of a 150 mg / 8 mL PLLA-loaded dispersion in the absence and presence of the nonionic surfactant PS80. [Figure 3] This image shows a comparison of three vials of SCULPTRA in and out of the presence of PS80. Left: no PS80, Center: 0.1% PS80, Right: 1% PS80. The samples were shaken, and images were acquired after 16 hours. Foaming decreases from left to right. [Figure 4] This shows a comparison of four vials of the SCULPTRA product, namely (from left to right) SCULPTRA, SCULPTRA + 1% glycerol, SCULPTRA + 2% glycerol, and SCULPTRA + 2% glycerol + 1% PEG400, demonstrating that neither glycerol nor PEG400 reduces PLLA foaming. [Figure 5] The image shows five vials with varying degrees of sedimentation. S2 is SCULPTRA, and P1, P2, P3, and P4 are various unsterilized PLLA formulations described in the examples. [Figure 6] The Turbiscan backscatter output identifies the various peaks and plateaus present in the SCULPTRA / PLLA formulation, namely the sedimentation, intermediate phase, and foaming phase. [Figure 7] The permeability values ​​of seven SCULPTRA / PLLA formulations, as well as the evaluation of the effects of viscosity modifiers and PS80, are shown. [Figure 8] This shows the backscatter values ​​of the foam from four SCULPTRA / PLLA formulations. [Figure 9] The graph shows the permeability values ​​of eight SCULPTRA / PLLA formulations, particularly the permeability values ​​of each formulation during its intermediate phase. The arrow on the right side of the graph indicates that the SCULPTRA value after 22 hours is approximately 40% permeability. [Figure 10]The backscatter values ​​of eight SCULPTRA / PLLA formulations, particularly the foam phase of each formulation, are shown. The arrow on the right side of the figure indicates that the SCULPTRA value after 22 hours is approximately 45% backscatter, and the difference is dramatic in the presence of PS80. [Modes for carrying out the invention]

[0025] Detailed explanation of this disclosure The compositions disclosed herein are ready-to-use injectable compositions comprising a hydrogel containing non-animal-derived polymer microspheres or fine particles, water and a cellulose derivative gelling agent, and polysorbate 80. The methods disclosed herein are methods for using the ready-to-use injectable compositions for restorative or reconstructive surgery, cosmetic dermatology, facial contouring, body contouring, and gingival augmentation.

[0026] Given that ready-to-use injectable compositions reduce the potential for errors or inconsistencies when reconstituting freeze-dried or lyophilized compositions, the compositions and methods of use represent a significant improvement over the prior art. Ready-to-use compositions and their methods of use are further improved over the prior art, considering their superior properties in terms of composition stability and reducing foaming and sedimentation of ready-to-use products.

[0027] The purpose of this disclosure is to further stabilize ready-to-use products for storage before administration in a ready-to-use form by overcoming the possibility of errors or inconsistencies when reconstituting the contents of vials and by reducing foaming and sedimentation of ready-to-use products. Accordingly, the compositions and methods described herein offer considerable advantages over the prior art.

[0028] I. Definition The following terms are expected to be well understood by those skilled in the art, but their definitions are provided below to facilitate the explanation of the subject matter of this disclosure.

[0029] The terms “a” or “an” can refer to one or more of its entities, i.e., to multiple referents. Therefore, the terms “a” or “an,” “one or more,” and “at least one” are used interchangeably in this specification. In addition, a reference to an “element” with the indefinite article “a” or “an” does not exclude the possibility that there are two or more of the elements, unless the context clearly requires that only one of the elements exists.

[0030] Throughout this specification, any reference to “one embodiment,” “a particular embodiment,” “a particular aspect,” or “a particular aspect” means that any specific feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment of this disclosure. Therefore, occurrences of the phrase “in one embodiment” or “in a particular embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, any specific feature, structure, or characteristic can be combined in any suitable manner in one or more embodiments.

[0031] As used herein, the terms “about” or “approximately” preceding a number indicate a value within a range of plus or minus 10% of the given value.

[0032] As will be understood by those skilled in the art, for any and all purposes, particularly with respect to providing written explanations, all scopes disclosed herein also encompass any and all possible subscopes, as well as combinations thereof. Any listed scope can be readily recognized as sufficiently describing and enabling that the same scope may be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can readily be decomposed into a lower third, a middle third, an upper third, etc. As will be understood by those skilled in the art, all terms such as “maximum,” “at least,” “greater than,” and “less than” include the numbers listed and refer to scopes that may later be decomposed into subscopes, as discussed above. Finally, as will be understood by those skilled in the art, a scope includes each individual member. Thus, for example, a group having 1 to 3 cells means a group having one, two, or three cells. Similarly, a group having 1 to 5 cells means a group having one, two, three, four, or five cells, etc.

[0033] As used herein, “control” refers to an alternative sample used in an experiment for comparative purposes. A control may be “positive” or “negative.” “Control sample” or “reference sample” refers, as used herein, to a sample or reference that serves as a counter for comparison with an experimental sample. For example, the experimental sample may contain compounds A, B, and C in a vial, and the control may be a sample of the same type that has been processed in the same manner as the experimental sample but lacks one or more of compounds A, B, or C.

[0034] As used herein, the term “effective dose” means an amount sufficient to achieve a desired therapeutic and / or preventive effect, for example, an amount that results in the prevention of one or more outcomes or an increase in one or more outcomes.

[0035] As used herein, the terms “individual,” “patient,” or “subject” may refer to an individual organism, vertebrate, mammal, or human. In preferred embodiments, the individual, patient, or subject is human.

[0036] As used herein, the term “soft tissue” refers to tissue that connects, supports, or surrounds other structures and organs of the body. Soft tissue includes muscle, fibrous tissue, and fat.

[0037] As used herein, the term “soft tissue augmentation” refers to any type of soft tissue volume augmentation, including, but not limited to, facial contouring (e.g., more prominent cheeks, chin, or lips), correction of concave deformities (e.g., post-traumatic or HIV-related lipid atrophy), and correction of deep age-related facial grooves. Thus, soft tissue augmentation may be used for cosmetic purposes or for medical purposes, such as after trauma or degenerative disease. Soft tissue augmentation further refers to skin filling, body contouring, and gingival filling.

[0038] As used herein, the terms “particulate matter” and “microsphere” are used to some extent interchangeably, the only distinction being that microspheres are spherical, while particulate matter is non-spherical.

[0039] As used herein, the term “non-animal origin” refers to sources that exclude animals but include sources such as yeast, bacteria, or synthetic sources.

[0040] As used herein, the term “bioabsorbable” refers to a degradation event(s). Bioabsorbable substances are removed from the body, organs, tissues, sites, or cells over a period of time, either by being soluble, phagocytosed, or simply broken down over a period of time. The substance or its degradation products may be metabolized, incorporated into other molecules or compounds, or excreted.

[0041] As used herein, the term “sterile” means free from pathogenic microorganisms or from which pathogenic microorganisms have been removed.

[0042] As used herein, the term “sterilized” refers to a process that does not contain living organisms and generally does not contain living microorganisms.

[0043] As used herein, the term “injectable” means the ability to inject the compositions of this disclosure through a 21G, 22G, 23G, 24G, 25G, 26G, 27G, or 30G needle.

[0044] This technology is not limited to the specific embodiments described herein, but is intended as a single example of individual embodiments of this technology. As will be apparent to those skilled in the art, many modifications and variations of this technology can be made without departing from its spirit and scope. In addition to those enumerated herein, functionally equivalent methods and apparatus within the scope of this technology will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of this technology. This technology is not limited to specific methods, reagents, compound compositions, or biological systems, and these are, of course, subject to change. It should also be understood that the terminology used herein is intended solely to describe specific embodiments and is not intended to limit them.

