Immediately usable cosmetic composition

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 to U.S. Application No. 62 / 926,935, filed October 28, 2019, which is incorporated herein by reference in its entirety.

[0002] Field The present disclosure relates to ready-to-use implants for subcutaneous or intradermal injection, which can be used in humans as dermal fillers in restorative or plastic surgery and in cosmetic dermatology to fill wrinkles, fine lines, cracks in the skin, fill scars, fill gum tissue, reshape various areas of the body, and reshape the face. [Background technology]

[0003] background The applicant sells a product under the trade name SCULPTRA, supplied as a sterile, lyophilized powder in glass vials, each containing poly-L-lactic acid (PLLA), sodium carboxymethylcellulose (CMC), and mannitol. Prior to administration, the contents of the vial must be reconstituted by adding an aqueous solution or water to the vial. See U.S. Patent Nos. 7,731,758 and 8,414,657.

[0004] The need to reconstitute the contents of the vial introduces the potential for error, either in the case of contamination if the volume of liquid added to the vial is not sterile, or in the case of inconsistencies in the concentration of the final product if too little or too much volume is used to reconstitute the contents of the vial.

[0005] An objective of the present disclosure is to overcome the potential for error or inconsistency in reconstituting the contents of the vial and to further stabilize the ready-to-use product for storage prior to administration in a ready-to-use form by mitigating foaming and settling of the ready-to-use product. [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 Summary of the Invention

[0007] Summary of the Disclosure FIELD OF THE DISCLOSURE The present disclosure relates generally to stable, ready-to-use injectable implants and methods for using the implants to perform restorative or cosmetic skin surgery.

[0008] In one aspect, the present disclosure relates to a composition comprising: (a) microspheres or microparticles of at least one polymer of non-animal origin 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) polysorbate 80 in an amount of 0.05% to 1% by weight.

[0009] In some embodiments, the at least one polymer is a lactic acid selected from poly-L-lactic acid, poly-D-lactic acid, and mixtures thereof. In some embodiments, the at least one polymer is poly-L-lactic acid. In some embodiments, the 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, the 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 the cellulose derivative gelling agent to polysorbate 80 is 100:1 to 1:1. In some embodiments, the ratio of the cellulose derivative gelling agent to polysorbate 80 is 50:1 to 10:1.

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

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

[0015] In some embodiments, the composition further comprises a local anesthetic. In some embodiments, the local anesthetic is an amide-type or ester-type local anesthetic. In some embodiments, the local anesthetic is bupivacaine, butanilicaine, carticaine, cinchocaine (dibucaine), cribucaine, ethyl parapiperidinoacetylaminobenzoate, etidocaine, lignocaine (lidocaine), mepivacaine, oxethazaine, prilocaine, ropivacaine, tricaine, trimecaine, vadocaine, articaine, levobupivacaine, amylocaine, cocaine, propanoic acid, or the like. The benzocaine, chlormecaine, cyclomethycaine, proxymetacaine, amethocaine (tetracaine), benzocaine, butacaine, butoxycaine, butyl aminobenzoate, chloroprocaine, dimethocaine (larocaine), oxybuprocaine, piperocaine, parethoxycaine, procaine (novocaine), propoxycaine, and tricaine, or a combination 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, a 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 another embodiment, the present disclosure relates to a pre-filled syringe or vial containing the composition of any one of the described embodiments.

[0019] In another aspect, the present disclosure relates to an injectable implant comprising the composition of any one of the described aspects. In some aspects, the injectable implant is for intradermal or subcutaneous injection into the body of a subject in need thereof.

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

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

[0022] In some embodiments, the injections are for skin filling, body contouring, facial contouring, and gum filling. In some embodiments, skin filling is selected from wrinkle filling, fine line filling, skin crack filling, scar filling, and combinations thereof. In some embodiments, gum filling includes filling gaps between tooth bases. In some embodiments, facial and body contouring is selected from creating pronouncements, correcting concave deformities, correcting age-related facial grooves, and augmenting or repairing contour defects in hard or soft tissues of the face and body due to aging, injury, and acquired or congenital deformities of the face or body.