[0045] As used herein, the phrase “ready-to-use composition” refers to a composition of the Disclosure that does not require the composition to be reconstituted or to have one or more components added before use. The ready-to-use compositions of the Disclosure are ready to be injected into a target once the ready-to-use composition is drawn into or placed in a device used for injection, such as a syringe and needle.

[0046] As used herein, the trade name "SCULPTRA" refers to a lyophilized or dehydrated product containing 150 mg of poly-L-lactic acid (PLLA), 90 mg of carboxymethylcellulose (CMC), and 127.5 mg of mannitol, all of which are combined in a sealed container / vial.

[0047] II. Fillers Fillers, such as skin fillers, are used to repair, restore, or augment contour defects of hard or soft tissues of the body resulting from aging, injury, or acquired or congenital deformities of the face, body, and internal organs. Fillers can be natural or synthetic substances used to reduce wrinkles and / or fine lines, restore lost volume, moisturize skin, soften nasolabial folds, augment and contour lips, improve scars (pitted, hypertrophic, and keloid scars), strengthen weakened vocal cords, and provide other soft tissue improvements. Substances used include fats, paraffin, human collagen, bovine collagen, silicones, hyaluronic acid, lactic acid, and glycolic acid. In 1981, the FDA approval of bovine collagen ushered in a new era of soft tissue fillers. Since then, many soft tissue fillers have emerged. The dramatic increase in the number of fillers currently available and for research purposes has been driven by many factors, including advances in biotechnology and a growing emphasis on cosmetic appearance in society. With the introduction of new fillers, it is continuously necessary to evaluate the risk / benefit profile and define its limitations in order to maximize patient cosmetic outcomes and safety.

[0048] In some embodiments, the compositions of the present disclosure include (a) microspheres or fine particles of at least one non-animal polymer selected from the group consisting of lactic acid polymers, glycolic acid polymers, and lactic acid-glycolic acid copolymers; (b) a hydrogel comprising water and a cellulose derivative gelling agent; and (c) a surfactant.

[0049] In some embodiments, the surfactant may be selected from one or more of the group consisting of polyoxyethylene(20) sorbitan monolaurate (PS20), polyoxyethylene(20) sorbitan monopalmitate (PS40), polyoxyethylene(20) sorbitan monostearate (PS60), polyoxyethylene(20) sorbitan, PEG-20 stearate, PEG-32 stearate, caprylocaproyl polyoxy-8 glyceride, lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, polyglycerols and fatty acid esters, such as polyglyceryl-3 oleate, polyglyceryl-6 dioleate, polyglyceryl-6 isostearate, poloxamer 188, poloxamer 407, sodium docusate, PEG-40 castor oil, and polysorbate 80 (PS80). In some embodiments, the surfactant is polysorbate 80.

[0050] In some embodiments, the surfactant is present in an amount of about 0.05% to about 1% by weight.

[0051] In some embodiments, the surfactant is present in amounts of about 0.05% by weight, about 0.06% by weight, about 0.07% by weight, about 0.08% by weight, about 0.09% by weight, about 0.10% by weight, about 0.15% by weight, about 0.2% by weight, about 0.25% by weight, about 0.3% by weight, about 0.35% by weight, about 0.4% by weight, about 0.45% by weight, about 0.5% by weight, about 0.55% by weight, about 0.6% by weight, about 0.65% by weight, about 0.7% by weight, about 0.75% by weight, about 0.8% by weight, about 0.85% by weight, about 0.9% by weight, about 0.95% by weight, or about 1% by weight. In some embodiments, the surfactant is present in amounts of 0.05% by weight, 0.06% by weight, 0.07% by weight, 0.08% by weight, 0.09% by weight, 0.10% by weight, 0.15% by weight, 0.2% by weight, 0.25% by weight, 0.3% by weight, 0.35% by weight, 0.4% by weight, 0.45% by weight, 0.5% by weight, 0.55% by weight, 0.6% by weight, 0.65% by weight, 0.7% by weight, 0.75% by weight, 0.8% by weight, 0.85% by weight, 0.9% by weight, 0.95% by weight, or 1% by weight.

[0052] In some embodiments, at least one polymer of the microspheres or fine particles is selected from synthetic aliphatic polyester particles, such as polylactic acid, polycaprolactone, glycolic acid, polyglycolic acid, or copolymers thereof. In some embodiments, at least one polymer is poly-L-lactic acid, poly-D-lactic acid, or a mixture thereof. In some embodiments, at least one polymer is poly-L-lactic acid.

[0053] In some embodiments, at least one polymer is present in an amount of 5 mg / mL to 50 mg / mL. In some embodiments, at least one polymer is present in an amount of about 5 mg / mL to about 50 mg / mL. In some embodiments, at least one polymer is present in an amount of 5 mg / mL to 20 mg / mL. In some embodiments, at least one polymer is present in an amount of about 5 mg / mL to about 20 mg / mL. In some embodiments, at least one polymer is present in an amount of 5 mg / mL to 10 mg / mL. In some embodiments, at least one polymer is present in an amount of about 5 mg / mL to about 10 mg / mL. In some embodiments, at least one polymer is present in an amount of 10 mg / mL to 20 mg / mL. In some embodiments, at least one polymer is present in an amount of about 10 mg / mL to about 20 mg / mL. In some embodiments, at least one polymer is present in an amount of 15 mg / mL to 20 mg / mL. In some embodiments, at least one polymer is present in an amount of about 15 mg / mL to about 20 mg / mL. In some embodiments, at least one polymer is present in an amount of 17 mg / mL to about 18 mg / mL. In some embodiments, at least one polymer is present in an amount of about 17 mg / mL to about 18 mg / mL.

[0054] In some embodiments, at least one polymer is present in concentrations of approximately 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, and 27 mg / mL. It exists in mg / mL, approximately 28 mg / mL, approximately 29 mg / mL, approximately 30 mg / mL, approximately 31 mg / mL, approximately 32 mg / mL, approximately 33 mg / mL, approximately 34 mg / mL, approximately 35 mg / mL, approximately 36 mg / mL, approximately 37 mg / mL, approximately 38 mg / mL, approximately 39 mg / mL, approximately 40 mg / mL, approximately 41 mg / mL, approximately 42 mg / mL, approximately 43 mg / mL, approximately 44 mg / mL, approximately 45 mg / mL, approximately 46 mg / mL, approximately 47 mg / mL, approximately 48 mg / mL, approximately 49 mg / mL, or approximately 50 mg / mL.

[0055] In some embodiments, at least one polymer is 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL mg / mL, 28mg / mL, 29mg / mL, 30mg / mL, 31mg / mL, 32mg / mL, 33mg / mL, 34mg / mL, 35mg / mL, 36mg / mL, 37mg / mL, 38mg / mL, 39mg / mL mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, or 50 mg / mL.

[0056] In some embodiments, the concentration of at least one polymer is the same as the concentration of the microspheres or fine particles, since they contain at least one polymer.

[0057] In some embodiments, the cellulose derivative gelling agent is selected from the group consisting of carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and ethylhydroxyethylcellulose. In some embodiments, the composition comprises at least one cellulose derivative gelling agent. In some embodiments, the composition comprises two cellulose derivative gelling agents. In some embodiments, the cellulose derivative gelling agent is carboxymethylcellulose. In some embodiments, the cellulose derivative gelling agent is sodium carboxymethylcellulose. In some embodiments, two or more.

[0058] In some embodiments, the cellulose derivative gelling agent is present in an amount of 0.5% to 4% by weight. In some embodiments, the cellulose derivative gelling agent is present in an amount of about 0.5% to about 4% by weight. In some embodiments, the cellulose derivative gelling agent is present in an amount of 1% to 3% by weight. In some embodiments, the cellulose derivative gelling agent is present in an amount of about 1% to about 3% by weight. In some embodiments, the cellulose derivative gelling agent is present in an amount of 1% to 2% by weight. In some embodiments, the cellulose derivative gelling agent is present in an amount of about 1% to about 2% by weight. In some embodiments, the cellulose derivative gelling agent is present in an amount of 2% to 3% by weight. In some embodiments, the cellulose derivative gelling agent is present in an amount of about 2% to about 3% by weight.