[0023] [The present invention 1001] (a) microspheres or microparticles of at least one polymer of non-animal origin 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; (c) polysorbate 80 in an amount of 0.05% by weight to 1% by weight; A composition comprising: [The present invention 1002] 1001. The composition of claim 1001, wherein said at least one polymer is a lactic acid selected from poly-L-lactic acid, poly-D-lactic acid, and mixtures thereof. [The present invention 1003] 1002. The composition of claim 1002, wherein said at least one polymer is poly-L-lactic acid. [The present invention 1004] 1001. The composition of claim 10, wherein said at least one polymer is present in an amount of 5 mg / mL to 50 mg / mL. [The present invention 1005] 1001. The composition of claim 10, wherein said cellulose derivative gelling agent is carboxymethyl cellulose or hydroxypropyl methyl cellulose. [The present invention 1006] 1005. The composition of claim 10, wherein said cellulose derivative gelling agent is carboxymethyl cellulose. [The present invention 1007] 1006. The composition of claim 10, wherein the carboxymethylcellulose is sodium carboxymethylcellulose. [The present invention 1008] 1006. The composition of claim 1006, wherein the cellulose derivative gelling agent is present in an amount of 0.5% to 4% by weight. [The present invention 1009] 1008. The composition of claim 10, wherein said cellulose derivative gelling agent is present in an amount of 2% by weight. [The present invention 1010] 1001. The composition of claim 1001, wherein said polysorbate 80 is present in an amount of 0.05% by weight. [The present invention 1011] 1001. The composition of the present invention, exhibiting a viscosity of less than 100 mPas. [The present invention 1012] 1011. The composition of the present invention, exhibiting a viscosity of less than 60 mPas. [The present invention 1013] 1001. The composition of the present invention, which exhibits a viscosity of 5 to 45 mPas. [The present invention 1014] 1001. The composition of the present invention, wherein the ratio of said cellulose derivative gelling agent to said polysorbate 80 is 100:1 to 1:1. [The present invention 1015] 1014. The composition of the present invention, wherein the ratio of said cellulose derivative gelling agent to said polysorbate 80 is 50:1 to 10:1. [The present invention 1016] 1001. The composition of claim 1001, wherein said microspheres or microparticles are bioabsorbable. [The present invention 1017] The composition of claim 1016, wherein said microspheres or microparticles are bioabsorbable within a period of about 1 year to about 3 years. [The present invention 1018] 1001. The composition of the present invention, comprising microspheres or microparticles at a concentration of 5 to 20 mg / mL. [The present invention 1019] 1018. The composition of claim 10, comprising microspheres or microparticles at a concentration of 17-18 mg / mL. [The present invention 1020] 1001. The composition of claim 10, wherein said microspheres or microparticles are about 20-100 μm in size. [The present invention 1021] The composition of claim 10, wherein said microspheres or microparticles exhibit a median particle size of about 40 μm. [The present invention 1022] 1001. The composition of the present invention, wherein said microspheres or microparticles exhibit a molecular weight of 50 to 500 kDa. [The present invention 1023] 1022. The composition of claim 1022, wherein said microspheres or microparticles have a molecular weight of 50 to 200 kDa. [The present invention 1024] The composition of any one of claims 1001 to 1023, further comprising a local anesthetic. [The present invention 1025] The composition of the present invention 1024, wherein the local anesthetic is an amide-type or ester-type local anesthetic. [The present invention 1026] The local anesthetic may be bupivacaine, butanilicaine, carticaine, cinchocaine (dibucaine), cribucaine, ethyl parapiperidinoacetylaminobenzoate, etidocaine, lignocaine (lidocaine), mepivacaine, oxethazaine, prilocaine, ropivacaine, tricaine, trimecaine, vadocaine, articaine, levobupivacaine, amylocaine, cocaine, propanocaine, chlormecaine, cinnamo ... The composition of any one of claims 1024 to 1025, wherein the compound is selected from the group consisting of clomethicaine, proxymetacaine, amethocaine (tetracaine), benzocaine, butacaine, butoxycaine, butyl aminobenzoate, chloroprocaine, dimethocaine (larocaine), oxybuprocaine, piperocaine, parethoxycaine, procaine (novocaine), propoxycaine, and tricaine, or a combination thereof. [The present invention 1027] The composition of any one of claims 1001 to 1026, which is sterile. [The present invention 1028] 1027. The composition of the present invention, wherein sterility is achieved by irradiation or heat sterilization. [The present invention 1029] The composition of any of claims 1001 to 1028, further comprising sodium chloride, a phosphate buffer, and a pharmaceutically acceptable carrier. [The present invention 1030] Any of the compositions of 1001 to 1029 of the present invention, which has a sodium chloride concentration of 0.9% w / v. [The present invention 1031] Any of the compositions of 1001 to 1030 of the present invention, which is injectable. [The present invention 1032] The composition of claim 1031, wherein the injectable composition is an injectable implant. [The present invention 1033] A pre-filled syringe or vial containing any one of the compositions of inventions 1001 to 1032. [The present invention 1034] An injectable implant comprising any one of the compositions of inventions 1001 to 1032. [This invention 1035] The injectable implant of the present invention 1034, which is for intradermal or subcutaneous injection into the body of a subject in need thereof. [The present invention 1036] A method for performing a restorative or cosmetic dermatological treatment, comprising injecting a subject with any one of the compositions of inventions 1001 to 1032. [This invention 1037] 1036. The method of claim 1036, wherein said injection is intradermal, subdermal, subcutaneous, intramuscular, submuscular, or intragingival. [The present invention 1038] 1036. The method of claim 1036, wherein said injection is into one or more tissues of the oral cavity. [This invention 1039] 1039. The method of any one of claims 1036 to 1038, wherein said injection is for skin filling, body contouring, facial contouring, and gum filling. [The present invention 1040] The method of claim 1039, wherein the skin filling is selected from wrinkle filling, fine line filling, skin crack filling, scar filling, and combinations thereof. [The present invention 1041] The method of claim 1039, wherein filling the gums comprises filling gaps between the bases of the teeth. [The present invention 1042] The method of claim 1039, wherein the facial and body contouring is selected from creating pronouncement structural features, correcting concave deformities, correcting age-related facial grooves, and augmenting or repairing contour defects in the hard or soft tissues of the face and body caused by aging, injury, and acquired or congenital deformities of the face or body. The following detailed description is exemplary and explanatory and is intended to provide further explanation of the present invention. [Brief explanation of the drawings]

[0024] [Figure 1]Raw Turbiscan data (for the sample PLLA-2.25%CMC-0.05%PS80-S2) are shown: transmittance (top) and backscattering (bottom) through the sample solution at different heights (x-axis) of the vial containing the sample. [Figure 2] 1 shows backscattering versus time from bubbles or foams in the absence and presence of nonionic surfactant PS80 for a 150 mg / 8 mL PLLA loaded dispersion. [Figure 3] A comparison of three vials of SCULPTRA with or without PS80 is shown. None on the left, 0.1% PS80 in the middle, and 1% PS80 on the right. The samples were shaken and images were taken after 16 hours. Foaming decreases from left to right. [Figure 4] A comparison of four vials of SCULPTRA product is shown: (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] Five vials with varying degrees of sedimentation are shown: S2 is SCULPTRA, and P1, P2, P3, and P4 are various non-sterile PLLA formulations described in the Examples. [Figure 6] 1 shows turbiscan backscattering traces identifying various peaks and plateaus with three distinct regions found in the SCULPTRA / PLLA formulation: sediment, mesophase, and foam. [Figure 7] 1 shows the permeability values ​​of seven SCULPTRA / PLLA formulations and an evaluation of the effect of viscosity modifiers and PS80. [Figure 8] 1 shows backscattering values ​​for foams of four SCULPTRA / PLLA formulations. [Figure 9] The figure shows the transmittance values ​​for eight SCULPTRA / PLLA formulations, specifically the mesophase of each formulation. The arrow on the right side of the figure indicates that the value for SCULPTRA after 22 hours is approximately 40% transmittance. [Figure 10]The backscattering values ​​for eight SCULPTRA / PLLA formulations are shown, specifically the foam phase of each formulation. The arrow on the right side of the figure indicates that after 22 hours, the value for SCULPTRA is approximately 45% backscattering; the difference is dramatic in the presence of PS80. DETAILED DESCRIPTION OF THE INVENTION

[0025] Detailed Description of the Disclosure The compositions disclosed herein are ready-to-use injectable compositions comprising polymeric microspheres or microparticles of non-animal origin, a hydrogel comprising water and a cellulose derivative gelling agent, and polysorbate 80. The methods disclosed herein are methods of using the ready-to-use injectable compositions for restorative or plastic surgery, cosmetic dermatology, facial contouring, body contouring, and gum augmentation.