[0059] In some embodiments, the cellulose derivative gelling agent is present in amounts of 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, 0.9% by weight, 1% by weight, 1.25% by weight, 1.5% by weight, 1.75% by weight, 2% by weight, 2.25% by weight, 2.5% by weight, 2.75% by weight, 3% by weight, 3.25% by weight, 3.5% by weight, 3.75% by weight, or 4% by weight.

[0060] In some embodiments, the cellulose derivative gelling agent is present in amounts of about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 1.25% by weight, about 1.5% by weight, about 1.75% by weight, about 2% by weight, about 2.25% by weight, about 2.5% by weight, about 2.75% by weight, about 3% by weight, about 3.25% by weight, about 3.5% by weight, about 3.75% by weight, or about 4% by weight.

[0061] In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of 90 mg / mL to 200 mg / mL. In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of approximately 90 mg / mL to approximately 200 mg / mL. In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of 120 mg / mL to 200 mg / mL. In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of approximately 120 mg / mL to approximately 200 mg / mL. In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of 150 mg / mL to 200 mg / mL. In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of approximately 150 mg / mL to approximately 200 mg / mL. In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of 160 mg / mL to 190 mg / mL. In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of approximately 160 mg / mL to approximately 190 mg / mL. In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of 170 mg / mL to approximately 180 mg / mL. In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of approximately 170 mg / mL to approximately 180 mg / mL.

[0062] In some embodiments, the ratio of the cellulose derivative gelling agent to the surfactant is 100:1 to 1:1. In some embodiments, the ratio of the cellulose derivative gelling agent to the surfactant is approximately 100:1 to approximately 1:1.

[0063] In some embodiments, the ratio of cellulose derivative gelling agent to surfactant is 50:1 to 1:1. In some embodiments, the ratio of cellulose derivative gelling agent to surfactant is 50:1 to 10:1. In some embodiments, the ratio of cellulose derivative gelling agent to surfactant is approximately 50:1 to approximately 1:1. In some embodiments, the ratio of cellulose derivative gelling agent to surfactant is 20:1 to 1:1. In some embodiments, the ratio of cellulose derivative gelling agent to surfactant is approximately 20:1 to approximately 1:1. In some embodiments, the ratio of cellulose derivative gelling agent to surfactant is 10:1 to 1:1. In some embodiments, the ratio of cellulose derivative gelling agent to surfactant is approximately 10:1 to approximately 1:1. In some embodiments, the ratio of cellulose derivative gelling agent to surfactant is 5:1 to 1:1. In some embodiments, the ratio of cellulose derivative gelling agent to surfactant is approximately 5:1 to approximately 1:1.

[0064] In some embodiments, cellulose derivatives reduce, mitigate, or delay the sedimentation of particulate matter or microspheres in a composition compared to a composition lacking the cellulose derivative. In some embodiments, cellulose derivatives at concentrations of about 2% to about 3% by weight reduce, mitigate, or delay the sedimentation of particulate matter or microspheres in a composition compared to a composition lacking the cellulose derivative or a composition having a cellulose derivative at a concentration outside of about 2% to about 3% by weight. However, this does not reduce or mitigate foaming of particulate matter or microspheres.

[0065] In some embodiments, the cellulose derivative reduces, mitigates, or delays the settling rate of fine particles or microspheres in a composition ready for immediate use after shaking (resuspending) by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, compared to a control composition lacking the cellulose derivative or containing an amount outside of about 2% to about 3% by weight.

[0066] In some embodiments, after shaking (resuspending), the composition shows sedimentation of less than 20%, less than 15%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% when observed at 2 hours at 20-22°C, preferably substantially no sedimentation. In some embodiments, the composition shows sedimentation of less than 20%, less than 15%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% when observed at 20-22°C for about 2, about 6, about 12, about 24, or about 36 hours, preferably substantially no sedimentation. In some embodiments, the composition exhibits sedimentation of less than 20%, less than 15%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% when observed at 20–22°C after about 2–36 hours, about 2–24 hours, about 2–12 hours, about 2–6 hours, about 2–4 hours, about 12–36 hours, about 12–24 hours, or about 24–36 hours, and preferably substantially no sedimentation.

[0067] In some embodiments, the surfactant functions as a stabilizer in the composition. In some embodiments, the surfactant reduces the amount of foaming of the composition due to aggregation of fine particles or microspheres compared to compositions lacking the surfactant. In some embodiments, foaming of the composition does not occur or is reduced due to the presence of a surfactant, preferably polysorbate 80, at a concentration of 0.05 to 0.1% by weight, compared to compositions lacking the surfactant or having a surfactant at a concentration outside the range of 0.05 to 1% by weight or 0.05 to 0.1% by weight.

[0068] In some embodiments, the surfactant reduces or mitigates the amount of foam in a composition ready for immediate use after shaking by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% compared to a control composition that either lacks a surfactant, preferably polysorbate 80, or contains an amount outside the concentration of about 0.05% to about 1% by weight.

[0069] In some embodiments, the composition exhibits less than 20%, less than 15%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% foaming when observed 1 day after shaking at 20-22°C, preferably substantially no foaming. In some embodiments, the composition exhibits less than 20%, less than 15%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% foaming when observed about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 10, about 12, about 24, or about 36 hours after shaking at 20-22°C, preferably substantially no foaming. In some embodiments, the composition exhibits less than 20%, less than 15%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% foaming when observed after shaking at 20-22°C for about 0.5-36 hours, about 0.5-12 hours, about 0.5-6 hours, about 0.5-3 hours, about 0.5-2 hours, about 0.5-1.5 hours, about 0.5-1 hour, about 1-1.5 hours, about 1-2 hours, about 1-4 hours, about 1-6 hours, about 2-3 hours, about 2-4 hours, or about 2-6 hours, and preferably substantially no foaming.

[0070] In some embodiments, the composition is bioabsorbable. In some embodiments, the microspheres or particles are bioabsorbable. In some embodiments, the composition is bioabsorbed within a period of about 1 to 3 years. In some embodiments, the composition is bioabsorbed within a period of 1 to 3 years. In some embodiments, the microspheres or particles are bioabsorbed within a period of about 1 to 3 years. In some embodiments, the microspheres or particles are bioabsorbed within a period of 1 to 3 years.

[0071] In some embodiments, the composition comprises one or more thickeners selected from dextrin, hydroxyethyl starch, microcrystalline cellulose, carboxymethylated starch, acylated starch, xanthan gum, gellan gum, hyaluronic acid, carrageenan, pectin, and sodium alginate.

[0072] In some embodiments, the composition exhibits a viscosity of less than 100 mPas. In some embodiments, the composition exhibits a viscosity of less than approximately 100 mPas. In some embodiments, the composition exhibits a viscosity of less than 60 mPas. In some embodiments, the composition exhibits a viscosity of less than approximately 60 mPas.

[0073] In some embodiments, the composition exhibits a viscosity of 5 to 45 mPas. In some embodiments, the composition exhibits a viscosity of about 5 to about 45 mPas.

[0074] In some embodiments, the composition exhibits viscosities of 5-45 mPas, 10-45 mPas, 20-45 mPas, 30-45 mPas, 5-30 mPas, or 5-20 mPas, 5-10 mPas. In some embodiments, the composition exhibits viscosities of about 5-45 mPas, about 10-45 mPas, about 20-45 mPas, about 30-45 mPas, about 5-30 mPas, or about 5-20 mPas, 5-10 mPas.