[0026] The compositions and methods of use are a significant improvement over the state of the art, given that the ready-to-use injectable compositions mitigate the potential for error or inconsistency in reconstituting freeze-dried or lyophilized compositions. The ready-to-use compositions and methods of use are a further improvement over the prior art, given the stability of the compositions and their superior properties in mitigating foaming and settling of the ready-to-use products.

[0027] It is an object of the present disclosure to overcome the possibility of error or inconsistency in reconstituting the contents of the vial and to further stabilize the ready-to-use product for storage prior to administration in a ready-to-use form by reducing foaming and settling of the ready-to-use product. Thus, the compositions and methods described herein offer significant advantages over the prior art.

[0028] I. Definition Although the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the subject matter of the present disclosure.

[0029] The term "a" or "an" may refer to one or more of that entity, i.e., to a plurality of referents. Thus, the terms "a" or "an," "one or more," and "at least one" are used interchangeably herein. In addition, reference to an "element" by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that only one of the element is present.

[0030] Throughout this specification, references to "one embodiment," "an embodiment," "one aspect," or "an aspect" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0031] As used herein, the term "about" or "approximately" when preceding a numerical value indicates a range of plus or minus 10% of the value.

[0032] As will be understood by those skilled in the art, for any and all purposes, particularly with respect to providing a written description, all ranges disclosed herein encompass any and all possible subranges and combinations thereof. Any recited range can be readily recognized as fully descriptive and allowing for the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be easily broken down into a lower third, middle third, upper third, etc. As will be understood by those skilled in the art, all terms such as "up to," "at least," "greater than," "less than," etc., are inclusive of the recited numbers and refer to ranges that can be subsequently broken down into subranges as discussed above. Finally, as will be understood by those skilled in the art, a range includes each individual member. Thus, for example, a group having 1 to 3 cells refers to a group having 1, 2, or 3 cells. Similarly, a group having 1 to 5 cells refers to a group having 1, 2, 3, 4, or 5, etc. cells.

[0033] As used herein, a "control" is a substitute sample used in an experiment for comparison purposes. A control can be "positive" or "negative." A "control sample" or "reference sample," as used herein, refers to a sample or reference that serves as a control for comparison with an experimental sample. For example, an experimental sample may contain compounds A, B, and C in a vial, and a control may be the same type of sample that is treated identically to the experimental sample but lacks one or more of compounds A, B, or C.

[0034] As used herein, the term "effective amount" refers to an amount sufficient to achieve the desired therapeutic and / or prophylactic effect, e.g., an amount that results in prevention of one or more outcomes or an increase in one or more outcomes.

[0035] As used herein, the terms "individual," "patient," or "subject" can be an individual organism, a vertebrate, a mammal, or a human. In preferred aspects, the individual, patient, or subject is a human.

[0036] As used herein, the phrase "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 phrase "soft tissue augmentation" refers to any type of soft tissue volume augmentation, including, but not limited to, facial contouring (e.g., more pronounced cheeks, chin, or lips), correction of concave deformities (e.g., post-traumatic or HIV-associated lipid atrophy), and correction of deep aging-related facial grooves. Thus, soft tissue augmentation can be used for cosmetic purposes or for medical purposes, such as after trauma or degenerative disease. Soft tissue augmentation also refers to skin fillers, body contouring, and gum fillers.

[0038] As used herein, the terms "microparticle" and "microsphere" are used somewhat interchangeably, the only distinction being that microspheres are spherical and microparticles are non-spherical.

[0039] As used herein, the phrase "non-animal origin" refers to sources that exclude animals, but include sources such as yeast, bacterial, or synthetic.

[0040] As used herein, the term "bioabsorbable" refers to a degradation event or events. Bioabsorbable materials may be dissolved, phagocytosed, or simply broken down over a period of time so that the material is removed from the body, organ, tissue, site, or cell over a period of time. The material or its degradation products may be metabolized, incorporated into other molecules or compounds, or excreted.

[0041] As used herein, the term "sterile" refers to being free of or having been removed from pathogenic microorganisms.

[0042] As used herein, the term "sterile" refers to free from living organisms, and generally free from living microorganisms.

[0043] As used herein, the term "injectable" refers to the ability to inject a composition of the present disclosure through a 21G, 22G, 23G, 24G, 25G, 26G, 27G, or 30G needle.

[0044] The present technology is not limited with respect to the specific aspects described in this application, but is intended as a single illustration of each aspect of the technology. As will be apparent to those skilled in the art, many modifications and variations of the present technology can be made without departing from its spirit and scope. In addition to those enumerated herein, functionally equivalent methods and apparatuses within the scope of the present 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 the present technology. It is understood that the present technology is not limited to particular methods, reagents, compound compositions, or biological systems, which may, of course, vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0045] As used herein, the phrase "ready-to-use composition" refers to a composition of the present disclosure that does not require reconstitution of the composition or the addition of one or more additional components prior to use. The ready-to-use composition of the present disclosure is ready to be injected into a subject once the ready-to-use composition is drawn into or placed into 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 combined in a sealed container / vial.

[0047] II. Fillers Fillers, such as dermal fillers, are used to repair, restore, or augment contour defects in hard or soft tissues of the body due to 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 the skin, soften nasolabial folds, augment and contour lips, improve scars (dimples, hypertrophic, and keloid scars), strengthen weakened vocal cords, and provide other soft tissue enhancements. Materials used include fat, paraffin, human collagen, bovine collagen, silicone, hyaluronic acid, lactic acid, and glycolic acid. The FDA approval of bovine collagen in 1981 ushered in a new era of soft tissue fillers. Many soft tissue fillers have since emerged. The dramatic increase in the number of current and researched fillers is driven by many factors, including improvements in biotechnology and society's emphasis on aesthetic appearance. With the introduction of new fillers, there is an ongoing need to evaluate their risk / benefit profile and define their limitations to maximize cosmetic outcomes and safety for patients.

[0048] In some embodiments, the compositions of the present disclosure comprise: (a) microspheres or microparticles of at least one polymer of non-animal origin 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, docusate sodium, 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. In some embodiments, the surfactant is present in an amount of 0.05% to 1% by weight.

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

[0052] In some embodiments, at least one polymer of the microspheres or microparticles 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, the at least one polymer is present in an amount of about 15 mg / mL to about 20 mg / mL. In some embodiments, the at least one polymer is present in an amount of 17 mg / mL to 18 mg / mL. In some embodiments, the 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 at least about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, about 50 mg / mL, about 51 mg / mL, about 52 mg / mL, about 53 mg / mL, about 54 mg / mL, about 55 mg / mL, about 56 mg / mL, about 57 mg / mL, about 58 mg / mL, about 59 mg / mL, about 60 mg / mL, about 61 mg / mL, about 62 mg / mL, about 63 mg / mL, about 64 mg / mL, about 65 mg / mL, about 66 mg / mL, about 67 mg / mL, about The compound is present at about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 46 mg / mL, about 47 mg / mL, about 48 mg / mL, about 49 mg / mL, or about 50 mg / mL.

[0055] In some embodiments, at least one polymer is present in a concentration of 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, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / 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, 50 mg / mL, 51 mg / mL, 52 mg / mL, 53 mg / mL, 54 mg / mL, 55 mg / mL, 56 mg / mL, 57 mg / mL, 58 mg / mL, 59 mg / mL, 60 mg / mL, 61 mg / mL, 62 mg / mL, 63 mg / mL, 64 mg / mL, 65 mg / mL, 66 mg / mL, 67 mg / mL, 68 mg / mL, 69 mg / mL, 70 mg / mL, 71 mg / mL, 72 mg / mL, 73 mg / mL, 74 mg / mL, 75 mg / mL, 76 mg / 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 the at least one polymer is the same as the concentration of the microspheres or microparticles, since they comprise 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 at 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.25%, 3.5%, 3.75%, or 4% by weight.

[0060] In some embodiments, the cellulose derivative gelling agent is present at about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about 3%, about 3.25%, about 3.5%, about 3.75%, 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 about 90 mg / mL to about 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 about 120 mg / mL to about 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 about 150 mg / mL to about 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 about 160 mg / mL to about 190 mg / mL. In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of 170 mg / mL to 180 mg / mL. In some embodiments, the cellulose derivative gelling agent is present in the composition at a concentration of about 170 mg / mL to about 180 mg / mL.

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

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

[0064] In some embodiments, the cellulose derivative reduces, mitigates, or delays settling of microparticles or microspheres in the composition compared to a composition lacking the cellulose derivative. In some embodiments, the cellulose derivative at a concentration of about 2% to about 3% by weight reduces, mitigates, or delays settling of microparticles or microspheres in the composition compared to a composition lacking the cellulose derivative or 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 the microparticles or microspheres.

[0065] In some embodiments, the cellulose derivative reduces, mitigates, or slows the settling rate of microparticles or microspheres in the ready-to-use composition after shaking (resuspension) 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 either lacking the cellulose derivative or containing an amount outside of a concentration of about 2% to about 3% by weight.

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

[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 microparticles or microspheres compared to a composition lacking the surfactant. In some embodiments, foaming of the composition is eliminated or reduced due to the presence of a surfactant, preferably polysorbate 80, at a concentration of 0.05 to 0.1 wt %, compared to a composition lacking the surfactant or having a surfactant at a concentration outside the range of 0.05 to 1 wt % or 0.05 to 0.1 wt %.

[0068] In some embodiments, the surfactant reduces or mitigates the amount of foaming in the ready-to-use composition 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 either lacking the surfactant, preferably polysorbate 80, or containing an amount outside of a 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%, less than 1%, and preferably substantially no foaming when observed after 1 day at 20-22° C. In some embodiments, the composition exhibits less than 20%, less than 15%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, and preferably substantially no foaming when observed after 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 at 20-22° C. In some embodiments, the composition exhibits less than 20%, less than 15%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, and preferably substantially no foaming when observed at 20-22°C after shaking after 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.

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

[0071] In some embodiments, the composition comprises one or more thickening agents 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 about 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 about 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 a viscosity of 5 to 45 mPas, 10 to 45 mPas, 20 to 45 mPas, 30 to 45 mPas, 5 to 30 mPas, or 5 to 20 mPas, or 5 to 10 mPas. In some embodiments, the composition exhibits a viscosity of about 5 to about 45 mPas, about 10 to about 45 mPas, about 20 to about 45 mPas, about 30 to about 45 mPas, about 5 to about 30 mPas, or about 5 to about 20 mPas, or about 5 to about 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 microparticles are 20 to 100 μm in size. In some embodiments, the microspheres or microparticles are about 20 to about 100 μm in size. In some embodiments, the size can be length, diameter, or width. Generally, this refers to the diameter.

[0077] In some embodiments, the microspheres or microparticles are 20 to 100 μm, 20 to 80 μm, 20 to 60 μm, 20 to 40 μm, 30 to 100 μm, 40 to 100 μm, 50 to 100 μm, 60 to 100 μm, 70 to 100 μm, or 80 to 100 μm in size. In some embodiments, the microspheres or microparticles are about 20 to about 100 μm, about 20 to about 80 μm, about 20 to about 60 μm, about 20 to about 40 μm, about 30 to about 100 μm, about 40 to about 100 μm, about 50 to about 100 μm, about 60 to about 100 μm, about 70 to about 100 μm, or about 80 to about 100 μm in size.

[0078] In some embodiments, the microspheres or microparticles exhibit a molecular weight of 50 to 500 kDa. In some embodiments, the microspheres or microparticles exhibit a molecular weight of about 50 to about 500 kDa. In some embodiments, the microspheres or microparticles exhibit a molecular weight of 50 to 200 kDa. In some embodiments, the microspheres or microparticles exhibit a molecular weight of about 70 to about 200 kDa. In some embodiments, the microspheres or microparticles exhibit a molecular weight of 50 to 140 kDa. In some embodiments, the microspheres or microparticles exhibit 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, the local anesthetic is bupivacaine, butanilicaine, carticaine, cinchocaine (dibucaine), clibucaine, ethyl parapiperidinoacetylaminobenzoate, etidocaine, lignocaine (lidocaine), mepivacaine, oxethazaine, prilocaine, ropivacaine, tricaine, trimecaine, vadocaine, articaine, levobupivacaine, amylocaine, cocaine, propanoic acid, or the like. The benzocaine, chlormecaine, cyclomethycaine, proxymetacaine, amethocaine (tetracaine), benzocaine, butacaine, butoxycaine, butyl aminobenzoate, chloroprocaine, dimethocaine (larocaine), oxybuprocaine, piperocaine, parethoxycaine, procaine (novocaine), propoxycaine, and tricaine, or a combination 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 about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, or about 5 mg / mL.