[0075] In some embodiments, the composition exhibits a viscosity of less than 95 mPas, less than 90 mPas, less than 85 mPas, less than 80 mPas, less than 75 mPas, less than 70 mPas, less than 65 mPas, less than 60 mPas, less than 55 mPas, less than 50 mPas, less than 45 mPas, less than 40 mPas, less than 35 mPas, less than 30 mPas, less than 25 mPas, less than 20 mPas, less than 15 mPas, less than 10 mPas, or less than 5 mPas. In some embodiments, the composition exhibits a viscosity of less than about 95 mPas, less than about 90 mPas, less than about 85 mPas, less than about 80 mPas, less than about 75 mPas, less than about 70 mPas, less than about 65 mPas, less than about 60 mPas, less than about 55 mPas, less than about 50 mPas, less than about 45 mPas, less than about 40 mPas, less than about 35 mPas, less than about 30 mPas, less than about 25 mPas, less than about 20 mPas, less than about 15 mPas, less than about 10 mPas, or less than about 5 mPas.

[0076] In some embodiments, the microspheres or particles are 20 to 100 μm in size. In some embodiments, the microspheres or particles are approximately 20 to approximately 100 μm in size. In some embodiments, this size can be length, diameter, or width. Generally, this refers to diameter.

[0077] In some embodiments, the microspheres or particles are 20–100 μm, 20–80 μm, 20–60 μm, 20–40 μm, 30–100 μm, 40–100 μm, 50–100 μm, 60–100 μm, 70–100 μm, or 80–100 μm in size. In some embodiments, the microspheres or particles are approximately 20–approximately 100 μm, approximately 20–approximately 80 μm, approximately 20–approximately 60 μm, approximately 20–approximately 40 μm, approximately 30–approximately 100 μm, approximately 40–approximately 100 μm, approximately 50–approximately 100 μm, approximately 60–approximately 100 μm, approximately 70–approximately 100 μm, or approximately 80–approximately 100 μm in size.

[0078] In some embodiments, the microspheres or particles have a molecular weight of 50 to 500 kDa. In some embodiments, the microspheres or particles have a molecular weight of about 50 to about 500 kDa. In some embodiments, the microspheres or particles have a molecular weight of 50 to 200 kDa. In some embodiments, the microspheres or particles have a molecular weight of about 70 to about 200 kDa. In some embodiments, the microspheres or particles have a molecular weight of 50 to 140 kDa. In some embodiments, the microspheres or particles have a molecular weight of about 50 to about 140 kDa.

[0079] In some embodiments, the composition further comprises a local anesthetic. In some embodiments, the composition comprises at least one local anesthetic. In some embodiments, the local anesthetic is an amide-type local anesthetic. In some embodiments, the local anesthetic is an ester-type local anesthetic.

[0080] In some embodiments, local anesthetics include bupivacaine, butanilicaine, calticaine, cincocaine (dibucaine), cribucaine, parapiperidinoacetylaminobenzoate ethyl, etidocaine, lignocaine (lidocaine), mepivacaine, oxethazaine, prilocaine, ropivacaine, tricaine, trimecaine, budocaine, alticaine, levobupivacaine, amylocaine, cocaine, and propano. Selected from the group consisting of caine, chlormecaine, cyclomethicine, proximetacaine, ametokine (tetracaine), benzocaine, butacaine, butoxycaine, butyl aminobenzoate, chloroprocaine, dimethokine (larocaine), oxybuprocaine, pipelocaine, paretoxycaine, procaine (novocaine), propoxycaine, and tricaine, or combinations thereof.

[0081] In some embodiments, the concentration of the local anesthetic in the composition is 1 to 5 mg / mL. In some embodiments, the concentration of the local anesthetic in the composition is about 1 to about 5 mg / mL. In some embodiments, the concentration of the local anesthetic in the composition is 2 to 4 mg / mL. In some embodiments, the concentration of the local anesthetic in the composition is about 2 to about 4 mg / mL. In some embodiments, the concentration of the local anesthetic in the composition is 0.5 mg / mL, 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 3.5 mg / mL, 4 mg / mL, 4.5 mg / mL, or 5 mg / mL. In some embodiments, the concentration of the local anesthetic in the composition is approximately 0.5 mg / mL, approximately 1 mg / mL, approximately 1.5 mg / mL, approximately 2 mg / mL, approximately 2.5 mg / mL, approximately 3 mg / mL, approximately 3.5 mg / mL, approximately 4 mg / mL, approximately 4.5 mg / mL, or approximately 5 mg / mL.

[0082] In some embodiments, the composition is injectable. In some embodiments, the injectable composition is an injectable implant. In some embodiments, this disclosure relates to an injectable implant comprising any one of the compositions disclosed herein. In some embodiments, the injectable implant is for subdermal, intradermal, subcutaneous, intramuscular, submuscular, and intragingival injection.

[0083] In some embodiments, this disclosure relates to a pre-filled syringe containing any one of the compositions disclosed herein. In some embodiments, this disclosure relates to a pre-filled vial containing any one of the compositions disclosed herein.

[0084] In some embodiments, the kit includes a pre-filled syringe containing one of the compositions disclosed herein. In some embodiments, the kit includes a pre-filled vial containing one of the compositions disclosed herein, a syringe, and one or more subcutaneous needles. In some cases, the kit includes an antimicrobial composition for administration to the injection site.

[0085] In some embodiments, a kit is intended for use in carrying out the methods described herein. In some embodiments, the kit includes all the solutions, buffers, compounds, containers, and / or instructions necessary to carry out the methods described herein.

[0086] In some embodiments, the composition further comprises sodium chloride. In some embodiments, the composition exhibits a sodium chloride concentration of 0.9% w / v. In some embodiments, the composition further comprises a phosphate buffer. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises sodium chloride, a phosphate buffer, and a pharmaceutically acceptable carrier.

[0087] In some embodiments, the composition comprises one or more density improvers. In some embodiments, the density improvers may be selected from sorbitol, mannitol, and fructose.

[0088] In some embodiments, the composition includes a buffer. The buffer is a chemical compound(s) added to a solution that allows the solution to resist changes in pH as a result of either dilution or addition of a small amount of acid or base. An effective buffering system uses a solution containing a large amount of nearly equal concentrations of conjugate acid-base pairs (or buffer). The buffers used herein may be any pharmaceutically acceptable compound, including but not limited to salts of phosphates and citrates (complex acids and / or bases). In some embodiments, the buffer includes phosphate-buffered saline (PBS) or an alternative phosphate buffer.

[0089] In some embodiments, the composition has a pH of 5.5 to 7.5. In some embodiments, the composition has a pH of about 5.5 to about 7.5. In some embodiments, the composition has a pH of 6.5 to 7.5. In some embodiments, the composition has a pH of about 6.5 to about 7.5. In some embodiments, the composition has a pH of 5.5 to 6.5. In some embodiments, the composition has a pH of about 5.5 to about 6.5. In some embodiments, the composition has a pH of 5 to 7. In some embodiments, the composition has a pH of about 5 to about 7. In some embodiments, the composition has a pH of 6 to 7. In some embodiments, the composition has a pH of about 6 to about 7.

[0090] In some embodiments, the composition has a pH of 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5. In some embodiments, the composition has a pH of about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5.

[0091] In some embodiments, the composition is sterile. In some embodiments, the composition is sterile. In some embodiments, the composition is sterilized by filtration, heat sterilization, or irradiation sterilization. In some embodiments, the components of the composition are sterilized before the entire composition is mixed or formed, thus resulting in a composition comprising two or more components that were sterilized before forming the composition.

[0092] In some embodiments, poly-L-lactic acid (PLLA) is an active compound that stimulates collagen production.

[0093] In some embodiments, a ready-to-use composition comprises 150 mg of PLLA microparticles or microspheres (unirradiated), 10 mM phosphate buffer (pH 6.2), isotonic sodium chloride, 0.5% polysorbate 80, 180 mg of CMC, and 8 mL of water.