[0082] In some embodiments, the composition is injectable. In some embodiments, the injectable composition is an injectable implant. In some embodiments, the present 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, or intragingival injection.

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

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

[0085] In some embodiments, kits are contemplated for use in practicing the methods described herein, hi some embodiments, the kits contain all solutions, buffers, compounds, containers, and / or instructions sufficient to perform 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-increasing agents, hi some embodiments, the density-increasing agents may be selected from sorbitol, mannitol, and fructose.

[0088] In some embodiments, the composition includes a buffer. A buffer is a chemical compound or compounds added to a solution that allows the solution to resist changes in pH, either as a result of dilution or the addition of small amounts of acid or base. An effective buffer system uses a solution containing large amounts and approximately equal concentrations of conjugate acid-base pairs (or buffers). Buffers used herein can be any such pharmaceutically acceptable compounds, including, but not limited to, phosphate and citrate salts (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 aseptic. 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 mixing or forming the entire composition, thus resulting in a composition containing two or more components that are sterilized before forming the composition.

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

[0093] In some embodiments, the ready-to-use composition comprises 150 mg of PLLA microparticles or microspheres (non-irradiated), 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, the 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 containing sodium chloride was prepared and adjusted to pH 6.2. • A corresponding 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. • The corresponding amount of PS80 was added (0.05%) and mixed for about 20 minutes. The resulting solution was autoclaved at 125°C for 8 minutes.

[0096] Mixing of samples to produce final ready-to-use formulation 1 • Add 150mg 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 (terminally sterilized) Background Buffer 2 A 10 mM phosphate buffer solution containing sodium chloride was prepared and adjusted to pH 6.2. A corresponding amount of carboxymethylcellulose (22.5 mg / mL) was slowly added to the buffer solution while stirring, and the mixture was left overnight under stirring conditions until it was completely dissolved. • The corresponding amount of PS80 was added (0.05%) and mixed for about 20 minutes. • A corresponding amount of lidocaine hydrochloride (2.667 mg / mL) was added and mixed for approximately 20 minutes.

[0098] Mixing of samples to produce final ready-to-use formulation 1 • Add 150 mg of non-sterile 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. • Terminally sterilize the samples by autoclaving at 125°C for 8 minutes.

[0099] III. How to Use Fillers In some aspects, the present disclosure includes a method of performing a restorative or cosmetic dermatological treatment. In some aspects, the restorative or cosmetic dermatological treatment includes injecting a subject with a composition disclosed herein. In some aspects, the injection is subdermal, intradermal, subcutaneous, intramuscular, submuscular, or intragingival.

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

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

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

[0103] In some embodiments, the method of dermal filling comprises injecting the composition to fill a scar. In some embodiments, the method of dermal filling comprises injecting the composition to fill a depressed scar. In some embodiments, the method of dermal filling comprises injecting the composition to fill a hypertrophic scar. In some embodiments, the method of dermal filling comprises injecting the composition to fill a keloid scar.

[0104] In some embodiments, the dermal filling method involves the injection of a composition to restore and / or correct signs of facial fat loss (lipoatrophy) in individuals with human immunodeficiency virus (HIV).

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

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

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

[0108] In some embodiments, the facial contouring method comprises injecting a composition into the face to modify the facial contours, hi some embodiments, the facial contouring method comprises injecting a composition into the lips to augment the size and / or shape of the lips.

[0109] In some embodiments, the facial contouring method comprises injecting the composition into the face to increase facial symmetry. In some embodiments, the facial contouring method comprises injecting the composition to change the shape of the face to an oval, round, square, triangle, inverted triangle, rectangle, or oval. In some embodiments, the facial contouring method comprises injecting the composition to increase the overall width of the face. In some embodiments, the facial contouring method comprises injecting the composition to increase the overall length of the face.

[0110] In some embodiments, the facial contouring method comprises injecting the composition into the face to increase the width of the forehead and / or cheekbones, hi some embodiments, the facial contouring method comprises injecting the composition into the face to increase the length of the jawline.

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

[0112] In some embodiments, the facial contouring method comprises injecting a composition into the face to correct the appearance associated with retrognathia. In some embodiments, the facial contouring method comprises injecting a composition into the face to correct the appearance associated with prognathia.

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

[0114] In some embodiments, the body contouring method comprises injecting a composition into the body to modify the size and shape of the breasts, buttocks, sacrum, groin, lower back, abdomen, chest, feet, legs, knees, popliteal fossae, thighs, arms, hands, elbows, and / or pre-elbows.

[0115] In some embodiments, the body contouring method comprises injecting a composition into the body to fill a concave deformity. In some embodiments, the concave deformity is the result of age, disease, injury, or predisposition. In some embodiments, the body contouring method comprises injecting a composition into the body to reduce the appearance of cellulite. [Example]

[0116] Example 1 Improving the colloidal properties of therapeutic PLLA (poly-L-lactic acid) dispersions by adding nonionic surfactants and hydrocolloids Example 1 provides the experimental materials and design used in Examples 1-4. The examples demonstrate: (1) the addition of a nonionic surfactant eliminates PLLA foaming, (2) the addition of a hydrocolloid (polymeric thickener) slows the settling of PLLA particles, and (3) the synergistic effect between surfactants in the hydrocolloid in slowing the settling rate.

[0117] (Table 1) Materials TIFF2025124701000001.tif69128

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

[0119] To prepare the reconstituted SCULPTRA sample, targeting 150 mg of PLLA per 8 ml of water, 367.5 mg of homogenized lyophilized powder was used. This is based on a 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 blending lyophilized cakes from several vials of the same batch.

[0120] The colloidal properties of the PLLA dispersions were investigated with a Turbiscan Lab instrument (from Formulaction Inc.), which collects data along the height of the sample vial for: ● Passing through the vial Light transmittance , which increases as the turbidity of the sample decreases due to settling of dispersed particles over time. From vials Backscattering of light , which is substantial from opaque foam or bubbles, and therefore the backscattering values ​​can be used to track changes in foam and bubbles over time.

[0121] The light transmittance and backscattering of the compositions of the present disclosure allow for the determination of the amount of foaming and settling that occurs in the compositions. This determination allows for comparisons between different compositions. Data was collected at regular intervals so that the evolution of the colloidal system over time could be tracked.