[0094] In some embodiments, a ready-to-use composition comprises 150 mg of PLLA microparticles or microspheres (irradiated), lidocaine HCl (3 mg / mL), 10 mM phosphate buffer (pH 6.2), isotonic sodium chloride, 0.5% polysorbate 80, 180 mg of CMC, and 8 mL of water.

[0095] Preparation of Formulation 1: Sterile formulation without lidocaine Background buffer 1 ●A 10 mM phosphate buffer solution was prepared by adding sodium chloride and adjusted to pH 6.2. ●The appropriate amount of carboxymethylcellulose (22.5 mg / ml) was slowly added to the buffer solution while stirring, and left overnight under stirring conditions until completely dissolved. ●Add the appropriate amount of PS80 (0.05%) and mix for approximately 20 minutes. ●The resulting solution was autoclaved at 125°C for 8 minutes.

[0096] Mixing of samples to produce the final ready-to-use formulation 1 ● Add 150 mg of sterile PLLA to the vial. ● Add 8 mL of background buffer 1 to the vial containing PLLA. ●Vortex the sample vigorously for 1 minute until the PLLA is properly dispersed.

[0097] Preparation of Formulation 2: Sterile formulation containing lidocaine (final sterilization) Background buffer 2 ●A 10 mM phosphate buffer solution was prepared by adding sodium chloride and adjusted to pH 6.2. ●The appropriate amount of carboxymethylcellulose (22.5 mg / mL) was slowly added to the buffer solution while stirring, and left overnight under stirring conditions until completely dissolved. ●Add the appropriate amount of PS80 (0.05%) and mix for approximately 20 minutes. ●Add the appropriate amount of lidocaine hydrochloride (2.667 mg / mL) and mix for approximately 20 minutes.

[0098] Mixing of samples to produce the final ready-to-use formulation 1 ● Add 150 mg of unsterilized PLLA to the vial. ●Add 9 mL of background buffer 2 to the vial containing PLLA. ●Vortex the sample vigorously for 1 minute until the PLLA is properly dispersed. ● The sample is finally sterilized by autoclaving it at 125°C for 8 minutes.

[0099] III. Method of using fillers In some embodiments, the disclosure includes methods for performing restorative or cosmetic dermatological procedures. In some embodiments, the restorative or cosmetic dermatological procedure includes injecting a subject with a composition disclosed herein. In some embodiments, the injection is subdermal, intradermal, subcutaneous, intramuscular, submuscular, or intragingival injection.

[0100] In some embodiments, the methods of the present disclosure relate to intragingival injection for filling the gums as a result of receding gums. In some embodiments, the methods relate to injecting a composition into one or more tissues of the oral cavity.

[0101] In some embodiments, injections are used for skin filling, body contouring, facial contouring, and gingival filling.

[0102] In some embodiments, the injection of the compositions disclosed herein is for skin filling. In some embodiments, a skin filling method includes injecting the composition to fill skin cracks. In some embodiments, a skin filling method includes injecting the composition to fill fine lines on the face, neck, hands, feet, knees, and elbows. In some embodiments, a skin filling method includes injecting the composition to fill wrinkles on the face, neck, hands, feet, knees, and elbows. In some embodiments, a skin filling method includes injecting the composition to fill fine lines on the face, neck, hands, feet, knees, and elbows.

[0103] In some embodiments, the skin filling method includes injecting the composition to fill a scar. In some embodiments, the skin filling method includes injecting the composition to fill a sunken scar. In some embodiments, the skin filling method includes injecting the composition to fill a hypertrophied scar. In some embodiments, the skin filling method includes injecting the composition to fill a keloid scar.

[0104] In some embodiments, a skin filling method includes injecting a composition for restoring and / or correcting signs of facial fat loss (lipoatrophy) in a person having human immunodeficiency virus (HIV).

[0105] In some embodiments, the skin filling method includes injecting the composition into the back of the hand or the upper part of the foot.

[0106] In some embodiments, the skin filling method includes injecting a composition to strengthen weakened vocal cords.

[0107] In some embodiments, a skin filling method involves injecting a composition to restore volume lost in a part of the body as a result of aging, disease, or injury.

[0108] In some embodiments, a facial contouring method includes injecting a composition into the face to modify the facial contour. In some embodiments, a facial contouring method includes injecting a composition into the lips to enhance the size and / or shape of the lips.

[0109] In some embodiments, a facial contouring method includes injecting a composition into the face to increase the symmetry of the face. In some embodiments, a facial contouring method includes injecting a composition to change the shape of the face to oval, round, square, triangular, inverted triangular, rectangular, or elliptical. In some embodiments, a facial contouring method includes injecting a composition to increase the overall width of the face. In some embodiments, a facial contouring method includes injecting a composition to increase the overall length of the face.

[0110] In some embodiments, a facial contouring method includes injecting a composition into the face to increase the width of the forehead and / or cheekbones. In some embodiments, a facial contouring method includes injecting a composition into the face to increase the length of the jaw contour.

[0111] In some embodiments, a facial contouring method includes injecting a composition into the face to alter the size and / or shape of the jaw. In some embodiments, a facial contouring method includes injecting a composition into the face to alter the size and / or shape of the forehead. In some embodiments, a facial contouring method includes injecting a composition into the face to alter the size and / or shape of the cheeks. In some embodiments, a facial contouring method includes injecting a composition into the face to alter the size and / or shape of the eyebrows.

[0112] In some embodiments, a facial contouring method includes injecting a composition into the face to correct the appearance associated with mandibular retrusion. In some embodiments, a facial contouring method includes injecting a composition into the face to correct the appearance associated with mandibular prognathism.

[0113] In some embodiments, a body contouring method includes injecting a composition into the body to modify the size and shape of various sides of the body. In some embodiments, a body contouring method includes injecting a composition into the body to modify the size and shape of the sides of the body and increase symmetry.

[0114] In some embodiments, a body contouring method involves injecting a composition into the body to modify the size and shape of the breasts, buttocks, sacrum, groin, waist, abdomen, chest, feet, legs, knees, popliteal fossa, thighs, arms, hands, elbows, and / or forearms.

[0115] In some embodiments, a body contouring method includes injecting a composition into the body to fill in concave deformities. In some embodiments, the concave deformities are the result of age, disease, injury, or predisposition. In some embodiments, a body contouring method includes injecting a composition into the body to reduce the appearance of cellulite. [Examples]

[0116] Example 1 Improvement of colloidal properties of therapeutic PLLA (poly-L-lactic acid) dispersion by addition of nonionic surfactants and hydrophilic colloids. Example 1 provides the experimental materials and design used in Examples 1-4. The example demonstrates the following: (1) the addition of a nonionic surfactant eliminates foaming of PLLA, (2) the addition of a hydrophilic colloid (polymer thickener) slows down the sedimentation of PLLA particles, and (3) the synergistic effect between the hydrophilic colloid and surfactants in slowing down the sedimentation rate.

[0117] (Table 1) Materials TIFF0007881796000001.tif69128

[0118] The sample was prepared as follows: 150 mg of PLLA powder was weighed into a standard Turbiscan vial. The desired amount of CMC powder and buffer was then added, and the sample was placed in a magnetic stirrer until the CMC was completely dissolved. Alternatively, a buffer containing pre-dissolved CMC was added. As a final step, PS80 was added by pipetting a corresponding amount of 10% stock solution into a buffer of MILLIQ water. The dispersion was then mixed by vortexing at high intensity for 1 minute.

[0119] For the preparation of reconstituted SCULPTRA samples targeting 150 mg of PLLA per 8 ml of water, 367.5 mg of homogenized lyophilized powder was used. This is based on the nominal composition of 150 mg of PLLA, 90 mg of CMC, and 127.5 mg of mannitol per package / vial containing the lyophilized formulation. The homogenized SCULPTRA powder was obtained by grinding and mixing lyophilized cakes from several vials of the same batch.

[0120] The colloidal properties of the PLLA dispersion were investigated using a Turbiscan Lab instrument (from Formulaction Inc.). This instrument collects data along the height of the sample vial for the following purposes: ● Passing through the vial Light transmittance This increases as the turbidity of the sample decreases over time, because dispersed particles settle. ●From vial Backscattering of light This is substantial from an opaque foam or bubble, and therefore, the backscatter values ​​can be used to track changes in the foam and bubble over time.

[0121] The light transmittance and backscattering measures of the compositions disclosed herein allow for the determination of the amount of foaming and settling that occurs in the compositions. Determining this foaming and settling enables comparisons between various compositions. Data were collected at predetermined regular time intervals so that the temporal evolution of the colloidal system could be tracked.

[0122] Samples were prepared in standardized-sized Turbiscan glass vials. After initial mixing of the sample, partially settled PLLA particles were redispersed by shaking the vial before the start of the Turbiscan data acquisition cycle. The presented transmittance data were averaged over data collected at vial heights of 2mm–12mm, corresponding to the majority of the sample solution. The presented backscatter data were averaged over data at vial heights of 16mm–20mm, corresponding to the top of the sample dispersion containing foam. See Figure 1.

[0123] Example 2 Elimination of PLLA foam by adding the nonionic surfactant polysorbate 80. This example demonstrates the effect of adding a nonionic surfactant on the presence of persistent PLLA foam.

[0124] As shown in Figure 2, PLLA foam disappeared from the 0.05% PS80 concentrate. The presence of polysorbate 80 in the formulation clearly leads to the elimination of persistent PLLA foam in both PLLA-based formulations, as well as in the reconstituted lyophilized SCULPTRA formulation. Residual backscattering in the presence of PS80 stems is due to unstable surfactant-based foams, which disappear within approximately 2 hours after the start of the data acquisition cycle when the sample is shaken to redisperse the settled PLLA (less than 10% backscattering).

[0125] The stable formation of PLLA foam is thought to be related to the hydrophobicity of PLLA particles and insufficient wetting by water / buffer. Therefore, the mechanism behind foam elimination is very likely related to a decrease in the water / buffer interfacial tension, as well as the adsorption of surfactants on the surface of PLLA particles, which causes their surface hydrophilicity, and this is thought to result in good wetting of the particles by the aqueous solvent.

[0126] Based on the proposed mechanism, a surfactant concentration in a solution nearly above the critical micelle concentration is necessary for the foam-removing effect. It is important to consider the depletion of surfactant from the solution due to the adsorption of many small PLLA particles with a large surface area onto the surface. That is, if more PLLA particles are added per given volume, more surfactant needs to be added.

[0127] Example 3 Adding polysaccharide-based hydrophilic colloidal carboxymethylcellulose sodium slows down the sedimentation of PLLA particles. This experiment demonstrates how the addition of hydrophilic colloids affects the sedimentation of PLLA particles in a dispersion.

[0128] The results revealed that the addition of carboxymethylcellulose (CMC) significantly slowed the rate of increase in the transmittance of the sample compared to a PLLA dispersion prepared in bare buffer. The higher the amount of CMC added, the slower the increase in transmittance became over time. The low transmittance of light passing through the sample is related to its turbidity, which is due to the presence of PLLA particles suspended in most of the liquid. The settling rate of these particles is slow in the presence of carboxymethylcellulose, which increases the viscosity of the solution. Because the particles settle slowly, the transmittance does not increase much over time. The higher the concentration of CMC, the higher the viscosity of the solution and the slower the settling of the PLLA particles.

[0129] Considering the proposed mechanism, the target concentration of the added hydrophilic colloid depends on its properties, including molecular weight, degree of branching, modification of side groups, and other properties that affect the viscosity of the hydrophilic colloid polymer solution. The viscosity of 2.25% CMC in buffer, which yielded a similar rate of permeability increase for the SCULPTRA formulation, was 28 mPas, as measured by capillary viscosity. The concentrations of other hydrophilic colloids or different types of CMC need to be adjusted to yield similar viscosities. The addition of CMC had no significant effect on the foam stability of PLLA. This is related to the lack of surface activity of CMC.

[0130] Example 4 Synergistic effect between nonionic surfactant PS80 and polysaccharide-based hydrophilic colloid carboxymethylcellulose This experiment aims to demonstrate whether there is a synergistic effect between the surfactant and the hydrophilic colloidal thickener in (a) slowing down the sedimentation rate and (b) eliminating foam in PLLA.

[0131] A synergistic effect was observed between the hydrophilic colloid and the surfactant in slowing the sedimentation of PLLA particles. The presence of 0.5% polysorbate 80 resulted in the removal of PLLA foam (sample PLLA-buffer-0.5% PS80), but the removal rate of this formulation remained very high. On the other hand, the addition of PS80 to formulations containing carboxymethylcellulose resulted in slower removal compared to the corresponding PS80-free formulation. The synergistic effect appears to be independent of the PS80 concentration, as the same low removal rate was observed after the addition of 0.05% and 0.5% PS80. Therefore, the decrease in transmittance is thought to be related to the wetting of PLLA particles originally present in the foam and their transfer to the dispersion, where they contribute to turbidity. Similar synergistic effects can be expected for different PS80 concentrations, as long as they are above the PLLA particle wetting threshold.

[0132] Example 5 Buffer system for the stability of poly-L-lactic acid (PLLA) PLLA undergoes hydrolysis in aqueous solution, resulting in the release of lactic acid monomers and oligomers from the bulk polymer particles, as well as fragmentation of the bulk polymer. This process is autocatalyzed by the presence of degradation products (PLLA fragments or monomers) both in solution and within the bulk polymer. Sterilizing and storing PLLA in aqueous solution can lead to substantial degradation and unacceptable alterations to the formulation properties.

[0133] The degradation rate of PLLA can be affected by the buffer properties, such as the buffer ion composition (e.g., phosphate buffer, citrate, Bis-Tris), buffer pH, buffering capacity / buffer concentration, and cosolvent.

[0134] These studies evaluate the effectiveness of various buffer systems for maximizing the stability of PLLA or extending the shelf life of ready-to-use formulations.

[0135] Development and optimization of analytical methods Unsterilized PLLA (18SO229) and gamma-ray sterilized PLLA (1830200) were tested. ●150 mg of PLLA was prepared in 5 mL of MILLIQ aqueous dispersion. ●Accelerated decomposition was evaluated by mixing at 90°C for two weeks. ●To separate the water-insoluble undegraded material from the soluble decomposition products, it was filtered through a 0.22 μm MILIPORE filter. ●The filtrate (water-soluble portion) was treated with 1M NaOH and then analyzed by liquid chromatography to identify the decomposition of PLLA into lactic acid oligomers and lactic acid monomers. ●The remaining residue from the filter (water-insoluble) was dissolved in dichloromethane and analyzed by gel permeation chromatography (GPC). ● GPC reference sample: Undegraded material ○Untreated - PLLA powder received was dissolved in CH2Cl2. ○Filtered - Undecomposed PLLA dispersion dissolved in CH2CL2.

[0136] Liquid chromatography was used to determine the state of the standard and the standard after degradation. Analysis of the filtrate determined the presence of lactic acid monomers in sterile PLLA. No lactic acid oligomers were detected after treatment with 1M sodium hydroxide for 1 hour. The size of PLLA was determined using a type of size exclusion chromatography called gel permeation chromatography (GPC).

[0137] PLLA samples were obtained in two forms: (1) ground and unsterilized, and (2) ground and gamma-sterilized. The ground PLLA was characterized with respect to lactic acid content, molecular weight distribution of PLLA polymer, and autoclaving effect.