[0122] Samples were prepared in standardized Turbiscan glass vials. PLLA particles that partially settled after initial mixing of the sample were redispersed by shaking the vial before the start of the Turbiscan data collection cycle. The transmittance data presented were averaged for data collected at vial heights of 2 mm to 12 mm, which correspond to the majority of the sample solution. The backscattering data presented were averaged for vial heights of 16 mm to 20 mm, which correspond to the top of the sample dispersion, including the foam bubbles. See Figure 1.

[0123] Example 2 Eliminating foam in PLLA by adding the nonionic surfactant polysorbate 80 This example demonstrates the effect of adding a non-ionic surfactant on the presence of persistent PLLA bubbles.

[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 from an unstable surfactant-based foam, which disappears (less than 10% backscattering) within approximately 2 hours after the start of the data collection cycle when the sample is shaken to redisperse the settled PLLA.

[0125] Since the formation of stable PLLA bubbles is thought to be related to the hydrophobicity of PLLA particles and poor wetting by water / buffer solution, the mechanism behind bubble elimination is very likely related to the reduction of the water / buffer interfacial tension as well as the adsorption of surfactants on the surface of PLLA particles causing their surface hydrophilicity, which would result in good wetting of the particles by aqueous solvents.

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

[0127] Example 3 Addition of the polysaccharide-based hydrocolloid sodium carboxymethylcellulose slows down the sedimentation of PLLA particles This experiment demonstrates how the addition of hydrocolloids affects the sedimentation of PLLA particles in a dispersion.

[0128] The results revealed that the addition of carboxymethylcellulose (CMC) significantly slowed the rate of transmittance increase of the samples compared to PLLA dispersions prepared in bare buffer. The more CMC added, the slower the transmittance increase over time. The low light transmittance through the samples is related to their turbidity, which is due to the presence of PLLA particles suspended in the bulk of the liquid. The settling rate of these particles is slower in the presence of carboxymethylcellulose, which increases the viscosity of the solution. Because the particles settle more slowly, the transmittance does not increase significantly 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 added hydrocolloid depends on its properties, such as molecular weight, degree of branching, side group modification, and other properties that affect the viscosity of the hydrocolloid-polymer solution. The viscosity of 2.25% CMC in buffer, which resulted in a similar rate of permeability increase to the SCULPTRA formulation, was 28 mPas, as measured by capillary viscometry. The concentrations of other hydrocolloids or different types of CMC need to be adjusted to give similar viscosities. The addition of CMC did not significantly affect the stability of PLLA foams, which is related to the lack of surface activity of CMC.

[0130] Example 4 Synergistic effects between the nonionic surfactant PS80 and the polysaccharide-based hydrocolloid carboxymethylcellulose This experiment will demonstrate whether there is a synergistic effect between surfactants and hydrocolloid thickeners in (a) slowing down the settling rate and (b) eliminating bubbles in PLLA.

[0131] There was a synergistic effect between hydrocolloids and surfactants in slowing the sedimentation of PLLA particles. The presence of 0.5% polysorbate 80 resulted in the removal of PLLA foams (sample PLLA-buffer-0.5% PS80), but the removal rate of this formulation was still very high. On the other hand, the addition of PS80 to formulations containing carboxymethylcellulose slowed removal compared to the corresponding formulations without PS80. 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 likely related to the wetting of PLLA particles originally present in the foam and their migration into the bulk dispersion, where they contribute to turbidity. Similar synergistic effects are expected for different PS80 concentrations as long as they are above the PLLA particle wetting threshold.

[0132] Example 5 Buffer systems 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 and fragmentation of the bulk polymer. This process is self-catalyzed by the presence of degradation products (PLLA fragments or monomers) both in the solution and within the bulk polymer. Sterilizing and storing PLLA in aqueous solution can result in substantial degradation and unacceptable changes in formulation properties.

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

[0134] These studies evaluate the effectiveness of various buffer systems to maximize the stability of PLLA or extend its shelf life in ready-to-use formulations.

[0135] Analytical method development and optimization Unsterilized PLLA (18SO229) and gamma-sterilized PLLA (1830200) were tested. • 150 mg of PLLA was prepared in 5 mL of MILLIQ water dispersion. Accelerated decomposition was evaluated by mixing at 90°C for 2 weeks. • To separate the water insoluble undegraded material from the soluble degradation products, it was filtered through a 0.22 μm MILIPORE filter. The filtrate (water-soluble portion) was analyzed by liquid chromatography after treatment with 1 M NaOH to identify the degradation of PLLA into lactic acid oligomers and then lactic acid monomers. The residue of the filter (water-insoluble) portion was dissolved in dichloromethane and analyzed by gel permeation chromatography (GPC). GPC reference sample: Undecomposed material Untreated - PLLA powder as received was dissolved in CH2Cl2. Filtration - filtered undegraded PLLA dispersion dissolved in CH2CL2.

[0136] Liquid chromatography was used to determine the state of the standards and the degraded standards. The presence of lactic acid monomers in the sterilized PLLA was determined by analysis of the filtrate. No lactic acid oligomers were detected after treatment with 1 M sodium hydroxide for 1 hour. A type of size-exclusion chromatography called gel permeation chromatography (GPC) was used to determine the size of the PLLA.

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

[0138] The low molecular weight of the "degraded filtrate" is due to the visually observed high PLLA insolubility in CH2Cl2 after 2 weeks of degradation at 90 °C. The reason for this is likely a change in the ratio of amorphous PLLA / crystalline PLLA during degradation and eventual recrystallization above the glass transition temperature. Crystalline PLLA has low solubility in CH2Cl2, and only short polymer chains can enter the solution during the sample preparation step. An alternative possibility could be preferential degradation of the amorphous portion of PLLA, leaving the undegraded residue highly crystalline.

[0139] The low molecular weight of the "degraded filtrate" is due to the visually observed high PLLA insolubility in CH2Cl2 after 2 weeks of degradation at 90 °C, which is explained in the same way as the unsterilized sample = change in PLLA crystallinity upon high-temperature degradation.

[0140] The general conclusions are: ●Some of the residues from samples decomposed at 90°C are not solubilized in dichloromethane. • For samples digested at 90°C, presumably only the low molecular weight fraction of the polymer is solubilized, while the high molecular weight polymer still remains in the solid phase. ●There were no problems with solubility for the starting PLLA powder and the undecomposed sample.

[0141] There was a distinction between degraded unsterilized PLLA and degraded sterilized PLLA, and this distinction can be seen in a single chart. The amount of degraded filtrate was 37% for degraded unsterilized PLLA and 50% for degraded sterilized PLLA. This corresponds to the mass balance of the degraded samples using a 0.2 μm filter (degradation occurred at 90 °C for 2 weeks). However, both sets of experiments resulted in total PLLA recovery (lactic acid monomer + filtrate) of over 100%, which was due to experimental error. In later experiments, the filtration procedure was adjusted and a more accurate follow-up of the filtrate volume was used.

[0142] Additional experiments were performed on unsterilized PLLA in deionized water and sterilized PLLA in deionized water to evaluate samples subjected to (1) degradation at 40°C for 4 days and (2) autoclaving at 125°C for 8 minutes. The results are as follows: • Decomposition at 40°C is limited and there is no detectable lactic acid monomer. • The solubility of the PLLA filtrate after degradation at 40°C for 4 days was sufficient (only a small amount was insoluble and potentially an impurity). • Decomposition during autoclaving was limited. • The solubility of the filtered PLLA after autoclaving was sufficient, but only a small amount was insoluble. For sterilized and non-sterilized PLLA, the reproducibility of GPC results obtained on different occasions was good.

[0143] Evaluation of the stability of PLLA in different buffer solutions upon autoclaving and subsequent storage at 40°C for 30 days For PLLA recovery in filtration, we assumed 150 mg of PLLA for every 367.5 mg of lyophilized powder added. However, the variation in PLLA content in SCULPTRA samples was + / - 2%, and therefore the lack of PLLA in filtration of SCULPTRA samples is more likely the result of initial PLLA content variation than the result of PLLA degradation.

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

[0145] Given the substantial reduction in molecular weight of the lidocaine-containing samples, the experiment was repeated and the data obtained for freshly mixed samples containing lidocaine was highly reproducible.

[0146] In water, lidocaine is in equilibrium with the protonated form. At pH below pKa, the protonated form predominates, leading to acidic hydrolysis of lidocaine. GPC chromatography of non-autoclaved lidocaine-containing samples compared to autoclaved lidocaine-containing samples reveals a size shift, with the non-autoclaved lidocaine-containing sample's GPC output deviating at an earlier time point than the autoclaved lidocaine-containing sample. PLLA particles are hydrophobic, and their density can be significantly higher than that of water (density depends on the porosity of the particles). The colloidal stability of PLLA suspensions can be improved by the following functional ingredients: • Stabilizers - for example, by using polymers that adsorb to the PLLA particles and expose the PEO groups to the majority of the solution, preventing aggregation driven by hydrophobic interactions between the particles. • Viscosity enhancers - prevent or slow down settling by increasing the viscosity of the buffer solution through the formation of hydrogel type structures.

[0147] In some embodiments, an advantageous buffer system comprises: • 10mM phosphate buffer + NaCl, pH 6.2 + 3mg / mL lidocaine.

[0148] Example 6 Reduced foaming and settling Foaming in ready-to-use products can be very problematic. The core SCULPTRA composition includes PLLA, mannitol, and CMC, and the samples are capable of foaming.

[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 does not appear to show any significant PLLA foaming.

[0150] (Table 2) Sample Variations and Foaming TIFF2025124701000002.tif94165

[0151] Visual identification of 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 particle 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. Sample Variation and Sedimentation TIFF2025124701000003.tif132165

[0154] FIG. 5 identifies the degree of foaming and settling for samples S2, P1, P2, P3, and P4 in Table 3.

[0155] Turbiscan backscattering and transmittance were used to assess the various phases of the samples, namely the sediment, interphase, and foam phases (Figure 6).

[0156] The effects of the viscosity modifier and PS80 are evident in the mesophase transmittance results (Figure 7). Samples sediment more slowly with the addition of viscosity modifier, with CMC showing a significant effect and mannitol having only a small effect. PS80 has a small effect on sedimentation rate. The backscattering results are less pronounced than the transmittance results.

[0157] Addition of PS80 to SCULPTRA samples significantly reduces foaming (Figure 8). Studies of PS80 show that the addition of 0.1% to 1% results in samples exhibiting PLLA foaming, with rapid loss of foaming after shaking.

[0158] Table 4. Eight SCULPTRA / PLLA samples TIFF2025124701000004.tif92165

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

[0160] Figure 9 shows the transmittance values ​​for eight SCULPTRA / PLLA formulations, specifically the mesophase of each formulation. The arrow on the right side of the figure indicates that the SCULPTRA value after 22 hours was approximately 40% transmittance. There was no significant difference due to storage time for the CMC-containing samples. There was no significant difference for the buffered samples. The decrease in transmittance in the presence of PS80 is likely due to a reduction in particles in the foam entering the mesophase, thus increasing turbidity.

[0161] Figure 10 shows the backscattering values ​​for eight SCULPTRA / PLLA formulations, specifically the foam phase of each formulation. The arrows on the right side of the figure indicate that after 22 hours, SCULPTRA values ​​are approximately 45% backscattering; the difference is dramatic in the presence of PS80. In the presence of PS80, rapid collapse of the foam occurs.

[0162] Although CMC helps, at least to some extent, to prevent settling of PLLA particles due to their viscosity, CMC is not involved in PLLA foaming. The addition of PS80 functions both by preventing PLLA foaming and by slowing down the settling of PLLA particles compared to a mixture of PLLA and CMC alone.

[0163] The methods illustratively described herein may suitably be practiced in the absence of any element(s), limitation(s) not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," and the like, should be construed broadly and without limitation. Additionally, the terms and expressions used herein are used as terms of description and not of limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof. It is recognized that various modifications are possible within the scope of the present disclosure as claimed. Thus, while the present disclosure has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the present disclosure disclosed herein may be incorporated by those skilled in the art, and such modifications and variations are considered to be within the scope of the present disclosure.