[0138] The low molecular weight of the "decomposed extract" is due to the visual observation of high PLLA insolubility in CH2Cl2 after decomposition at 90°C for two weeks. This is likely due to the change in the ratio of amorphous PLLA to crystalline PLLA during decomposition and the final recrystallization above the glass transition temperature. Crystalline PLLA has low solubility in CH2Cl2, and only short polymerization chains can enter the solution during the sample preparation step. An alternative may be the preferential decomposition of the amorphous portion of PLLA, which leaves the undecomposed residue highly crystalline.

[0139] The low molecular weight of the "decomposed filtered sample" is due to the visual observation of high PLLA insolubility in CH2Cl2 after decomposition at 90°C for two weeks, and can be explained similarly to the change in PLLA crystallinity during high-temperature decomposition of unsterilized samples.

[0140] The general conclusion is as follows: ● Some of the residue from the sample decomposed at 90°C is not solubilized by dichloromethane. ●For samples decomposed at 90°C, it is likely that only the low molecular weight fraction of the polymer is solubilized, while the high molecular weight polymer remains in the solid phase. ●There were no problems with the solubility of the starting material, PLLA powder, and the undecomposed sample.

[0141] A distinction was made between decomposed unsterile PLLA and decomposed sterile PLLA. This distinction can be seen in a single chart. The amount of decomposed extract was 37% for decomposed unsterile PLLA and 50% for decomposed sterile PLLA. This corresponds to the mass balance of the decomposed sample using a 0.2 μm filter (decomposition occurred at 90°C for 2 weeks). However, experiments with both sets resulted in a total PLLA recovery (lactic acid monomer + extract) exceeding 100%, which was attributed to experimental error. Subsequent experiments adjusted the filtration procedure and used a more accurate follow-up for the filtrate volume.

[0142] Additional experiments were conducted on unsterilized PLLA in deionized water and sterilized PLLA in deionized water, and samples that underwent (1) decomposition at 40°C for 4 days and (2) autoclaving at 125°C for 8 minutes were evaluated. The results are as follows. ●Decomposition at 40°C is limited, and no detectable lactic acid monomers are found. ●The solubility of the PLLA sample after decomposition at 40°C for 4 days was sufficient (only a very small amount was insoluble and potentially an impurity). ● Disassembly during autoclaving was limited. ●The solubility of the PLLA sample after autoclaving was sufficient, but a very small amount remained insoluble. ●For both sterile and non-sterile PLLA, the reproducibility of GPC results obtained in different settings was good.

[0143] Evaluation of PLLA stability in different buffers during autoclaving and subsequent 30-day storage at 40°C. For PLLA recovery during filtration, we assumed 150 mg of PLLA for every 367.5 mg of added lyophilized powder. However, the variation in PLLA content in the SCULPTRA sample was + / - 2%, and therefore, the low amount of PLLA in the filtration of the SCULPTRA sample is more likely due to the initial variation in PLLA content than to PLLA degradation.

[0144] Samples prepared in pH 6.2 buffer, 50 mM high-buffering-capacity buffer, and 10 mg / mL with low PLLA loading showed good stability. The main observations regarding molecular weight of the filtered samples were as follows: (1) the molecular weight of all samples decreased compared to the corresponding reference; (2) the decrease in molecular weight was slightly smaller for samples prepared in pH 6.2 buffer and water at approximately pH 6 than for samples prepared in pH 7.3 buffer; and (3) the molecular weight of the sample containing 3 mg / mL of lidocaine decreased substantially.

[0145] Considering the substantial decrease in molecular weight of the lidocaine-containing sample, the experiment was repeated, and the reproducibility of the data obtained from the newly mixed sample containing lidocaine was good.

[0146] In water, lidocaine is in equilibrium with its protonated form. Below pH below pka, the protonated form is dominant, leading to acidic hydrolysis of lidocaine. GPC chromatography of unautoclaved lidocaine-containing samples compared to autoclaved lidocaine-containing samples reveals a size shift in the unautoclaved lidocaine-containing samples, with GPC output showing earlier detachment than in the autoclaved lidocaine-containing samples. PLLA particles are hydrophobic, and their density can be significantly higher than that of water (density depends on particle porosity). The colloidal stability of PLLA suspensions can be improved by the following functional components. ● Stabilizers - For example, by using polymers that adsorb to PLLA particles and expose PEO groups to the majority of the solution, aggregation driven by hydrophobic interactions between particles is prevented. ●Thickening agents - Prevent or slow down sedimentation by increasing the viscosity of the buffer solution through the formation of a hydrogel-type structure.

[0147] In some embodiments, a favorable buffer system includes: ● 10 mM phosphate buffer + NaCl, pH 6.2 + 3 mg / mL lidocaine.

[0148] Example 6 Decrease in foaming and settling Foaming in ready-to-use products can be a significant problem. The core SCULPTRA composition, containing PLLA, mannitol, and CMC, exhibits foaming properties.

[0149] Figure 3 identifies the effect of PS80 on foaming. SCULPTRA shows significant PLLA foaming, SCULPTRA + 0.1% PS80 shows less PLLA foaming, and SCULPTRA + 1% PS80 appears to show no significant PLLA foaming.

[0150] (Table 2) Variations of samples and foaming TIFF0007881796000002.tif94165

[0151] Visual identification of the sample vials corresponding to the samples listed in Table 2 reveals that the foaming of PLLA is not related to the freeze-drying process, the presence of mannitol, or the presence of CMC.

[0152] Furthermore, particle size and shape do not appear to determine the foaming of PLLA. Figure 4 suggests that neither glycerol nor PEG400 can reduce the foaming of PLLA.

[0153] (Table 3) Variations and sedimentation of samples TIFF0007881796000003.tif132165

[0154] Figure 5 identifies the degree of foaming and sedimentation of samples S2, P1, P2, P3, and P4 from Table 3.

[0155] Turbiscan backscattering and transmittance were used to evaluate various phases of the sample, namely the precipitated phase, intermediate phase, and foamed phase (Figure 6).

[0156] The effects of viscosity modifiers and PS80 are evident in the results of the intermediate phase transmittance (Figure 7). When viscosity modifiers were added, the sedimentation of the sample slowed down; CMC showed a significant effect, while mannitol had only a slight effect. PS80 had little effect on the sedimentation velocity. The backscattering results were not as pronounced as the transmittance results.

[0157] Adding PS80 to SCULPTRA samples significantly reduces foaming (Figure 8). Studies with PS80 show that adding 0.1% to 1% results in a rapid elimination of foaming after shaking in PLLA-containing samples.

[0158] (Table 4) Eight SCULPTRA / PLLA samples TIFF0007881796000004.tif92165

[0159] The PA-1 to PA-6 samples in Table 4 are present in 10 mM PBS, pH 6.2, and 3 mg / mL lidocaine.

[0160] Figure 9 shows the transmittance values ​​of eight SCULPTRA / PLLA formulations, particularly the intermediate phase of each formulation. The arrow on the right side of the figure indicates that the SCULPTRA value after 22 hours is approximately 40% transmittance. There were no significant differences due to storage time in the CMC-containing samples. There were no significant differences in the buffered samples. The decrease in transmittance in the presence of PS80 is likely due to a decrease in particles in the foam entering the intermediate phase, and therefore increased turbidity.

[0161] Figure 10 shows the backscatter values ​​of the foam phase for eight SCULPTRA / PLLA formulations, particularly for each formulation. The arrow on the right side of the figure indicates that the SCULPTRA value after 22 hours is approximately 45% backscatter, and the difference is dramatic in the presence of PS80. In the presence of PS80, rapid breakdown of the foam occurs.

[0162] CMC helps, at least to some extent, to avoid the sedimentation of PLLA particles due to its viscosity, but CMC is not related to the foaming of PLLA. The addition of PS80 works both to avoid the foaming of PLLA and to slow down the sedimentation of PLLA particles compared to a mixture of PLLA and CMC alone.

[0163] The methods described herein exemplarily may be adequately implemented in the absence of any elements(s) or limitations(s) not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted broadly and without limitation. Furthermore, the terms and expressions used herein are for illustrative purposes only and not limitation; the use of such terms and expressions is not intended to exclude any equivalents of the features or parts thereof shown or described. It is recognized that various modifications are possible within the scope of the claimed disclosure. Therefore, while the disclosure has been specifically disclosed by preferred embodiments and any features, modifications and variations of the disclosure disclosed herein may be invoked by those skilled in the art, and such modifications and variations should be understood to be within the scope of the disclosure.

[0164] This disclosure is described more broadly and generally herein. Each of the narrower species and subspecies groups that fall under the general disclosure also forms part of the Method. This includes a general description of the Method that includes conditions or negative limitations for removing any subject matter from a genus, whether or not the deleted material is specifically enumerated herein. The Art is not limited to the specific embodiments described in this application, but is intended as a single example of individual aspects of the Art. As will be apparent to those skilled in the art, many modifications and variations of the Art can be made without departing from its spirit and scope. In addition to those enumerated herein, functionally equivalent methods and apparatus within the scope of the Art will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the Art. The Art is not limited to specific methods, reagents, compound compositions, or biological systems, and these can, of course, be changed. It should also be understood that the terminology used herein is intended solely to describe specific embodiments and is not intended to limit them.

[0165] Those skilled in the art will readily understand that this disclosure is well adaptable to perform its purpose and to obtain the objectives and benefits mentioned, as well as those specific to them. Modifications and other uses therein will arise for those skilled in the art. These modifications are included within the spirit of this disclosure and are defined by the claims describing non-limiting embodiments of this disclosure.

[0166] In addition, if any feature or aspect of the present disclosure is described in terms of the Markush group, a person skilled in the art will recognize that the present disclosure is also described in terms of any individual member or subgroup of a member of the Markush group.

[0167] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated in their entirety by reference for all purposes.

[0168] However, any references to references, articles, publications, patents, patent publications, and patent applications cited herein should not be considered, as such, to be an acknowledgment or suggestion of any kind that they constitute valid prior art or form part of the general knowledge in any country of the world.

Claims

1. A ready-to-use composition for performing restorative or cosmetic dermatological procedures, (a) Microspheres or fine particles having a size of 20 to 100 μm and a molecular weight of 50 to 500 kDa, comprising at least one non-animal polymer in an amount of 10 to 30 mg / mL relative to the volume of the composition, wherein the at least one polymer is selected from the group consisting of lactic acid polymers, glycolic acid polymers, and lactic acid-glycolic acid copolymers, (b) A hydrogel comprising water and a cellulose derivative gelling agent, wherein the cellulose derivative gelling agent is present in an amount of 1% to 3% by weight relative to the weight of the composition and is selected from the group consisting of carboxymethylcellulose and hydroxypropylmethylcellulose, (c) Polysorbate 80 in an amount of about 0.1% to about 1% by weight relative to the weight of the composition Includes, The composition does not exhibit foaming when observed after shaking and at 20-22°C for one day, and The aforementioned ready-to-use composition is not reconstituted from a freeze-dried or lyophilized composition after storage and before administration. The aforementioned composition.

2. The composition according to claim 1, wherein the lactic acid is selected from the group consisting of poly-L-lactic acid, poly-D-lactic acid, and mixtures thereof.

3. The composition according to claim 1, wherein the at least one polymer is poly-L-lactic acid.

4. The composition according to claim 1, wherein the amount of at least one polymer is about 17 to about 18 mg / mL.

5. The composition according to claim 1, wherein the cellulose derivative gelling agent is carboxymethylcellulose.

6. The composition according to claim 1, wherein the cellulose derivative gelling agent is present in an amount of about 2% by weight relative to the weight of the composition.

7. The composition according to claim 1, wherein the polysorbate 80 is present in an amount of 0.5% by weight relative to the weight of the composition.

8. The at least one polymer is poly-L-lactic acid in an amount of 17 to 18 mg / mL relative to the volume of the composition; The cellulose derivative gelling agent is carboxymethylcellulose in an amount of 2% by weight relative to the weight of the composition; and The polysorbate 80 is present in an amount of 0.5% by weight relative to the weight of the composition. The composition according to claim 1.

9. The composition according to claim 1, having a viscosity of 5 to 45 mPas.

10. The composition according to claim 1, further comprising a local anesthetic.

11. The composition according to claim 10, wherein the local anesthetic is selected from the group consisting of bupivacaine, butanilicaine, calticaine, cincocaine, cribucaine, parapiperidinoacetylaminobenzoate ethyl, etidocaine, lignocaine, mepivacaine, oxethazaine, prilocaine, ropivacaine, tricaine, trimecaine, budocaine, alticaine, levobupivacaine, amylocaine, cocaine, propanocaine, chlormecaine, cyclomethicaine, proximetacaine, ametocaine, benzocaine, butacaine, butoxycaine, butyl aminobenzoate, chloroprocaine, dimethocaine, oxybuprocaine, pipelocaine, paretoxycaine, procaine, propoxycaine, tricaine, and combinations thereof.

12. The composition according to claim 1, further comprising sodium chloride, a phosphate buffer, and a pharmaceutically acceptable carrier.

13. The composition according to claim 12, wherein sodium chloride is present at a concentration of 0.9% w / v.

14. The composition according to claim 1, which exhibits at least a 5% reduction in sedimentation velocity compared to a control composition lacking the cellulose derivative gelling agent in an amount of 1% to 3% by weight relative to the weight of the composition.

15. The composition according to claim 1, which does not exhibit foaming when observed approximately 4 hours after shaking at 20-22°C.

16. A ready-to-use composition for performing a restorative or cosmetic dermatological procedure, (a) Microspheres or fine particles comprising, in an amount of 10 to 20 mg / mL relative to the volume of the composition, at least one polymer of non-animal origin, wherein the at least one polymer is selected from the group consisting of lactic acid polymers, glycolic acid polymers, and lactic acid-glycolic acid copolymers, (b) A hydrogel comprising water and a cellulose derivative gelling agent, wherein the cellulose derivative gelling agent is present in an amount of 160 to 180 mg / mL relative to the volume of the composition and is selected from the group consisting of carboxymethylcellulose and hydroxypropylmethylcellulose, (c) Polysorbate 80, wherein the ratio of the concentrations of the cellulose derivative gelling agent to the polysorbate 80 is about 20:1 to about 1:

1. Includes, The aforementioned composition did not exhibit foaming when observed after shaking and at 20-22°C for one day. The aforementioned ready-to-use composition is not reconstituted from a freeze-dried or lyophilized composition after storage and before administration. The aforementioned composition.

17. The composition according to claim 16, wherein the lactic acid is selected from the group consisting of poly-L-lactic acid, poly-D-lactic acid, and mixtures thereof.

18. The composition according to claim 16, wherein the ratio of the concentrations of the cellulose derivative gelling agent to the polysorbate 80 is about 10:1 to about 1:

1.

19. The composition according to claim 16, wherein the amount of the cellulose derivative gelling agent is about 170 to 180 mg / mL relative to the volume of the composition.

20. The composition according to claim 16, wherein the amount of at least one polymer is about 15 to 20 mg / mL relative to the volume of the composition.

21. The composition according to claim 16, which exhibits at least a 5% reduction in sedimentation velocity compared to a control composition lacking the cellulose derivative gelling agent in an amount of about 160 to 180 mg / mL relative to the volume of the composition.

22. The composition according to claim 16, which does not exhibit foaming when observed approximately 4 hours after shaking at 20-22°C.

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