[0164] The present disclosure has been described broadly and generically herein. Each of the narrower species and subspecies groupings falling within the generic disclosure also form part of the method. This includes the generic description of the method, including any condition or negative limitation removing any subject matter from the genus, regardless of whether the omitted material is specifically recited herein. The present technology is not limited to the specific embodiments described in this application, which are intended as single illustrations of individual aspects of the technology. As will be apparent to those skilled in the art, many modifications and variations of the present technology can be made without departing from its spirit and scope. Functionally equivalent methods and apparatuses within the scope of the present technology, in addition to those recited herein, will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to be within the scope of the present technology. It is understood that the present technology is not limited to particular methods, reagents, compounds, compositions, or biological systems, which may, of course, vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0165] Those skilled in the art will readily appreciate that the present disclosure is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. Modifications therein and other uses will occur to those skilled in the art. These modifications are encompassed within the spirit of the disclosure and are defined by the claims which set forth non-limiting embodiments of the disclosure.

[0166] Additionally, when features or aspects of the present disclosure are described in terms of a Markush group, those skilled in the art will recognize that the present disclosure is also thereby described in terms of any individual members or subgroups of members of the Markush group.

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

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

Claims

1. (a) microspheres or microparticles of at least one polymer of non-animal origin 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; (c) Polysorbate 80 in an amount of 0.05% to 1% by weight; A composition comprising:

2. 10. The composition of claim 1, wherein the at least one polymer is a lactic acid selected from poly-L-lactic acid, poly-D-lactic acid, and mixtures thereof.

3. The composition of claim 2, wherein the at least one polymer is poly-L-lactic acid.

4. The composition of claim 1, wherein the at least one polymer is present in an amount of 5 mg / mL to 50 mg / mL.

5. 2. The composition of claim 1, wherein the cellulose derivative gelling agent is carboxymethylcellulose or hydroxypropylmethylcellulose.

6. 6. The composition of claim 5, wherein the cellulose derivative gelling agent is carboxymethyl cellulose.

7. 7. The composition of claim 6, wherein the carboxymethylcellulose is sodium carboxymethylcellulose.

8. The composition of claim 6, wherein the cellulose derivative gelling agent is present in an amount of from 0.5% to 4% by weight.

9. 9. The composition of claim 8, wherein the cellulose derivative gelling agent is present in an amount of 2% by weight.

10. 10. The composition of claim 1, wherein the polysorbate 80 is present in an amount of 0.05% by weight.

11. 10. The composition of claim 1, exhibiting a viscosity of less than 100 mPas.

12. 12. The composition of claim 11, exhibiting a viscosity of less than 60 mPas.

13. 2. The composition of claim 1, which exhibits a viscosity of 5 to 45 mPas.

14. 2. The composition of claim 1, wherein the ratio of said cellulose derivative gelling agent to said Polysorbate 80 is from 100:1 to 1:

1.

15. 15. The composition of claim 14, wherein the ratio of said cellulose derivative gelling agent to said Polysorbate 80 is from 50:1 to 10:

1.

16. The composition of claim 1 , wherein the microspheres or microparticles are bioabsorbable.

17. 17. The composition of claim 16, wherein the microspheres or microparticles are bioabsorbable within a period of about 1 year to about 3 years.

18. 10. The composition of claim 1, comprising microspheres or microparticles at a concentration of 5 to 20 mg / mL.

19. 19. The composition of claim 18, comprising microspheres or microparticles at a concentration of 17-18 mg / mL.

20. 10. The composition of claim 1, wherein the microspheres or microparticles are about 20 to 100 μm in size.

21. 21. The composition of claim 20, wherein the microspheres or microparticles exhibit a median particle size of about 40 μm.

22. 2. The composition of claim 1, wherein the microspheres or microparticles exhibit a molecular weight of 50 to 500 kDa.

23. 23. The composition of claim 22, wherein the microspheres or microparticles exhibit a molecular weight of 50 to 200 kDa.

24. The composition of any one of claims 1 to 23, further comprising a local anesthetic.

25. 25. The composition of claim 24, wherein the local anesthetic is an amide or ester type local anesthetic.

26. The local anesthetic may be bupivacaine, butanilicaine, carticaine, cinchocaine (dibucaine), cribucaine, ethyl parapiperidinoacetylaminobenzoate, etidocaine, lignocaine (lidocaine), mepivacaine, oxethazaine, prilocaine, ropivacaine, tricaine, trimecaine, vadocaine, articaine, levobupivacaine, amylocaine, cocaine, propanocaine, chlormecaine, cinnamo ...

26. The composition of claim 24 or 25, wherein the active ingredient is selected from the group consisting of clomethycaine, proxymetacaine, amethocaine (tetracaine), benzocaine, butacaine, butoxycaine, butyl aminobenzoate, chloroprocaine, dimethocaine (larocaine), oxybuprocaine, piperocaine, parethoxycaine, procaine (novocaine), propoxycaine, and tricaine, or a combination thereof.

27. The composition of any one of claims 1 to 26, which is sterile.

28. 28. The composition of claim 27, wherein sterility is achieved by irradiation or heat sterilization.

29. The composition of any one of claims 1 to 28, further comprising sodium chloride, a phosphate buffer, and a pharmaceutically acceptable carrier.

30. 30. A composition according to any one of claims 1 to 29, exhibiting a sodium chloride concentration of 0.9% w / v.

31. The composition of any one of claims 1 to 30, which is injectable.

32. 32. The composition of claim 31, wherein the injectable composition is an injectable implant.

33. A pre-filled syringe or vial comprising the composition of any one of claims 1 to 32.

34. An injectable implant comprising the composition of any one of claims 1 to 32.

35. 35. The injectable implant of claim 34, for intradermal or subcutaneous injection into the body of a subject in need thereof.

36. 33. A method of performing a restorative or cosmetic dermatological procedure, comprising injecting a subject with a composition according to any one of claims 1 to 32.

37. 37. The method of claim 36, wherein the injection is intradermal, subdermal, subcutaneous, intramuscular, submuscular, or intragingival.

38. 37. The method of claim 36, wherein the injection is into one or more tissues of the oral cavity.

39. 39. The method of any one of claims 36 to 38, wherein the injections are for skin filling, body contouring, facial contouring, and gum filling.

40. 40. The method of claim 39, wherein the skin filling is selected from wrinkle filling, fine line filling, skin crack filling, scar filling, and combinations thereof.

41. 40. The method of claim 39, wherein filling the gums includes filling gaps between the bases of the teeth.

42. 40. The method of claim 39, wherein the facial and body contouring is selected from creating pronoun- cement structural features, correcting concave deformities, correcting age-related facial grooves, and augmenting or repairing contour defects in the hard or soft tissues of the face and body due to aging, injury, and acquired or congenital deformities of the face or body.

Images